US20110200671A1 - Method of treating a disease condition susceptible to baclofen therapy - Google Patents
Method of treating a disease condition susceptible to baclofen therapy Download PDFInfo
- Publication number
- US20110200671A1 US20110200671A1 US13/029,722 US201113029722A US2011200671A1 US 20110200671 A1 US20110200671 A1 US 20110200671A1 US 201113029722 A US201113029722 A US 201113029722A US 2011200671 A1 US2011200671 A1 US 2011200671A1
- Authority
- US
- United States
- Prior art keywords
- baclofen
- composition
- drug delivery
- delivery system
- controlled release
- 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
- KPYSYYIEGFHWSV-UHFFFAOYSA-N Baclofen Chemical compound OC(=O)CC(CN)C1=CC=C(Cl)C=C1 KPYSYYIEGFHWSV-UHFFFAOYSA-N 0.000 title claims abstract description 208
- 229960000794 baclofen Drugs 0.000 title claims abstract description 207
- 238000000034 method Methods 0.000 title claims abstract description 97
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 25
- 201000010099 disease Diseases 0.000 title claims abstract description 22
- 238000002560 therapeutic procedure Methods 0.000 title claims abstract description 19
- 238000012377 drug delivery Methods 0.000 claims abstract description 145
- 238000013270 controlled release Methods 0.000 claims abstract description 106
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 40
- 150000003839 salts Chemical class 0.000 claims abstract description 33
- 239000000203 mixture Substances 0.000 claims description 179
- 230000002496 gastric effect Effects 0.000 claims description 80
- 230000014759 maintenance of location Effects 0.000 claims description 66
- 239000002775 capsule Substances 0.000 claims description 53
- 230000036470 plasma concentration Effects 0.000 claims description 38
- 229920000642 polymer Polymers 0.000 claims description 37
- 238000000576 coating method Methods 0.000 claims description 36
- 239000000599 controlled substance Substances 0.000 claims description 35
- 239000011248 coating agent Substances 0.000 claims description 30
- 210000002784 stomach Anatomy 0.000 claims description 30
- 230000008961 swelling Effects 0.000 claims description 27
- 239000003795 chemical substances by application Substances 0.000 claims description 20
- 208000008238 Muscle Spasticity Diseases 0.000 claims description 17
- 208000018198 spasticity Diseases 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 239000000463 material Substances 0.000 claims description 16
- 208000024891 symptom Diseases 0.000 claims description 14
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical group CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 12
- 239000001856 Ethyl cellulose Substances 0.000 claims description 11
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 11
- 229920001249 ethyl cellulose Polymers 0.000 claims description 11
- 229920002125 Sokalan® Polymers 0.000 claims description 10
- 229920003176 water-insoluble polymer Polymers 0.000 claims description 7
- 208000007848 Alcoholism Diseases 0.000 claims description 6
- 206010021518 Impaired gastric emptying Diseases 0.000 claims description 6
- 208000028505 alcohol-related disease Diseases 0.000 claims description 6
- 208000001288 gastroparesis Diseases 0.000 claims description 6
- 230000002209 hydrophobic effect Effects 0.000 claims description 6
- 239000001993 wax Substances 0.000 claims description 6
- 206010011224 Cough Diseases 0.000 claims description 5
- 206010012335 Dependence Diseases 0.000 claims description 5
- 206010028391 Musculoskeletal Pain Diseases 0.000 claims description 5
- 206010047700 Vomiting Diseases 0.000 claims description 5
- 201000007930 alcohol dependence Diseases 0.000 claims description 5
- 229920001577 copolymer Polymers 0.000 claims description 5
- 239000007884 disintegrant Substances 0.000 claims description 5
- 239000004081 narcotic agent Substances 0.000 claims description 5
- 208000004296 neuralgia Diseases 0.000 claims description 5
- 208000021722 neuropathic pain Diseases 0.000 claims description 5
- 230000005586 smoking cessation Effects 0.000 claims description 5
- 208000031361 Hiccup Diseases 0.000 claims description 4
- 239000004584 polyacrylic acid Substances 0.000 claims description 4
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 3
- 239000000194 fatty acid Substances 0.000 claims description 3
- 229930195729 fatty acid Natural products 0.000 claims description 3
- 150000004665 fatty acids Chemical class 0.000 claims description 2
- 239000002195 soluble material Substances 0.000 claims description 2
- 208000035475 disorder Diseases 0.000 claims 3
- 229940126701 oral medication Drugs 0.000 claims 2
- 239000003921 oil Substances 0.000 claims 1
- 239000003826 tablet Substances 0.000 description 38
- 229940079593 drug Drugs 0.000 description 36
- 239000003814 drug Substances 0.000 description 36
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 35
- 239000000454 talc Substances 0.000 description 33
- 229910052623 talc Inorganic materials 0.000 description 33
- 229940033134 talc Drugs 0.000 description 33
- 235000012222 talc Nutrition 0.000 description 33
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 32
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 31
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 28
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 28
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 28
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 28
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 26
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 22
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 22
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 22
- 239000000243 solution Substances 0.000 description 22
- 229930195725 Mannitol Natural products 0.000 description 21
- 239000004615 ingredient Substances 0.000 description 21
- 239000000594 mannitol Substances 0.000 description 21
- 235000010355 mannitol Nutrition 0.000 description 21
- 239000002552 dosage form Substances 0.000 description 20
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 19
- 239000007789 gas Substances 0.000 description 17
- 239000008109 sodium starch glycolate Substances 0.000 description 17
- 229920003109 sodium starch glycolate Polymers 0.000 description 17
- 229940079832 sodium starch glycolate Drugs 0.000 description 17
- 235000017557 sodium bicarbonate Nutrition 0.000 description 16
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 16
- 238000010521 absorption reaction Methods 0.000 description 14
- 235000019359 magnesium stearate Nutrition 0.000 description 14
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 13
- 238000004090 dissolution Methods 0.000 description 13
- 239000011159 matrix material Substances 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 239000008187 granular material Substances 0.000 description 12
- 239000000017 hydrogel Substances 0.000 description 12
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 11
- 239000007903 gelatin capsule Substances 0.000 description 11
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 11
- 229920000136 polysorbate Polymers 0.000 description 11
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 229960004667 ethyl cellulose Drugs 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 10
- 230000001148 spastic effect Effects 0.000 description 10
- 230000004584 weight gain Effects 0.000 description 10
- 235000019786 weight gain Nutrition 0.000 description 10
- 206010039897 Sedation Diseases 0.000 description 9
- 239000008351 acetate buffer Substances 0.000 description 9
- 239000010408 film Substances 0.000 description 9
- 229950008882 polysorbate Drugs 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 230000036280 sedation Effects 0.000 description 9
- SOGAXMICEFXMKE-UHFFFAOYSA-N Butylmethacrylate Chemical compound CCCCOC(=O)C(C)=C SOGAXMICEFXMKE-UHFFFAOYSA-N 0.000 description 8
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 8
- 229920000148 Polycarbophil calcium Polymers 0.000 description 8
- 239000002202 Polyethylene glycol Substances 0.000 description 8
- -1 R-baclofen Chemical compound 0.000 description 8
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 8
- 235000010443 alginic acid Nutrition 0.000 description 8
- 229920000615 alginic acid Polymers 0.000 description 8
- 239000000783 alginic acid Substances 0.000 description 8
- 229960001126 alginic acid Drugs 0.000 description 8
- 150000004781 alginic acids Chemical class 0.000 description 8
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 8
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 8
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 8
- 229920001223 polyethylene glycol Polymers 0.000 description 8
- 239000008213 purified water Substances 0.000 description 8
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 7
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 7
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 7
- 239000006185 dispersion Substances 0.000 description 7
- 239000012530 fluid Substances 0.000 description 7
- 230000030135 gastric motility Effects 0.000 description 7
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 235000012054 meals Nutrition 0.000 description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 7
- 239000008108 microcrystalline cellulose Substances 0.000 description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 description 7
- 229950005134 polycarbophil Drugs 0.000 description 7
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 229920002678 cellulose Polymers 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 230000008602 contraction Effects 0.000 description 6
- 238000007667 floating Methods 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- 230000000717 retained effect Effects 0.000 description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
- JKNCOURZONDCGV-UHFFFAOYSA-N 2-(dimethylamino)ethyl 2-methylprop-2-enoate Chemical compound CN(C)CCOC(=O)C(C)=C JKNCOURZONDCGV-UHFFFAOYSA-N 0.000 description 5
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 5
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 5
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- NEDGUIRITORSKL-UHFFFAOYSA-N butyl 2-methylprop-2-enoate;2-(dimethylamino)ethyl 2-methylprop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound COC(=O)C(C)=C.CCCCOC(=O)C(C)=C.CN(C)CCOC(=O)C(C)=C NEDGUIRITORSKL-UHFFFAOYSA-N 0.000 description 5
- 230000001419 dependent effect Effects 0.000 description 5
- 239000001530 fumaric acid Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 4
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 4
- 229920003141 Eudragit® S 100 Polymers 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 229920003091 Methocel™ Polymers 0.000 description 4
- 229920002594 Polyethylene Glycol 8000 Polymers 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 239000000227 bioadhesive Substances 0.000 description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 229920003086 cellulose ether Polymers 0.000 description 4
- 229960000913 crospovidone Drugs 0.000 description 4
- 238000013461 design Methods 0.000 description 4
- 238000009501 film coating Methods 0.000 description 4
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 4
- 210000000936 intestine Anatomy 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 229960001855 mannitol Drugs 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 210000004379 membrane Anatomy 0.000 description 4
- 150000002734 metacrylic acid derivatives Chemical class 0.000 description 4
- 239000000178 monomer Substances 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 4
- 239000011148 porous material Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 230000002035 prolonged effect Effects 0.000 description 4
- 238000004088 simulation Methods 0.000 description 4
- 235000010413 sodium alginate Nutrition 0.000 description 4
- 239000000661 sodium alginate Substances 0.000 description 4
- 229940005550 sodium alginate Drugs 0.000 description 4
- 230000002459 sustained effect Effects 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 239000004408 titanium dioxide Substances 0.000 description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000012736 aqueous medium Substances 0.000 description 3
- 229940098005 baclofen 10 mg Drugs 0.000 description 3
- 235000021152 breakfast Nutrition 0.000 description 3
- 239000001569 carbon dioxide Substances 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 239000004359 castor oil Substances 0.000 description 3
- 235000019438 castor oil Nutrition 0.000 description 3
- 239000008199 coating composition Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 235000020937 fasting conditions Nutrition 0.000 description 3
- 239000007888 film coating Substances 0.000 description 3
- 230000030136 gastric emptying Effects 0.000 description 3
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 235000010981 methylcellulose Nutrition 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 229960002900 methylcellulose Drugs 0.000 description 3
- 239000011859 microparticle Substances 0.000 description 3
- 230000003232 mucoadhesive effect Effects 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 235000021590 normal diet Nutrition 0.000 description 3
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 3
- 229920000058 polyacrylate Polymers 0.000 description 3
- 229940069328 povidone Drugs 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 210000001187 pylorus Anatomy 0.000 description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 3
- 229940032147 starch Drugs 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000007723 transport mechanism Effects 0.000 description 3
- 229920003169 water-soluble polymer Polymers 0.000 description 3
- KPYSYYIEGFHWSV-QMMMGPOBSA-N Arbaclofen Chemical compound OC(=O)C[C@@H](CN)C1=CC=C(Cl)C=C1 KPYSYYIEGFHWSV-QMMMGPOBSA-N 0.000 description 2
- 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
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 229920001661 Chitosan Polymers 0.000 description 2
- 208000020401 Depressive disease Diseases 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 229920003119 EUDRAGIT E PO Polymers 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229920003149 Eudragit® E 100 Polymers 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000945318 Homo sapiens Calponin-1 Proteins 0.000 description 2
- 101000652736 Homo sapiens Transgelin Proteins 0.000 description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 2
- 208000007101 Muscle Cramp Diseases 0.000 description 2
- 208000002740 Muscle Rigidity Diseases 0.000 description 2
- 208000010428 Muscle Weakness Diseases 0.000 description 2
- 206010028372 Muscular weakness Diseases 0.000 description 2
- QQONPFPTGQHPMA-UHFFFAOYSA-N Propene Chemical group CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 206010041349 Somnolence Diseases 0.000 description 2
- 208000005392 Spasm Diseases 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 102100031013 Transgelin Human genes 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000002998 adhesive polymer Substances 0.000 description 2
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 2
- 239000001639 calcium acetate Substances 0.000 description 2
- 235000011092 calcium acetate Nutrition 0.000 description 2
- 229960005147 calcium acetate Drugs 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 229940105329 carboxymethylcellulose Drugs 0.000 description 2
- 229960000541 cetyl alcohol Drugs 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 239000007931 coated granule Substances 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 239000007891 compressed tablet Substances 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 229960001681 croscarmellose sodium Drugs 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- 238000009506 drug dissolution testing Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 235000011087 fumaric acid Nutrition 0.000 description 2
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 2
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 2
- 229960003943 hypromellose Drugs 0.000 description 2
- 238000005213 imbibition Methods 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000013563 matrix tablet Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 229940117841 methacrylic acid copolymer Drugs 0.000 description 2
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 2
- 239000008185 minitablet Substances 0.000 description 2
- 230000004899 motility Effects 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 230000002572 peristaltic effect Effects 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 229960001407 sodium bicarbonate Drugs 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- JJAHTWIKCUJRDK-UHFFFAOYSA-N succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate Chemical compound C1CC(CN2C(C=CC2=O)=O)CCC1C(=O)ON1C(=O)CCC1=O JJAHTWIKCUJRDK-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 2
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- 239000003185 4 aminobutyric acid B receptor stimulating agent Substances 0.000 description 1
- 229920002126 Acrylic acid copolymer Polymers 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 206010009346 Clonus Diseases 0.000 description 1
- 241000252095 Congridae Species 0.000 description 1
- 239000004971 Cross linker Substances 0.000 description 1
- PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 description 1
- 229920003135 Eudragit® L 100-55 Polymers 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 description 1
- 108010011459 Exenatide Proteins 0.000 description 1
- 229940123431 GABA B receptor agonist Drugs 0.000 description 1
- 241000237858 Gastropoda Species 0.000 description 1
- 108010061711 Gliadin Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-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
- 108010041872 Islet Amyloid Polypeptide Proteins 0.000 description 1
- 102000036770 Islet Amyloid Polypeptide Human genes 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 102000004856 Lectins Human genes 0.000 description 1
- 108090001090 Lectins Proteins 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 241000176964 Mononeuron Species 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 108010016076 Octreotide Proteins 0.000 description 1
- 239000008896 Opium Substances 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- VVWYOYDLCMFIEM-UHFFFAOYSA-N Propantheline Chemical compound C1=CC=C2C(C(=O)OCC[N+](C)(C(C)C)C(C)C)C3=CC=CC=C3OC2=C1 VVWYOYDLCMFIEM-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 230000001663 anti-spastic effect Effects 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229940067342 baclofen 25 mg Drugs 0.000 description 1
- 229940035070 baclofen injection Drugs 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 229940092738 beeswax Drugs 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000035587 bioadhesion Effects 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000004204 candelilla wax Substances 0.000 description 1
- 229940073532 candelilla wax Drugs 0.000 description 1
- 235000013868 candelilla wax Nutrition 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 229940082500 cetostearyl alcohol Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 229920006037 cross link polymer Polymers 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 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
- HYPPXZBJBPSRLK-UHFFFAOYSA-N diphenoxylate Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 HYPPXZBJBPSRLK-UHFFFAOYSA-N 0.000 description 1
- 229960004192 diphenoxylate Drugs 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000008387 emulsifying waxe Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 229960001519 exenatide Drugs 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 210000003736 gastrointestinal content Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000002575 gastroscopy Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000005456 glyceride group Chemical class 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- IUJAMGNYPWYUPM-UHFFFAOYSA-N hentriacontane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCC IUJAMGNYPWYUPM-UHFFFAOYSA-N 0.000 description 1
- KUQWZSZYIQGTHT-UHFFFAOYSA-N hexa-1,5-diene-3,4-diol Chemical compound C=CC(O)C(O)C=C KUQWZSZYIQGTHT-UHFFFAOYSA-N 0.000 description 1
- 239000007970 homogeneous dispersion Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 229940124512 hyoscine hydrobromide Drugs 0.000 description 1
- 239000012728 immediate-release (IR) tablet Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 229940090044 injection Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 210000001153 interneuron Anatomy 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- RDOIQAHITMMDAJ-UHFFFAOYSA-N loperamide Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)N(C)C)CCN(CC1)CCC1(O)C1=CC=C(Cl)C=C1 RDOIQAHITMMDAJ-UHFFFAOYSA-N 0.000 description 1
- 229960001571 loperamide Drugs 0.000 description 1
- 238000009593 lumbar puncture Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 239000004200 microcrystalline wax Substances 0.000 description 1
- 235000019808 microcrystalline wax Nutrition 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 230000037023 motor activity Effects 0.000 description 1
- 210000002161 motor neuron Anatomy 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 239000003149 muscarinic antagonist Substances 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 229940043348 myristyl alcohol Drugs 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000008388 non-ionic emulsifying wax Substances 0.000 description 1
- 229960002700 octreotide Drugs 0.000 description 1
- 239000012735 once-a-day formulation Substances 0.000 description 1
- 229960001027 opium Drugs 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000008855 peristalsis Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960004633 pirenzepine Drugs 0.000 description 1
- RMHMFHUVIITRHF-UHFFFAOYSA-N pirenzepine Chemical compound C1CN(C)CCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 RMHMFHUVIITRHF-UHFFFAOYSA-N 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 230000000379 polymerizing effect Effects 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 208000028173 post-traumatic stress disease Diseases 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 108010029667 pramlintide Proteins 0.000 description 1
- 229960003611 pramlintide Drugs 0.000 description 1
- NRKVKVQDUCJPIZ-MKAGXXMWSA-N pramlintide acetate Chemical compound C([C@@H](C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CCCCN)[C@@H](C)O)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 NRKVKVQDUCJPIZ-MKAGXXMWSA-N 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 229960000697 propantheline Drugs 0.000 description 1
- 230000001141 propulsive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- LACQPOBCQQPVIT-SEYKEWMNSA-N scopolamine hydrobromide trihydrate Chemical compound O.O.O.Br.C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 LACQPOBCQQPVIT-SEYKEWMNSA-N 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000009491 slugging Methods 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 238000010972 statistical evaluation Methods 0.000 description 1
- 229940012831 stearyl alcohol Drugs 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000009498 subcoating Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- MHXBHWLGRWOABW-UHFFFAOYSA-N tetradecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC MHXBHWLGRWOABW-UHFFFAOYSA-N 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 230000001550 time effect Effects 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 239000012178 vegetable wax Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
-
- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4891—Coated capsules; Multilayered drug free capsule shells
-
- 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
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/34—Tobacco-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- the present invention relates to an effective method of treating a disease condition susceptible to baclofen therapy, said method comprising administering a controlled release drug delivery system of baclofen or its pharmaceutically acceptable salts or its derivatives.
- Baclofen is indicated in many disease conditions such as for alleviating signs and symptoms of spasticity resulting from multiple sclerosis, particularly for the relief of flexor spasms and concomitant pain, clonus and muscular rigidity; in treatment of gastroparesis, non ulcer dydpepsia, gastroesophageal reflux diseases, for the treatment of depression or other psychological conditions, such as posttraumatic stress disorders, alcohol related disorders such as alcohol dependence is a chronic disorder that results from a variety of genetic, physiological and environmental factors, for promoting smoking cessation; for reducing addiction liability of narcotic agents; in the treatment of emesis; as an anti-tussive for the treatment of cough; in treating neuropathic pain and in treating musculoskeletal pain.
- baclofen is used for the treatment of spasticity.
- Spasticity is one of the components of the upper motor neuron (UHM) syndrome but should not be considered in isolation when it comes to management strategies.
- Baclofen is used as a muscle relaxant and an anti-spastic agent for a variety of neurological disorders. It is a GABA-B receptor agonist that depresses the monosynaptic and polysynaptic excitation of mononeurons and interneurons.
- the most commonly used dosage form of racemic baclofen is the immediate release (IR) tablet (10-20 mg) to be administered three times a day.
- IR immediate release
- a serum concentration of 8Ong/ml or more is considered an effective concentration.
- baclofen therapy involves administration of 10 mg or 20 mg immediate release tablets three times a day. The dose ranges from 30 mg to 100 mg/day in divided doses.
- a once-a-day or twice-a-day (b.i.d.) dosage formulation with the same therapeutic effectiveness as the conventional baclofen therapy could vastly improve patients' compliance with treatment. These will also improve the outcome of therapy, as a greater number of patients will adhere to treatment plan.
- gastric motility presents a significant resistance to preventing the passage of a dosage form into the colon for more than 8 hours. This resistance is due to the strong propulsive movements of the gut, particularly the occurrence of a periodic housekeeper wave that would sweep any physical object from the stomach into the intestine. (see T max in FIG. 1 and Table 7 when the systems were given in the fed state in the morning). The reasons for such shortfalls are suspected to lie in the nature of gastric motility and gastric emptying (See page 145 of E. A. Klausner et al, Journal of Controlled release 90 (2003), 143-162).
- the EP 1849462 A2 claims a method of alleviating signs and symptoms of spasticity in human patient comprising orally administering to said human patients once in a day a controlled drug delivery system comprising an effective daily dose of baclofen or its pharmaceutically acceptable salt wherein said method is associated with reduced level of sedation in said patients as compared to conventional baclofen therapy with immediate release tablets administered three times a day on the same total daily dose. It further related to a method wherein the daily dose of baclofen or its pharmaceutically acceptable salt ranges from about 15 mg to about 80 mg. Particularly the method was useful when the daily dose of racemic baclofen was 30 mg or 45 mgs.
- baclofen It was therefore an important benefit that the scope of industrial applicability and marketability of baclofen was increased because it could be used in a wider range of circumstances than previously possible when the risk of sedation might have precluded its use. Also, the invention could be particularly useful for treating patients who have a predisposition to suffering sedation as a side effect.
- the improved method of the present invention is useful for treating disease conditions such as spasticity, gastroparesis, gastro-esophageal reflux diseases, for the treatment of depression or other psychological conditions, alcohol related disorders such as alcohol dependence, smoking cessation, addiction liability of narcotic agents, emesis, cough, hiccoughs, neuropathic pain and musculoskeletal pain.
- disease conditions such as spasticity, gastroparesis, gastro-esophageal reflux diseases
- alcohol related disorders such as alcohol dependence, smoking cessation, addiction liability of narcotic agents, emesis, cough, hiccoughs, neuropathic pain and musculoskeletal pain.
- the present invention seeks to provide an improved method of treating a disease condition susceptible to baclofen therapy.
- FIG. 1 depicts the mean plasma concentration profile of baclofen vs time in hours when administered in the form of a controlled release drug delivery system administered by healthy volunteers in the evening and the morning in fed condition with normal diet.
- FIG. 2 illustrates a gastric retention controlled release drug delivery system in the form of capsules in the unswollen state and expanded due to swelling upon contact with aqueous medium for 6 hours.
- FIG. 3 depicts the graph of the mean plasma baclofen concentration time profiles at steady-state for baclofen 60 mg controlled release drug delivery system in the form of capsule administered by healthy human volunteers under fed (normal meal) condition in evening once daily for 7 days according to the present invention; and baclofen 60 mg controlled release drug delivery system in the form of capsule administered healthy human volunteers under fed (normal meal) condition in morning.
- FIG. 4 depicts one of the embodiments of the controlled release drug delivery system used in the method of the present invention.
- the controlled release drug delivery system is in the form of a coated capsule.
- the first region of the second composition is in the form of a hard gelatin capsule filled with baclofen and other excipients.
- the second region of the second composition is a sub coating applied on the filled hard gelatin capsules.
- the sub-coated second composition is further coated with the third composition which contains expandable components and film former.
- the third composition is further coated with a first composition.
- the term “morning” as it is used herein with respect to the dosing of the controlled release drug delivery system of the invention means that the controlled release drug delivery system is orally administered early in the day after the patient has awakened from overnight sleep, generally between about 6:00 am and 11:00 am. In one preferred embodiment, the dosing was done at 8:30 am, post breakfast which was given at 8:00 am.
- evening as it is used herein with respect to the dosing of the controlled release drug delivery system of the invention means that the controlled release drug delivery system is orally administered later in the day before the human subject goes to bed for the night sleep, generally between about 7:00 pm and 10:00 pm, after the human subject has taken dinner. In one preferred embodiment, the dosing was done at 7:00 pm, post dinner which was given at 6:30 pm.
- immediate release refers to release obtained from conventional dosage form of baclofen that are given more than once-a-day for delivering baclofen to a human subject in need thereof.
- baclofen refers to 4-amino-3-(p-cholorophenyl)-butyric acid or its pharmaceutically acceptable salt thereof or its derivatives.
- the term includes R-baclofen, S-Baclofen and their mixtures including the racemate.
- the racemate refers to a mixture of R and S-baclofen in equal proportions.
- C max is the highest plasma concentration of the drug attained within the dosing interval, i.e. about 24 hours.
- C min is the minimum plasma concentration of the drug attained within the dosing interval, i.e. about 24 hours.
- T max is the time period which elapses after administration of the composition at which the plasma concentration of the drug attains the highest plasma concentration of drug attained within the dosing interval (i.e. about 24 hours).
- T max is the time period which elapses after administration of the composition at which the plasma concentration of the drug attains the highest plasma concentration of drug attained within the dosing interval (i.e. about 24 hours).
- AUC as used herein, means area under the plasma concentration-time curve, as calculated by the trapezoidal rule over the complete 24-hour interval.
- the fluctuation index is calculated as (C max ⁇ C min )/C avg ⁇ 100 wherein C avg is calculated as ratio of AUC (0-24) to 24 hours.
- the total daily dose of baclofen or its pharmaceutically acceptable salt or its derivatives present in the controlled release drug delivery system used in practicing the method of the present invention ranges from 1 mg to about 150 mg, preferably about 5 mg to about 80 mgs.
- the amount of the total daily dose may be slightly different depending upon the disease condition for which the system of the present invention is used. Also the dose is dependent on the derivative or salt of baclofen that is employed. For instance, when the system of the present invention is used to treat gastroparesis with the use of an enriched form of enantiomer of baclofen such as R-baclofen, the amount of the daily dose of baclofen that may be used may range from about 5 mg to 10 mg.
- the amount of the total daily dose of baclofen may range from 10 mg to 120 mg.
- the dose of the baclofen may be titrated and increased from a lower range to a higher range, depending upon the need.
- baclofen is given initially at a daily dose of 15 mg for initial few days and then the amount of total daily dose is increased to 30 mg to 40 mg for later period of treatment.
- the system when the method uses controlled release drug delivery system, the system is administered in the fed condition. It is known that the pH of the gastric contents in the fed condition is about 4.3-5.4 whereas in the fasted state the pH of the gastric contents is about 1.4-2.1 (See T. T. Kararli, Biopharm. Drug. Disposition, 16, 351-380, 1995).
- the in vitro studies such as measurement of the swelling index and/or the in vitro dissolution of baclofen or its pharmaceutically acceptable salt is determined at a pH of about 4.5, for example, in an aqueous medium of acetate buffer that provides a pH of 4.5.
- the method of the present invention provides an improved therapy during the later half of the dosing interval. Particularly, there is an improved therapy in controlling the early morning symptoms of the disease condition.
- FIG. 2 illustrates an embodiment of a gastric retention controlled release drug delivery system in the form of a swellable capsule useful in the method of the present invention.
- the swelling or expandable nature of the capsule is depicted by the photographic images of the coated capsule in 4.5 acetate buffer at the end of 6 hours.
- the initial dimensions were 22.65 mm in length and 8.92 mm in diameter.
- the capsules were swollen and expanded to a length of 38.23 mm and 19.79 in diameter.
- the open pylorus has a diameter of ⁇ 15 mm in humans and objects greater than this size will have a difficulty in passing into the intestine (Stanley S. Davis in Drug Discovery Toady, Volume 10, No 4, February 2005, page 249-257).
- aspects of the present invention provide a method of treating a disease condition susceptible to baclofen therapy, said method comprising orally administering once-a-day in the evening a controlled release drug delivery system comprising baclofen or its pharmaceutically acceptable salt or its derivatives and pharmaceutically acceptable excipients.
- an oral controlled release drug delivery system that does not itself possess the characteristics for gastric retention (as distinct from controlled release) can be retained in the stomach by extraneous means (that means not forming a part of, or not directly associated with, the, oral controlled release drug delivery system).
- Gastric retention may be achieved, for example, by co-administering agents that slow the gastric motility or utilizing any alternate means that reduces gastric motility.
- the present invention therefore encompasses not only the gastric retention controlled release drug delivery system (as a single dosage form) but also any other controlled release drug delivery system that gets retained in the stomach not because of it's own characteristics, but because of other factors extrinsic or external to the drug delivery system.
- agents that may be used to enhance the gastric retention of the controlled release drug delivery system by reducing gastric motility include, but are not limited to, amylin agonist like pramlintide, exendins and its analogs, exenatide and its derivatives, atropine and related compounds, antimuscarinic agents like propantheline, pirenzepine, hyoscine hydrobromide, antidiahhoeral compounds such as diphenoxylate, loperamide, octreotide, opium and any other active ingredient that causes reduction in the gastric motility or active ingredients that show reduction in gastric motility as one of the side effects.
- the controlled drug delivery systems useful in the practice of the present invention are typically characterized by release of about 30% to 40% of baclofen or its pharmaceutically acceptable salt in first hour in acidic media; about 50% in 4 hours; about 60% in 8 hours.
- the method of the present invention preferably provides a mean plasma concentration of baclofen at 16 hrs post administration in the range of about 40% to 90% of the mean peak plasma concentration, more preferably, about 55% to 80% of the mean peak plasma concentration. Further the method provides a fluctuation index of less than 200, preferably, less than 170 wherein fluctuation index is calculated as (C max ⁇ C min )/C avg ⁇ 100 wherein C avg is calculated as AUC (0-24) /24.
- the controlled drug delivery system of baclofen of the present invention produces a bi-modal plasma concentration-time profile (i.e., two distinct peaks) wherein a first peak in the plasma concentration is obtained at an earlier time between 2 hours to 8 hours, preferably 2 to 4 hours and the second peak is obtained at a later time point of time at about 8 hours to 18 hours, preferably 10 to 14 hours when orally administered to human subjects.
- a bi-modal plasma concentration-time profile may be advantageous in that it provides a second peak of baclofen at a time point of about 8 hours to 18 hours, preferably, about 12 hours. The profile is particularly useful in relief of early morning symptoms of the disease condition.
- the method of the present invention provides a therapeutic benefit which is assured at the time of awakening when the symptoms are generally more pronounced. It would be most beneficial to have highest peak plasma concentrations around the time of most frequent occurrence of symptoms.
- the method of the present invention allows administration of the controlled release drug delivery at night time before sleep and provides a second plasma peak of baclofen at much later point of time which coincides with the wakening time where the system achieves therapeutic plasma levels at the more appropriate time. The appearance of the second peak is important for providing an optimum relief of early morning symptoms of the disease condition.
- the method of the present invention when the method of the present invention is practiced by administering a controlled release drug delivery system of baclofen or its pharmaceutically acceptable salt or its derivatives, to a patient in the evening, for example at about 6:00-about 8:00 pm, for relief of the symptoms over a duration of 24 hrs with high plasma levels of baclofen sustained in the next morning, for example, between about 7:00 am and about 11:00 am, particularly for optimum relief of early morning symptoms.
- the controlled release drug delivery system is in the form of coated particles comprising baclofen or its pharmaceutically acceptable salt.
- the coated particles can be in the form of beads, granules, mini tablets.
- the drug may be present along with the excipients or may be loaded onto the particles.
- the particles can consist of the encapsulation of thousands of micro-particles, each measuring 200-500 micrometers in diameter. These microparticles can be delivered in caplets.
- the controlled release drug delivery system is in the form of matrix systems wherein the baclofen or its pharmaceutically acceptable salts are embedded in a matrix comprising polymers that retard the release of the drug.
- the polymer that may be used in the matrix of the controlled release drug delivery system may be selected from hydrophilic polymers, hydrophobic material like waxes and the like and mixtures thereof.
- the controlled release drug delivery system used in the method of the present invention is designed such that it is retained in the stomach because of the characteristics of the formulation i.e. because of particular features of the system incorporated into the design of the system.
- the features by which the controlled release drug delivery system is retained in stomach for longer period of duration may be because of various mechanisms such as either the floating nature of the system or the swelling and expanding nature of system or bio-adhesive nature of systems or due to special shapes of the system, all leading to retention of the system in the gastric environment.
- the system is expandable systems. This type of system is easily swallow able and reaches a significantly larger size in the stomach due to swelling or unfolding processes that prolong their gastric retention. After the complete release of the active ingredient, their dimensions are minimized with subsequent evacuation from the stomach. Gastroretentivity is enhanced by the combination of substantial dimensions with high rigidity of the dosage form to withstand the peristalsis and mechanical contractility of the stomach.
- the system can be a bio or muco-adhesive system.
- bioadhesive polymers which can adhere to the epithelial surface in the stomach.
- Gastric mucoadhesion does not tend to be strong enough to impart to dosage forms the ability to resist the strong propulsion forces of the stomach wall.
- the continuous production of mucous by the gastric mucosa to replace the mucous that is lost through peristaltic contractions and the dilution of the stomach content also seem to limit the potential of mucoadhesion as a gastroretentive force.
- Some of the most excipients that may be used in these systems to impart bioadhesion include, but are not limited to, polycarbophil, carbopol, lectins, chitosan and gliadin and the like and mixtures thereof.
- the systems are based on floating mechanism.
- This type of drug delivery system has a bulk density less than gastric fluids and thus remains buoyant in the stomach without affecting gastric emptying rate for a prolonged period of time. While the system is floating on the gastric contents, the drug is released slowly at the desired rate from the system, after release of drug; the residual system is emptied from the stomach. This results in an increased gastric retention time and a better control of the fluctuations in plasma drug concentration.
- This particular type of system can be obtained by use of either non-effervescent materials or by use of gas-generating material.
- Excipients used most commonly in these systems include hydroxypropyl methyl cellulose (HPMC), polyacrylate polymers, polyvinyl acetate, Carbopol, agar, sodium alginate, calcium chloride, polyethylene oxide and polycarbonates.
- HPMC hydroxypropyl methyl cellulose
- polyacrylate polymers polyvinyl acetate
- Carbopol agar
- sodium alginate calcium chloride
- polyethylene oxide polycarbonates
- Other materials that may be used include sodium alginate and sodium bicarbonate, multiple unit floating pills that generate carbon dioxide when ingested, floating mini capsules with a core of sodium bicarbonate, lactose and polyvinylpyrrolidone coated with hydroxypropyl methylcellulose (HPMC), and floating systems based on ion exchange resin technology.
- sodium alginate and sodium bicarbonate multiple unit floating pills that generate carbon dioxide when ingested
- floating mini capsules with a core of sodium bicarbonate lactose and polyvinylpyrrolidone coated with hydroxypropyl methylcellulose (HPMC), and floating systems based on ion exchange resin technology.
- HPMC hydroxypropyl methylcellulose
- the system when the controlled release drug delivery system is in the form of a gastric retention drug delivery system, the system may be superporous hydrogels or lipid carrier matrix or may be based on foam based technology.
- the polymers that are used may be crosslinked polymers such as polyacrylic acid, polyacrylamide, poly (N-isoproyl-acrylamide), polyethylene oxide, poly (hydroxyethyl methacryalate), polyvinylpyrrolidone, poly (vinyl alcohol) and carboxymethylcellulose.
- These hydrogels have the ability to absorb water, and if the water content absorbed exceeds 95% of the total weight, it is called supersabsorbent hydrogel.
- the imbibition of water by the hydrogel creates a space in the structure which is known as effective pore size.
- the pore size of the hydrogel varies from 10 to 100 manometers for microporous and 100 nanometers to 10 micrometers for macroporous hydrogels.
- the superporous hydrogels are prepared by addition of a monomer, initiator, and cross-linker. The monomer is polymerized to form superporous hydrogel having a large pore size.
- superdisintegrants such as cross-linked Ac-Di-Sol, Prmojel and crospovidone are utilized as a composite material for the preparation of superporous hydrogel composite.
- the mechanical properties superporous hydrogel can be further improved by acidification of the ionizable groups of the polymer, which then enables the superporous hydrogel to withstand stresses of gastric contractions.
- a controlled release drug delivery system is in the form of matrix core that are dependent at least in part upon the diffusion and/or erosion properties of excipients within the composition.
- controlled release matrices contain an effective amount of a baclofen or its pharmaceutically acceptable salt.
- the amount of the baclofen present in the controlled release matrix can vary in an amount of from 40% to 90% by weight of the matrix tablet dry weight.
- baclofen or its pharmaceutically acceptable salts is present in an amount from 60% to 80%, and in other embodiment at 70% by weight of the matrix tablet dry weight.
- the controlled release matrix can be multiparticulate or uniparticulate, and can be coated with at least one functional or non-functional coating, or an immediate release coating containing a baclofen salt or other drug.
- Functional coatings include by way of example controlled release polymeric coatings, enteric polymeric coatings, and the like.
- Non-functional coatings are coatings that do not affect drug release but which affect other properties (e.g., they may enhance the chemical, biological, or the physical appearance of the controlled release formulation).
- a preferred embodiment of such as controlled release drug delivery system useful in the practice of the present invention swells in a dimensionally unrestrained manner to increase its size to promote gastric retention of the system in the stomach. It may be noted that this is just one way of achieving the gastric retention of the controlled release drug delivery system and is provided as an illustration, by way of example only. Any other suitable means of gastric retention that leads to the desired plasma levels as described above are the may be applied in the practice of the present invention.
- the swelling and therefore, in turn the measurement of the gastric retention may be done by various ways, for example, in vivo by gastroscopy or radiology such as scintiographic studies or by in vitro methods such as for example, measurement of the swelling index of the controlled release drug delivery system.
- a swelling capacity can be an indicator of gastric retention.
- the dimensions such as diameter and height of the system were measured with the help of Vernier Calipers.
- the dosage form may be placed in a USP dissolution apparatus (Type II-Paddle type of apparatus) in pH 4.5 acetate buffer at 37 ⁇ 0.5° C. at 50 rpm.
- the dimensions of the dosage form are measured initially and then placed into the dissolution apparatus. At specified time intervals, the dissolution apparatus was stopped and the dosage form was removed with the help of spatula in a Petri-dish and the dimensions were recorded.
- the gastric retention controlled release drug delivery system is a coated capsule the swelling index at 1 hour to 8 hours in acetate buffer is recorded in Table 7.
- FIG. 2 illustrates an embodiment of the controlled release drug delivery system in the form of capsules useful in the practice of the method of the present invention.
- the swelling or expandable nature of the capsule is depicted by the photographic images of the coated capsule in pH 4.5 acetate buffer at the end of 6 hours.
- the initial dimensions were 22.65 mm in length and 8.92 mm in diameter.
- the capsules were swollen and expanded to a length of 38.23 mm and 19.79 in diameter.
- the open pylorus has diameter of 12 mm ⁇ 18 mm in humans and objects greater than this size will have a difficulty in passing into the intestine (See Research J. Pharm. and Tech.; October-December 2008 pp. 345-348).
- the gastric emptying time and thereby, the retention of the dosage form of any discrete dosage form is delayed in the presence of food.
- a change in the motility pattern of the stomach occurs towards the fasting mode, and it is believed that a discrete dosage form is swept away by the housekeeper wave.
- size achieved after expansion does remain an important factor in the present system and preferably the volume is more than 9000 mm 3 at the end of 4 hours.
- the method comprises orally administering once-a-day in the evening a gastric retention controlled release drug delivery system comprising baclofen or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients wherein the gastric retention controlled release drug delivery system comprises a first composition having an immediately releasing fraction of the baclofen dose which is released within about 1 hour when tested in one litre of 4.5 pH acetate buffer in USP type II dissolution apparatus with sinkers rotating at a 50 rpm and at a temperature of 37 ⁇ 0.5° C.
- the first composition and the second composition occupy separate regions in the system
- at least one of the excipients in the controlled drug delivery system is selected from the group consisting of swellable polymer, gas generating agent, superdisintegrant and mixtures thereof, which excipient causes the system to swell in a dimensionally unrestrained manner to increase its size to promote gastric retention of the system in the stomach.
- the gastric retention controlled release drug delivery system is in the form of a coated capsule.
- the second composition includes at least two separate regions, first region comprising baclofen or its pharmaceutically acceptable salt and a second region comprising an excipient selected from the group consisting of swellable polymers, gas generating agents, super-disintegrants and mixtures thereof.
- the second composition includes at least two separate regions, first region comprising baclofen or its pharmaceutically acceptable salt.
- the first region of the second composition comprises a slow release fraction of the total dose of baclofen that is present in the gastric retention controlled drug delivery system used in the method of the present invention.
- the amount of baclofen present in second composition is designed to release in a controlled or slow manner.
- the ratio of the immediately releasing fraction and the slow release fraction ranges from about 1:1 to 1:3, preferably 1:1 to 1:1.5.
- the gastric retention controlled release drug delivery system comprises a total dose of 60 mg of the dose
- 35 mg of baclofen is present in the second composition
- 25 mg of baclofen is present in first composition.
- the first region of the second composition comprises along with baclofen or its pharmaceutically acceptable salts, excipients selected from the group consisting of swellable polymers, gas generating agents and superdisintegrants or mixture thereof.
- the first region of the second composition is in the form of a core of hard gelatin capsule filled with a mixture comprising a fraction of the baclofen, one or more excipients selected from the group consisting of swellable polymers, gas generating agents and superdisintegrants.
- the second region of the second composition comprises one or more excipients selected from the group consisting of swellable polymers, gas generating agents and superdisintegrants. The difference between the first region and the second region is that the first region contains baclofen and the second region does not contain baclofen.
- Categories of the swellable polymers that may be used in the gastric retention controlled release drug delivery system used in the method of the present invention include, but are not limited to, cellulose derivatives, alginic acid and its derivatives, starch and its derivatives, gums, polyacrylic acid and the like and mixtures thereof.
- Cellulose ethers and esters are available in different viscosity grades. The grades may be expressed in terms of viscosity and/or in terms of number average molecular weight. The viscosity and number average molecular weight are related to each other. Such grades of the cellulose ethers are described in terms of number average molecular weight and degree of polymerization.
- the cellulose derivatives that may be used include, but are not limited to, cellulose ethers, cellulose esters and the like.
- suitable cellulose ethers include hydroxypropyl methyl cellulose, available from Dow Chemicals under the trade name Methocel, hydroxypropyl cellulose low substituted, hydroxypropyl cellulose, available from Aqualon under the trade name Klucel, hydroxyethyl cellulose, available from Aqualon under the trade name Natrosol and Cellosize available from Amerchol Corporation, carboxymethylcellulose sodium, available under the trade name Akucell.
- Methocel is available in various viscosity grades. The typical viscosities, unless specified, are expressed for a 2% w/v aqueous solution measured at 20° C.
- K100 LVP having viscosity ranging from about 80 to about 120
- K4MP having medium viscosity ranging from about 3000 to about 5600
- K15 M having high viscosity ranging from about 12,000 to about 21,000
- K100 MP having high viscosity ranging from about 80, 000 to about 120,000
- Klucel is available in different viscosity grades.
- Klucel HF (1% w/v) solution shows a viscosity ranging from about 1500 to about 3000.
- Klucel MF (2% w/v) solution shows a viscosity ranging from about 4000 to about 6500.
- Klucel GF (2% w/v) solution shows a viscosity ranging from about 150 to about 400.
- Klucel JF (5% w/v) solution shows a viscosity ranging from about 150 to about 400.
- Klucel LF (5% w/v) solution shows a viscosity ranging from about 75 to about 150
- Klucel EF (10% w/v) solution shows a viscosity ranging from about 200 to about 600.
- Different types of viscosity grades of Natrosol 250 are available such as HHR having 1% w/v solution 3400 to about 5000, H4R having viscosity ranging from about 2600 to about 3300, HR having viscosity ranging from about 1500 to about 2500 and MHR having viscosity ranging from about 800 to about 1500.
- Low viscosity grades of Natrosol include, but are not limited to, MR, KR, GR, ER, JR and LR.
- Carboxymethyl cellulose is available as low viscosity Akucell AF 0303 (1% w/v) showing a viscosity ranging from about 10 to about 15 mPas.
- the medium viscosity grade of Akucell AF2785 shows a viscosity ranging from about 1500 to about 2500.
- the 1% w/v solution of high viscosity grade of Akucell AF3085 shows a viscosity ranging from about 8000 to about 1200.
- HPC hydroxypropyl cellulose
- Alginic acid which is available in different viscosity grades. The viscosities depend on the molecular weight. Typically, a 0.5% w/w aqueous dispersion shows a viscosity of approximately 10 mPas while a 2% w/w aqueous dispersion shows a viscosity of approximately 2000 mPas.
- Sodium alginate is also available in different viscosity grades. Typically, a 1% w/v aqueous solution shows a viscosity of 20 to about 400 mPas.
- Polyvinyl pyrrolidone of high viscosity may be employed.
- a swellable polymer that may be used in a drug delivery system suitable for use in the method of the present invention is a pH dependent polymer that is soluble below about pH 5 and is swellable and permeable above pH 5.
- the pH dependent polymer is an acrylate polymer obtained by polymerizing dimethylamino ethyl methacrylate with neutral methacrylate esters.
- the pH dependent polymer is a polymer obtained by polymerization of the monomers namely, butyl methacrylate, 2-dimethyl aminoethyl methacrylate and methyl methacrylate.
- This polymer, poly (butyl methacrylate, (2-dimethyl aminoethyl) methacrylate, methyl methacrylate) may be prepared from different molar ratios of the monomers. However, preferably, the butyl methacrylate, 2-dimethyl aminoethyl methacrylate and methyl methacrylate molar ratio is about 1:2:1.
- This preferred polymer butyl methacrylate, 2-dimethyl amionethyl methacrylate and methyl methacrylate with a molar ratio of about 1:2:1 is available in different physical forms under the trade names Eudragit E 100, Eudragit E 12.5 and Eudragit EPO.
- Eudragit E 100 is in the form of granules
- Eudragit E 12.5 is available in the form of 12.5% w/v solution in an organic solvent
- Eudragit E PO is available in powder form.
- the swellable polymer may be present in an amount ranging from about 1% to about 40%, preferably about 5% to about 30% and most preferably about 10% by weight of the gastric retention controlled release drug delivery system used in the method of the present invention.
- the gas generating agent used in the gastric retention controlled release drug delivery system of the present invention may include a single component that generates gas upon contact with the gastric fluid, or may include a gas generating couple.
- Gas generating components that may be used in the present invention include solids that liberate gas, especially carbon dioxide or nitrogen, for example under the action of body fluid or the hydrogen ions present therein. Examples include carbonates such as calcium carbonate, bicarbonates such as sodium or potassium bicarbonate, sulfites such as sodium sulfite, sodium bisulfite, or sodium metabisulfite, and the like, ammonium cations or sodium azide or mixtures thereof. These salts may be used alone or in combination with an acid source as a gas generating couple.
- the acid source may be an edible organic acid, a salt of an edible organic acid, or mixtures thereof.
- organic acids include citric acid, malic acid, succinic acid, tartaric acid, fumaric acid, maleic acid, ascorbic acid, glutamic acid, alginic acid, acrylic acid and their salts, and mixtures thereof.
- Sodium bicarbonate is used as the preferred gas generating agent.
- the organic acid may also be a polymer, for example acrylic acid polymers and copolymers such as acrylate polymers available under the tradenames Carbopol®, Eudragit® L-100-55, Eudragit® S-100, Noveon® AA1, which react with carbonates or bicarbonates of alkali or alkali earth metal compounds to generate gas.
- acrylic acid polymers and copolymers such as acrylate polymers available under the tradenames Carbopol®, Eudragit® L-100-55, Eudragit® S-100, Noveon® AA1, which react with carbonates or bicarbonates of alkali or alkali earth metal compounds to generate gas.
- These are generally used as auxiliary acid sources and may also have properties of themselves generating internal pressure by swelling when in contact with an aqueous medium.
- the gas-generating agent is used in an amount ranging from about 0.5% to about 50%, preferably in the range of 5% to about 10% by weight of the gastric retention controlled release drug delivery system used in the method of
- superdisintegrants examples include, but are not limited to, crosslinked sodium carboxymethyl cellulose, crosslinked polyvinylpyrrolidone, sodium starch glycolate, ion exchange resins and mixtures thereof.
- the superdisintegrants may be used in an amount ranging from about 0.5% to about 30%, preferably about 3% to about 10% by weight of the gastric retention controlled release drug delivery system used in the method of the present invention.
- the first region of the second composition may further include one or more rate controlling excipients.
- release rate controlling excipients include, but are not limited to, water insoluble polymers and hydrophobic materials such as waxes. Hydrophobic materials apart from acting as release rate controlling excipients, because of their low density, can also enhance the gastric retention of the coated capsule of the present invention.
- hydrophobic materials examples include, but are not limited to, waxes, carnauba wax, vegetable wax, fruit wax, microcrystalline wax, bees wax, hydrocarbon wax, paraffin wax, cetyl esters wax, nonionic emulsifying wax, anionic emulsifying wax, candelilla wax, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, lauryl alcohol, myristyl alcohol, hydrogenated vegetable oil, hydrogenated castor oil, a fatty acids, a fatty acid esters, or mixtures thereof.
- the amount of the hydrophobic material present in second region of the second composition of the gastric retention drug delivery system used in the method of the present invention ranges from about 0.1% to about 10% by weight of the gastric retention controlled release drug delivery system used in the method of the present invention.
- water soluble materials such as mannitol, lactose, lactitol, xylitol, sucrose or mixtures thereof or any other sugar alcohol may also be present in the third second composition of the gastric retention controlled release drug delivery system.
- the amount of such material may be from about 0% to about 60%, preferably about 15% to about 50% by weight of the second composition of the gastric retention controlled release drug delivery system used in the method of the present invention.
- the weight ratio of second region of the second composition to the first region of the second composition is about 25:1.
- the weight ratio of third composition to the second composition is about 25:1.
- the gastric retention controlled release drug delivery system comprises a third composition.
- the third composition is present in between the first composition and the second composition.
- the third composition when the second composition is in the form of a coated capsule, the third composition is in the form of a coating that is applied to the second composition.
- the third composition is applied to the second composition in the form of coating surrounding the second composition.
- the third composition comprises a water insoluble polymer and one or more excipients selected from the group consisting of swellable polymers, gas generating agents and superdisintegrants.
- the water insoluble polymer present in the third composition are insoluble in gastric milieu and is selected from the group consisting of ethyl cellulose, methacrylic acid-ethyl acrylate copolymers, polyacrylic acid and mixtures thereof.
- the third composition forms a film capable of expanding and maintaining its physical integrity in the gastric milieu.
- the third composition may further comprise one or more swellable polymers such as Carbopol® polymers, PemulenTM polymeric emulsifiers and Noveon® polycarbophils.
- a high molecular weight acrylic acid polymer crosslinked with divinyl glycol is employed. This may be used in amount ranging from about 0.1% by weight to about 10% by weight, preferably about 1% to about 2% by weight of the gastric retention controlled release drug delivery system.
- the third composition is in the form of a membrane or a film that surrounds the second composition which is either in the form of a compressed core or a capsule filled with excipients.
- the presence of the excipients of third composition cause the film to stretch and expand in size to form a balloon like system.
- the membrane or the film made up of the third composition provides strength and elasticity to the system in the gastric milieu. Because of the elastic and stretchable nature of the membrane, the system can withstand the contractions of the stomach and not break open and continues to release baclofen over a desirable period of time.
- a bioadhesive polymer such as polycarbophil
- the system in addition to swelling also achieves bioadhesive effect causing gastric retention.
- the membrane of the third composition may comprise of additional plasticizers which adds to the stretchable elastic nature of the polymer, causing better expansion and stretching of the system leading to increase in size sufficient enough to cause gastric retention.
- the first composition present in gastric retention controlled release drug delivery system used in the method of the present invention comprises an immediately releasing fraction of the baclofen dose which is released within about 1 hour when tested in one litre of 4.5 pH acetate buffer in USP Type II dissolution apparatus with sinkers rotating at a 50 rpm and at a temperature of 37 ⁇ 0.5° C.
- This first composition occupies a region separate within gastric retention controlled drug delivery system which is physically distinct from the region occupied by the second composition.
- the first composition is present in the form of a coating wherein the composition comprises an excipient that does not hinder in the immediate release of the fraction of the baclofen dose.
- the first composition when the first composition is in the form of a coating, the first composition comprises water soluble polymers such as low viscosity water soluble polymers used in the top coating for example, hydroxypropyl methyl cellulose or methyl cellulose or any other cellulose derivative of very low viscosity which does not hinder the immediate release of fraction of the total dose baclofen present in the gastric retention controlled release drug delivery system.
- water soluble polymers such as low viscosity water soluble polymers used in the top coating for example, hydroxypropyl methyl cellulose or methyl cellulose or any other cellulose derivative of very low viscosity which does not hinder the immediate release of fraction of the total dose baclofen present in the gastric retention controlled release drug delivery system.
- a method of the present invention useful for optimum relief of early morning symptoms of the disease condition comprising administration of a controlled release drug delivery system of baclofen or its pharmaceutically acceptable salt, to the patient in the evening example at about 6:00-about 8:00 pm, for relief of the symptoms over a duration of 24 hrs with high plasma levels of baclofen sustained in the next morning, for example between about 7:00 am and about 11:00 am, particularly for optimum relief of early morning symptoms.
- a randomized, open-label, two-treatment, two-period, two-sequence, multiple dose, crossover study was conducted to assess bioavailability and steady state pharmacokinetics of baclofen 30 mg capsules prepared as per Example 1 was given once daily, under fed (normal meal) conditions, for 8 consecutive days in patients suffering from spasticity. Baclofen 10 mg immediate release tablets were given three times a day at 8 hour interval, with the initial dose administered under fasting condition, for 8 consecutive days, in 24 spastic subjects receiving stable daily doses of baclofen.
- spastic patients showed better pharmacokinetic profile when the controlled drug delivery system of the present invention was administered by spastic patients on fed state in the evening in comparison to the pharmacokinetic profile achieved when the controlled drug delivery system of the present invention was administered on fed state in the morning wherein the study was a two way crossover, wherein one arm administered the controlled drug delivery system of the present invention and the other arm administered equivalent dose of baclofen in the form of immediate release tablets administered three times a day.
- This example represents an embodiment of the controlled release drug delivery system which is gastric retention drug delivery system comprising baclofen. It is prepared according to formulae given Table 1 below.
- Table 1 gives the formula for the preparation of the first region of the second composition.
- the first region is the formulation that is filled into gelatin capsules.
- the polymer hydroxypropylmethyl cellulose, low viscosity that does not function as a rate controlling polymer but only serve as a aid in binding on slugging to process the slug.
- This formulation does not contain any excipient that is characterized as a rate controlling excipient.
- HPC-HXF Hydroxypropyl cellulose
- Colloidal silicon dioxide and Mannitol (intra-granular) were sifted and collected together.
- the material was resifted through ASTM #40 sieved and collected.
- the sifted material was loaded into a suitable blender and mixed for a period of 10 minutes.
- Magnesium stearate and Talc were added as lubricants and further mixed for 5 minutes.
- the blend was slugged using 20 mm flat-faced round punches using a single rotary compression machine.
- the slugs were milled to achieve a particle size suitable for capsule filing.
- Opadry II Clear and mannitol were sifted.
- the hard gelatin capsules of size ‘0’ capsules were filled with the milled material and added extragranularly to the milled blend.
- Table 2 gives the formula for the preparation of the second region of the second composition which is also referred to as subcoat composition.
- the filled capsules were coated with a sub coat composition prepared by dispersing Eudragit, polyvinyl pyrrolidone, alginic acid, Sodium bicarbonate, Sodium starch glycolate, Mannitol 25 and Talc in isopropyl alcohol containing polysorbate 20. The dispersion was passed through a coarse screen to ensure homogenous dispersion.
- the filled capsules were loaded into a suitable perforated coating pan (36′′) and the capsules were coated with a second subcoat composition to a weight gain of about 25%.
- Table 3 provides the details of the third composition of film forming polymer insoluble in gastric milieu and one or more disintegrants and/or gas generating agents
- the sub coated filled capsules were further coated with a coating dispersion for Film-coating comprising a water insoluble polymer.
- the coating suspension was prepared by dispersing ingredients of table 3 in isopropyl alcohol. Sequentially the dispersion was screened to ensure uniform homogeneous dispersion and absence of lumps.
- the sub-coated capsules were loaded into a suitable perforated coating pan (48′′) and were coated to a weight gain of about 25% using the coating solution.
- Table 4 above provides a first composition comprising fraction of the baclofen in a protective thin film coating composition.
- the double layer coated capsules were further coated with a coating dispersion using commonly available Opadry ready to use composition in which baclofen was dispersed using an overhead stirrer.
- the gastric retention controlled drug delivery based on swelling and expanding mechanism, useful in the method of the present invention were checked for swelling index at various time points in pH 4.5 buffer.
- the capsules were allowed to swell under stirring using a USP Type assembly rotating at 75 rpm speed.
- the swelling nature of the coated capsule of the present invention is also depicted by the photographic images of the coated capsule in 4.5 Acetate buffer in the FIG. 2 .
- a gastric retention drug delivery system comprising baclofen was prepared as mentioned in Table 8 below.
- Baclofen, fumaric acid, mannitol, hydroxypropyl cellulose, sodium bicarbonate, colloidal silicon dioxide, talc and magnesium stearate were mixed to obtain a blend and this was filled in size 0 hard gelatin capsules.
- the filled capsules were coated with a coating suspension containing alginic acid, sodium bicarbonate, sodium starch glycolate, mannitol, povidone, talc, polysorbate in isopropyl alcohol to a weight gain of about 25% by weight of the core capsules.
- a coating solution comprising polycarbophil, sodium bicarbonate, methacrylic acid copolymer, Eudragit S-100, mannitol, sodium starch glycolate, polysorbate, PEG, talc and diethyl phthalate in isopropyl alcohol, the solution being coated to about 18% by weight.
- a top coat comprising baclofen, povidone, talc and Tween was introduced on the capsules to a weight gain of about 1.5%, using a coating solution in purified water.
- a gastric retention drug delivery system comprising baclofen was prepared as mentioned in Table 9 below.
- the first region of the second composition was obtained by blending the excipients listed in Table 10 with baclofen and filling it in a hard gelatin capsule. The capsule was then coated with a second region of the second composition and third composition similar to example 2 described above.
- a gastric retention drug delivery system comprising baclofen was obtained as mentioned in Table 10 below.
- the coated tablets were obtained as mentioned in examples above.
- the core coated with the subcoat was placed in 100 ml of 0.01N HCl and pH 4.5 buffers. It was found that the sub-coated tablets remained at the base of the vessel and began to disintegrate after about 3 minutes, and fully disintegrated in about 6 minutes.
- the controlled release drug delivery system was obtained as per Table 11 below.
- the core of the controlled release drug delivery system was obtained by passing baclofen, lactose, hydroxyethyl cellulose, sodium starch glycolate, sodium bicarbonate and a part of HPMC K4M through ASTM (American Society for Testing and Materials) sieve #40 and mixing the ingredients to obtain a dry powder blend. An aqueous solution of HPMC K4M was then used to granulate the dry powder blend. The granules thus obtained were passed through a suitable sieve and dried. The dry granules were lubricated with a mixture of Prosolv SMCC 90, talc, PEG 8000 and HPMC K4M, and compressed to obtain the cores. The cores were then coated with an aqueous solution containing baclofen and Opadry II to obtain the gastric retention controlled drug delivery system of the present invention.
- the tablets thus obtained were subjected to dissolution testing at 37° C. using United States Pharmacopoeia Type II (paddle) dissolution apparatus at 50 rpm.
- the dissolution medium used was 1000 ml of 0.1N HCl.
- the tablets achieved floatation in about 10 minutes.
- the results of the dissolution test are recorded in Table 12 below.
- the controlled release drug delivery system was obtained as per Table 13 below—
- Amount in mg per % by weight Ingredients tablet of the tablet Baclofen 22.5 2.25 mannitol 260.0 26.0 Hydroxyethyl cellulose (HEC 250 H) 200 20.0 Sodium starch glycolate 250 25.0 Sodium bicarbonate 80.0 8.0 Hydroxypropyl methylcellulose (3000-5600 4.5 0.45 mPaa) Silicified microcrystalline cellulose 90 9 Talc 24 2.4 Polyethylene glycol (PEG 8000) 10 1 Coat Baclofen 7.50 7.5 Low viscosity Hydroxypropyl 24.0 2.4 methylcellulose (4-6 mPas) talc 10.0 1.0 Titanium dioxide 11.0 1.1 Propylene glycol 5.00 0.5
- the core of the gastric retention controlled drug delivery system was obtained by passing baclofen, mannitol, hydroxyethyl cellulose, sodium starch glycolate and sodium bicarbonate through ASTM (American Society for Testing and Materials) sieve #40 and mixing the ingredients to obtain a dry powder blend.
- An aqueous solution of HPMC K4M was then used to granulate the dry powder blend.
- the granules thus obtained were passed through a suitable sieve and dried.
- the dry granules were lubricated with a mixture of Prosolv SMCC 90, talc and PEG 8000, and compressed to obtain the cores.
- the cores were then coated with a hydro-alcoholic solution of a mixture of baclofen, HPMC E5, talc, propylene glycol and titanium dioxide to obtain the gastric retention controlled drug delivery system of the present invention.
- the tablets thus obtained were subjected to dissolution testing at 37° C. using United States Pharmacopoeia Type II (paddle) dissolution apparatus at 50 rpm.
- the dissolution medium used was 1000 ml of 0.1N HCl.
- the tablets achieved floatation in about 6 minutes.
- the results of the dissolution test are recorded in Table 14 below.
- the controlled release drug delivery system of the present invention was obtained as given in Table 15 below.
- baclofen, hydroxyethylcellulose, a part of sodium starch glycolate, a part of microcrystalline cellulose and a part of polyvinylpyrrolidone were mixed together and granulated with isopropanol and lubricated with talc and magnesium stearate to form the core granulation.
- the remaining parts of baclofen, microcrystalline cellulose, polyvinylpyrrolidone and sodium starch glycolate were mixed together and granulated with water to form the coat granulation.
- the core granulations were compressed and the coat was applied on the core using compression coating.
- the gastric retention controlled drug delivery system thus obtained in the form of coated tablets shows a high degree of swellability in a short time, has sufficient strength for handling as well as remaining intact in aqueous fluids, and is capable of providing a biphasic controlled release profile.
- Example 1 Comparison of morning dosing and evening dosing in single dose study in healthy volunteers.
- the coated capsules of Example 1 were tested for bioavailability in normal volunteers in the fed condition at different timings, that is, administration in the morning or in the evening Twenty four healthy volunteers were enrolled for the study and twenty two of them completed both the periods of the study.
- a randomized, open label, two treatment, two period, two sequence, single dose crossover study was carried out to assess the effect of the dosage time administration (i.e. after morning and evening administration) on the pharmacokinetics of the baclofen 60 mg extended release coated capsules of Example 1 which are suitable for once a day administration.
- Example 1 The coated capsules of Example 1 where administered by human volunteers in the evening at 7:00 pm in the fed condition.
- the volunteers had a normal diet for the dinner as well as morning breakfast.
- the human volunteers had a breakfast at 8:00 am and the dosing of the coated capsules was done at 8:30 am.
- the pharmacokinetic parameters that were evaluated are tabulated in Table 17.
- Pharmacokinetic study on Baclofen 60 mg as described in Example 1 were performed by using method of Nonparametric superposition in WinNonlin 5.0 of Pharsight Corporation, USA.
- Software used for performing simulation WinNonlin (version 5.0) of Pharsight Corporation, USA.
- the method used for performing simulation was Non-parametric superposition method.
- Nonparametric superposition function is used to predict drug concentrations after multiple dosing at steady state, and is based on non-compartmental results describing single dose data. The predictions are based upon an accumulation ratio computed from the elimination rate constant.
- PK Sampling points considered for simulation were 0.0 (Pre-dose), 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0, 16.0, 20.0, 24.0, 30.0 and 36.0 hours. Data of both morning & Evening dose have been simulated for 7 consecutive days and dosing interval of 24 hr (once daily dose) has been considered. The mean plasma concentration profile is presented in table 18 and FIG. 3 . The steady state data results are reported in Table 19 and 20 below.
- Tables 19 The data tabulated in Tables 19 indicates that when the claimed controlled release drug delivery system was administered every 24 hours as an evening dose of baclofen for consecutively 7 days (simulated data using software) wherein the plasma levels at steady state (for 7 days) shows lesser peak plasma concentration compared to the peak plasma concentration achieved at a steady state level as compared to the plasma levels achieved after morning dosing.
- FIG. 3 indicates a much flattened plasma baclofen concentration time profiles after evening dosing compared to the morning dosing.
- a randomized, open-label, two-treatment, two-period, two-sequence, multiple dose, crossover study to assess bioavailability and steady State pharmacokinetics of baclofen 30 mg controlled release drug delivery system of the present invention was given once daily, under fed (normal meal) conditions in the morning time, for 8 consecutive days in patients suffering from spasticity.
- Baclofen 10 mg immediate release tablets were given three times a day at 8 hour interval, with the initial dose administered under fasting condition, for 8 consecutive days, in 24 Spastic subjects receiving stable daily doses of baclofen.
- a randomized, open-label, two-treatment, two-period, two-sequence, multiple dose, crossover study to assess bioavailability and steady State pharmacokinetics of baclofen 30 mg controlled release drug delivery system of the present invention was given once daily in the evening time, under fed (normal meal) conditions, for 8 consecutive days in patients suffering from spasticity.
- Baclofen 10 mg immediate release tablets were given three times a day at 8 hour interval, with the initial dose administered under fasting condition, for 8 consecutive days, in 24 Spastic subjects receiving stable daily doses of baclofen.
- the T max was prolonged when the same composition was administered in the evening in comparison to the morning.
- the T/R ratio of the AUC i.e extent of absorption was found to be better when the controlled release system was administered in the evening in comparison to the administration in the morning.
- the rate of absorption was better when the controlled release system was administered in the evening in comparison to the morning.
- Baclofen is mixed with mannitol, starch and talc.
- the mixture is granulated with solution of dimethylamino ethyl methacrylate with neutral methacrylate esters.
- the granules are lubricated with talc and are filled into hard gelatin capsules.
- the capsule is further coated with a solution of immediate release fraction of baclofen which is dispersed in a film coating solution of low viscosity hydroxypropyl methylcellulose.
- Specified amounts of Baclofen may be taken and mixed with specified amounts of microcrystalline cellulose and Croscarmellose sodium.
- the blend is uniformly mixed and the powder blend is granulated with a polymeric hydro-alcoholic solution of ethyl-cellulose in a fluidized bed granulator.
- the granules so formed are further coated with hydro-alcoholic solution of ethyl-cellulose.
- These coated granules represent a reservoir type of controlled drug delivery system wherein the release of baclofen is controlled by the matrix as well the reservoir mechanism.
- the coated granules may be filled into hard gelatin capsules or may be compressed into tablets of size of about 2 millimeter (2 mm) and then filled into hard gelatin capsules.
- Controlled release drug delivery system of baclofen of the present invention may be obtained in the form of a bilayer tablet that is functionally coated. Portion of baclofen is incorporated in the second layer for the immediate release and portion of baclofen is incorporated in the first layer for the controlled release.
- Specified amounts of baclofen, Hydroxypropyl methylcellulose (12,000 to 21000 mPas), lactose anhydrous, polyvinyl pyrrolidone and colloidal silicon dioxide are sieved and mixed thoroughly.
- Stearic acid and talc are sieved and mixed with the blend, to obtain the composition of the first layer.
- baclofen, silicified microcrystalline cellulose, colloidal silicon dioxide, sodium lauryl sulfate and crospovidone were sieved and mixed thoroughly to obtain a blend.
- This blend was lubricated with magnesium stearate, to obtain the composition of the second layer.
- the two compositions were compressed using standard concave punches to obtain bilayer tablets.
- the compressed tablets were coated with the coating composition to a weight gain of about 8% by weight of the core.
- An orifice of size of about 500 microns was drilled on the side of the tablet that contained the second layer.
- Non-pareil seeds NPS 81.4 81.4 Baclofen 13.0 13.0 Hypromellose, Methocel E 5.6 5.6 Purified Water, USP q.s q.s Functional coating Ethylcellulose 8.5 8.5 Hydroxy propyl methylcellulose 2.12 2.12 Purified Water, USP q.s q.s
- baclofen Specified quantities of baclofen are mixed geometrically with polyethylene oxide, sodium carboxymethylcellulose, lactose anhydrous and microcrystalline cellulose. The mixture is sifted and blended in a double polythene bag till a uniform mixture is obtained. The blend is granulated with a binding solution of polyvinyl pyrrolidone in isopropyl alcohol. The dried granules are lubricated with colloidal silicon dioxide, purified talc and magnesium stearate by mixing for 2 minutes. The mini tablets have a diameter of about 1.5 mm and a length of about 2 mm.
- baclofen Specified amounts of baclofen are loaded in a fluid bed chamber.
- a coating solution of ethyl cellulose, polyvinyl pyrrolidone, castor oil and lubricant is prepared by dissolving the ingredients in isopropyl alcohol. Baclofen is then film coated with this coating solution.
- These film-coated baclofen microparticles particles are subsequently dry blended in a cube mixer with a mixture of sodium alginate powder, hydroxypropylmethylcellulose powder and calcium acetate powder. This mixture is filled in hard gelatin capsules.
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Addiction (AREA)
- Neurology (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- Physical Education & Sports Medicine (AREA)
- Biomedical Technology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pulmonology (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
- The present invention relates to an effective method of treating a disease condition susceptible to baclofen therapy, said method comprising administering a controlled release drug delivery system of baclofen or its pharmaceutically acceptable salts or its derivatives.
- The present invention also relates to an effective method of treating disease conditions susceptible to baclofen therapy, said method comprising administering a controlled release drug delivery system of baclofen or its pharmaceutically acceptable salts or its derivatives and to the use of baclofen for such treatment.
- U.S. Pat. No. 3,471,548 disclosed 4-amino-3-(p-chlorophenyl)butyric acid). 4-amino-3-(p-chlorophenyl)butyric acid) designates the R-isomers, the S-isomer and mixtures of R and S isomers including the racemate. Baclofen is indicated in many disease conditions such as for alleviating signs and symptoms of spasticity resulting from multiple sclerosis, particularly for the relief of flexor spasms and concomitant pain, clonus and muscular rigidity; in treatment of gastroparesis, non ulcer dydpepsia, gastroesophageal reflux diseases, for the treatment of depression or other psychological conditions, such as posttraumatic stress disorders, alcohol related disorders such as alcohol dependence is a chronic disorder that results from a variety of genetic, physiological and environmental factors, for promoting smoking cessation; for reducing addiction liability of narcotic agents; in the treatment of emesis; as an anti-tussive for the treatment of cough; in treating neuropathic pain and in treating musculoskeletal pain.
- Clinical studies wherein baclofen is used for the treatment of spasticity have indicated that its major site of action is the spinal cord. Spasticity is one of the components of the upper motor neuron (UHM) syndrome but should not be considered in isolation when it comes to management strategies. Baclofen is used as a muscle relaxant and an anti-spastic agent for a variety of neurological disorders. It is a GABA-B receptor agonist that depresses the monosynaptic and polysynaptic excitation of mononeurons and interneurons. Currently, the most commonly used dosage form of racemic baclofen is the immediate release (IR) tablet (10-20 mg) to be administered three times a day. A serum concentration of 8Ong/ml or more is considered an effective concentration.
- There is a wide inter-subject variation in the absorption and elimination of baclofen, but on an average it is rapidly and extensively absorbed after oral administration. Plasma elimination half-life of baclofen is approximately 3.5 hours (range 2 to 6 hours). Baclofen is excreted mainly by the kidneys in unchanged form although 15% is metabolized in the liver. Conventional baclofen therapy involves administration of 10 mg or 20 mg immediate release tablets three times a day. The dose ranges from 30 mg to 100 mg/day in divided doses. Baclofen is also available in the USA for chronic use as an injection to be administered by the intrathecal route in single bolus test doses (via spinal catheter or lumbar puncture), and as implantable pumps approved by the Food and Drug Administration specifically for the administration of baclofen injection into the intrathecal space.
- Frequent administration of immediate release baclofen tablets leads to fluctuations in plasma concentration producing peaks and troughs. Peaks in plasma concentration are associated with side effects, such as drowsiness (sedation), dizziness and muscle weakness and troughs cause inadequate control of muscle spasm. Side effects, like drowsiness and muscle weakness, are considered as major deterrents to the prescribers for up titration of the dosage for optimization of therapy. It is a matter of general concern, with conventional baclofen therapy, that the medication has to be administered frequently. Medication noncompliance among patients with medical illnesses has been reported to range from 15% to 85%. Although many factors are associated with medication non-compliance, it is thought that physicians can help promote compliance by prescribing medications that require a minimal number of doses.
- A once-a-day or twice-a-day (b.i.d.) dosage formulation with the same therapeutic effectiveness as the conventional baclofen therapy could vastly improve patients' compliance with treatment. These will also improve the outcome of therapy, as a greater number of patients will adhere to treatment plan.
- Although a single daily administration of the full daily dose (referred to as “high dose” to signify the higher amount of baclofen in a single sustained release tablet compared to that in one immediate release tablet even though the total daily dose remains the same) would be convenient however, the problem was that when baclofen was given in single high daily doses as sustained or controlled release preparation the bioavailability was reduced. This problem was studied by Merino et al (Proc. Eur. Congr. Biopharm. Pharmacokinet., 3rd (1987) 2, 564-73) and Biopharmaceutics and Drug Disposition (1989), 10(3), 279-97). The authors made significant conclusions about absorption of baclofen:
-
- 1. The lipophilicity of the drug at the actual pH values is negligible and therefore passive absorption mechanism for baclofen will be virtually inoperative and aqueous pore diffusion will be limited in view of the molecular weight of the drug. This limits the mechanisms by which baclofen can be absorbed to active or carrier mediated transport.
- 2. The absorption from the small intestine could occur due to the presence of a carrier mediated transport mechanism
- 3. No absorption could occur in the colon because of the absence of a carrier mediated transport mechanism.
- 4. Absorption of baclofen occurs by specialized transport mechanism which is saturable at higher concentrations and thus the use of high doses of baclofen is not recommended.
- 5. It can therefore be predicted that if controlled release formulations of baclofen are to be considered, they should be designed so that they would release most of the drug before reaching the illeo-caecal junction, i.e within no more than 8 hours.
- Further, it is known that gastric motility presents a significant resistance to preventing the passage of a dosage form into the colon for more than 8 hours. This resistance is due to the strong propulsive movements of the gut, particularly the occurrence of a periodic housekeeper wave that would sweep any physical object from the stomach into the intestine. (see Tmax in FIG. 1 and Table 7 when the systems were given in the fed state in the morning). The reasons for such shortfalls are suspected to lie in the nature of gastric motility and gastric emptying (See page 145 of E. A. Klausner et al, Journal of Controlled release 90 (2003), 143-162). The motor activity in the fed state is induced 5-10 min after ingestion of a meal and persists as long as food remains in the stomach, which may be from as short as about 2 hrs to as long as about 6 hrs, typically 3-4 hrs. In this period the contraction are of intermediate amplitudes. At the end of the fed phase, the motility pattern changes and goes into a fasted mode characterized by four periods of peristaltic activity over a 2 hr period. The aim of this activity is to clear the stomach and the small intestine of indigestible debris. It has four phases of which the third phase is known as the housekeeper phase characterized by very high amplitude contractions lasting for 5-15 minutes. Anything in the stomach is expected to be cleared due to these strong contractions or otherwise cause the problems of blocking of the pyloric sphincter or accumulation of the object in the stomach after it is repeatedly ingested by the human subject. It is also not possible to use a dosage form that would resist such housekeeper waves because it will be totally unacceptable for safety reasons to allow the accumulation of the residual dosage form in the stomach.
- Nevertheless with the doubts whether a controlled drug delivery systems would provide adequate bioavailability, the present inventors proceeded to design and test a once-a-day controlled drug delivery system for baclofen to investigate possibilities of overcoming the drawbacks of poor absorption of baclofen in the lower parts of the intestine and obtain adequate bioavailability and a plasma profile with lower fluctuation in plasma levels. Two of such controlled drug delivery systems were disclosed in the pending patent applications US 20040180088 and US 20080107732. The bioavailability of baclofen from these controlled drug delivery systems containing 30 mg of baclofen was compared to the bioavailability of baclofen in the fed state (normal diet) from immediate release tablets (15 mg tablets given twice a day) in a comparative, open label, randomized two-way cross-over study in twelve healthy volunteers. It was found that the relative bioavailability of baclofen from the gastric retention controlled drug delivery system was 80% of the bioavailability from the immediate release tablets. These results were achieved by improving the design of prior known controlled drug delivery systems by incorporating features that cause the systems to expand in the gastric fluids and consequently be retained over longer periods in the stomach. However, this alone was not sufficient and an additional design feature in these systems was that they released a fraction of the drug in a more absorbable immediate release form that contributed to baclofen levels only for the initial duration of the 24 hr dosing nevertheless it obtained 24 hrs desired plasma levels by combining the more absorbable form with the slow release form which is criticized in the prior art as being “poorly absorbable”.
- The inventors proceeded further to investigate whether this extent of absorption of baclofen from these once-a-day controlled drug delivery systems would also be obtained in patients suffering from spasticity and whether it was adequate to provide the desired efficacy over the duration of a day. It was surprisingly found that while the controlled release drug delivery demonstrated an efficacy equivalent to the immediate release baclofen tablets it also showed lower levels of sedation. Thus, a method of alleviating signs and symptoms of spasticity in human patient using once a day therapy was discovered for the first time. The method provided the benefit of reduced levels of sedation as compared to therapy with immediate release tablets and was claimed in US 20070265343 (European patent application EP 1849 462 A2 the contents of which are incorporated herein by reference). The EP 1849462 A2 claims a method of alleviating signs and symptoms of spasticity in human patient comprising orally administering to said human patients once in a day a controlled drug delivery system comprising an effective daily dose of baclofen or its pharmaceutically acceptable salt wherein said method is associated with reduced level of sedation in said patients as compared to conventional baclofen therapy with immediate release tablets administered three times a day on the same total daily dose. It further related to a method wherein the daily dose of baclofen or its pharmaceutically acceptable salt ranges from about 15 mg to about 80 mg. Particularly the method was useful when the daily dose of racemic baclofen was 30 mg or 45 mgs. The finding invention was surprising because instead of continuous treatment, in the sense of multiple daily dosing, with baclofen for patients suffering from spasticity which leads to the side effect of sedation, using an intermittent, in the sense of once a day, dosing amounting to the same overall daily dosage not only allows effective treatment of the underlying condition of spasticity but also reduces or eliminates the side effect of sedation. This was particularly surprising since the administration of a once a day formulation lead to higher plasma levels than the equivalent multiple dosing regimen and thus would ordinarily be expected to be associated with increased sedation as a side effect. Without wishing to be bound by theory, it is believed that the unexpected success of the formulations used arose as a consequence that they are retained in the stomach for longer than other systems. It was therefore an important benefit that the scope of industrial applicability and marketability of baclofen was increased because it could be used in a wider range of circumstances than previously possible when the risk of sedation might have precluded its use. Also, the invention could be particularly useful for treating patients who have a predisposition to suffering sedation as a side effect.
- It has surprisingly been found that when controlled release drug delivery system comprising baclofen or its pharmaceutically acceptable salt or its derivative was administered to human subjects in the evening in the fed state, the maximum plasma concentration of baclofen (Cmax) achieved after administration of the system in evening was sustained over a longer duration (see
FIG. 1 andFIG. 3 ) than compared to that after administration of the system in the morning in the fed state. Surprisingly when the system was administered in the evening, it was observed that the duration over which absorption of baclofen occurred was prolonged and higher plasma levels were maintained during the latter half of the dosing period as compared to those obtained by morning dosing. Evening dosing thus can provide an optimum maintenance of relief from the systems of the disease condition by maintaining baclofen levels at higher therapeutic effective plasma concentrations even in the latter half of the dosing period. - The improved method of the present invention is useful for treating disease conditions such as spasticity, gastroparesis, gastro-esophageal reflux diseases, for the treatment of depression or other psychological conditions, alcohol related disorders such as alcohol dependence, smoking cessation, addiction liability of narcotic agents, emesis, cough, hiccoughs, neuropathic pain and musculoskeletal pain.
- In various aspects and embodiments, the present invention seeks to provide an improved method of treating a disease condition susceptible to baclofen therapy.
- The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
- Many aspects of the invention can be better understood with reference to the following figures. The figures only represent one of the embodiments of the present invention. The embodiments are meant only for the purpose of illustration of the present invention. The components in the drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the present invention.
-
FIG. 1 depicts the mean plasma concentration profile of baclofen vs time in hours when administered in the form of a controlled release drug delivery system administered by healthy volunteers in the evening and the morning in fed condition with normal diet. -
FIG. 2 illustrates a gastric retention controlled release drug delivery system in the form of capsules in the unswollen state and expanded due to swelling upon contact with aqueous medium for 6 hours. -
FIG. 3 depicts the graph of the mean plasma baclofen concentration time profiles at steady-state for baclofen 60 mg controlled release drug delivery system in the form of capsule administered by healthy human volunteers under fed (normal meal) condition in evening once daily for 7 days according to the present invention; and baclofen 60 mg controlled release drug delivery system in the form of capsule administered healthy human volunteers under fed (normal meal) condition in morning. -
FIG. 4 depicts one of the embodiments of the controlled release drug delivery system used in the method of the present invention. The controlled release drug delivery system is in the form of a coated capsule. The first region of the second composition is in the form of a hard gelatin capsule filled with baclofen and other excipients. The second region of the second composition is a sub coating applied on the filled hard gelatin capsules. The sub-coated second composition is further coated with the third composition which contains expandable components and film former. The third composition is further coated with a first composition. - The term “morning” as it is used herein with respect to the dosing of the controlled release drug delivery system of the invention means that the controlled release drug delivery system is orally administered early in the day after the patient has awakened from overnight sleep, generally between about 6:00 am and 11:00 am. In one preferred embodiment, the dosing was done at 8:30 am, post breakfast which was given at 8:00 am.
- The term “evening” as it is used herein with respect to the dosing of the controlled release drug delivery system of the invention means that the controlled release drug delivery system is orally administered later in the day before the human subject goes to bed for the night sleep, generally between about 7:00 pm and 10:00 pm, after the human subject has taken dinner. In one preferred embodiment, the dosing was done at 7:00 pm, post dinner which was given at 6:30 pm.
- The term “immediate release” refers to release obtained from conventional dosage form of baclofen that are given more than once-a-day for delivering baclofen to a human subject in need thereof.
- The term “baclofen” as used herein refers to 4-amino-3-(p-cholorophenyl)-butyric acid or its pharmaceutically acceptable salt thereof or its derivatives. The term includes R-baclofen, S-Baclofen and their mixtures including the racemate. The racemate refers to a mixture of R and S-baclofen in equal proportions.
- The term “Cmax” is the highest plasma concentration of the drug attained within the dosing interval, i.e. about 24 hours. Thus, when a drug delivery system used in an embodiment of the method of the present invention provides a bi-modal plasma profiles with two peaks then Cmax represents the higher plasma concentration.
- The term “Cmin” is the minimum plasma concentration of the drug attained within the dosing interval, i.e. about 24 hours.
- The term “Tmax” is the time period which elapses after administration of the composition at which the plasma concentration of the drug attains the highest plasma concentration of drug attained within the dosing interval (i.e. about 24 hours). Thus, when a drug delivery system used in an embodiment of the method of the present invention provides a bi-modal plasma profiles with two peaks, the time at which the highest Cmax achieved is considered at as the Tmax.
- The term “AUC” as used herein, means area under the plasma concentration-time curve, as calculated by the trapezoidal rule over the complete 24-hour interval.
- The fluctuation index is calculated as (Cmax−Cmin)/Cavg×100 wherein Cavg is calculated as ratio of AUC(0-24) to 24 hours.
- The total daily dose of baclofen or its pharmaceutically acceptable salt or its derivatives present in the controlled release drug delivery system used in practicing the method of the present invention, ranges from 1 mg to about 150 mg, preferably about 5 mg to about 80 mgs. The amount of the total daily dose may be slightly different depending upon the disease condition for which the system of the present invention is used. Also the dose is dependent on the derivative or salt of baclofen that is employed. For instance, when the system of the present invention is used to treat gastroparesis with the use of an enriched form of enantiomer of baclofen such as R-baclofen, the amount of the daily dose of baclofen that may be used may range from about 5 mg to 10 mg. In another instance, when the system of the present invention is used to treat a disease condition related to alcohol related disorders, the amount of the total daily dose of baclofen may range from 10 mg to 120 mg. In certain cases, the dose of the baclofen may be titrated and increased from a lower range to a higher range, depending upon the need. For example, in an embodiment wherein the controlled release drug delivery system used in treating alcohol craving and intake, baclofen is given initially at a daily dose of 15 mg for initial few days and then the amount of total daily dose is increased to 30 mg to 40 mg for later period of treatment.
- In one embodiment of the present invention, when the method uses controlled release drug delivery system, the system is administered in the fed condition. It is known that the pH of the gastric contents in the fed condition is about 4.3-5.4 whereas in the fasted state the pH of the gastric contents is about 1.4-2.1 (See T. T. Kararli, Biopharm. Drug. Disposition, 16, 351-380, 1995). Since the controlled release drug delivery system is, according to the invention, administered in the fed condition, in order to mimic the swelling characteristics and the retention in the stomach, the in vitro studies, such as measurement of the swelling index and/or the in vitro dissolution of baclofen or its pharmaceutically acceptable salt is determined at a pH of about 4.5, for example, in an aqueous medium of acetate buffer that provides a pH of 4.5.
- Referring to
FIG. 3 , it is evident from the graph that the absorptive phase of baclofen lasts longer when the controlled release drug delivery system of baclofen is administered in the evening. Whereas absorption continues upto at least about 5 hrs in the case of morning dosing as reflected by the time of occurrence of a second peak in the plasma profile, absorption can be seen to be prolonged and continue at least upto about 12 hrs after evening dosing. This was an unpredicted and surprising finding. It was also evident and pleasantly surprising that after the occurrence of the second peak in the plasma level profile, the plasma concentration declined very rapidly in the case where the controlled drug delivery system was administered in the morning but declined comparatively slowly when the controlled drug delivery system was administered in the evening. Further it was observed as shown in Table 13 that the mean plasma concentration achieved during the later half of the dosing interval at steady state, were higher when the system was administered with meals in the evening according to the invention as compared to the mean plasma concentration achieved after administration in the morning. Thus, the method of the present invention provides an improved therapy during the later half of the dosing interval. Particularly, there is an improved therapy in controlling the early morning symptoms of the disease condition. -
FIG. 2 illustrates an embodiment of a gastric retention controlled release drug delivery system in the form of a swellable capsule useful in the method of the present invention. The swelling or expandable nature of the capsule is depicted by the photographic images of the coated capsule in 4.5 acetate buffer at the end of 6 hours. The initial dimensions were 22.65 mm in length and 8.92 mm in diameter. At the end of 6 hours the capsules were swollen and expanded to a length of 38.23 mm and 19.79 in diameter. It is known that the open pylorus has a diameter of ˜15 mm in humans and objects greater than this size will have a difficulty in passing into the intestine (Stanley S. Davis in Drug Discovery Toady, Volume 10,No 4, February 2005, page 249-257). - Aspects of the present invention provide a method of treating a disease condition susceptible to baclofen therapy, said method comprising orally administering once-a-day in the evening a controlled release drug delivery system comprising baclofen or its pharmaceutically acceptable salt or its derivatives and pharmaceutically acceptable excipients.
- A person skilled in the art will understand that an oral controlled release drug delivery system that does not itself possess the characteristics for gastric retention (as distinct from controlled release) can be retained in the stomach by extraneous means (that means not forming a part of, or not directly associated with, the, oral controlled release drug delivery system). Gastric retention may be achieved, for example, by co-administering agents that slow the gastric motility or utilizing any alternate means that reduces gastric motility. The present invention therefore encompasses not only the gastric retention controlled release drug delivery system (as a single dosage form) but also any other controlled release drug delivery system that gets retained in the stomach not because of it's own characteristics, but because of other factors extrinsic or external to the drug delivery system. Examples of agents that may be used to enhance the gastric retention of the controlled release drug delivery system by reducing gastric motility include, but are not limited to, amylin agonist like pramlintide, exendins and its analogs, exenatide and its derivatives, atropine and related compounds, antimuscarinic agents like propantheline, pirenzepine, hyoscine hydrobromide, antidiahhoeral compounds such as diphenoxylate, loperamide, octreotide, opium and any other active ingredient that causes reduction in the gastric motility or active ingredients that show reduction in gastric motility as one of the side effects.
- In one embodiment, the controlled drug delivery systems useful in the practice of the present invention are typically characterized by release of about 30% to 40% of baclofen or its pharmaceutically acceptable salt in first hour in acidic media; about 50% in 4 hours; about 60% in 8 hours. The method of the present invention preferably provides a mean plasma concentration of baclofen at 16 hrs post administration in the range of about 40% to 90% of the mean peak plasma concentration, more preferably, about 55% to 80% of the mean peak plasma concentration. Further the method provides a fluctuation index of less than 200, preferably, less than 170 wherein fluctuation index is calculated as (Cmax−Cmin)/Cavg×100 wherein Cavg is calculated as AUC(0-24)/24.
- In one particular embodiment, the controlled drug delivery system of baclofen of the present invention produces a bi-modal plasma concentration-time profile (i.e., two distinct peaks) wherein a first peak in the plasma concentration is obtained at an earlier time between 2 hours to 8 hours, preferably 2 to 4 hours and the second peak is obtained at a later time point of time at about 8 hours to 18 hours, preferably 10 to 14 hours when orally administered to human subjects. Such a bi-modal plasma concentration-time profile may be advantageous in that it provides a second peak of baclofen at a time point of about 8 hours to 18 hours, preferably, about 12 hours. The profile is particularly useful in relief of early morning symptoms of the disease condition. The method of the present invention provides a therapeutic benefit which is assured at the time of awakening when the symptoms are generally more pronounced. It would be most beneficial to have highest peak plasma concentrations around the time of most frequent occurrence of symptoms. In one instance, the method of the present invention allows administration of the controlled release drug delivery at night time before sleep and provides a second plasma peak of baclofen at much later point of time which coincides with the wakening time where the system achieves therapeutic plasma levels at the more appropriate time. The appearance of the second peak is important for providing an optimum relief of early morning symptoms of the disease condition. For example, when the method of the present invention is practiced by administering a controlled release drug delivery system of baclofen or its pharmaceutically acceptable salt or its derivatives, to a patient in the evening, for example at about 6:00-about 8:00 pm, for relief of the symptoms over a duration of 24 hrs with high plasma levels of baclofen sustained in the next morning, for example, between about 7:00 am and about 11:00 am, particularly for optimum relief of early morning symptoms.
- In certain embodiments, the controlled release drug delivery system is in the form of coated particles comprising baclofen or its pharmaceutically acceptable salt. The coated particles can be in the form of beads, granules, mini tablets. The drug may be present along with the excipients or may be loaded onto the particles. The particles can consist of the encapsulation of thousands of micro-particles, each measuring 200-500 micrometers in diameter. These microparticles can be delivered in caplets.
- In another embodiment, the controlled release drug delivery system is in the form of matrix systems wherein the baclofen or its pharmaceutically acceptable salts are embedded in a matrix comprising polymers that retard the release of the drug. The polymer that may be used in the matrix of the controlled release drug delivery system may be selected from hydrophilic polymers, hydrophobic material like waxes and the like and mixtures thereof.
- In certain embodiments, the controlled release drug delivery system used in the method of the present invention is designed such that it is retained in the stomach because of the characteristics of the formulation i.e. because of particular features of the system incorporated into the design of the system. The features by which the controlled release drug delivery system is retained in stomach for longer period of duration may be because of various mechanisms such as either the floating nature of the system or the swelling and expanding nature of system or bio-adhesive nature of systems or due to special shapes of the system, all leading to retention of the system in the gastric environment.
- Following are the embodiments of the gastric retention controlled release drug delivery system that are used in practicing the method of the present invention.
- In one embodiment, the system is expandable systems. This type of system is easily swallow able and reaches a significantly larger size in the stomach due to swelling or unfolding processes that prolong their gastric retention. After the complete release of the active ingredient, their dimensions are minimized with subsequent evacuation from the stomach. Gastroretentivity is enhanced by the combination of substantial dimensions with high rigidity of the dosage form to withstand the peristalsis and mechanical contractility of the stomach.
- In alternate embodiment, the system can be a bio or muco-adhesive system. These types of systems are used as a delivery device within the lumen to enhance drug absorption in a site specific manner. This approach involves the use of bioadhesive polymers, which can adhere to the epithelial surface in the stomach. Gastric mucoadhesion does not tend to be strong enough to impart to dosage forms the ability to resist the strong propulsion forces of the stomach wall. The continuous production of mucous by the gastric mucosa to replace the mucous that is lost through peristaltic contractions and the dilution of the stomach content also seem to limit the potential of mucoadhesion as a gastroretentive force. Some of the most excipients that may be used in these systems to impart bioadhesion include, but are not limited to, polycarbophil, carbopol, lectins, chitosan and gliadin and the like and mixtures thereof.
- In yet another embodiment of the present invention, the systems are based on floating mechanism. This type of drug delivery system has a bulk density less than gastric fluids and thus remains buoyant in the stomach without affecting gastric emptying rate for a prolonged period of time. While the system is floating on the gastric contents, the drug is released slowly at the desired rate from the system, after release of drug; the residual system is emptied from the stomach. This results in an increased gastric retention time and a better control of the fluctuations in plasma drug concentration. This particular type of system can be obtained by use of either non-effervescent materials or by use of gas-generating material. When such systems are based on non-effervescent materials, these types of systems, after swallowing, swells unrestrained via imbibitions of gastric fluid to an extent that it prevents their exit from the stomach. One of the formulation methods of such dosage forms involves the mixing of the drug with a gel, which swells in contact with gastric fluid after oral administration and maintains a relative integrity of shape and a bulk density of less than one within the outer gelatinous barrier. The air trapped by the swollen polymer confers buoyancy to these dosage forms. Excipients used most commonly in these systems include hydroxypropyl methyl cellulose (HPMC), polyacrylate polymers, polyvinyl acetate, Carbopol, agar, sodium alginate, calcium chloride, polyethylene oxide and polycarbonates.
- When the systems are gas-generating or effervescent type, then these buoyant systems utilize matrices prepared with swellable polymers such as methocel, polysaccharides (e.g., chitosan), effervescent components (e.g., sodium bicarbonate, citric acid or tartaric acid). The system is so prepared that upon arrival in the stomach; carbon dioxide is released, causing the formulation to float in the stomach. Other materials that may be used include sodium alginate and sodium bicarbonate, multiple unit floating pills that generate carbon dioxide when ingested, floating mini capsules with a core of sodium bicarbonate, lactose and polyvinylpyrrolidone coated with hydroxypropyl methylcellulose (HPMC), and floating systems based on ion exchange resin technology.
- In certain embodiments, when the controlled release drug delivery system is in the form of a gastric retention drug delivery system, the system may be superporous hydrogels or lipid carrier matrix or may be based on foam based technology. When the system is in the form of superporous hydrogels, the polymers that are used may be crosslinked polymers such as polyacrylic acid, polyacrylamide, poly (N-isoproyl-acrylamide), polyethylene oxide, poly (hydroxyethyl methacryalate), polyvinylpyrrolidone, poly (vinyl alcohol) and carboxymethylcellulose. These hydrogels have the ability to absorb water, and if the water content absorbed exceeds 95% of the total weight, it is called supersabsorbent hydrogel. The imbibition of water by the hydrogel creates a space in the structure which is known as effective pore size. The pore size of the hydrogel varies from 10 to 100 manometers for microporous and 100 nanometers to 10 micrometers for macroporous hydrogels. In one embodiment, the superporous hydrogels are prepared by addition of a monomer, initiator, and cross-linker. The monomer is polymerized to form superporous hydrogel having a large pore size. In preferred embodiment, superdisintegrants such as cross-linked Ac-Di-Sol, Prmojel and crospovidone are utilized as a composite material for the preparation of superporous hydrogel composite. The mechanical properties superporous hydrogel can be further improved by acidification of the ionizable groups of the polymer, which then enables the superporous hydrogel to withstand stresses of gastric contractions.
- In yet another embodiment, the baclofen or its pharmaceutically acceptable salt are incorporated in a lipid carrier matrix. Such matrix systems have numerous advantages such as no additional solvent requirement for solubilization of drug, ease of availability, biocompatibility, biodegradability. The lipid matrix that may be excipients selected from a group consisting of glycerides and polyethylene glycol (PEG) esters. One excipient that is commercially available under the brand name of Gelucire is suitable according to the present invention. Various other lipid matrix systems may be employed to arrive at the bi-modal release pattern of baclofen when the patient administers the controlled release drug delivery system of the present invention.
- In other embodiments of the present invention, a controlled release drug delivery system is in the form of matrix core that are dependent at least in part upon the diffusion and/or erosion properties of excipients within the composition. In this embodiment controlled release matrices contain an effective amount of a baclofen or its pharmaceutically acceptable salt. The amount of the baclofen present in the controlled release matrix can vary in an amount of from 40% to 90% by weight of the matrix tablet dry weight. For example, in certain embodiments baclofen or its pharmaceutically acceptable salts is present in an amount from 60% to 80%, and in other embodiment at 70% by weight of the matrix tablet dry weight. The controlled release matrix can be multiparticulate or uniparticulate, and can be coated with at least one functional or non-functional coating, or an immediate release coating containing a baclofen salt or other drug. Functional coatings include by way of example controlled release polymeric coatings, enteric polymeric coatings, and the like. Non-functional coatings are coatings that do not affect drug release but which affect other properties (e.g., they may enhance the chemical, biological, or the physical appearance of the controlled release formulation).
- A preferred embodiment of such as controlled release drug delivery system useful in the practice of the present invention swells in a dimensionally unrestrained manner to increase its size to promote gastric retention of the system in the stomach. It may be noted that this is just one way of achieving the gastric retention of the controlled release drug delivery system and is provided as an illustration, by way of example only. Any other suitable means of gastric retention that leads to the desired plasma levels as described above are the may be applied in the practice of the present invention. The swelling and therefore, in turn the measurement of the gastric retention may be done by various ways, for example, in vivo by gastroscopy or radiology such as scintiographic studies or by in vitro methods such as for example, measurement of the swelling index of the controlled release drug delivery system.
- Those embodiments where the gastric retention controlled drug delivery system is based on the expanding and swelling, a swelling capacity can be an indicator of gastric retention. According to one useful procedure, in order to estimate the swelling capacity, the dimensions such as diameter and height of the system were measured with the help of Vernier Calipers. The dosage form may be placed in a USP dissolution apparatus (Type II-Paddle type of apparatus) in pH 4.5 acetate buffer at 37±0.5° C. at 50 rpm. The dimensions of the dosage form are measured initially and then placed into the dissolution apparatus. At specified time intervals, the dissolution apparatus was stopped and the dosage form was removed with the help of spatula in a Petri-dish and the dimensions were recorded. The swelling index may be determined as a ratio of volume at particular time to initial volume. Volume may conveniently be calculated by applying formula for volume of cylinder, assuming capsules are of at least approximately cylindrical shape. Volume of Cylinder-πr2 h, where r=diameter/2, h=length of capsule. Swelling Index is calculated as the ratio of the final volume and the initial volume. Generally, the swelling index of the gastric retention controlled drug delivery system used in the method of the present invention ranges from 2 to 20, preferably 5 to 15. One embodiment of the present invention, in which the gastric retention controlled release drug delivery system is a coated capsule the swelling index at 1 hour to 8 hours in acetate buffer is recorded in Table 7.
-
FIG. 2 illustrates an embodiment of the controlled release drug delivery system in the form of capsules useful in the practice of the method of the present invention. The swelling or expandable nature of the capsule is depicted by the photographic images of the coated capsule in pH 4.5 acetate buffer at the end of 6 hours. The initial dimensions were 22.65 mm in length and 8.92 mm in diameter. At the end of 6 hours the capsules were swollen and expanded to a length of 38.23 mm and 19.79 in diameter. It is known that the open pylorus has diameter of 12 mm˜18 mm in humans and objects greater than this size will have a difficulty in passing into the intestine (See Research J. Pharm. and Tech.; October-December 2008 pp. 345-348). The gastric emptying time and thereby, the retention of the dosage form of any discrete dosage form is delayed in the presence of food. At the end of the fed mode, a change in the motility pattern of the stomach occurs towards the fasting mode, and it is believed that a discrete dosage form is swept away by the housekeeper wave. However, size achieved after expansion does remain an important factor in the present system and preferably the volume is more than 9000 mm3 at the end of 4 hours. - Embodiments of controlled release drug delivery system useful in the method of the present invention are described in our previous United States patent publications US 20040180088 A1 and United States patent publication US20080107732A1, which are incorporated herein by reference.
- According to one embodiment of the present invention, the method comprises orally administering once-a-day in the evening a gastric retention controlled release drug delivery system comprising baclofen or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients wherein the gastric retention controlled release drug delivery system comprises a first composition having an immediately releasing fraction of the baclofen dose which is released within about 1 hour when tested in one litre of 4.5 pH acetate buffer in USP type II dissolution apparatus with sinkers rotating at a 50 rpm and at a temperature of 37±0.5° C. and a second composition having a slow release fraction of the baclofen dose wherein the first composition and the second composition occupy separate regions in the system, and at least one of the excipients in the controlled drug delivery system is selected from the group consisting of swellable polymer, gas generating agent, superdisintegrant and mixtures thereof, which excipient causes the system to swell in a dimensionally unrestrained manner to increase its size to promote gastric retention of the system in the stomach.
- In another embodiment, the gastric retention controlled release drug delivery system is in the form of a coated capsule. In this particular embodiment, the second composition includes at least two separate regions, first region comprising baclofen or its pharmaceutically acceptable salt and a second region comprising an excipient selected from the group consisting of swellable polymers, gas generating agents, super-disintegrants and mixtures thereof.
- The second composition includes at least two separate regions, first region comprising baclofen or its pharmaceutically acceptable salt. The first region of the second composition comprises a slow release fraction of the total dose of baclofen that is present in the gastric retention controlled drug delivery system used in the method of the present invention. The amount of baclofen present in second composition is designed to release in a controlled or slow manner. Generally the ratio of the immediately releasing fraction and the slow release fraction ranges from about 1:1 to 1:3, preferably 1:1 to 1:1.5. For example, in one embodiment when the gastric retention controlled release drug delivery system comprises a total dose of 60 mg of the dose, 35 mg of baclofen is present in the second composition and 25 mg of baclofen is present in first composition.
- In this particular construction, the first region of the second composition comprises along with baclofen or its pharmaceutically acceptable salts, excipients selected from the group consisting of swellable polymers, gas generating agents and superdisintegrants or mixture thereof. In particularly embodiment, the first region of the second composition is in the form of a core of hard gelatin capsule filled with a mixture comprising a fraction of the baclofen, one or more excipients selected from the group consisting of swellable polymers, gas generating agents and superdisintegrants. The second region of the second composition comprises one or more excipients selected from the group consisting of swellable polymers, gas generating agents and superdisintegrants. The difference between the first region and the second region is that the first region contains baclofen and the second region does not contain baclofen.
- Categories of the swellable polymers that may be used in the gastric retention controlled release drug delivery system used in the method of the present invention include, but are not limited to, cellulose derivatives, alginic acid and its derivatives, starch and its derivatives, gums, polyacrylic acid and the like and mixtures thereof. Cellulose ethers and esters are available in different viscosity grades. The grades may be expressed in terms of viscosity and/or in terms of number average molecular weight. The viscosity and number average molecular weight are related to each other. Such grades of the cellulose ethers are described in terms of number average molecular weight and degree of polymerization. The cellulose derivatives that may be used include, but are not limited to, cellulose ethers, cellulose esters and the like. Examples of suitable cellulose ethers include hydroxypropyl methyl cellulose, available from Dow Chemicals under the trade name Methocel, hydroxypropyl cellulose low substituted, hydroxypropyl cellulose, available from Aqualon under the trade name Klucel, hydroxyethyl cellulose, available from Aqualon under the trade name Natrosol and Cellosize available from Amerchol Corporation, carboxymethylcellulose sodium, available under the trade name Akucell. Methocel is available in various viscosity grades. The typical viscosities, unless specified, are expressed for a 2% w/v aqueous solution measured at 20° C. For example, K100 LVP having viscosity ranging from about 80 to about 120, K4MP having medium viscosity ranging from about 3000 to about 5600, K15 M having high viscosity ranging from about 12,000 to about 21,000; K100 MP having high viscosity ranging from about 80, 000 to about 120,000; Klucel is available in different viscosity grades. For example, Klucel HF (1% w/v) solution shows a viscosity ranging from about 1500 to about 3000. Klucel MF (2% w/v) solution shows a viscosity ranging from about 4000 to about 6500. Klucel GF (2% w/v) solution shows a viscosity ranging from about 150 to about 400. Klucel JF (5% w/v) solution shows a viscosity ranging from about 150 to about 400. Klucel LF (5% w/v) solution shows a viscosity ranging from about 75 to about 150 and Klucel EF (10% w/v) solution shows a viscosity ranging from about 200 to about 600. Different types of viscosity grades of
Natrosol 250 are available such as HHR having 1% w/v solution 3400 to about 5000, H4R having viscosity ranging from about 2600 to about 3300, HR having viscosity ranging from about 1500 to about 2500 and MHR having viscosity ranging from about 800 to about 1500. Low viscosity grades of Natrosol include, but are not limited to, MR, KR, GR, ER, JR and LR. Carboxymethyl cellulose is available as low viscosity Akucell AF 0303 (1% w/v) showing a viscosity ranging from about 10 to about 15 mPas. The medium viscosity grade of Akucell AF2785 shows a viscosity ranging from about 1500 to about 2500. The 1% w/v solution of high viscosity grade of Akucell AF3085 shows a viscosity ranging from about 8000 to about 1200. Some preferred dosage forms for use in the practice of the present invention use hydroxypropyl cellulose (HPC) having viscosity of about 100,000 cps. It is also possible to use Alginic acid which is available in different viscosity grades. The viscosities depend on the molecular weight. Typically, a 0.5% w/w aqueous dispersion shows a viscosity of approximately 10 mPas while a 2% w/w aqueous dispersion shows a viscosity of approximately 2000 mPas. Sodium alginate is also available in different viscosity grades. Typically, a 1% w/v aqueous solution shows a viscosity of 20 to about 400 mPas. Polyvinyl pyrrolidone of high viscosity may be employed. Another example of a swellable polymer that may be used in a drug delivery system suitable for use in the method of the present invention is a pH dependent polymer that is soluble below about pH 5 and is swellable and permeable above pH 5. Preferably the pH dependent polymer is an acrylate polymer obtained by polymerizing dimethylamino ethyl methacrylate with neutral methacrylate esters. In a more preferred embodiment of the present invention the pH dependent polymer is a polymer obtained by polymerization of the monomers namely, butyl methacrylate, 2-dimethyl aminoethyl methacrylate and methyl methacrylate. This polymer, poly (butyl methacrylate, (2-dimethyl aminoethyl) methacrylate, methyl methacrylate) may be prepared from different molar ratios of the monomers. However, preferably, the butyl methacrylate, 2-dimethyl aminoethyl methacrylate and methyl methacrylate molar ratio is about 1:2:1. This preferred polymer butyl methacrylate, 2-dimethyl amionethyl methacrylate and methyl methacrylate with a molar ratio of about 1:2:1 is available in different physical forms under the tradenames Eudragit E 100, Eudragit E 12.5 and Eudragit EPO.Eudragit E 100 is in the form of granules, Eudragit E 12.5 is available in the form of 12.5% w/v solution in an organic solvent and Eudragit E PO is available in powder form. - The swellable polymer may be present in an amount ranging from about 1% to about 40%, preferably about 5% to about 30% and most preferably about 10% by weight of the gastric retention controlled release drug delivery system used in the method of the present invention.
- The gas generating agent used in the gastric retention controlled release drug delivery system of the present invention may include a single component that generates gas upon contact with the gastric fluid, or may include a gas generating couple. Gas generating components that may be used in the present invention include solids that liberate gas, especially carbon dioxide or nitrogen, for example under the action of body fluid or the hydrogen ions present therein. Examples include carbonates such as calcium carbonate, bicarbonates such as sodium or potassium bicarbonate, sulfites such as sodium sulfite, sodium bisulfite, or sodium metabisulfite, and the like, ammonium cations or sodium azide or mixtures thereof. These salts may be used alone or in combination with an acid source as a gas generating couple. The acid source may be an edible organic acid, a salt of an edible organic acid, or mixtures thereof. Examples of organic acids that may be used include citric acid, malic acid, succinic acid, tartaric acid, fumaric acid, maleic acid, ascorbic acid, glutamic acid, alginic acid, acrylic acid and their salts, and mixtures thereof. Sodium bicarbonate is used as the preferred gas generating agent. The organic acid may also be a polymer, for example acrylic acid polymers and copolymers such as acrylate polymers available under the tradenames Carbopol®, Eudragit® L-100-55, Eudragit® S-100, Noveon® AA1, which react with carbonates or bicarbonates of alkali or alkali earth metal compounds to generate gas. These are generally used as auxiliary acid sources and may also have properties of themselves generating internal pressure by swelling when in contact with an aqueous medium. The gas-generating agent is used in an amount ranging from about 0.5% to about 50%, preferably in the range of 5% to about 10% by weight of the gastric retention controlled release drug delivery system used in the method of the present invention.
- Examples of superdisintegrants that can be used in gastric retention drug delivery systems useful in the practice of the present invention include, but are not limited to, crosslinked sodium carboxymethyl cellulose, crosslinked polyvinylpyrrolidone, sodium starch glycolate, ion exchange resins and mixtures thereof. The superdisintegrants may be used in an amount ranging from about 0.5% to about 30%, preferably about 3% to about 10% by weight of the gastric retention controlled release drug delivery system used in the method of the present invention.
- In another embodiment, the first region of the second composition may further include one or more rate controlling excipients. Examples of release rate controlling excipients include, but are not limited to, water insoluble polymers and hydrophobic materials such as waxes. Hydrophobic materials apart from acting as release rate controlling excipients, because of their low density, can also enhance the gastric retention of the coated capsule of the present invention. Examples of the hydrophobic materials that may be used include, but are not limited to, waxes, carnauba wax, vegetable wax, fruit wax, microcrystalline wax, bees wax, hydrocarbon wax, paraffin wax, cetyl esters wax, nonionic emulsifying wax, anionic emulsifying wax, candelilla wax, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, lauryl alcohol, myristyl alcohol, hydrogenated vegetable oil, hydrogenated castor oil, a fatty acids, a fatty acid esters, or mixtures thereof. Generally, the amount of the hydrophobic material present in second region of the second composition of the gastric retention drug delivery system used in the method of the present invention ranges from about 0.1% to about 10% by weight of the gastric retention controlled release drug delivery system used in the method of the present invention.
- Apart from the above mentioned excipients, water soluble materials such as mannitol, lactose, lactitol, xylitol, sucrose or mixtures thereof or any other sugar alcohol may also be present in the third second composition of the gastric retention controlled release drug delivery system. When present, the amount of such material may be from about 0% to about 60%, preferably about 15% to about 50% by weight of the second composition of the gastric retention controlled release drug delivery system used in the method of the present invention.
- In one particular embodiment, the weight ratio of second region of the second composition to the first region of the second composition is about 25:1. The weight ratio of third composition to the second composition is about 25:1.
- In another embodiment, the gastric retention controlled release drug delivery system comprises a third composition. The third composition is present in between the first composition and the second composition. In certain embodiment, when the second composition is in the form of a coated capsule, the third composition is in the form of a coating that is applied to the second composition. The third composition is applied to the second composition in the form of coating surrounding the second composition. The third composition comprises a water insoluble polymer and one or more excipients selected from the group consisting of swellable polymers, gas generating agents and superdisintegrants. The water insoluble polymer present in the third composition are insoluble in gastric milieu and is selected from the group consisting of ethyl cellulose, methacrylic acid-ethyl acrylate copolymers, polyacrylic acid and mixtures thereof. In preferred embodiments, the third composition forms a film capable of expanding and maintaining its physical integrity in the gastric milieu.
- In certain embodiments, in addition to the water insoluble polymers that are insoluble in gastric milieu, the third composition may further comprise one or more swellable polymers such as Carbopol® polymers, Pemulen™ polymeric emulsifiers and Noveon® polycarbophils. In one particular embodiment, a high molecular weight acrylic acid polymer crosslinked with divinyl glycol is employed. This may be used in amount ranging from about 0.1% by weight to about 10% by weight, preferably about 1% to about 2% by weight of the gastric retention controlled release drug delivery system. In preferred embodiments, the third composition is in the form of a membrane or a film that surrounds the second composition which is either in the form of a compressed core or a capsule filled with excipients. The presence of the excipients of third composition, cause the film to stretch and expand in size to form a balloon like system. The membrane or the film made up of the third composition provides strength and elasticity to the system in the gastric milieu. Because of the elastic and stretchable nature of the membrane, the system can withstand the contractions of the stomach and not break open and continues to release baclofen over a desirable period of time. In another preferred embodiment, where a bioadhesive polymer such as polycarbophil is incorporated, the system in addition to swelling also achieves bioadhesive effect causing gastric retention. The membrane of the third composition may comprise of additional plasticizers which adds to the stretchable elastic nature of the polymer, causing better expansion and stretching of the system leading to increase in size sufficient enough to cause gastric retention.
- The first composition present in gastric retention controlled release drug delivery system used in the method of the present invention, comprises an immediately releasing fraction of the baclofen dose which is released within about 1 hour when tested in one litre of 4.5 pH acetate buffer in USP Type II dissolution apparatus with sinkers rotating at a 50 rpm and at a temperature of 37±0.5° C. This first composition occupies a region separate within gastric retention controlled drug delivery system which is physically distinct from the region occupied by the second composition. In one embodiment, the first composition is present in the form of a coating wherein the composition comprises an excipient that does not hinder in the immediate release of the fraction of the baclofen dose. Preferably, when the first composition is in the form of a coating, the first composition comprises water soluble polymers such as low viscosity water soluble polymers used in the top coating for example, hydroxypropyl methyl cellulose or methyl cellulose or any other cellulose derivative of very low viscosity which does not hinder the immediate release of fraction of the total dose baclofen present in the gastric retention controlled release drug delivery system.
- According to another aspect of the invention, a method of the present invention useful for optimum relief of early morning symptoms of the disease condition is provided, said method comprising administration of a controlled release drug delivery system of baclofen or its pharmaceutically acceptable salt, to the patient in the evening example at about 6:00-about 8:00 pm, for relief of the symptoms over a duration of 24 hrs with high plasma levels of baclofen sustained in the next morning, for example between about 7:00 am and about 11:00 am, particularly for optimum relief of early morning symptoms.
- In one embodiment, a randomized, open-label, two-treatment, two-period, two-sequence, multiple dose, crossover study was conducted to assess bioavailability and steady state pharmacokinetics of baclofen 30 mg capsules prepared as per Example 1 was given once daily, under fed (normal meal) conditions, for 8 consecutive days in patients suffering from spasticity. Baclofen 10 mg immediate release tablets were given three times a day at 8 hour interval, with the initial dose administered under fasting condition, for 8 consecutive days, in 24 spastic subjects receiving stable daily doses of baclofen. In one study, the dosing of the baclofen 30 mg capsules (Test=t) was done in morning time and in another study, the dosing of the baclofen 30 mg capsules was done in evening time, both on fed condition.
- The pharmacokinetic results in terms of bioavailability, i.e Cmax, Tmax, AUC were recorded and compared with the bioavailability parameters achieved by equivalent dose of immediate release baclofen that was administered three times a day (Reference=R). In one embodiment of the present invention, the method of treating spasticity was practiced. In this particular embodiment it was surprisingly found that the spastic patients showed better pharmacokinetic profile when the controlled drug delivery system of the present invention was administered by spastic patients on fed state in the evening in comparison to the pharmacokinetic profile achieved when the controlled drug delivery system of the present invention was administered on fed state in the morning wherein the study was a two way crossover, wherein one arm administered the controlled drug delivery system of the present invention and the other arm administered equivalent dose of baclofen in the form of immediate release tablets administered three times a day.
- While the present invention is disclosed generally above, additional aspects are further discussed and illustrated with reference to the examples below. However, the examples are presented merely to illustrate the invention and should not be considered as limitations thereto.
- This example represents an embodiment of the controlled release drug delivery system which is gastric retention drug delivery system comprising baclofen. It is prepared according to formulae given Table 1 below.
-
TABLE 1 first region of second composition S. Qty in % by weight of the No. Ingredients mg drug delivery system 1 Baclofen 35 3.25 2 Mannitol 324 30.12 3 Hydroxypropyl Cellulose -mw 80 7.43 1150; apparent viscosity 1500-3000 at 1% w/ v 4 Colloidal silicon dioxide 5 0.46 5 Talc 12.5 1.66 6 Magnesium stearate 12.5 1.16 7 Hydrogenated Vegetable oil 20.0 1.86 8 Mannitol 46.0 4.27 9 Water soluble protective 20.0 1.85 film coating based on low viscosity hydroxypropyl- methyl cellulose - First Region of Second Composition
- Table 1 gives the formula for the preparation of the first region of the second composition. The first region is the formulation that is filled into gelatin capsules. The polymer hydroxypropylmethyl cellulose, low viscosity that does not function as a rate controlling polymer but only serve as a aid in binding on slugging to process the slug. This formulation does not contain any excipient that is characterized as a rate controlling excipient.
- Baclofen, Hydroxypropyl cellulose (HPC-HXF), Colloidal silicon dioxide and Mannitol (intra-granular) were sifted and collected together. The material was resifted through ASTM #40 sieved and collected. The sifted material was loaded into a suitable blender and mixed for a period of 10 minutes. Magnesium stearate and Talc were added as lubricants and further mixed for 5 minutes. The blend was slugged using 20 mm flat-faced round punches using a single rotary compression machine. The slugs were milled to achieve a particle size suitable for capsule filing. Opadry II Clear and mannitol were sifted. The hard gelatin capsules of size ‘0’ capsules were filled with the milled material and added extragranularly to the milled blend.
-
TABLE 2 second region of second composition comprising a mixture of disintegrants, gas generating agent and water soluble polymer S. qty in % by weight of the No. Ingredients mg drug delivery system 10 Alginic acid 60.06 5.60 11 Sodium bicarbonate 15.58 1.45 12 Sodium starch glycolate 30.03 2.79 13 Mannitol 15.00 1.40 14 Povidone 18.36 1.70 15 Basic butylated methacrylate 18.38 1.70 Copolymer 16 Talc 3.89 0.36 17 Polysorbate 1.22 0.11 18 Isopropyl alcohol (IPA) q.s q.s - Second Region of Second Composition
- Table 2 gives the formula for the preparation of the second region of the second composition which is also referred to as subcoat composition. The filled capsules were coated with a sub coat composition prepared by dispersing Eudragit, polyvinyl pyrrolidone, alginic acid, Sodium bicarbonate, Sodium starch glycolate, Mannitol 25 and Talc in isopropyl
alcohol containing polysorbate 20. The dispersion was passed through a coarse screen to ensure homogenous dispersion. The filled capsules were loaded into a suitable perforated coating pan (36″) and the capsules were coated with a second subcoat composition to a weight gain of about 25%. -
TABLE 3 Third composition of film forming polymer insoluble in gastric milieu and one or more disintegrants and/or gas generating agents S. Qty in % by weight of the No. Ingredients mg drug delivery system 19 Polycarbophil 8.95 0.83 20 Methacrylic acid 66.15 6.14 Copolymer, Type C 21 Sodium bicarbonate 17.88 1.66 22 Sodium starch glycolate 21.50 1.99 23 Mannitol 71.52 6.64 24 Polyethylene glycol 2.69 0.25 25 Diethyl Phthalate 8.95 0.83 26 Polysorbate 1.07 0.09 27 Talc 4.46 0.41 28 Isopropyl alcohol (IPA) q.s q.s - Table 3 provides the details of the third composition of film forming polymer insoluble in gastric milieu and one or more disintegrants and/or gas generating agents
- The sub coated filled capsules were further coated with a coating dispersion for Film-coating comprising a water insoluble polymer. The coating suspension was prepared by dispersing ingredients of table 3 in isopropyl alcohol. Sequentially the dispersion was screened to ensure uniform homogeneous dispersion and absence of lumps. The sub-coated capsules were loaded into a suitable perforated coating pan (48″) and were coated to a weight gain of about 25% using the coating solution.
-
TABLE 4 first composition of gastric retention controlled drug delivery system Amount % by weight of the S. No. Ingredients in mg drug delivery system 29. Baclofen 25.00 2.3 30. HPMC low 35.00 3.25 viscosity 31. Purified water q.s - Table 4 above provides a first composition comprising fraction of the baclofen in a protective thin film coating composition. The double layer coated capsules were further coated with a coating dispersion using commonly available Opadry ready to use composition in which baclofen was dispersed using an overhead stirrer.
- The controlled release drug delivery system of example 1 were tested for in vitro dissolution in pH 4.5 buffer in USP Type II with sinkers,
RPM 50, Temperature-37.5° C. as well as in pH 6.8 buffer. The results of the in vitro dissolution are given below: -
TABLE 5 In vitro Dissolution results in 4.5 acetate buffer Time (hrs) % Drug Release in pH 4.5 Buffer 1 41 2 44 4 46 6 49 8 54 12 67 16 79 20 88 24 95 -
TABLE 6 In vitro dissolution results Time (hrs) % Drug Release in pH 6.8 Buffer 0.5 39 1.0 43 1.5 46 2.0 53 2.5 65 3.0 77 3.5 88 4.0 97 5.0 101 6.0 102 - The gastric retention controlled drug delivery based on swelling and expanding mechanism, useful in the method of the present invention were checked for swelling index at various time points in pH 4.5 buffer. The capsules were allowed to swell under stirring using a USP Type assembly rotating at 75 rpm speed. Swelling Index was calculated as a ratio of volume at particular time to initial volume. Volume was calculated by applying formula for volume of cylinder, assuming capsules are of cylindrical shape. Volume of Cylinder-πr2 h, where r=diameter/2, h=Length of capsule. Swelling Index is calculated as the ratio of the final volume and the initial volume.
-
TABLE 7 Swelling index of the coated capsules of example 1 Swelling Index Time Drug delivery system of example 1 (in hours) 1 2 3 4 5 6 1 3.15 3.78 3.96 3.40 4.14 3.20 2 4.12 4.09 5.44 4.20 5.46 4.83 3 5.38 5.97 6.38 5.76 6.67 6.15 4 6.77 7.33 7.00 6.90 7.92 7.48 5 8.13 9.02 8.79 8.96 10.05 9.68 6 10.31 10.61 9.97 10.08 11.37 10.91 7 12.46 12.29 11.24 12.63 11.94 13.39 8 12.87 12.94 12.11 14.18 13.54 13.69 - The swelling nature of the coated capsule of the present invention is also depicted by the photographic images of the coated capsule in 4.5 Acetate buffer in the
FIG. 2 . - A gastric retention drug delivery system comprising baclofen was prepared as mentioned in Table 8 below.
-
TABLE 8 Composition details mg per weight of drug % by weight of the Ingredients delivery system drug delivery system First region of the second composition Baclofen 22.5 5.49 Fumaric acid 10.0 2.44 Mannitol 264.5 64.5 Hydroxypropyl cellulose 68.0 16.59 Sodium bicarbonate 30.0 7.32 Colloidal silicon dioxide 5.0 1.22 Talc 5.0 1.22 Magnesium stearate 5.0 1.22 Second region of the second composition Alginic acid 54.35 Coated to a Sodium bicarbonate 10.87 weight gain of Sodium starch glycolate 27.17 about 25% by Mannitol 13.59 weight of the core Polyvinylpyrrolidone 16.30 Talc 3.26 Polysorbate 1.09 Third composition Polycarbophil 4.41 Coated to a Sodium bicarbonate 8.82 weight gain of Methacrylic acid copolymer 35.29 about 18% by Eudragit S-100 8.82 weight Mannitol 35.29 Sodium starch glycolate 10.29 Polysorbate 0.59 Polyethylene glycol 1.47 Talc 2.35 Diethyl phthalate 6.62 First composition Baclofen 7.5 Coated to a Polyvinylpyrrolidone 1.50 weight gain of Talc 2.25 about 1.2% by Tween 0.40 weight of the coated core - Baclofen, fumaric acid, mannitol, hydroxypropyl cellulose, sodium bicarbonate, colloidal silicon dioxide, talc and magnesium stearate were mixed to obtain a blend and this was filled in
size 0 hard gelatin capsules. The filled capsules were coated with a coating suspension containing alginic acid, sodium bicarbonate, sodium starch glycolate, mannitol, povidone, talc, polysorbate in isopropyl alcohol to a weight gain of about 25% by weight of the core capsules. This was followed by introduction of the outer coat using a coating solution comprising polycarbophil, sodium bicarbonate, methacrylic acid copolymer, Eudragit S-100, mannitol, sodium starch glycolate, polysorbate, PEG, talc and diethyl phthalate in isopropyl alcohol, the solution being coated to about 18% by weight. Finally, a top coat comprising baclofen, povidone, talc and Tween was introduced on the capsules to a weight gain of about 1.5%, using a coating solution in purified water. - A gastric retention drug delivery system comprising baclofen was prepared as mentioned in Table 9 below.
-
TABLE 9 Quantity (% w/w of the drug Ingredients (mg/capsule) delivery system First region of the second composition Baclofen 22.5 5.49 Fumaric acid 10.0 2.44 Mannitol 200.5 48.90 Polycarbophil 108.0 26.34 Sodium bicarbonate 54.0 13.17 Colloidal silicon dioxide 5.0 1.22 Talc 5.0 1.22 Magnesium stearate 5.0 1.22 - The first region of the second composition was obtained by blending the excipients listed in Table 10 with baclofen and filling it in a hard gelatin capsule. The capsule was then coated with a second region of the second composition and third composition similar to example 2 described above.
- A gastric retention drug delivery system comprising baclofen was obtained as mentioned in Table 10 below.
-
TABLE 10 mg per weight of drug % w/w of the drug Ingredients delivery system delivery system First Region of the second composition Baclofen 22.5 3.38 Fumaric acid 10.0 1.50 Mannitol 264.50 39.77 Crospovidone 55.0 8.27 Sodium bicarbonate 30.0 4.51 Silicified microcrystalline 253.0 38.05 cellulose Polyvinylpyrrolidone 15.0 2.26 Colloidal silicon dioxide 5.0 0.75 Talc 5.0 0.75 Magnesium stearate 5.0 0.75 Hydroxypropyl methylcellulose 20.49 Second Region of the second composition Alginic acid 60.39 Coated to a weight Sodium bicarbonate 12.08 gain of about 20% by Sodium starch glycolate 30.20 weight of the seal Mannitol 15.10 coated core Polyvinylpyrrolidone 18.12 Talc 3.62 polysorbate 1.21 Third composition Polycarbophil 4.00 Coated to a weight Sodium bicarbonate 8.00 gain of about 12% by Methacryalic acid copolymer 31.99 weight of the core Eudragit S-100 8.00 with the seal coat and Mannitol 31.99 the subcoat Sodium starch glycolate 9.33 Polysorbate 0.53 Polyethylene glycol 1.33 Talc 2.13 Diethyl phthalate 4.00 First Composition Baclofen 7.5 Coated to a weight Polyvinylpyrrolidone 1.50 gain of about 1.2% Talc 2.25 by weight of the Polysorbate 0.40 coated core - The coated tablets were obtained as mentioned in examples above. The core coated with the subcoat was placed in 100 ml of 0.01N HCl and pH 4.5 buffers. It was found that the sub-coated tablets remained at the base of the vessel and began to disintegrate after about 3 minutes, and fully disintegrated in about 6 minutes.
- The controlled release drug delivery system was obtained as per Table 11 below.
-
TABLE 11 Amount in mg per % by weight Ingredients tablet of the tablet Baclofen 20 2 Lactose 30 3 Hydroxyethyl cellulose (HEC 250 H) 400 4 Sodium starch glycolate 150 15 Sodium bicarbonate 40 4 Hydroxypropyl methylcellulose (3000- 136 13.6 5600 mPaa) Silicified microcrystalline cellulose 90 9.0 Talc 24 2.4 Polyethylene glycol (PEG 8000) 10 1.0 Hydroxypropyl methylcellulose (3000- 100 10 5600 mPaa) Coat Baclofen 10.0 1 Low viscosity Hydroxypropyl 45.0 4.5 methylcellulose aqueous coating - The core of the controlled release drug delivery system was obtained by passing baclofen, lactose, hydroxyethyl cellulose, sodium starch glycolate, sodium bicarbonate and a part of HPMC K4M through ASTM (American Society for Testing and Materials) sieve #40 and mixing the ingredients to obtain a dry powder blend. An aqueous solution of HPMC K4M was then used to granulate the dry powder blend. The granules thus obtained were passed through a suitable sieve and dried. The dry granules were lubricated with a mixture of Prosolv SMCC 90, talc, PEG 8000 and HPMC K4M, and compressed to obtain the cores. The cores were then coated with an aqueous solution containing baclofen and Opadry II to obtain the gastric retention controlled drug delivery system of the present invention.
- The tablets thus obtained were subjected to dissolution testing at 37° C. using United States Pharmacopoeia Type II (paddle) dissolution apparatus at 50 rpm. The dissolution medium used was 1000 ml of 0.1N HCl. The tablets achieved floatation in about 10 minutes. The results of the dissolution test are recorded in Table 12 below.
-
TABLE 12 Time % drug released in 0.1 N HCl 0 0 1 39 2 44 4 53 6 60 8 66 12 77 - The controlled release drug delivery system was obtained as per Table 13 below—
-
Amount in mg per % by weight Ingredients tablet of the tablet Baclofen 22.5 2.25 mannitol 260.0 26.0 Hydroxyethyl cellulose (HEC 250 H) 200 20.0 Sodium starch glycolate 250 25.0 Sodium bicarbonate 80.0 8.0 Hydroxypropyl methylcellulose (3000-5600 4.5 0.45 mPaa) Silicified microcrystalline cellulose 90 9 Talc 24 2.4 Polyethylene glycol (PEG 8000) 10 1 Coat Baclofen 7.50 7.5 Low viscosity Hydroxypropyl 24.0 2.4 methylcellulose (4-6 mPas) talc 10.0 1.0 Titanium dioxide 11.0 1.1 Propylene glycol 5.00 0.5 - The core of the gastric retention controlled drug delivery system was obtained by passing baclofen, mannitol, hydroxyethyl cellulose, sodium starch glycolate and sodium bicarbonate through ASTM (American Society for Testing and Materials) sieve #40 and mixing the ingredients to obtain a dry powder blend. An aqueous solution of HPMC K4M was then used to granulate the dry powder blend. The granules thus obtained were passed through a suitable sieve and dried. The dry granules were lubricated with a mixture of Prosolv SMCC 90, talc and PEG 8000, and compressed to obtain the cores. The cores were then coated with a hydro-alcoholic solution of a mixture of baclofen, HPMC E5, talc, propylene glycol and titanium dioxide to obtain the gastric retention controlled drug delivery system of the present invention.
- The tablets thus obtained were subjected to dissolution testing at 37° C. using United States Pharmacopoeia Type II (paddle) dissolution apparatus at 50 rpm. The dissolution medium used was 1000 ml of 0.1N HCl. The tablets achieved floatation in about 6 minutes. The results of the dissolution test are recorded in Table 14 below.
-
TABLE 14 dissolution Time % drug released in 0.1 N HCl 0 0 1 55 2 63 4 75 6 83 8 91 12 99 - The controlled release drug delivery system of the present invention was obtained as given in Table 15 below.
-
TABLE 15 details of the composition Quantity Ingredients (mg/tab) % by weight Baclofen 30.0 32.25 Hydroxy ethyl cellulose (Natrosol 250 H) 197.50 212.36 Sodium starch glycolate 217.50 233.8 Microcrystalline cellulose 435.0 467.74 Sodium bicarbonate 10.0 10.75 Polyvinylpyrrolidone 22.0 23.65 Talc 9.0 9.67 Magnesium stearate 9.0 9.67 - A part of baclofen, hydroxyethylcellulose, a part of sodium starch glycolate, a part of microcrystalline cellulose and a part of polyvinylpyrrolidone, were mixed together and granulated with isopropanol and lubricated with talc and magnesium stearate to form the core granulation. The remaining parts of baclofen, microcrystalline cellulose, polyvinylpyrrolidone and sodium starch glycolate were mixed together and granulated with water to form the coat granulation. The core granulations were compressed and the coat was applied on the core using compression coating. The gastric retention controlled drug delivery system thus obtained in the form of coated tablets shows a high degree of swellability in a short time, has sufficient strength for handling as well as remaining intact in aqueous fluids, and is capable of providing a biphasic controlled release profile.
- Comparison of morning dosing and evening dosing in single dose study in healthy volunteers. The coated capsules of Example 1 were tested for bioavailability in normal volunteers in the fed condition at different timings, that is, administration in the morning or in the evening Twenty four healthy volunteers were enrolled for the study and twenty two of them completed both the periods of the study. A randomized, open label, two treatment, two period, two sequence, single dose crossover study was carried out to assess the effect of the dosage time administration (i.e. after morning and evening administration) on the pharmacokinetics of the baclofen 60 mg extended release coated capsules of Example 1 which are suitable for once a day administration.
- The coated capsules of Example 1 where administered by human volunteers in the evening at 7:00 pm in the fed condition. The volunteers had a normal diet for the dinner as well as morning breakfast. The human volunteers had a breakfast at 8:00 am and the dosing of the coated capsules was done at 8:30 am. The mean plasma Profile Vs time in hours in provided in Table 16 and the graph is presented in
FIG. 1 . The pharmacokinetic parameters that were evaluated are tabulated in Table 17. -
TABLE 16 Mean plasma profile when administered by healthy volunteers in morning and evening Vs Time in hours Plasma profile achieved by Plasma profile achieved by administration of example administration of example Time in hours 1 in the morning 1 in the evening 0 0 0 1 140.0 89.7 2 281.15 194.75 3 261.50 213.12 4 250.175 191.36 5 296.02 180.22 6 276.9 163.35 8 183.21 152.37 10 146.77 183.71 12 130.26 201.35 16 75.46 124.18 20 47.176 66.50 24 32.73 40.92 -
TABLE 17 Pharmacokinetic parameters Study 1 (Evening Study 2 (Morning Parameters Administration) Administration) AUC(0-t) (ng · hr · ml−1) 3432.4552 (% CV = 22.5) 3402.6867 (% CV = 19.9) AUC(0-∞) (ng · hr · ml−1) 3541.8082 (% CV = 22.8) 3476.8758 (% CV = 20.2) Ln Cmax (ng · ml−1) 253.239 (% CV = 23.4) 346.714 (% CV = 22.6) Tmax (hr) 8.0 (% CV = 60.6) 5.0 (% CV = 48.2) - A simulation was done with single dose data (twenty two subjects) of dosage time effect (i.e. after morning and evening administration). Pharmacokinetic study on Baclofen 60 mg as described in Example 1 were performed by using method of Nonparametric superposition in WinNonlin 5.0 of Pharsight Corporation, USA. Software used for performing simulation: WinNonlin (version 5.0) of Pharsight Corporation, USA. The method used for performing simulation was Non-parametric superposition method. Nonparametric superposition function is used to predict drug concentrations after multiple dosing at steady state, and is based on non-compartmental results describing single dose data. The predictions are based upon an accumulation ratio computed from the elimination rate constant. PK Sampling points considered for simulation were 0.0 (Pre-dose), 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0, 16.0, 20.0, 24.0, 30.0 and 36.0 hours. Data of both morning & Evening dose have been simulated for 7 consecutive days and dosing interval of 24 hr (once daily dose) has been considered. The mean plasma concentration profile is presented in table 18 and
FIG. 3 . The steady state data results are reported in Table 19 and 20 below. -
TABLE 18 Mean plasma concentration Vs time in hours Plasma profile achieved by Plasma profile achieved by administration of example administration of example Time in hours 1 in the morning 1 in the evening 0 35.561 44.610 1 172.5 130.7 2 310.6 232.2 3 287.875 247.067 4 273.53 221.8 5 316.4 207.2 6 294.3 186.9 10 158.6 200.16 12 139.4 214.35 16 81.3 132.6 20 50.9 72.1 24 35.6 44.61 -
TABLE 19 Summary of statistical evaluation of simulated baclofen steady state data (n = 22) System according to example 1 System according to example 1 administered in the evening administered in the morning (PM) (Treatment A) (AM) (Treatment B) Parameters Meant ± SD AUC0-24 (ng · h/mL) 3637.5346 ± 830.61288 3550.6908 ± 715.23662 Cmax (ng/mL) 282.517 ± 61.5016 377.449 ± 78.1262 Cmin (ng/mL) 44.610 ± 17.2971 35.561 ± 17.6041 Tmax (h) 6.818 4.682 Tmax* (h) 5.00 5.00 Fluctuation (%) 160.128 ± 32.4217 236.634 ± 55.6358 T1/2 (h) 5.2801 ± 0.77668 6.3479 ± 1.38080 *Median value - The data tabulated in Tables 19 indicates that when the claimed controlled release drug delivery system was administered every 24 hours as an evening dose of baclofen for consecutively 7 days (simulated data using software) wherein the plasma levels at steady state (for 7 days) shows lesser peak plasma concentration compared to the peak plasma concentration achieved at a steady state level as compared to the plasma levels achieved after morning dosing.
FIG. 3 indicates a much flattened plasma baclofen concentration time profiles after evening dosing compared to the morning dosing. - A randomized, open-label, two-treatment, two-period, two-sequence, multiple dose, crossover study to assess bioavailability and steady State pharmacokinetics of baclofen 30 mg controlled release drug delivery system of the present invention was given once daily, under fed (normal meal) conditions in the morning time, for 8 consecutive days in patients suffering from spasticity. Baclofen 10 mg immediate release tablets were given three times a day at 8 hour interval, with the initial dose administered under fasting condition, for 8 consecutive days, in 24 Spastic subjects receiving stable daily doses of baclofen.
- The pharmacokinetic results in terms of bioavailability, i.e Cmax, Tmax and AUC were recorded which were in comparison with the equivalent dose of immediate release baclofen that was administered three times a day (Reference=R).
-
TABLE 20 Mean plasma concentration Vs time in hours when controlled drug delivery system is administered in morning Plasma profile achieved by administration of 30 mg Plasma profile achieved by Time in baclofen controlled drug administration of 10 mg hours delivery system of present baclofen immediate release on 8 day invention by spastic tablets administered by spastic (168 hours) patients in the morning patients three times a day 0 63.97 111.85 1 148.83 247.52 2 209.79 241.27 3 201.54 204.27 4 203.02 166.41 5 211.91 — 6 210.27 — 8 184.1 99.5 10 157.3 172.9 11 — 172.46 12 140.87 — 16 102.34 119.14 20 73.79 178.74 24 50.27 107.50 -
TABLE 21 Summary of the pharmacokinetic parameters obtained on once- a-day administration of baclofen controlled release drug delivery system in morning Vs immediate release baclofen tablets three times a day (number of patients = 11) Least square means Controlled Immediate release Release drug delivery baclofen Ratio 90% PK system 30 mg tablets of confidence variables baclofen (A) (B) A/B % CV interval AUC(0-∞) 3027.44 3555.03 85.16 16.53 74.52-97.31 Cmax 242.26 254.04 95.36 17.88 82.56-110.15 Tmax 5 2 11 - A randomized, open-label, two-treatment, two-period, two-sequence, multiple dose, crossover study to assess bioavailability and steady State pharmacokinetics of baclofen 30 mg controlled release drug delivery system of the present invention was given once daily in the evening time, under fed (normal meal) conditions, for 8 consecutive days in patients suffering from spasticity. Baclofen 10 mg immediate release tablets were given three times a day at 8 hour interval, with the initial dose administered under fasting condition, for 8 consecutive days, in 24 Spastic subjects receiving stable daily doses of baclofen.
- The pharmacokinetic results in terms of bioavailability, i.e Cmax, Tmax and AUC were recorded which were in comparison with the equivalent dose of immediate release baclofen that was administered three times a day (Reference=R).
-
TABLE 22 Mean plasma concentration Vs time in hours when controlled drug delivery system is administered in the evening Plasma profile achieved by Plasma profile achieved by Time in administration of 30 mg administration of 10 mg hours baclofen controlled drug baclofen immediate release on 8 day delivery system by spastic tablets administered by spastic (168 hours) patients in the evening patients three times a day 0 55.77 120.92 1 99.55 312.48 2 162.24 277.37 3 197.24 224.54 4 205.98 190.125 5 205.08 — 6 191.50 — 8 265.33 103.45 10 236.59 152.40 11 — 191.60 12 198.26 197.01 16 117.19 103.51 18 — 202.33 20 73.05 — 24 43.94 111.21 -
TABLE 23 Summary of the pharmacokinetic parameters obtained on once- a-day administration of baclofen controlled release drug delivery system in evening Vs immediate release baclofen tablets three times a day. (number of patients = 12) Least square means Controlled Immediate release Release drug delivery baclofen Ratio PK system 30 mg tablets of % 90% variables baclofen (A) (B) A/B CV C.I AUC(0-∞) 3431.56 3947.06 86.94 12.78 79.12-95.53 Cmax 286.71 304.83 94.05 22.35 79.87-110.75 T max8 1 - The values indicate that the bioavailability achieved when the baclofen controlled release drug delivery system prepared similar to example 1 in the spastic patients in comparison to the equivalent dose of immediate release baclofen tablets, when administered in the evening on fed condition in comparison to the bioavailability achieved when the baclofen controlled release capsules as per example 1 when administered in the morning. The Tmax was prolonged when the same composition was administered in the evening in comparison to the morning. The T/R ratio of the AUC i.e extent of absorption was found to be better when the controlled release system was administered in the evening in comparison to the administration in the morning. The rate of absorption was better when the controlled release system was administered in the evening in comparison to the morning.
- Prophetic examples of controlled release drug delivery systems are provided below. It should be understood that the constituents and/or proportions of the constituents in these coatings as well as the amounts thereof may be varied in order to achieve formulations possessing different release characteristics. In all instances wherein prophetic examples are provided these compositions are intended to be exemplary and it should be understood that the specific procedures, constituents, amounts thereof and the like may be varied in order to obtain a composition possessing desired properties.
-
-
TABLE 24 Details of the controlled release drug delivery system Sr. Mg per Percent by No. Ingredients capsule weight Sustained release granules 1. Baclofen 22.5 14.5 2. Mannitol 80.4 60.5 3. Starch 65 21.8 4. Dimethylamino ethyl 20 10 methacrylate with neutral methacrylate esters 5. Talc 3 1.5 6. Magnesium stearate 2 1.0 Immediate release coating 6. Baclofen 7.5 13.0 7. Hydroxypropyl methylcellulose 24.0 41.7 (4-6 mPas) 8. Talc 10.0 17.4 9. Propylene glycol 5.0 8.7 10. Titanium dioxide 11.0 19.1 11. Purified Water USP q.s - Baclofen is mixed with mannitol, starch and talc. The mixture is granulated with solution of dimethylamino ethyl methacrylate with neutral methacrylate esters. The granules are lubricated with talc and are filled into hard gelatin capsules. The capsule is further coated with a solution of immediate release fraction of baclofen which is dispersed in a film coating solution of low viscosity hydroxypropyl methylcellulose.
-
-
TABLE 25 Details of the controlled release drug delivery system Sr. mg per Percent by No. Ingredients capsule weight 1 Baclofen 35 70 2 Ethyl cellulose 7.5 15 3 Microcrystalline cellulose 4.25 8.5 4 Croscarmellose sodium 0.25 0.5 5 Ethyl alcohol q.s q.s 6 Purified water q.s q.s - Specified amounts of Baclofen may be taken and mixed with specified amounts of microcrystalline cellulose and Croscarmellose sodium. The blend is uniformly mixed and the powder blend is granulated with a polymeric hydro-alcoholic solution of ethyl-cellulose in a fluidized bed granulator. The granules so formed are further coated with hydro-alcoholic solution of ethyl-cellulose. These coated granules represent a reservoir type of controlled drug delivery system wherein the release of baclofen is controlled by the matrix as well the reservoir mechanism. The coated granules may be filled into hard gelatin capsules or may be compressed into tablets of size of about 2 millimeter (2 mm) and then filled into hard gelatin capsules.
-
-
TABLE 26a Details of the controlled release drug delivery system in the form of bilayer coated compressed tablet Percent by weight mg per of the drug delivery Ingredients tablet system Composition of the First Layer Baclofen 35 11.25 Hydroxypropyl methylcellulose 20.00 10.0 (12,000 to 21000 mPas) Lactose anhydrous 88.50 44.25 Polyvinylpyrrolidone 6.5 3.25 Colloidal silicon dioxide 2.0 1.00 Stearic acid 2.0 3.00 Talc 4.00 1.00 Composition of the second Layer Baclofen 25 mg 25 Silicified microcrystalline cellulose 205.0 70.7 Crospovidone 72.5 25.0 Colloidal silicon dioxide 7.2 2.5 Sodium lauryl sulfate 2.90 1.0 Magnesium stearate 2.4 0.83 -
TABLE 26b Functional coating composition Percent w/w mg per core tablet dry weight Ingredients of the core 8% weight gain Functional Coating of water insoluble 77.52 8 polymeric coating of ethylcellulose commercially available as Aquacoat EC30 D* Ethyl cellulose 20.93 69.21 Sodium lauryl sulphate 0.7752 2.56 Cetyl alcohol 1.55 5.12 Dibutyl sebacate 5.81 19.21 Triethyl citrate 1.16 3.83 water q.s q.s - Controlled release drug delivery system of baclofen of the present invention may be obtained in the form of a bilayer tablet that is functionally coated. Portion of baclofen is incorporated in the second layer for the immediate release and portion of baclofen is incorporated in the first layer for the controlled release.
- Composition of First Controlled Release Layer:
- Specified amounts of baclofen, Hydroxypropyl methylcellulose (12,000 to 21000 mPas), lactose anhydrous, polyvinyl pyrrolidone and colloidal silicon dioxide are sieved and mixed thoroughly. Stearic acid and talc are sieved and mixed with the blend, to obtain the composition of the first layer.
- Composition of the Second Layer:
- For the immediate release fraction, baclofen, silicified microcrystalline cellulose, colloidal silicon dioxide, sodium lauryl sulfate and crospovidone were sieved and mixed thoroughly to obtain a blend. This blend was lubricated with magnesium stearate, to obtain the composition of the second layer. The two compositions were compressed using standard concave punches to obtain bilayer tablets. The compressed tablets were coated with the coating composition to a weight gain of about 8% by weight of the core. An orifice of size of about 500 microns was drilled on the side of the tablet that contained the second layer.
-
-
TABLE 27 Drug loading on non-pareil seeds mg per % by weight of Ingredients dosage form the dosage from Non-pareil seeds (NPS) 81.4 81.4 Baclofen 13.0 13.0 Hypromellose, Methocel E 5.6 5.6 Purified Water, USP q.s q.s Functional coating Ethylcellulose 8.5 8.5 Hydroxy propyl methylcellulose 2.12 2.12 Purified Water, USP q.s q.s - The non-pareil seeds are loaded with a baclofen suspended in specified amounts of hypromellose in purified water. The loaded non-pareil seeds are then functionally coated with ethyl cellulose in a fluidized bed coating apparatus. The weight gain of the functional coating can range from about 10-20% by weight of the non-pareil seeds.The functionally coated pellets may be further coated with an immediate release fraction of baclofen to achieve an immediate release of baclofen followed by controlled release of the baclofen. The details are given in the following table 27a.
-
TABLE 27a Immediate release coating Immediate release coating 1 Baclofen 7.5 13.0 2 Hydroxypropyl methylcellulose 24.0 41.7 (4-6 mPas) 3 Talc 10.0 17.4 4 Propylene glycol 5.0 8.7 Titanium dioxide 11.0 19.1 6 Purified Water USP q.s -
-
TABLE 28 Compressed dosage form of baclofen having a muco-adhesive polymer in matrix Percent by weight of mg per the controlled release Ingredients tablet drug delivery system Baclofen 5 10 Polyethylene oxide 3.5 7 Sodium carboxy methyl-cellulose 1.5 3 Lactose anhydrous 10 20 Microcrystalline cellulose 25.9 51.8 Polyvinyl pyrrolidone 2.5 5 Colloidal silica 0.05 0.1 Purified talc 0.05 0.1 Magnesium stearate 0.5 1.0 - Specified quantities of baclofen are mixed geometrically with polyethylene oxide, sodium carboxymethylcellulose, lactose anhydrous and microcrystalline cellulose. The mixture is sifted and blended in a double polythene bag till a uniform mixture is obtained. The blend is granulated with a binding solution of polyvinyl pyrrolidone in isopropyl alcohol. The dried granules are lubricated with colloidal silicon dioxide, purified talc and magnesium stearate by mixing for 2 minutes. The mini tablets have a diameter of about 1.5 mm and a length of about 2 mm.
-
-
TABLE 29 Microparticulate dosage form of baclofen having a muco-adhesive polymer coating mg per Percent by weight of the dosage controlled release drug Ingredients form delivery system Baclofen 12.5 25 Ethyl cellulose 3.3 6.6 magnesium stearate 0.4 0.89 Castor oil 0.4 0.72 Polyvinyl pyrrolidone 0.4 0.72 Polyethylene oxide 25.0 50 Hydroxypropyl methyl cellulose 6.6 13.12 (80,000-1,20,000 mPas) Calcium acetate 0.8 1.57 - Specified amounts of baclofen are loaded in a fluid bed chamber. A coating solution of ethyl cellulose, polyvinyl pyrrolidone, castor oil and lubricant is prepared by dissolving the ingredients in isopropyl alcohol. Baclofen is then film coated with this coating solution. These film-coated baclofen microparticles particles are subsequently dry blended in a cube mixer with a mixture of sodium alginate powder, hydroxypropylmethylcellulose powder and calcium acetate powder. This mixture is filled in hard gelatin capsules.
- Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of them mean “including but not limited to”, and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.
- Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.
- The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.
Claims (33)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14/107,245 US9610269B2 (en) | 2010-02-17 | 2013-12-16 | Method of treating a disease condition susceptible to baclofen therapy |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN429/MUM/2010 | 2010-02-17 | ||
IN429MU2010 | 2010-02-17 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/107,245 Continuation US9610269B2 (en) | 2010-02-17 | 2013-12-16 | Method of treating a disease condition susceptible to baclofen therapy |
Publications (1)
Publication Number | Publication Date |
---|---|
US20110200671A1 true US20110200671A1 (en) | 2011-08-18 |
Family
ID=44369806
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/029,722 Abandoned US20110200671A1 (en) | 2010-02-17 | 2011-02-17 | Method of treating a disease condition susceptible to baclofen therapy |
US14/107,245 Active 2031-07-18 US9610269B2 (en) | 2010-02-17 | 2013-12-16 | Method of treating a disease condition susceptible to baclofen therapy |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/107,245 Active 2031-07-18 US9610269B2 (en) | 2010-02-17 | 2013-12-16 | Method of treating a disease condition susceptible to baclofen therapy |
Country Status (4)
Country | Link |
---|---|
US (2) | US20110200671A1 (en) |
JP (1) | JP2013519726A (en) |
CA (1) | CA2790164A1 (en) |
WO (1) | WO2011101866A2 (en) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9180108B2 (en) | 2011-10-27 | 2015-11-10 | Medtronic, Inc. | Baclofen formulations and methods for making same |
US9579289B2 (en) | 2015-02-20 | 2017-02-28 | Osmotica Kereskedelmi Es Szolgaltato Kft | Controlled release dosage form |
US9622997B2 (en) | 2012-06-01 | 2017-04-18 | Lynn Health Science Institute, Inc. | Methods for treating insomnia |
EP3167879A1 (en) * | 2015-11-10 | 2017-05-17 | Evonik Technochemie GmbH | Gastric retention active delivery systems |
US10172800B2 (en) | 2015-02-20 | 2019-01-08 | Osmotica Kereskedelmi Es Szolgaltato Kft | Controlled release dosage form with enhanced pharmacokinetics |
US10300032B2 (en) | 2015-02-20 | 2019-05-28 | Osmotica Kereskedelmi Es Szolgaltato Kft | Controlled release dosage form |
US10987328B2 (en) | 2015-02-20 | 2021-04-27 | Osmotica Kereskedelmi Es Szolgaltato Kft | Controlled release dosage form |
CN114450002A (en) * | 2019-07-29 | 2022-05-06 | 萨欧国际研究有限公司 | Stable formulations of 4-amino-3-substituted butyric acid derivatives |
WO2023006880A1 (en) * | 2021-07-29 | 2023-02-02 | Nutrition & Biosciences Usa 1, Llc | Controlled release coating agent |
US11654124B2 (en) | 2019-07-29 | 2023-05-23 | Amneal Pharmaceuticals Llc | Stabilized formulations of 4-amino-3-substituted butanoic acid derivatives |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8652527B1 (en) | 2013-03-13 | 2014-02-18 | Upsher-Smith Laboratories, Inc | Extended-release topiramate capsules |
US9101545B2 (en) | 2013-03-15 | 2015-08-11 | Upsher-Smith Laboratories, Inc. | Extended-release topiramate capsules |
FR3014692B1 (en) * | 2013-12-18 | 2016-01-29 | Ethypharm Sa | ORAL PHARMACEUTICAL COMPOSITIONS WITH GASTRIC RETENTION. |
JP6823539B2 (en) * | 2017-05-26 | 2021-02-03 | 株式会社ファンケル | Gastric retention tablets |
US20220287981A1 (en) * | 2019-08-16 | 2022-09-15 | Amd Pharma Ltd. | Adhesive drug delivery microparticles and a product comprising thereof |
MX2022010322A (en) | 2020-02-19 | 2022-09-19 | Safeevac Inc | Visual signaling system. |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6261601B1 (en) * | 1997-09-19 | 2001-07-17 | Ranbaxy Laboratories Limited | Orally administered controlled drug delivery system providing temporal and spatial control |
US20020119192A1 (en) * | 2000-09-22 | 2002-08-29 | Vishwanathan Narayanan Badri | Controlled release formulations for oral administration |
US20030031711A1 (en) * | 2001-05-29 | 2003-02-13 | Fara John W. | Method of treating gastroesophageal reflux disease and nocturnal acid breakthrough |
WO2005101983A2 (en) * | 2004-03-25 | 2005-11-03 | Sun Pharmaceutical Industries Limited | Gastric retention system |
US20070265343A1 (en) * | 2006-04-26 | 2007-11-15 | Sun Pharmaceutical Advanced Research Company Ltd. | Method for alleviating signs and symptoms of spasticity |
US20080206332A1 (en) * | 2007-01-11 | 2008-08-28 | Kidney David J | Sustained release oral dosage forms of a prodrug of r-baclofen and methods of treatment |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE9803760D0 (en) | 1998-11-04 | 1998-11-04 | Jan Hedner | Methods to treat and diagnose the restless legs syndrome and the corresponding agents |
WO2003011255A1 (en) * | 2001-07-04 | 2003-02-13 | Sun Pharmaceutical Industries Limited | Gastric retention controlled drug delivery system |
US20090214650A1 (en) | 2006-02-01 | 2009-08-27 | Alkermes, Inc. | Methods of Treating alcoholism and alcohol related disorders using combination drug therapy and swellable polymers |
WO2007106957A1 (en) * | 2006-03-21 | 2007-09-27 | Laboratoires Smb S.A. | Multiple units controlled-release floating dosage forms |
KR20090065524A (en) * | 2006-09-04 | 2009-06-22 | 파나세아 바이오테크 리미티드 | Programmable buoyant delivery technology |
-
2011
- 2011-02-17 CA CA2790164A patent/CA2790164A1/en not_active Abandoned
- 2011-02-17 WO PCT/IN2011/000099 patent/WO2011101866A2/en active Application Filing
- 2011-02-17 US US13/029,722 patent/US20110200671A1/en not_active Abandoned
- 2011-02-17 JP JP2012553444A patent/JP2013519726A/en not_active Withdrawn
-
2013
- 2013-12-16 US US14/107,245 patent/US9610269B2/en active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6261601B1 (en) * | 1997-09-19 | 2001-07-17 | Ranbaxy Laboratories Limited | Orally administered controlled drug delivery system providing temporal and spatial control |
US20020119192A1 (en) * | 2000-09-22 | 2002-08-29 | Vishwanathan Narayanan Badri | Controlled release formulations for oral administration |
US20030031711A1 (en) * | 2001-05-29 | 2003-02-13 | Fara John W. | Method of treating gastroesophageal reflux disease and nocturnal acid breakthrough |
WO2005101983A2 (en) * | 2004-03-25 | 2005-11-03 | Sun Pharmaceutical Industries Limited | Gastric retention system |
US20070265343A1 (en) * | 2006-04-26 | 2007-11-15 | Sun Pharmaceutical Advanced Research Company Ltd. | Method for alleviating signs and symptoms of spasticity |
US20080206332A1 (en) * | 2007-01-11 | 2008-08-28 | Kidney David J | Sustained release oral dosage forms of a prodrug of r-baclofen and methods of treatment |
Non-Patent Citations (1)
Title |
---|
Guilleminault et al., "Effect of Baclofen on Sleep-Related Periodic Leg Movements." Ann Neurol 1984:15;234-239. * |
Cited By (34)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10076506B2 (en) | 2011-10-27 | 2018-09-18 | Saol International Limited | Baclofen formulations and methods for making same |
US10813900B2 (en) | 2011-10-27 | 2020-10-27 | Saol International Limited | Baclofen formulations and methods for making same |
US10420740B2 (en) | 2011-10-27 | 2019-09-24 | Saol International Limited | Baclofen formulations and methods for making same |
US9597304B2 (en) | 2011-10-27 | 2017-03-21 | Saol International Limited | Baclofen formulations and methods for making same |
US9180108B2 (en) | 2011-10-27 | 2015-11-10 | Medtronic, Inc. | Baclofen formulations and methods for making same |
US9622997B2 (en) | 2012-06-01 | 2017-04-18 | Lynn Health Science Institute, Inc. | Methods for treating insomnia |
US10300032B2 (en) | 2015-02-20 | 2019-05-28 | Osmotica Kereskedelmi Es Szolgaltato Kft | Controlled release dosage form |
US10532031B2 (en) | 2015-02-20 | 2020-01-14 | Osmotica Kereskedelmi Es Szolgaltato Kft | Controlled release dosage form with enhanced pharmacokinetics |
US9801841B2 (en) | 2015-02-20 | 2017-10-31 | Osmotica Kereskedelmi és Szolgáltató KFT | Controlled release dosage form |
US11717483B2 (en) | 2015-02-20 | 2023-08-08 | Osmotica Kereskedelmi Es Szolgaltato Kft | Controlled release dosage form with enhanced pharmacokinetics |
US11679088B2 (en) | 2015-02-20 | 2023-06-20 | Osmotica Kereskedelmi Es Szolgaltato Kft | Controlled release dosage form |
US11090281B2 (en) | 2015-02-20 | 2021-08-17 | Osmotica Kereskedelmi Es Szolgaltato Kft | Controlled release dosage form |
US10172800B2 (en) | 2015-02-20 | 2019-01-08 | Osmotica Kereskedelmi Es Szolgaltato Kft | Controlled release dosage form with enhanced pharmacokinetics |
US10213404B2 (en) | 2015-02-20 | 2019-02-26 | Osmotica Kereskedelmi Es Szolgaltato Kft | Controlled release dosage form |
US10213402B2 (en) | 2015-02-20 | 2019-02-26 | Osmotica Kereskedelmi Es Szolgaltato Kft | Controlled release dosage form |
US10213403B2 (en) | 2015-02-20 | 2019-02-26 | Osmotica Kereskedelmi Es Szolgaltato Kft | Controlled release dosage form |
US10987328B2 (en) | 2015-02-20 | 2021-04-27 | Osmotica Kereskedelmi Es Szolgaltato Kft | Controlled release dosage form |
US9585843B2 (en) | 2015-02-20 | 2017-03-07 | Osmotica Kereskedelmi es Szoloaltato Kft | Controlled release dosage form |
US10471031B2 (en) | 2015-02-20 | 2019-11-12 | Osmotica Kereskedelmi Es Szolgaltato Kft | Controlled release dosage form |
US9655858B2 (en) | 2015-02-20 | 2017-05-23 | Osmotica Kereskedelmi Es Szolgaltato Kft | Controlled release dosage form |
US10987312B2 (en) | 2015-02-20 | 2021-04-27 | Osmotica Kereskedelmi Es Szolgaltato Kft | Controlled release dosage form with enhanced pharmacokinetics |
US10610505B2 (en) | 2015-02-20 | 2020-04-07 | Osmotica Kereskedelmi Es Szolgaltato Kft | Controlled release dosage form |
US9579289B2 (en) | 2015-02-20 | 2017-02-28 | Osmotica Kereskedelmi Es Szolgaltato Kft | Controlled release dosage form |
US10682307B2 (en) | 2015-11-10 | 2020-06-16 | Evonik Operations Gmbh | Gastric retention active delivery systems |
KR102095885B1 (en) | 2015-11-10 | 2020-04-01 | 에보니크 오퍼레이션즈 게엠베하 | Stomach stay active delivery system |
EP3167879A1 (en) * | 2015-11-10 | 2017-05-17 | Evonik Technochemie GmbH | Gastric retention active delivery systems |
WO2017080833A1 (en) * | 2015-11-10 | 2017-05-18 | Evonik Technochemie Gmbh | Gastric retention active delivery systems |
CN108348474A (en) * | 2015-11-10 | 2018-07-31 | 赢创工业化学有限公司 | gastric retention type active delivery system |
KR20180079334A (en) * | 2015-11-10 | 2018-07-10 | 에보닉 테크노케미 게엠베하 | Upper stay active transmission system |
CN114450002A (en) * | 2019-07-29 | 2022-05-06 | 萨欧国际研究有限公司 | Stable formulations of 4-amino-3-substituted butyric acid derivatives |
EP4003323A4 (en) * | 2019-07-29 | 2023-05-03 | Amneal Pharmaceuticals LLC | Stabilized formulations of 4-amino-3-substituted butanoic acid derivatives |
US11654124B2 (en) | 2019-07-29 | 2023-05-23 | Amneal Pharmaceuticals Llc | Stabilized formulations of 4-amino-3-substituted butanoic acid derivatives |
US11931328B2 (en) | 2019-07-29 | 2024-03-19 | Amneal Pharmaceuticals Llc | Stabilized formulations of 4-amino-3-substituted butanoic acid derivatives |
WO2023006880A1 (en) * | 2021-07-29 | 2023-02-02 | Nutrition & Biosciences Usa 1, Llc | Controlled release coating agent |
Also Published As
Publication number | Publication date |
---|---|
US20140105973A1 (en) | 2014-04-17 |
WO2011101866A2 (en) | 2011-08-25 |
US9610269B2 (en) | 2017-04-04 |
CA2790164A1 (en) | 2011-08-25 |
JP2013519726A (en) | 2013-05-30 |
WO2011101866A3 (en) | 2011-10-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9610269B2 (en) | Method of treating a disease condition susceptible to baclofen therapy | |
US9474721B2 (en) | Abuse-resistant formulations | |
US6476006B2 (en) | Composition and dosage form for delayed gastric release of alendronate and/or other bis-phosphonates | |
US7674480B2 (en) | Rapidly expanding composition for gastric retention and controlled release of therapeutic agents, and dosage forms including the composition | |
US6426091B1 (en) | Sustained-release theophylline tablet | |
JP4744142B2 (en) | Sustained release formulation containing lamotrigine | |
AU2001268719A1 (en) | Composition and dosage form for delayed gastric release of alendronate and/or other bis-phosphonates | |
CZ2003199A3 (en) | Quick expanding composition for controlled release of a medicament and retention thereof in stomach and medicinal forms containing such composition | |
JP5671609B2 (en) | Pharmaceutical composition comprising hydromorphone and naloxone | |
WO2006039022A2 (en) | Controlled regional oral delivery | |
JP2009522272A (en) | Intragastric release pulse system for drug delivery | |
CZ2001901A3 (en) | Pharmaceutical composition representing system of controlled delivery of a medicament for oral administration, providing time and local control | |
US20140050784A1 (en) | Pharmaceutical compositions of memantine | |
US20020119192A1 (en) | Controlled release formulations for oral administration | |
JP2006507216A (en) | Sustained release solid formulation as a novel drug delivery system with reduced risk of dose dumping | |
CZ20001200A3 (en) | Preparation for controlled administration of active substances | |
GR1009149B (en) | Pharmaceutical fomula comprising a fumaric acid ester - production method thereof | |
KR102039344B1 (en) | An orally administered sustained-release triple-layer tablet containing pregabalin | |
BG107055A (en) | Orally administered controlled delivery system for once daily administration of ciprofloxacin | |
EP2010158B1 (en) | Controlled release formulations comprising uncoated discrete unit(s) and an extended release matrix | |
RU2820820C2 (en) | Pharmaceutical compositions of acotiamide and proton pump inhibitor | |
CN109069434B (en) | Highly swellable sustained release trilayer tablet containing pregabalin | |
WO2008050188A2 (en) | Sustained release pharmaceutical compositions of alfuzosin and process for preparation thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: SUN PHARMA ADVANCED RESEARCH COMPANY, LTD., INDIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:DHARMADHIKARI, NITIN BHALACHANDRA;ZALA, YASHORAJ RUPSINH;REEL/FRAME:026093/0542 Effective date: 20110318 |
|
AS | Assignment |
Owner name: SUN PHARMA ADVANCED RESEARCH COMPANY, LTD., INDIA Free format text: CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNEE'S PREVIOUSLY RECORDED ON REEL 026093 FRAME 0542. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT OF ASSIGNOR'S INTEREST;ASSIGNORS:DHARMADHIKAN, NITIN BHALACHANDRA;ZALA, YASHORAJ RUPSINH;REEL/FRAME:026320/0135 Effective date: 20110318 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |