US20010007664A1 - Use of lipids as adjuvents in the production of solid medicinal forms by the melt extrusion process - Google Patents
Use of lipids as adjuvents in the production of solid medicinal forms by the melt extrusion process Download PDFInfo
- Publication number
- US20010007664A1 US20010007664A1 US09/000,389 US38998A US2001007664A1 US 20010007664 A1 US20010007664 A1 US 20010007664A1 US 38998 A US38998 A US 38998A US 2001007664 A1 US2001007664 A1 US 2001007664A1
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- United States
- Prior art keywords
- lipids
- melt
- production
- melt extrusion
- tablets
- Prior art date
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- Granted
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- 150000002632 lipids Chemical class 0.000 title claims abstract description 15
- 238000001125 extrusion Methods 0.000 title claims abstract description 14
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 8
- 239000007787 solid Substances 0.000 title claims abstract description 5
- 239000000155 melt Substances 0.000 title description 13
- 238000000034 method Methods 0.000 title description 3
- 229940079593 drug Drugs 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 9
- 235000010445 lecithin Nutrition 0.000 claims description 6
- 239000000787 lecithin Substances 0.000 claims description 6
- 150000002327 glycerophospholipids Chemical class 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 23
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 23
- 239000004480 active ingredient Substances 0.000 description 17
- 238000003490 calendering Methods 0.000 description 13
- 229920000642 polymer Polymers 0.000 description 13
- 239000000203 mixture Substances 0.000 description 12
- 239000000654 additive Substances 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 238000000465 moulding Methods 0.000 description 5
- 239000000902 placebo Substances 0.000 description 5
- 229940068196 placebo Drugs 0.000 description 5
- 229960001722 verapamil Drugs 0.000 description 5
- 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 4
- 229930195725 Mannitol Natural products 0.000 description 4
- -1 fatty acid esters Chemical class 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
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 238000004140 cleaning Methods 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 3
- 229960001597 nifedipine Drugs 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229920013821 hydroxy alkyl cellulose Polymers 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 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 2
- 229940067606 lecithin Drugs 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 239000006082 mold release agent Substances 0.000 description 2
- 229920001169 thermoplastic Polymers 0.000 description 2
- DUXYWXYOBMKGIN-UHFFFAOYSA-N trimyristin Chemical compound CCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCC DUXYWXYOBMKGIN-UHFFFAOYSA-N 0.000 description 2
- PVNIQBQSYATKKL-UHFFFAOYSA-N tripalmitin Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCC PVNIQBQSYATKKL-UHFFFAOYSA-N 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- ONCLVQFEAFTXMN-UHFFFAOYSA-N (1-hexadecanoyloxy-3-hydroxypropan-2-yl) octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC(CO)COC(=O)CCCCCCCCCCCCCCC ONCLVQFEAFTXMN-UHFFFAOYSA-N 0.000 description 1
- DMBUODUULYCPAK-UHFFFAOYSA-N 1,3-bis(docosanoyloxy)propan-2-yl docosanoate Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCCCCCC DMBUODUULYCPAK-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 229920001479 Hydroxyethyl methyl 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
- 230000001464 adherent effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 229920013820 alkyl cellulose Polymers 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229940106189 ceramide Drugs 0.000 description 1
- 150000001783 ceramides Chemical class 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- UHUSDOQQWJGJQS-UHFFFAOYSA-N glycerol 1,2-dioctadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCCCCCCCCCCC UHUSDOQQWJGJQS-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000006069 physical mixture Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000004416 thermosoftening plastic Substances 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229920003169 water-soluble polymer Polymers 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
Definitions
- the present invention relates to the use of lipids as aids in the production of solid drug forms by melt extrusion.
- Known mold release agents for conventional processes are, for example, fatty acid esters or fatty acid salts, with only magnesium stearate normally being used in practice. Magnesium stearate is normally added to the granules which contain active ingredient and are ready before tabletting.
- melt-processable cellulose derivatives such as hydroxypropylcellulose are, as water-soluble polymers, very suitable for producing tablets by solvent-free melt extrusion/calendering. It is possible by admixture of other ancillary substances, eg. HPMC (hydroxypropylmethylcellulose) polymers which are swellable in water, to control the dissolution times of such tablets in the gastrointestinal tract, as is disclosed, for example, in DE-A 4226753.
- HPMC hydroxypropylmethylcellulose
- the lipids which are suitable according to the invention are mono-, di- and triglycerides of naturally occurring fatty acids, for example glycerol monostearate, glycerol distearate, glycerol tristearate, glycerol tripalmitate, glycerol trimyristate, glycerol tribehenate, glycerol palmitate stearate or glyceride mixtures occurring in natural oils, preferably hydrogenated castor oil.
- naturally occurring fatty acids for example glycerol monostearate, glycerol distearate, glycerol tristearate, glycerol tripalmitate, glycerol trimyristate, glycerol tribehenate, glycerol palmitate stearate or glyceride mixtures occurring in natural oils, preferably hydrogenated castor oil.
- Ceramides are furthermore also suitable for this purpose.
- Preferred lipids are, in particular, phospholipids, with phosphoglycerides such as lecithins being particularly preferred. Hydrogenated lecithins such as soybean and egg lecithins are very particularly preferred.
- the lipids can be used in amounts of 0.1- 10%, preferably 1-5%, of the total weight of the preparations containing active ingredient.
- compositions containing active ingredient can contain as matrix polymers melt-processable polymers, for example
- carboxyalkylcelluloses such as carboxymethylcelluloses, alkylcelluloses such as methylcellulose,
- hydroxyalkylcelluloses such as hydroxymethyl-, hydroxyethyl-, hydroxypropyl- and hydroxybutylcellulose
- hydroxyalkylcelluloses such as hydroxyethylmethyl- and hydroxypropylmethylcellulose, or mixtures thereof.
- Preferred polymers are hydroxypropylcelluloses and polymers based on vinylpyrrolidone.
- Suitable active ingredients are all active ingredients which do not decompose under the conditions of melt extrusion.
- the amount of the active component in the complete preparation can vary within wide limits depending on the activity and release rate.
- the content of active ingredient can be in the range from 0.1 to 90%, preferably from 0.5 to 60%, of the total weight of the preparation. The only condition is that the preparation is still melt-processable.
- the preparations may furthermore contain conventional pharmaceutical ancillary substances such as bulking agents, colorants, disintegrants or stabilizers in conventional amounts.
- the components are processed in a conventional way in extruders, preferably in single or twin screw extruders at a temperature in the range from 50 to 200° C.
- the shaping of the polymer melt which contains active ingredient and is free of solvent to give the preparations according to the invention can take place, for example, by calendering the extrudate and by converting the extrudate with rotating knives into pellets which have identical volumes and have a solidified surface but are still moldable, and subsequently compressing to tablets in conventional tabletting machines.
Abstract
Description
- The present invention relates to the use of lipids as aids in the production of solid drug forms by melt extrusion.
- The production of solid drug forms by melt extrusion is disclosed, for example, in U.S. Pat. No. 4,880,585, wherein the drug form is produced from the melt, which contains active ingredient and is still plastic, with the aid of a molding calender which directly molds tablets from the melt.
- It has long been known that, in almost all cases when tablets are made from granules, satisfactory results are achieved only if a small amount of a lubricant is added to the formulations, after the granulation but before the tabletting, and this is deposited as a fine film on the outsides of the granule particles and thus prevents adhesion of the granules to the tabletting punches. The effect of these lubricants is very great although it is necessary to add only very small amounts to the granules (generally about 0.1 to 1% by weight; cf. H. Sucker, P. Fuchs. P. Speiser: Pharmazeutische Technologie; Georg Thieme Verlag, Stuttgart (1991), pages 259-260).
- Known mold release agents for conventional processes are, for example, fatty acid esters or fatty acid salts, with only magnesium stearate normally being used in practice. Magnesium stearate is normally added to the granules which contain active ingredient and are ready before tabletting.
- In the production of drug forms by melt extrusion in conjunction with a tabletting process such as calendering, it is crucial that the melt does not adhere to the surfaces of the calender rolls because, otherwise, there is no release from the molds. It also has to be taken into account in calendering to produce tablets that the compression process in the calender results in tablets which have a typical fin which is formed at the interface of the pairs of molding rolls which are in contact only at the surface. Following the calendering, this fin must be removed mechanically, generally after cooling/hardening of the melt tablets, in order to provide the tablets with a homogeneous surface structure. The success of this deflashing depends crucially on the consistency of the cooled melt containing active ingredient. This means that despite the calendering being satisfactory (no adhesion of the melt in the calender), deflashing of the resulting tablets is not necessarily possible. Many polymers form thermoplastic melts even in the presence of large amounts of active ingredients and/or ancillary substances, and these are highly flexible after cooling and can be flexed over wide ranges without breakage. In these cases, removal of the fins is very difficult and often completely impossible, although there are no problems with the extrusion and the calendering too.
- Thus, it is crucial for the use of a formulation for producing tablets by melt extrusion/calendering that, besides the complete mixture having good thermoplasticity, in particular it is also possible to reduce the tendency to adhere during the calendering and control the plasticity of the cooled melt in order to ensure deflashing of the tablets.
- Melt-processable cellulose derivatives such as hydroxypropylcellulose are, as water-soluble polymers, very suitable for producing tablets by solvent-free melt extrusion/calendering. It is possible by admixture of other ancillary substances, eg. HPMC (hydroxypropylmethylcellulose) polymers which are swellable in water, to control the dissolution times of such tablets in the gastrointestinal tract, as is disclosed, for example, in DE-A 4226753.
- However, it has now been found that, in many cases when hydroxypropylcelluloses are used as water-soluble, thermoplastic polymer component, although the resulting melts can be extruded satisfactorily, they
- (a) in many cases showed an extreme tendency to adhere during the calendering,
- (b) did not permit removal of the fin because of excessive plasticity of the cooled melts (containing active ingredient) in the case of the calendered tablets, and
- (c) caused considerable problems in cleaning the extruders because of the great tendency of the melt to adhere.
- It is an object of the present invention to find aids which make it possible, especially when hydroxypropylcelluloses are used as matrix polymers in the production of drug forms by melt extrusion, to solve the abovementioned problems.
- We have found that this object is achieved by using lipids as mold release agents and lubricants in the production of drug forms by melt extrusion.
- The lipids which are suitable according to the invention are mono-, di- and triglycerides of naturally occurring fatty acids, for example glycerol monostearate, glycerol distearate, glycerol tristearate, glycerol tripalmitate, glycerol trimyristate, glycerol tribehenate, glycerol palmitate stearate or glyceride mixtures occurring in natural oils, preferably hydrogenated castor oil.
- Ceramides are furthermore also suitable for this purpose.
- Preferred lipids are, in particular, phospholipids, with phosphoglycerides such as lecithins being particularly preferred. Hydrogenated lecithins such as soybean and egg lecithins are very particularly preferred.
- The lipids can be used in amounts of 0.1- 10%, preferably 1-5%, of the total weight of the preparations containing active ingredient.
- The preparations containing active ingredient can contain as matrix polymers melt-processable polymers, for example
- polyvinylpyrrolidone,
- copolymers of N-vinylpyrrolidone and vinyl acetate with up to 50% by weight of vinyl acetate,
- carboxyalkylcelluloses such as carboxymethylcelluloses, alkylcelluloses such as methylcellulose,
- hydroxyalkylcelluloses such as hydroxymethyl-, hydroxyethyl-, hydroxypropyl- and hydroxybutylcellulose,
- hydroxyalkylcelluloses such as hydroxyethylmethyl- and hydroxypropylmethylcellulose, or mixtures thereof.
- Preferred polymers are hydroxypropylcelluloses and polymers based on vinylpyrrolidone.
- Suitable active ingredients are all active ingredients which do not decompose under the conditions of melt extrusion.
- The amount of the active component in the complete preparation can vary within wide limits depending on the activity and release rate. Thus, the content of active ingredient can be in the range from 0.1 to 90%, preferably from 0.5 to 60%, of the total weight of the preparation. The only condition is that the preparation is still melt-processable.
- The preparations may furthermore contain conventional pharmaceutical ancillary substances such as bulking agents, colorants, disintegrants or stabilizers in conventional amounts.
- Otherwise, the components are processed in a conventional way in extruders, preferably in single or twin screw extruders at a temperature in the range from 50 to 200° C. The shaping of the polymer melt which contains active ingredient and is free of solvent to give the preparations according to the invention can take place, for example, by calendering the extrudate and by converting the extrudate with rotating knives into pellets which have identical volumes and have a solidified surface but are still moldable, and subsequently compressing to tablets in conventional tabletting machines.
- It is possible to mix the ancillary substances into the melt or solution of active ingredients and polymers. It is furthermore possible to incorporate the ancillary substances together with the active ingredient into the polymer melt. In addition, mixtures of ancillary substances, the active ingredient and the polymers can be directly melted. It is generally customary for a physical mixture of ancillary substances, active ingredients and the polymers to be melted together.
- It has been found, surprisingly, that addition of even small amounts of lipids is able to prevent adhesion of the melts containing active ingredient.
- Addition of only 3% by weight of lecithin reduces the melt adhesion of the extruded composition so much that the formulations can be calendered without restrictions. The cleaning of the extruder to remove the otherwise viscous, highly adhesive melt residues is considerably simplified because lecithin-containing formulas show scarcely any adhesion to metal and can be removed en bloc from the metal parts of the extruder which are still hot after completion of the extrusion. The plasticity of the cooled melt is also beneficially affected so that deflashing of the tablets (removal of fins) takes place considerably better.
- All the tests were carried out in a twin screw extruder (ZSK-40 extruder from Werner und Pfleiderer, Stuttgart). The extruder comprised 4 heatable sections, and it was possible to heat the extruder head and the slit die separately. The temperature settings are to be found in the table. The extruded melt was discharged in the form of a strip 12-14 cm wide through a slit die and subsequently directly compressed to tablets in a molding calender consisting of a pair of counter-rotating molding rolls (coolable). The tablets had an elongate, rod-like shape (oblong tablets without bar). The raw materials listed in the table have previously been mixed in a gyro-wheel mixer and fed as mixture into the extruder via a weigh feeder delivering 20 to 30 kg/h. The extruder conveyor was operated in all cases at 100 to 150 rpm.
- For comparison purposes, formulations in which no lipid was used were processed. Although extrusion was possible in all these cases, calendering was not, because it was impossible to remove the tablets from the pairs of molding rolls in the calender. In addition, cleaning of the parts of the extruder coming into contact with the product was considerably more difficult in these cases (composition strongly adherent to metal surfaces) than with lipid-containing formulations.
TABLE 1 Ancillary Ex. Active ingredient Polymer substance Lipid Weight No. (a) (b) (c) (d) + (e) a:b:c:d:e T1 T2 T3 T4 TH TD 1 Verapamil HCl HPC HPMC-100 Cast. 46/29/20/5/0 80 100 100 100 100 100 2 Verapamil HCl HPC HPMC-100 Lec. 49/38/10/3/0 80 100 110 110 110 110 3 Verapamil HCl HPC HPMC-4 Lec. 48/32/18/3/0 80 100 110 110 110 110 4 Verapamil HCl HPC HPMC-4 Lec. 50/37/10/3/0 80 100 110 110 110 110 5 Vcrapamil HCl HPC HPMC-100 Lec. + cast. 50/35/10/2.5/2.5 80 100 110 110 110 110 6 Verapamil HCl HPC HPMC-100 Cast. 50/33/10/7/0 80 100 105 110 110 110 7 Nifedipine HPC HPMC-100 Lec. 7.7/69.3/20/3/0 90 110 100 110 110 115 8 Nifedipine HPC HPMC-100 Lec. 23.1/51.9/20/5/0 90 110 110 110 120 120 9 Nifedipine HPC HPMC-100 Cast. 23.1/51.9/20/5/0 90 110 120 120 120 120 10 1) HPC — — 20/80/0/0/0 140 140 140 140 140 130 11 1) HPC — — 21.9/78.1/0/0/0 140 140 140 140 140 130 12 Placebo HPC Mannitol — 0/60/40/0/0 90 120 100 100 120 120 13 Placebo HPC — — 0/100/0/0/0 100 120 110 120 120 120 14 1) HPC Mannitol Lec. 18.2/36.8/40/5/0 90 120 100 100 110 110 15 Placebo HPC Mannitol Lec. 0/55/40/5/0 90 120 100 100 120 120 16 1) HPC Mannitol Lec. 9/46/40/5/0 90 120 100 100 110 110 17 2) HPC HPMC-100 — 10.4/49.6/40/0/0 130 110 110 110 110 115 18 Placebo HPC HPMC-100 Lec. 0/58/40/2/0 90 110 100 110 110 110 19 2) HPC HPMC-100 Lec. 19.8/38.2/40/2/0 90 105 95 105 105 110 20 Placebo VA-64 Lactose Lec. 0/55/40/5/0 80 100 110 110 120 130
Claims (4)
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19531277A DE19531277A1 (en) | 1995-08-25 | 1995-08-25 | Use of lipids as an aid in the production of solid dosage forms by the melt extrusion process |
DE19531277 | 1995-08-25 | ||
DE19531277.5 | 1995-08-25 | ||
PCT/EP1996/003667 WO1997007786A2 (en) | 1995-08-25 | 1996-08-21 | Use of lipids as adjuvents in the production of solid medicinal forms by the melt extrusion process |
Publications (2)
Publication Number | Publication Date |
---|---|
US20010007664A1 true US20010007664A1 (en) | 2001-07-12 |
US6387401B2 US6387401B2 (en) | 2002-05-14 |
Family
ID=7770352
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/000,389 Expired - Lifetime US6387401B2 (en) | 1995-08-25 | 1996-08-21 | Use of lipids as adjuvents in the production of solid medicinal forms by the melt extrusion process |
Country Status (13)
Country | Link |
---|---|
US (1) | US6387401B2 (en) |
EP (1) | EP0845982B1 (en) |
AR (1) | AR003345A1 (en) |
AT (1) | ATE210970T1 (en) |
AU (1) | AU6875396A (en) |
BR (1) | BR9610234A (en) |
CA (1) | CA2227272C (en) |
DE (2) | DE19531277A1 (en) |
DK (1) | DK0845982T3 (en) |
ES (1) | ES2170259T3 (en) |
HR (1) | HRP960381A2 (en) |
WO (1) | WO1997007786A2 (en) |
ZA (1) | ZA967170B (en) |
Cited By (3)
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WO2005105039A1 (en) * | 2004-05-04 | 2005-11-10 | Boehringer Ingelheim International Gmbh | Solid pharmaceutical form comprising an ltb4 antagonist |
US20090050262A1 (en) * | 2005-02-17 | 2009-02-26 | Jorg Rosenberg | Production of Dosing Molds from Active Substance-Containing Melts |
US20100119597A1 (en) * | 1999-07-30 | 2010-05-13 | Clarke Allan J | Multi-component pharmaceutical dosage form |
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JP2002532389A (en) * | 1998-12-08 | 2002-10-02 | ファレス ファーマシューティカル リサーチ エヌブイ | Phospholipid composition |
DE19916383A1 (en) * | 1999-03-31 | 2000-10-05 | Schering Ag | Pharmaceutical composition with an extrusion |
US7364752B1 (en) | 1999-11-12 | 2008-04-29 | Abbott Laboratories | Solid dispersion pharamaceutical formulations |
EP1175205B1 (en) | 1999-11-12 | 2006-06-14 | Abbott Laboratories | Solid dispersion comprising ritonavir, fenofibrate or griseofulvin |
DE10026699A1 (en) * | 2000-05-30 | 2001-12-06 | Basf Ag | Formulation based on heparin, glycosaminoglycan or heparinoid and use of the formulation and the formulation base |
DE10026698A1 (en) * | 2000-05-30 | 2001-12-06 | Basf Ag | Self-emulsifying active ingredient formulation and use of this formulation |
US7842308B2 (en) * | 2001-01-30 | 2010-11-30 | Smithkline Beecham Limited | Pharmaceutical formulation |
US7883721B2 (en) | 2001-01-30 | 2011-02-08 | Smithkline Beecham Limited | Pharmaceutical formulation |
US20050175687A1 (en) * | 2001-01-30 | 2005-08-11 | Mcallister Stephen M. | Pharmaceutical formulations |
GB0102342D0 (en) | 2001-01-30 | 2001-03-14 | Smithkline Beecham Plc | Pharmaceutical formulation |
TW200526274A (en) | 2003-07-21 | 2005-08-16 | Smithkline Beecham Plc | Pharmaceutical formulations |
US8025899B2 (en) | 2003-08-28 | 2011-09-27 | Abbott Laboratories | Solid pharmaceutical dosage form |
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WO2005053656A1 (en) * | 2003-12-04 | 2005-06-16 | Pfizer Products Inc. | Spray-congeal process using an extruder for preparing multiparticulate crystalline drug compositions containing preferably a poloxamer and a glyceride |
AR048033A1 (en) * | 2004-03-12 | 2006-03-22 | Smithkline Beecham Plc | PHARMACEUTICAL COMPOSITION TO MOLD COMPONENTS THAT INCLUDE COPOLIMERO OF POLY (MET) ACRYLATE, COVER, CONNECTOR OR SPACER OF CAPSULA MOLDED BY INJECTION THAT HAS THE PHARMACEUTICAL COMPOSITION AND FORM OF PHARMACEUTICAL MULTI-COMPONENT COMPONENTS |
PL2200588T3 (en) * | 2007-09-25 | 2019-09-30 | Solubest Ltd. | Compositions comprising lipophilic active compounds and method for their preparation |
JP2011503048A (en) | 2007-11-08 | 2011-01-27 | グラクソ グループ リミテッド | Pharmaceutical formulation |
CN102119026A (en) * | 2008-06-13 | 2011-07-06 | 葛兰素集团有限公司 | Hydroxypropyl cellulose capsule shell |
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AT511581A1 (en) * | 2011-05-26 | 2012-12-15 | G L Pharma Gmbh | ORAL RETARDANT FORMULATION |
US9511028B2 (en) | 2012-05-01 | 2016-12-06 | Johnson & Johnson Consumer Inc. | Orally disintegrating tablet |
DE102017106216A1 (en) * | 2017-03-22 | 2018-09-27 | Amw Gmbh | Extruded depot form for sustained release of active ingredient |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
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FR2581541B1 (en) * | 1985-05-09 | 1988-05-20 | Rhone Poulenc Sante | NOVEL PHARMACEUTICAL COMPOSITIONS FOR THE EXTENDED RELEASE OF AN ACTIVE INGREDIENT AND THEIR PREPARATION METHOD |
DE4226753A1 (en) | 1992-08-13 | 1994-02-17 | Basf Ag | Preparations containing active substances in the form of solid particles |
EP0744941B1 (en) * | 1994-02-16 | 2003-06-04 | Abbott Laboratories | Process for preparing fine particle pharmaceutical formulations |
DE4413350A1 (en) * | 1994-04-18 | 1995-10-19 | Basf Ag | Retard matrix pellets and process for their production |
US5965161A (en) | 1994-11-04 | 1999-10-12 | Euro-Celtique, S.A. | Extruded multi-particulates |
DE19504832A1 (en) * | 1995-02-14 | 1996-08-22 | Basf Ag | Solid drug preparations |
-
1995
- 1995-08-25 DE DE19531277A patent/DE19531277A1/en not_active Withdrawn
-
1996
- 1996-08-20 HR HR19531277.5A patent/HRP960381A2/en not_active Application Discontinuation
- 1996-08-21 AU AU68753/96A patent/AU6875396A/en not_active Abandoned
- 1996-08-21 DE DE59608516T patent/DE59608516D1/en not_active Expired - Lifetime
- 1996-08-21 AT AT96929292T patent/ATE210970T1/en not_active IP Right Cessation
- 1996-08-21 ES ES96929292T patent/ES2170259T3/en not_active Expired - Lifetime
- 1996-08-21 CA CA002227272A patent/CA2227272C/en not_active Expired - Lifetime
- 1996-08-21 DK DK96929292T patent/DK0845982T3/en active
- 1996-08-21 WO PCT/EP1996/003667 patent/WO1997007786A2/en active IP Right Grant
- 1996-08-21 US US09/000,389 patent/US6387401B2/en not_active Expired - Lifetime
- 1996-08-21 BR BR9610234A patent/BR9610234A/en not_active Application Discontinuation
- 1996-08-21 EP EP96929292A patent/EP0845982B1/en not_active Expired - Lifetime
- 1996-08-23 AR ARP960104102A patent/AR003345A1/en unknown
- 1996-08-23 ZA ZA9607170A patent/ZA967170B/en unknown
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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US20100119597A1 (en) * | 1999-07-30 | 2010-05-13 | Clarke Allan J | Multi-component pharmaceutical dosage form |
US8440224B2 (en) | 1999-07-30 | 2013-05-14 | Capsugel Belgium Nv | Multi-component pharmaceutical dosage form |
WO2005105039A1 (en) * | 2004-05-04 | 2005-11-10 | Boehringer Ingelheim International Gmbh | Solid pharmaceutical form comprising an ltb4 antagonist |
US20070237823A1 (en) * | 2004-05-04 | 2007-10-11 | Thomas Bock | Solid Pharmaceutical Form Comprising and Ltb4 Antagonist |
JP2007536299A (en) * | 2004-05-04 | 2007-12-13 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Solid pharmaceutical form containing LTB4 antagonite |
US20090050262A1 (en) * | 2005-02-17 | 2009-02-26 | Jorg Rosenberg | Production of Dosing Molds from Active Substance-Containing Melts |
Also Published As
Publication number | Publication date |
---|---|
DK0845982T3 (en) | 2002-03-25 |
WO1997007786A3 (en) | 1997-04-03 |
DE19531277A1 (en) | 1997-02-27 |
AU6875396A (en) | 1997-03-19 |
BR9610234A (en) | 1999-06-29 |
AR003345A1 (en) | 1998-07-08 |
EP0845982B1 (en) | 2001-12-19 |
ATE210970T1 (en) | 2002-01-15 |
CA2227272A1 (en) | 1997-03-06 |
ZA967170B (en) | 1998-03-02 |
US6387401B2 (en) | 2002-05-14 |
WO1997007786A2 (en) | 1997-03-06 |
HRP960381A2 (en) | 1998-02-28 |
DE59608516D1 (en) | 2002-01-31 |
ES2170259T3 (en) | 2002-08-01 |
EP0845982A2 (en) | 1998-06-10 |
CA2227272C (en) | 2007-12-11 |
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