WO2005034918A1 - Pellets containing a pharmaceutical ingredient - Google Patents
Pellets containing a pharmaceutical ingredient Download PDFInfo
- Publication number
- WO2005034918A1 WO2005034918A1 PCT/HU2004/000094 HU2004000094W WO2005034918A1 WO 2005034918 A1 WO2005034918 A1 WO 2005034918A1 HU 2004000094 W HU2004000094 W HU 2004000094W WO 2005034918 A1 WO2005034918 A1 WO 2005034918A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- weight
- pellets
- active ingredient
- sodium chloride
- potassium chloride
- Prior art date
Links
- 239000008188 pellet Substances 0.000 title claims abstract description 80
- 239000004615 ingredient Substances 0.000 title abstract description 9
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims abstract description 44
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 44
- 239000004480 active ingredient Substances 0.000 claims abstract description 44
- 238000005453 pelletization Methods 0.000 claims abstract description 38
- 238000000034 method Methods 0.000 claims abstract description 30
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 24
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 24
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 24
- 239000001103 potassium chloride Substances 0.000 claims abstract description 22
- 235000011164 potassium chloride Nutrition 0.000 claims abstract description 22
- 239000011780 sodium chloride Substances 0.000 claims abstract description 22
- 230000008569 process Effects 0.000 claims abstract description 18
- 238000002360 preparation method Methods 0.000 claims abstract description 16
- 239000000654 additive Substances 0.000 claims abstract description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 9
- 230000001737 promoting effect Effects 0.000 claims abstract description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims description 26
- 239000002245 particle Substances 0.000 claims description 23
- 239000011248 coating agent Substances 0.000 claims description 19
- 238000000576 coating method Methods 0.000 claims description 19
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 18
- 235000013870 dimethyl polysiloxane Nutrition 0.000 claims description 15
- 239000004205 dimethyl polysiloxane Substances 0.000 claims description 15
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 11
- 229940079593 drug Drugs 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 238000005563 spheronization Methods 0.000 claims description 8
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 7
- 238000005507 spraying Methods 0.000 claims description 7
- -1 {2- (3, 4- dimethoxyphenyl) ethyl }methylamino Chemical group 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 239000000839 emulsion Substances 0.000 claims description 2
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims 1
- GFNWSKLPHRHAOE-WLHGVMLRSA-N (e)-but-2-enedioic acid;4-chloro-5-[3-[2-(3,4-dimethoxyphenyl)ethyl-methylamino]propylamino]-1h-pyridazin-6-one Chemical compound OC(=O)\C=C\C(O)=O.C1=C(OC)C(OC)=CC=C1CCN(C)CCCNC1=C(Cl)C=NNC1=O GFNWSKLPHRHAOE-WLHGVMLRSA-N 0.000 abstract description 4
- 238000013270 controlled release Methods 0.000 abstract 1
- 235000002639 sodium chloride Nutrition 0.000 description 15
- 238000005243 fluidization Methods 0.000 description 12
- 239000007788 liquid Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 239000012752 auxiliary agent Substances 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 230000007423 decrease Effects 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 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 3
- 230000000181 anti-adherent effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000013265 extended release Methods 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 239000007888 film coating Substances 0.000 description 3
- 238000009501 film coating Methods 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 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 3
- 239000002609 medium Substances 0.000 description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 239000003416 antiarrhythmic agent Substances 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 229960004667 ethyl cellulose Drugs 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 229950008882 polysorbate Drugs 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 229920002689 polyvinyl acetate Polymers 0.000 description 2
- 239000011118 polyvinyl acetate Substances 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 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 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 235000010919 Copernicia prunifera Nutrition 0.000 description 1
- 244000180278 Copernicia prunifera Species 0.000 description 1
- 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 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 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 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- IYKJEILNJZQJPU-UHFFFAOYSA-N acetic acid;butanedioic acid Chemical compound CC(O)=O.OC(=O)CCC(O)=O IYKJEILNJZQJPU-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 239000003831 antifriction material Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000004566 building material Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229940117841 methacrylic acid copolymer Drugs 0.000 description 1
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000005498 phthalate group Chemical group 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 238000004381 surface treatment Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
Definitions
- the invention relates to pellets containing a pharmaceutical ingredient, namely 5-chloro-4- [ ⁇ 3- ( ⁇ 2- (3,4-dimethoxyphenyl) ethyl ⁇ methyl ami no) - propyl ⁇ amino] -3 (2H) -pyridazinone (E) -2-butenedioate (1:1) of the formula (I) (CAS: 190333-92-7),
- sustained release pharmaceutical dosage forms are pharmaceuticals containing drug-loaded pellets.
- Pellets are spherical agglomerates 0,2-2 mm in diameter, which may be coated with one or more layer (s) regulating the release of the active agent and filled into hard gelatine capsules or tabletted.
- the capsules or tablets are disintegrated or distributed into individual pellets, which are then thoroughly mixed with the content of the stomach, and the discharge of the pellets from the stomach becomes more uniform.
- a high active agent concentration cannot develop during the release of the active ingredient from the pellets, thus the plasma concentration becomes more even.
- plasma concentration also becomes more even, the therapeutic activity of the composition becomes more favourable and the likelihood of the occurrence of side-effects considerably decreases .
- Pellets can be prepared according to a number of methods, which all can be based on the following tree principles: 1. layering 2. extrusion-spherofonization 3. build-up granulation
- a mixture of the particles of the active ingredient and/or the auxiliary agents of small particle size is applied in layers onto a nearly lsodiametric seed material of larger particle size than the particles of said active ingredient and/or the auxiliary agents.
- the application can be performed in a conventional coating drum, in a centrifugal granulating equipment or fluidization spraying apparatus.
- the active ingredient can be sprayed onto the surface of the inert granules from a solution.
- the high solubility (exceeding 600 mg/ml) of the active ingredient is disadvantageous from the viewpoint of the layering pelletization as well.
- the active ingredient is mixed with the auxiliary agents and a liquid, the wet mass is fed into an extruder having holes of about 1 mm in diameter, and the extrudate is formed into uniform, nearly spherical particles in a rotary spheronization machine.
- a mixture of the active ingredient and the auxiliary agents is mixed in a mixer or in a centrifugal or fluidization granulator, while a liquid is fed into the machine.
- the particles of the powder mixture adhere to each other and become spherical upon the effect of shear forces and abrasive orces .
- the last step of all pelletization processes is drying of the particles and separation of the fraction having a particle size suitable for further processing.
- the quality of the pelletization technology can be characterized by the product fraction, that is by the ratio of the mass of the pellets having the desired particle size to the total mass of the pellets.
- the pellets of unsuitable size are namely recycled to the manufacturing process and processed repeatedly, which results in an increase of the production time, costs of material and energy and the intensity of the labour involved in the procedure.
- the preferable particle size varies between 0.5 mm and 1.0 mm, in case of pellets compressed into tablets between 0.3 mm and 0.6 mm.
- pellets of bigger particle size such as 0.8 - 1.6 mm or 1.0 - 2.0 mm, in order to decrease the amount of the coating material necessary for the coating modifying the release of the active ingredient.
- excipipents may be fillers, lubricants, antiadhesives , disintegrants or drug release promoting additives, buffers, surfactants, surface-active substances, pelletization promoting additives or glidants (Isaac Ghebre-Sellassie: Pharmaceutical Pelletization Technology, Marcel Dekker, Inc., New York, Basel, 1989) .
- fillers which can be used for the pelletization e.g. calcium sul ate, calcium hydrophosphate , lactose, mannitol, szaccharose, starch and microcrystalline cellulose are mentioned.
- Suitable binders are e.g. gelatine, hydroxypropyl cellulose, hydroxypropyl-methyl cellulose, methylcellulose, polyvinyl pyrrolidone, szaccharose and starch.
- As lubricant calcium stearate, hydrogenated vegetable oil, magnesium stearate, mineral oil, polyethylene glycol , glycerine and propylene glycol may be applied.
- the pellets may also contain antiadhesives, such as kaolin, talk or silicon dioxide, furthermore disintegrants or drug release promoting agents, e.g. alginates, sodium carboxymethyl cellulose, crospovidon, starch, pre-gelatinized starch, sodium carboxymethyl starch, or e.g. ethyl- cellulose, carnauba vax, shellac.
- Antiadhesives such as kaolin, talk or silicon dioxide
- furthermore disintegrants or drug release promoting agents e.g. alginates, sodium carboxymethyl cellulose, crospovidon, starch, pre-gelatinized starch, sodium carboxymethyl starch, or e.g. ethyl- cellulose, carnauba vax, shellac.
- Buffers such as citrate, phosphate, carbonate and hydro- carbonate salts
- surface-active additives such as polysorbate, sodium laurylsulfate
- substances promoting spheronization
- micro- crystalline cellulose or a mixture of micro- crystalline cellulose and sodium carboxymethyl cellulose may also be used for the pellets.
- Glidants applied during pelletization include e.g. colloidal silicon dioxide, magnesium stearate, talc and starch.
- the ratio of the product fraction is about 60% by weight. That is why every technical solution resulting in an increase in the product fraction in addition to the maintenance of other important characteristics of the pellets - such as a nearly spherical shape and a suitable quality of the surface - is of high importance.
- pelletization is a complicated pharmaceutical operation requiring a special equipment and intensive labour.
- the pellets are optionally supplied with a water-insoluble film coating.
- the dissolution of the active ingredient occurs by diffusion through the coating.
- the dissolution rate is determined by the diffusion coefficient of the active ingredient, the thickness of the coating and the concentration gradient of the active ingredient. Considering that the solubility of certain active ingredients depends on the pH of the dissolution mixture, in such cases the composition of the pellets should be independent of the pH of the releasing medium.
- the release of the active ingredient in an aqueous medium from pellets prepared according to methods known from the prior art and containing said compound in an amount of 10% by weight fluctuates considerably in the physiological pH interval , and at a pH value of 6.8 characteristic of the bowels the release of the active ingredient does not meet the requirements specified in the European Pharmacopoeia (Edition 4, Directorate for the Quality of Medicines of the Council of Europe, France, 2003) . According to said requirements the amount of the active ingredient released within 45 minutes should be as high as at least 70% related to the total amount of the active ingredient.
- the aim of the invention was to elaborate a pharmaceutical composition
- a pharmaceutical composition comprising as active ingredient 5-chloro-4- [ ⁇ 3- ( ⁇ 2- (3, 4-d ⁇ methoxy- phenyl) ethyl ⁇ methylam ⁇ no) -propyl ⁇ am ⁇ no] -3 (2H) - pyridazinone (E) -2-butene-d ⁇ oate (1:1), furthermore a process for the preparation thereof, which process is suitable for the preparation of pellets in up-to-date fluidization roto- granulators and high-shear mixing machines providing the preparation of the product fraction (that is the ratio of pellets used for further processing) in a high yield, that is in a yield of at least 75%, preferably more that 80%, and in a suitable quality.
- the invention is based on the surprising recognition that if in the course of the pelletization process 10 to 60% by weight of sodium chloride and/or potassium chloride are added to the powder mixture to be pelletized in addition to at most 80% by weight of 5-chloro-4- [ ⁇ 3- ( ⁇ 2- (3,4-d ⁇ methoxyphenyl) ethyl ⁇ methylam ⁇ no) - propyl ⁇ ammo] -3 (2H) -pyridazinone (E) -2-butene- dioate (1:1) and 10 to 60% by weight of microcrystalline cellulose, pellets very advantageous in shape (approximately spherical) and having a particle size suitable for pharmaceutical purposes can be produced with a product fraction exceeding 80%. Besides, from the thus-obtained pellets a nearly total release of the active ingredient can be achieved at a speed independent of the pH of the medium.
- nearly spherical pellets comprising the pharmaceutical ingredient 5- chloro-4- [ ⁇ 3- ( ⁇ 2- (3, 4-d ⁇ methoxyphenyl) ethyl ⁇ - methylamino) propyl ⁇ amino] -3 (2H) -pyridazinone (E) -2-butenedioate (1:1), whereby said pellets contain, in addition to the active ingredient, 10 to 60% by weight of sodium chloride and/or potassium chloride, 10 to 60% by weight of microcrystalline cellulose and optionally other pharmaceutically acceptable auxiliary agents and/or pelletization promoting additives.
- dimethyl polysiloxane is emulged in the pelletizing liquid.
- the particle size of the thus- obtained pellets can be controlled much better, the size or the pellets is more uniform and the product fraction may exceed even 90%.
- Similar results can be achieved when xanthane gum is dissolved in the pelletezing liquid, or when the pelletizing liquid contains both dimethyl poly- siloxane and xanthane gum.
- the pharmaceutical compositions containing pelletized active ingredient are usually prepared in dosage unit forms. During the pelletization process the concentration of the active ingredient is determined by the single dose of the active agent finished in a dose unit so that the weight of the pellets containing a single dose of the active ingredient should vary between 50 to 1500 mg, preferably between 100 to 700 mg. In the knowledge of the weight of the pellets containing a single dose of the active ingredient the sodium chloride and/or potassium chloride and microcrystalline cellulose content of the pellet can be determined.
- the premix used for the preparation of the pellets according to the invention possessing advantageous properties should contain a total amount of at least 10% by weight of the excipients. If the active ingredient content of the pellets is lower than 80% by weight as a consequence of the lower dose, the sodium chloride and/or potassium chloride and microcrystalline cellulose content may be increased. The two types of excipients can be used in nearly identical amounts.
- microcrystalline cellulose used for the preparation of pellets according to the invention
- quality of the microcrystalline cellulose used for the preparation of pellets according to the invention there are no restrictions.
- Various types of microcrystalline cellulose of different particle size and of different density may freely be applied. Even the application of microcrystalline cellulose with a low moisture content is not required, since during pelletization the substance mixture is moistened with water or contacted with an aqueous solution or dispersion.
- mixtures of various types of microcrystalline cellulose formed with colloidal silicon dioxide can also be used, which contain about 98% by weight of microcrystalline cellulose and about 2% by weight of colloidal silicon dioxide.
- both sodium chloride and potassium chloride can be used to advantage, but due to their different physiological effects it is preferable to chose their concentrations on the basis of the extracellular physiological concentration.
- choosing e.g. 10% by weight as sodium chloride/potassium chloride concentration preferably 9.5% by weight of sodium chloride and 0,5% by weight of potassium chloride can be applied.
- the quality of the pellets and the quantity of the amount of pellets falling into the preferable particle size region can be improved.
- xanthane gum or dimethyl polysiloxane may be used.
- These auxiliary agents are dissolved or disperged either individually or together in water used for the pelletization, and added to the premix to be pelletized in the beginning of the pelletization procedure.
- Xanthane gum used in the compositions according to the invention is a natural polysaccharide produced by the microorganism Xantomonas campestris .
- the skeleton of xanthane gum such as that of cellulose, consists of 1,4- glucopyranose units, while the side-chains contain mannose, acetate and glucuronic acid.
- the average molecular weight is a few million Dalton.
- xanthane gum is mostly used to increase the stability of suspensions used for coating of medicines or films (e.g. Hungarian patent specification No. 202120) or as a viscosity-increasing agent (The United States Pharmacopoeia ed. 26., 2003, United States Pharmacopoeial Convention, Inc, Rockwille, USA) or as a matrix building material for extended release tablets .
- xanthane gum increases the stability of the pellets. This advantageous effect of this substance has not so far been mentioned in the literature and could not be aforeseen.
- Xanthane gum can be used in the pelletization liquid in an amount of not exceeding 2% by weight related to the final weight of the pellet.
- Dimethyl polysiloxane used in the compositions according to the invention is a liquid substance, a completely methylated polymeric siloxane having a viscosity value between 100 and 1000 centistokes.
- the aqueous dimethyl polysiloxane dispersions are commercially available products, which are used for surface treatments, as skin softening additives for pharmaceutical and cosmetic compositions, as antifriction agents for tabletting or as antiadhesives for film-coating (Hungarian patent specification No. 190,693).
- the United States Pharmacopoeia USP 26 classifies dimethyl polysiloxane into the group of antifoam additives.
- a surprising - and so far fully unknown - property of dimethyl polysiloxane is that in the course of pelletization, when emulged in an amount of not exceeding 5% by weight into water or an aqueous colloidal solution of xanthane gum used for the pelletization, it improves the spherical shape of the pellets and augments the ratio of the product fraction.
- the pellets according to the invention can be prepared by build-up (high-shear or roto- fluidization) or by extrusion-spheronization methods known from the literature.
- the powdered active ingredient is mixed with sodium chloride and/or potassium chloride and microcrystalline cellulose
- the mixture is homogenized and the thus-obtained powdered premix is moistened with water or with an aqueous solution of the binder (s) and/or other, pharmaceutically acceptable excipients.
- the mixture is converted into pellets of the desired particle size by using an appropriate equipment (extruder- spheronizator-drier , high-shear granulator- drier, rotoizidization apparatus).
- the product fraction having the desired particle size is isolated by size, e.g. by sieving.
- the pellet fraction having an unsuitable particle size is recycled to the pelletization process after grinding.
- pellets having the same particle size were prepared according to Example 1 comprising 10% by weight of 5-chloro-4-[ ⁇ 3-( ⁇ 2- (3, 4-d ⁇ methoxyphenyl) - ethyl ⁇ -methylamino) propyl ⁇ amino] -3 (2H) -pyridazinone (E) -2-butenedioate (1:1), 20% by weight of microcrystalline cellulose, 64.3% by weight of sodium chloride, 3.4% by weight of potassium chloride, 0.67% by weight of colloidal silicon dioxide, 0.17% by weight of xanthane gum and 1.46% by weight of dimethyl polysiloxane.
- Table 2 The data of the release of the active ingredient are provided in Table 2. It can be established that from the pellets according to the invention the dissolution of the active ingredient is quick, it is practically complete - independently of the pH of the releasing medium - within 15 minutes .
- the pellets according to the invention are particularly suitable for further coating operations.
- film- forming substances soluble in water e.g. hydroxypropyl-methyl cellulose, polyvinyl alcohol
- insoluble in water e.g. ethyl cellulose, ethyl acrylate - methyl methacrylate copolymer, polyvinyl acetate
- a solubility depending on the pH of the aqueous medium e.g. cellulose acetate phtalate, hydroxypropyl-methyl cellulose acetate succinate, ethyl acrylate methacrylic acid copolymer
- Coating can be carried out with an aqueous or organic solution or an aqueous dispersion of the film-forming substances.
- immediate release a coating soluble in water
- extended release a coating insoluble in water
- delayed release a coating with a solubility depending on the pH of the dissolution medium
- the quality and quantity of the coating substance are to be determined on the basis of the dissolution profile, that is the desired dependence of the release on time.
- pellets according to the invention and the preparation thereof are illustrated by the following Example without limiting the scope of protection to said Example.
- the mixture was transferred to a fluidization rotogranulator of Glatt GPCG1 type, a mixture of a solution of 2 g of xanthane gum in 500 ml of ion-exchanged water and 50 g of 35% dimethyl polysiloxane and further 1000 ml of ion-exchanged water were sprayed onto it.
- Spraying speed of the pelletizing liquid was set at 50 ml/mm, pressure of the spraying air was 2.5 bar.
- the speed of the rotor was set at 450 rev/min in the first 15 minutes of the pelletization and later kept at 600 rev/min.
- Speed by volume of the fluidization air was kept at 60 m 3 /hour in the first 15 minutes of the pelletization and later at 90 m 3 /hour.
- the temperature of the fluidization air was set at 25 °C in the firs part of the pelletization and at 40 °C for the drying procedure.
- the dried pellets were passed through sieves having hole widths of 1.6 mm and 0.8 mm, respectively and divided into 3 fractions .
- the product fraction that is the amount of the granules in the range between 0.8 mm and 1.6 mm, amounts to 96% by weight.
- a fluidization apparatus of Glatt GPCGl type was equipped with a bottom spraying Wurster insert, and 500 g of the product fraction were fed into the container.
- As coating liquid 200.0 g of an aqueous polymeric dispersion containing 30% of polyvinyl acetate (trademark name: Kollicoat SR) were applied.
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Abstract
The invention relates to pellets containing a pharmaceutical ingredient, namely 5-chloro-4-[{3-({2-(3,4-dimethoxyphenyl)ethyl}methylamino)-propyl}amino]-3 (2H)-pyridazinone (E)-2-butene-dioate (1 : 1) (CAS: 190333-92-7), and a process for the preparation thereof. The pellets according to the invention are nearly spherical in shape and contain, in addition to the active ingredient, 10 to 60 % by weight of sodium chloride and/or potassium chloride, 10 to 60 % by weight of micro-crystalline cellulose and optionally other pharmaceutically acceptable excipients and/or pelletization promoting additives. Said pellets are particularly suitable to be coated with a layer ensuring a controlled release of the active ingredient.
Description
PELLETS CONTAINING A PHARMACEUTICAL INGREDIENT
Field of the invention
The invention relates to pellets containing a pharmaceutical ingredient, namely 5-chloro-4- [ {3- ({2- (3,4-dimethoxyphenyl) ethyl } methyl ami no) - propyl }amino] -3 (2H) -pyridazinone (E) -2-butenedioate (1:1) of the formula (I) (CAS: 190333-92-7),
and a process for the preparation thereof.
Technical background of the invention
5-Chloro- -[{3-({2-(3,4-dimethoxyphenyl) ethyl } - methylamino) propyl } -amino] -3 (2H) -pyridazinone (E) -2-butenedioate (1:1) is a pharmaceutical
ingredient having antiarrhytmic activity. In the course of the therapeutic application of this ingredient extended release pharmaceutical dosage forms are much more effective than immediate release dosage forms , as they provide a uniform therapeutic effect and enable a decrease in the number of both the side-effects and the drug administrations.
The most advantageous forms of sustained release pharmaceutical dosage forms are pharmaceuticals containing drug-loaded pellets. Pellets are spherical agglomerates 0,2-2 mm in diameter, which may be coated with one or more layer (s) regulating the release of the active agent and filled into hard gelatine capsules or tabletted. When administering these compositions to patients, in the stomach the capsules or tablets are disintegrated or distributed into individual pellets, which are then thoroughly mixed with the content of the stomach, and the discharge of the pellets from the stomach becomes more uniform. In this way a high active agent concentration cannot develop during the release of the active ingredient from the pellets, thus the plasma concentration becomes more even. Thus plasma concentration also becomes more even, the
therapeutic activity of the composition becomes more favourable and the likelihood of the occurrence of side-effects considerably decreases .
From the beginning of the 1970s a special equipment is available for the preparation of pellets. This equipment serves basically for the purpose of extrusion-spheronization, centrifugal granulation, fluidization rotogranulation and high-shear mixing processes. By applying said equipment pellets can be produced directly, within only a few hours from a suitable powder mixture. Recently especially the application of fluidization rotary granulators and high-shear pelletizing machines combined with vacuo or microwave drying has become frequent, because by using such an equipment the production of pellets can be performed in a single apparatus (Isaac Ghebre-Sellassie: Pharmaceutical Pelletization Technology, Marcel Dekker, Inc. , New York, Basel, 1989).
Pellets can be prepared according to a number of methods, which all can be based on the following tree principles:
1. layering 2. extrusion-spherofonization 3. build-up granulation
By the layering method a mixture of the particles of the active ingredient and/or the auxiliary agents of small particle size is applied in layers onto a nearly lsodiametric seed material of larger particle size than the particles of said active ingredient and/or the auxiliary agents. The application can be performed in a conventional coating drum, in a centrifugal granulating equipment or fluidization spraying apparatus. In certain cases in the fluidization machines the active ingredient can be sprayed onto the surface of the inert granules from a solution. However, according to Hungarian patent specification No. 199,677 the high solubility (exceeding 600 mg/ml) of the active ingredient is disadvantageous from the viewpoint of the layering pelletization as well.
In case of the extrusion-spheronization process the active ingredient is mixed with the auxiliary agents and a liquid, the wet mass is fed into an extruder having holes of about 1 mm
in diameter, and the extrudate is formed into uniform, nearly spherical particles in a rotary spheronization machine.
According to the build-up granulation process a mixture of the active ingredient and the auxiliary agents is mixed in a mixer or in a centrifugal or fluidization granulator, while a liquid is fed into the machine. During this process the particles of the powder mixture adhere to each other and become spherical upon the effect of shear forces and abrasive orces .
The last step of all pelletization processes is drying of the particles and separation of the fraction having a particle size suitable for further processing. The quality of the pelletization technology can be characterized by the product fraction, that is by the ratio of the mass of the pellets having the desired particle size to the total mass of the pellets. The pellets of unsuitable size are namely recycled to the manufacturing process and processed repeatedly, which results in an increase of the production time, costs of material and energy and the intensity of the labour involved in the procedure.
In case of pellets filled into capsules the preferable particle size varies between 0.5 mm and 1.0 mm, in case of pellets compressed into tablets between 0.3 mm and 0.6 mm. In case of active ingredients readily soluble in water it is expedient to use pellets of bigger particle size, such as 0.8 - 1.6 mm or 1.0 - 2.0 mm, in order to decrease the amount of the coating material necessary for the coating modifying the release of the active ingredient.
In addition to the active ingredient pharmaceutically acceptable excipients are also applied for the pelletization, which promote the formation of pellets of appropriate shape and surface. Such excipipents may be fillers, lubricants, antiadhesives , disintegrants or drug release promoting additives, buffers, surfactants, surface-active substances, pelletization promoting additives or glidants (Isaac Ghebre-Sellassie: Pharmaceutical Pelletization Technology, Marcel Dekker, Inc., New York, Basel, 1989) .
As fillers which can be used for the pelletization e.g. calcium sul ate, calcium hydrophosphate , lactose, mannitol, szaccharose,
starch and microcrystalline cellulose are mentioned. Suitable binders are e.g. gelatine, hydroxypropyl cellulose, hydroxypropyl-methyl cellulose, methylcellulose, polyvinyl pyrrolidone, szaccharose and starch. As lubricant calcium stearate, hydrogenated vegetable oil, magnesium stearate, mineral oil, polyethylene glycol , glycerine and propylene glycol may be applied.
The pellets may also contain antiadhesives, such as kaolin, talk or silicon dioxide, furthermore disintegrants or drug release promoting agents, e.g. alginates, sodium carboxymethyl cellulose, crospovidon, starch, pre-gelatinized starch, sodium carboxymethyl starch, or e.g. ethyl- cellulose, carnauba vax, shellac. Buffers (such as citrate, phosphate, carbonate and hydro- carbonate salts) , surface-active additives (such as polysorbate, sodium laurylsulfate) and substances promoting spheronization (e.g. micro- crystalline cellulose or a mixture of micro- crystalline cellulose and sodium carboxymethyl cellulose) may also be used for the pellets. Glidants applied during pelletization include e.g. colloidal silicon dioxide, magnesium stearate, talc and starch.
In the conventional pelletization methods the ratio of the product fraction is about 60% by weight. That is why every technical solution resulting in an increase in the product fraction in addition to the maintenance of other important characteristics of the pellets - such as a nearly spherical shape and a suitable quality of the surface - is of high importance.
Several methods aiming at increasing the product fraction have been published. According to the European patent specification No. 288,732 during extrusion-spheronization process organic acids (such as citric, tartaric, maleic, fumaπc, succinic acid) applied in the composition in an amount of 5 to 50% by weight improve the plasticity of the wet mass and thus enable the preparation of harder pellets with particles of a narrow size range. At the same time this method cannot be used for the formulation of acid-sensitive active ingredients.
According to a publication of G.A. Hileman et al . (Drug Dev. and Ind. Pharmacy, 19(4), 483- 491, 1993) in case of the preparation of pellets with high active agent content the application of microcrystalline cellulose containing a
slight amount of sodium carboxymethyl cellulose promote the formation of high-quality pellets.
In the process disclosed in the International patent application No. WO 94/08567 0.03% by weight of polysorbate is applied in order to increase the ratio of product fraction.
According to the process disclosed in Hungarian patent specification No. 198,396 a coating powder containing 5 to 98% by weight of low- substituted hydroxypropyl cellulose (containing 4 to 20% of hydroxypropyl group) is applied during the pelletization.
On the basis of the above facts it can be established that pelletization is a complicated pharmaceutical operation requiring a special equipment and intensive labour.
In order to achieve a prolonged release of the active ingredient the pellets are optionally supplied with a water-insoluble film coating. In case of such dosage forms the dissolution of the active ingredient occurs by diffusion through the coating. The dissolution rate is determined by the diffusion coefficient of the active
ingredient, the thickness of the coating and the concentration gradient of the active ingredient. Considering that the solubility of certain active ingredients depends on the pH of the dissolution mixture, in such cases the composition of the pellets should be independent of the pH of the releasing medium.
The known 5-chloro-4- [ { 3- ( {2- (3, 4-dimethoxy- phenyl) ethyl }methylamino) propyl }amino] -3 (2H) - pyridazinone (E) -2-butenedioate (1:1), an antiarrhytmic ingredient, belongs to the group of the active ingredients problematical from the viewpoint of the preparation of prolonged release pellets . The release of the active ingredient in an aqueous medium from pellets prepared according to methods known from the prior art and containing said compound in an amount of 10% by weight fluctuates considerably in the physiological pH interval , and at a pH value of 6.8 characteristic of the bowels the release of the active ingredient does not meet the requirements specified in the European Pharmacopoeia (Edition 4, Directorate for the Quality of Medicines of the Council of Europe, Strasbourg, 2003) . According to said requirements the amount of the active ingredient released within 45 minutes should be as high as
at least 70% related to the total amount of the active ingredient.
The aim of the invention was to elaborate a pharmaceutical composition comprising as active ingredient 5-chloro-4- [ {3- ({2- (3, 4-dιmethoxy- phenyl) ethyl }methylamιno) -propyl }amιno] -3 (2H) - pyridazinone (E) -2-butene-dιoate (1:1), furthermore a process for the preparation thereof, which process is suitable for the preparation of pellets in up-to-date fluidization roto- granulators and high-shear mixing machines providing the preparation of the product fraction (that is the ratio of pellets used for further processing) in a high yield, that is in a yield of at least 75%, preferably more that 80%, and in a suitable quality.
Summary of the invention
The invention is based on the surprising recognition that if in the course of the pelletization process 10 to 60% by weight of sodium chloride and/or potassium chloride are added to the powder mixture to be pelletized in addition to at most 80% by weight of 5-chloro-4- [ {3- ( {2- (3,4-dιmethoxyphenyl) ethyl }methylamιno) - propyl} ammo] -3 (2H) -pyridazinone (E) -2-butene-
dioate (1:1) and 10 to 60% by weight of microcrystalline cellulose, pellets very advantageous in shape (approximately spherical) and having a particle size suitable for pharmaceutical purposes can be produced with a product fraction exceeding 80%. Besides, from the thus-obtained pellets a nearly total release of the active ingredient can be achieved at a speed independent of the pH of the medium.
Details of the invention
According to an aspect of the present invention there are provided nearly spherical pellets comprising the pharmaceutical ingredient 5- chloro-4- [{3- ({2- (3, 4-dιmethoxyphenyl) ethyl } - methylamino) propyl }amino] -3 (2H) -pyridazinone (E) -2-butenedioate (1:1), whereby said pellets contain, in addition to the active ingredient, 10 to 60% by weight of sodium chloride and/or potassium chloride, 10 to 60% by weight of microcrystalline cellulose and optionally other pharmaceutically acceptable auxiliary agents and/or pelletization promoting additives.
According to another aspect of the present invention there is provided a process for the preparation of nearly spherical pellets
containing the pharmaceutical ingredient 5- chloro-4- [ {3- ({2- (3,4-dimethoxyphenyl) ethyl } - methylamino) propyl } -amino] -3 (2H) -pyridazinone (E) -2-butene-dioate (1:1), which comprises admixing at most 80% of the active ingredient with 10 to 60% by weight of microcrystalline cellulose, 10 to 60% by weight of sodium chloride and/or potassium chloride and optionally other, pharmaceutically acceptable auxiliary agents and/or additives promoting pelletization, converting the thus-obtained mixture into pellets by high-shear mixing, rotofluidization or extrusion-spheronization method, preferably by rotofluidization by spraying water or preferably an aqueous dimethyl polysiloxane emulsion and/or an aqueous solution of xanthane gum, drying the pellets, separating the desired product fraction and optionally coating the pellets with a layer to modify the drug release.
In order to achieve a further improvement in the efficiency of the pelletization dimethyl polysiloxane is emulged in the pelletizing liquid. In this way the particle size of the thus- obtained pellets can be controlled much better, the size or the pellets is more uniform and the product fraction may exceed even 90%. Similar
results can be achieved when xanthane gum is dissolved in the pelletezing liquid, or when the pelletizing liquid contains both dimethyl poly- siloxane and xanthane gum. The exact mechanism of the effect of sodium chloride and/or potassium chloride, dimethyl polysiloxane and xanthane gum is not known at the moment, but it can be supposed that the formation of a more uniform particle size may be the result of a decrease in the solubility of the active ingredient upon the effect of the ionic filler materials, an increase in the plasticity of the powder mixture to be pelletized and some advantageous changes of the cohesion between the particles .
The pharmaceutical compositions containing pelletized active ingredient are usually prepared in dosage unit forms. During the pelletization process the concentration of the active ingredient is determined by the single dose of the active agent finished in a dose unit so that the weight of the pellets containing a single dose of the active ingredient should vary between 50 to 1500 mg, preferably between 100 to 700 mg.
In the knowledge of the weight of the pellets containing a single dose of the active ingredient the sodium chloride and/or potassium chloride and microcrystalline cellulose content of the pellet can be determined. The premix used for the preparation of the pellets according to the invention possessing advantageous properties should contain a total amount of at least 10% by weight of the excipients. If the active ingredient content of the pellets is lower than 80% by weight as a consequence of the lower dose, the sodium chloride and/or potassium chloride and microcrystalline cellulose content may be increased. The two types of excipients can be used in nearly identical amounts.
As to the quality of the microcrystalline cellulose used for the preparation of pellets according to the invention, there are no restrictions. Various types of microcrystalline cellulose of different particle size and of different density may freely be applied. Even the application of microcrystalline cellulose with a low moisture content is not required, since during pelletization the substance mixture is moistened with water or contacted with an aqueous solution or dispersion. In addition to
the so-called pure or monocomponent micro- crystalline cellulose varieties mixtures of various types of microcrystalline cellulose formed with colloidal silicon dioxide can also be used, which contain about 98% by weight of microcrystalline cellulose and about 2% by weight of colloidal silicon dioxide.
From the viewpoint of pelletization both sodium chloride and potassium chloride can be used to advantage, but due to their different physiological effects it is preferable to chose their concentrations on the basis of the extracellular physiological concentration. This constitutes a weight ratio of sodium chloride to potassium chloride of about 20:1. Thus, choosing e.g. 10% by weight as sodium chloride/potassium chloride concentration, preferably 9.5% by weight of sodium chloride and 0,5% by weight of potassium chloride can be applied.
Furthermore, by applying excipients in the compositions of the pellets according to the invention, the quality of the pellets and the quantity of the amount of pellets falling into the preferable particle size region can be improved. For this purpose xanthane gum or
dimethyl polysiloxane may be used. These auxiliary agents are dissolved or disperged either individually or together in water used for the pelletization, and added to the premix to be pelletized in the beginning of the pelletization procedure.
Xanthane gum used in the compositions according to the invention is a natural polysaccharide produced by the microorganism Xantomonas campestris . The skeleton of xanthane gum, such as that of cellulose, consists of 1,4- glucopyranose units, while the side-chains contain mannose, acetate and glucuronic acid. The average molecular weight is a few million Dalton.
In the pharmaceutical industry xanthane gum is mostly used to increase the stability of suspensions used for coating of medicines or films (e.g. Hungarian patent specification No. 202120) or as a viscosity-increasing agent (The United States Pharmacopoeia ed. 26., 2003, United States Pharmacopoeial Convention, Inc, Rockwille, USA) or as a matrix building material for extended release tablets . When used for pelletization, xanthane gum increases the
stability of the pellets. This advantageous effect of this substance has not so far been mentioned in the literature and could not be aforeseen. Xanthane gum can be used in the pelletization liquid in an amount of not exceeding 2% by weight related to the final weight of the pellet.
Dimethyl polysiloxane used in the compositions according to the invention is a liquid substance, a completely methylated polymeric siloxane having a viscosity value between 100 and 1000 centistokes. The aqueous dimethyl polysiloxane dispersions are commercially available products, which are used for surface treatments, as skin softening additives for pharmaceutical and cosmetic compositions, as antifriction agents for tabletting or as antiadhesives for film-coating (Hungarian patent specification No. 190,693). The United States Pharmacopoeia (USP 26) classifies dimethyl polysiloxane into the group of antifoam additives. A surprising - and so far fully unknown - property of dimethyl polysiloxane is that in the course of pelletization, when emulged in an amount of not exceeding 5% by weight into water or an aqueous colloidal solution of xanthane gum used for the
pelletization, it improves the spherical shape of the pellets and augments the ratio of the product fraction.
The pellets according to the invention can be prepared by build-up (high-shear or roto- fluidization) or by extrusion-spheronization methods known from the literature. In the course of the pelletization process the powdered active ingredient is mixed with sodium chloride and/or potassium chloride and microcrystalline cellulose The mixture is homogenized and the thus-obtained powdered premix is moistened with water or with an aqueous solution of the binder (s) and/or other, pharmaceutically acceptable excipients. The mixture is converted into pellets of the desired particle size by using an appropriate equipment (extruder- spheronizator-drier , high-shear granulator- drier, roto luidization apparatus). Then the product fraction having the desired particle size is isolated by size, e.g. by sieving. The pellet fraction having an unsuitable particle size is recycled to the pelletization process after grinding.
The advantageous effect of sodium chloride, potassium chloride and dimethyl polysiloxane used as excipients for the pelletization manifests itself in the fact that even in case of a pharmaceutical quality product their price is low, so their application results in a reduction of the manufacturing costs .
Besides, due to the relatively high water- solubility of the applied sodium chloride and potassium chloride - which is independent of the pH of the dissolution medium - these substances promote the complete and pH- mdependent release of poorly soluble active ingredients .
In case of pellets prepared according to methods known from the prior art containing 10% by weight of 5-chloro-4- [ {3- ( {2- (3, 4-dιmethoxy- phenyl) ethyl }methylamιno) propyl }amιno] -3 (2H) - pyridazinone (E) -2-butenedioate (1:1) and micro- crystalline cellulose, the dissolution of the active ingredient from the pellets in the physiological pH interval does not meet the requirements specified in the European Pharmacopoeia (Edition 4, Directorate for the Quality of Medicines of the Council of Europe, Strasbourg, 2003) . According to the said
requirements the amount of the active ingredient released within 45 minutes should be as high as at least 70% related to the total amount of the active ingredient. The data characteristic of the release of the active ingredient from the pellets composed as specified in the prior art are shown in Table 1.
Table 1
For the purpose of comparison pellets having the same particle size (1.0 - 1.6 mm) were prepared according to Example 1 comprising 10% by weight of 5-chloro-4-[{3-({2- (3, 4-dιmethoxyphenyl) - ethyl } -methylamino) propyl}amino] -3 (2H) -pyridazinone (E) -2-butenedioate (1:1), 20% by weight of microcrystalline cellulose, 64.3% by weight of sodium chloride, 3.4% by weight of potassium chloride, 0.67% by weight of colloidal silicon dioxide, 0.17% by weight of xanthane gum and
1.46% by weight of dimethyl polysiloxane. The data of the release of the active ingredient are provided in Table 2. It can be established that from the pellets according to the invention the dissolution of the active ingredient is quick, it is practically complete - independently of the pH of the releasing medium - within 15 minutes .
Table 2 pH 6,8 pH 7 Time pH 1.2 (phosphate distilled (min) ( 0.1 M HC1) buffer) water 15 96.6 98.4 100.7 30 97.9 100.9 100.9 45 97.8 100.9 101.3 60 97.8 101.1 101.7 120 97.1 99.2 101.4
The pellets according to the invention are particularly suitable for further coating operations. In the course of coating film- forming substances soluble in water (e.g. hydroxypropyl-methyl cellulose, polyvinyl alcohol) , insoluble in water (e.g. ethyl cellulose, ethyl acrylate - methyl methacrylate copolymer, polyvinyl acetate) or showing a solubility depending on the pH of the aqueous
medium (e.g. cellulose acetate phtalate, hydroxypropyl-methyl cellulose acetate succinate, ethyl acrylate methacrylic acid copolymer) can be used. Coating can be carried out with an aqueous or organic solution or an aqueous dispersion of the film-forming substances. Depending on the characteristics of the film coating immediate release (a coating soluble in water) , extended release (a coating insoluble in water) or delayed release (a coating with a solubility depending on the pH of the dissolution medium) can be prepared. The quality and quantity of the coating substance are to be determined on the basis of the dissolution profile, that is the desired dependence of the release on time.
The pellets according to the invention and the preparation thereof are illustrated by the following Example without limiting the scope of protection to said Example.
Example
Preparation of pellets containing 5-chloro-4- [{3-({2-(3,4-dimethoxyphenyl) ethyl } -methyl- ammo) propyl }amιno] -3 (2H) -pyridazinone (E) -2- butene-dioate (1:1)
185 g of 5-chloro-4-[{3-({2-(3,4-dιmethoxy- phenyl) ethyl }methylamιno) propyl }amιno] -3 (2H) - pyridazinone (E) -2-butene-dιoate (1:1), 370 g of microcrystalline cellulose, 8 g of colloidal silicon dioxide, 770.0 g of sodium chloride and 40.2 g of potassium chloride were mixed in an acid-proof vessel . The mixture was transferred to a fluidization rotogranulator of Glatt GPCG1 type, a mixture of a solution of 2 g of xanthane gum in 500 ml of ion-exchanged water and 50 g of 35% dimethyl polysiloxane and further 1000 ml of ion-exchanged water were sprayed onto it. Spraying speed of the pelletizing liquid was set at 50 ml/mm, pressure of the spraying air was 2.5 bar. The speed of the rotor was set at 450 rev/min in the first 15 minutes of the pelletization and later kept at 600 rev/min. Speed by volume of the fluidization air was kept at 60 m3/hour in the first 15 minutes of the pelletization and later at 90 m3/hour. The temperature of the fluidization air was set at
25 °C in the firs part of the pelletization and at 40 °C for the drying procedure.
The dried pellets were passed through sieves having hole widths of 1.6 mm and 0.8 mm, respectively and divided into 3 fractions . The product fraction, that is the amount of the granules in the range between 0.8 mm and 1.6 mm, amounts to 96% by weight.
For the preparation of sustained release composition a fluidization apparatus of Glatt GPCGl type was equipped with a bottom spraying Wurster insert, and 500 g of the product fraction were fed into the container. As coating liquid 200.0 g of an aqueous polymeric dispersion containing 30% of polyvinyl acetate (trademark name: Kollicoat SR) were applied. To the said dispersion 8.4 g of propylene glycol dissolved in 240 g of water were added. Coating was carried out under the following conditions:
- temperature of the fluidization air: 60 °C
- rate of feed: 8 ml/min
- pressure of spraying: 2 bar
Claims
1. Pellets in nearly spherical shape comprising pharmaceutically active 5-chloro-4- [ {3- ( {2- (3, 4- dimethoxyphenyl) ethyl }methylamino) propyl Jamino] - 3 (2H) -pyridazinone (E) -2-butenedioate (1:1) of the formula (I) ,
whereby said pellets contain, in addition to the active ingredient, 10 to 60% by weight of sodium chloride and/or potassium chloride, 10 to 60% by weight of microcrystalline cellulose and optionally other pharmaceutically acceptable excipients and/or pelletization promoting additives .
2. Pellets according to claim 1, wherein the pellet has a particle size in the range between
0.2 mm and 2 mm, preferably between 0.5 mm and 1.6 mm.
3. Pellets according to claim 2 comprising 0.4 to 60% by weight of 5-chloro-4- [ {3- ( {2- (3, 4- dimethoxyphenyl) ethyl Jmethylamino) propyl }amino] - 3 (2H) -pyridazinone (E) -2-butenedioate (1:1) as active ingredient, 20 to 60% by weight of sodium chloride and/or potassium chloride, 20 to 60% by weight of microcrystalline cellulose, 0.5 to 3.0% by weight of dimethyl polysiloxane and/or 0.1 to 1.0% by weight of xanthane gum and, if desired, 0.1 to 0.6% by weight of colloidal silicon dioxide.
4. Pellets according to claim 3, wherein the total amount of the potassium chloride and sodium chloride is 20 to 60% by weight.
5. Pellets according to claim 4, wherein the weight ratio of the sodium chloride:potassium chloride is about 20:1.
6. Pellets according to claim 5 optionally supplied with a coating to modify the drug release and having a particle size between 0.8 mm and 1.6 mm, comprising as active ingredient 35 to 45% by weight of 5-chloro-4- [ {3- ( {2- (3, 4- dimethoxyphenyl) ethyl }methylamιno) propyl } - ammo] -3 (2H) -pyridazinone (E) -2-butenedioate (1:1) in admixture with 25 to 35% by weight of microcrystalline cellulose, 2.0 to 3% by weight of potassium chloride, 50 to 60% by weight of sodium chloride, 1.4 to 1.8% by weight of dimethyl polysiloxane, 0.1 to 0.2% by weight of xanthane gum and 0.4 to 0.6% by weight of colloidal silicon dioxide.
7. A process for the preparation of pellets according to any of claims 1 to 9, which comprises admixing at most 80% of 5-chloro-4- [ {3- ({2- (3,4-dιmethoxyphenyl) ethyl }methylamιno) - propyl } -ammo] -3 (2H) -pyridazinone (E) -2-butene- dioate (1:1) with 10 to 60% by weight of micro- crystalline cellulose, 10 to 60% by weight of sodium chloride and/or potassium chloride and optionally other, pharmaceutically acceptable excipients and/or pelletization promoting additives, converting the thus-obtained mixture into pellets by high-shear blending, rotofluidization or extrusion-spheronization method, preferably by rotofluidization by spraying water or preferably an aqueous dimethyl polysiloxane emulsion and/or an aqueous solution of xanthane gum, drying the pellets, separating the desired product fraction and optionally coating the pellets with a layer to modify the drug release.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU0303383A HU227115B1 (en) | 2003-10-10 | 2003-10-10 | Pellets containing pyridazinone derivative |
HUP0303383 | 2003-10-10 |
Publications (1)
Publication Number | Publication Date |
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WO2005034918A1 true WO2005034918A1 (en) | 2005-04-21 |
Family
ID=89981704
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/HU2004/000094 WO2005034918A1 (en) | 2003-10-10 | 2004-10-08 | Pellets containing a pharmaceutical ingredient |
Country Status (2)
Country | Link |
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HU (1) | HU227115B1 (en) |
WO (1) | WO2005034918A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2011503186A (en) * | 2007-11-14 | 2011-01-27 | ジデケル,マヌエル | A novel extract of Deschampsia antarctica Desv. With antineoplastic activity |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN114028577B (en) * | 2021-10-20 | 2024-07-02 | 珠海市东辰制药有限公司 | Silica pill core and preparation method thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003010150A1 (en) * | 2001-07-26 | 2003-02-06 | EGIS Gyógyszergyár Rt. | Polymorph salt of a pyridazinone derivative for the treatment of arrythmia |
-
2003
- 2003-10-10 HU HU0303383A patent/HU227115B1/en not_active IP Right Cessation
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2004
- 2004-10-08 WO PCT/HU2004/000094 patent/WO2005034918A1/en active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003010150A1 (en) * | 2001-07-26 | 2003-02-06 | EGIS Gyógyszergyár Rt. | Polymorph salt of a pyridazinone derivative for the treatment of arrythmia |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2011503186A (en) * | 2007-11-14 | 2011-01-27 | ジデケル,マヌエル | A novel extract of Deschampsia antarctica Desv. With antineoplastic activity |
Also Published As
Publication number | Publication date |
---|---|
HU227115B1 (en) | 2010-07-28 |
HU0303383D0 (en) | 2003-12-29 |
HUP0303383A2 (en) | 2005-04-28 |
HUP0303383A3 (en) | 2005-06-28 |
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