CA2229621A1 - Solid, at least two-phase formulations of an opioid analgesic with delayed release - Google Patents
Solid, at least two-phase formulations of an opioid analgesic with delayed release Download PDFInfo
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- CA2229621A1 CA2229621A1 CA 2229621 CA2229621A CA2229621A1 CA 2229621 A1 CA2229621 A1 CA 2229621A1 CA 2229621 CA2229621 CA 2229621 CA 2229621 A CA2229621 A CA 2229621A CA 2229621 A1 CA2229621 A1 CA 2229621A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
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- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
A solid, at least two-phase formulation of at least one opioid analgesic in a matrix, where each of the two phases contains at least one opioid with an in vitro release rate by the Ph.Eur.
paddle method of more than 50% by weight of active ingredient after one hour.
paddle method of more than 50% by weight of active ingredient after one hour.
Description
BASF AktlengesellsccAao222g62l 1998-o3-ll 0.Z. 0050/47837 Solid, at least two-phase formulations of an opioid analgesic with delayed release 5 Descripti~n The present invention relates to solid, at least two-phase form~ tions of at least one opioid analgesic, where each of the two phases contains at least one opioid, with an in vitro release 10 rate det~rm;ne~ by the Ph.Eur. paddle method of more than 50% by weight after one hour. The invention furthe --e relates to a process for producing such formulations.
Opioid drug forms disclosed to date release the active ingredient 15 either with no delay or with classical slowing of release. Such forms with classical slowing of release have either a coating which acts to slow release or contain a homogeneous phase of the active ingredient in an ancillary substance matrix. One-stage release profiles are accordingly achieved. However, the 20 disadvantage of classical slowing of release is that release o~
the active ingredient starts relatively slowly, which also results in delayed onset of the analgesic effect. Another disadvantage of slowing release by means of a coating is that dose dumping may occur if the coating is damaged by the - 25 peristalsis in the digestive tract. This may result in an init:ial dose so large as to be outside the therapeutic range.
Thus, EP-A 271 193 describes hydromorphone formulations for A~; n; stration twice a day which contain the active ingredient in 30 a matrix and with which up to 42.5% by weight of the active ingredient are released after one hour. Formulations of this t~rpe consist of a homogeneous phase.
EP-A 543 541 describes preparations of the active ingredient 35 flutamide which have a rapid release phase as outer shell and a core which has a release-slowing coating.
It is an object of the present invention to find drug forms which permit both a rapid rise in level of the active ingredient for 40 rapidly ~;m; n; ~hing severe pain and a slow release for pro~onged pain control.
we have found that this object is achieved by dosage forms which display at least biphasic release of the active ingredient. The 45 solid, at least two-phase drug forms for oral ~m; n; ~tration, where each phase comprises at least one opioid analgesic, show an in vitro release rate measured by the Ph.Eur. p~l~ method of ~CA 0222962l l998-03-ll ~ BASF Aktiengesellschaft 960833 O.Z. 0050/47837 more than 50% of the active ingredient after one hour. Preferred drug forms have a release rate of from 55 up to 80% after one hour, up to 85% a~ter two hours, 60 to 95% after four hours and from 65 to l00~ after eight hours. Particularly preferred release 5 rates are from 56 to 70% in the first hour. The drug forms are particularly in~en~ed for Al' ; n; ctration twice a day. Unless otherwise mentioned, the in vitro release rates are det~r~;ned by the Ph. Eur. paddle method at l00 rpm in 0.l N HCl at 37~C with W
detection at 270 nm.
Opioid analgesics for the purpose of this invention are:
morphine, codeine, ethylmorphine, dihydrocodeine, hydLc -rphone, oxycodone, hydroco~one, thebacon, levorphanol, pethidine, 15 ketobe~i~e, levomethadone, normethadone, fenpipramide, dextromoramide, clofenadol, pentazocine, tili~;ne~ naloxone, piritramide, fentanyl, nefopam, tramadol and buprenorphine or their physiologically tolerated salts.
20 Preferred opioids are:
codeine, dihydrocodeine, hydrocodone, hydromorphone, morphine, dihydromorphine, oxymorphone, tramadol or mixtures thereof.
Very particularly preferred opioids are selected from the group 25 of hydromorphone, morphine, tramadol or their physiologically tolerated salts.
The claimed drug forms comprise therapeutically effective amoun1s of the opioid active ingredients. In the case of tramadol, 50 -30 l000 mg of tramadol hydrochloride are employed per drug form,preferably l00 to 600 mg. This preferably comprises 5 - 50~ by weight in the IR phase and 50 - 95% by weight in the SR phase.
In the case of morphine or its physiologically tolerated salts 35 such as morphine sulfate or morphine hydrochloride, l0 mg, 30 mg, 60 mg, l00 mg, 200 mg or 500 mg of active ingredient are employe per drug form, preferably comprising l - 20% by weight in the I~.
phase and 80 - 99% by weight in the SR phase.
40 In the case of hydromorphone, the drug forms comprise l - 150 mg, preferably 2 - 60 mg, in particular 2 - 30 mg, preferably comprising l - 15% by weight in the IR phase and 85 - 99% by weight in the SR phase.
45 The drug forms consist of at least two phases, each phase comprising at least one opioid in a matrix. The opioids can be identical or different. The various phases each display a BASF Aktiengesellschaft 960833 O.Z. 0050/47837 different release profile, one phase being rapid release (IR
phase; instant release) and intended to achieve a rapid onset of the analgesic effect, while the other phase shows slow release (SR phase, sustained release), in order to achieve an additi~
5 prolonged effect.
The control of release can in each case be achieved by the composition of the matrix of the individual phases. This matrix can consist of low molecular weight ancillary substAnc~s and~or 10 polymeric binders. The release is not controlled by a release-slowing coating.
Rapid release matrices may, for example, be obt~;n~ by the following compositions of ancillary substances:
a) suitable polymeric binders are synthetic or semisynthetic polymers such as water-soluble homo- or copolymers of N-vinylpyrrolidone (NVP) with Fikentscher K values up to 30, with preferred comonomers being vinyl esters, especially vinyl acetate, also hydroxyalkylcelluloses such as hydroxypropylcellulose, alkylcelluloses such as ethylcellulose, as well as polyethylene glycols, preferably those having molecular weights of from 1000 to 20000. Also suitable are methacrylic acid copolymers (Eudragit types) 03 polyvinyl alcohol. Also suitable as binders are natural polymers such as starch or else starch derivatives such as hydroxyethyl starch, oxidized starches or pregelatini~e~
starches.
30 b) suitable bulking agents are sugars, for example lactose, glucose or sucrose, sugar alcohols such as maltitol, mannitol, sorbitol, xylitol and isomalt, also degraded starches such as dextrins, especially maltodextrin. Also suitable are microcrystalline cellulose or inorganic salts such as calcium phosphate, dicalcium phosphate or sodium chlorider and, where appropriate, also alkali metal carbonates such as Na2CO3.
c) suitable disintegrants are sodium starch glycolate, crosslinked polyvinylpyrrolidone, crosslinked carboxymethylcellulose, bentonites, alginates or croscarmellose.
. ., BA~F Aktiengesellschaft 960833 O.Z. 0050~47837 d) suitable water-soluble wetting agents or water-soluble surfactants are sodium lauryl sulfate, sorbitan fatty acid esters, salts of bile acids and similar phAr~ceu~ic~lly acceptable surface-active substances.
e) further phA ~eutical additives such as colors and~or - flavors.
The various components can be employed in the matrix in the lO following amounts:
a) 0 - 80% by weight b) 0 - 99% by weight c) 1 - 8% by weight 15 d) 0.1 - ~0% by weight e) 0.1 - 5~ by weight The stated amounts are based on the total amount of the ancillary substances ~a) to (e), with the amounts of a) and b) being chosen ~ 20 in each case so that the total amount of 100% by weight results.
The slow-release phase may comprise the following ingredients:
Suitable polymeric binders are:
A) soluble homo- and copolymers of NVP with K values from 10 l:o 100, preferred comonomers being vinyl esters such as vinyl propionate or, in particular, vinyl acetate, also polyvinyl alcohol, polyvinyl acetate, partially hydrolyzed polyvinyl acetate, s) alkylcelluloses such as methylcellulose or ethylce~tllo~e, hydroxyalkylcelluloses such as hydroxypropylcellulose, hydroxyethylcellulose, and hydroxypropylmethylcellulose, furthermore cellulose esters such as cellulose acetate, cellulose acetate propionate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate phthalate and uncrosslinked carboxymethylcellulose, C) methacrylic acid copolymers, with ethyl acrylate being preferred as comonomer, A~;noAlkyl methacrylate copolymers.
It is also possible to employ mixtures of polymers A), B) and/or 45 C), for example mixtures of 0 - 90% by weight of A), 10 - 70% by weight of B) and 0 - 20% by weight of C).
' BASF A~tiengesellschaft 960833 O.Z. 0050/47837 Each of the phases may furthermore contain additional pharmaceutical ancillary substances such as lubricants, fl~vor improvers, emulsifiers etc.
5 The drug forms may also comprise more than two opioid-cont~ining phases when a more pronounced gradation of the slow release is to be achieved. The drug forms may furthermore additionally contain nonopioid-cont~in;ng phases which may comprise other analgesics such as nonsteroidal antiinflammatory analgesics.
The drug forms according to the invention are preferably in the form of open multilayer tablets in which each phase forms a layer. The drug forms may also be in the form of closed 1~ in~ted tablets in which the rapid release phase forms the outer coati~g 15 while the core is formed by one or more slow-release phases.
Suitable multiphase drug forms are also inlay tablets (bull-eye tablets) or multiparticulate forms in which individual granule:~, pellets or other particles which correspond to the slow-release phase are incorporated into a rapid-release phase.
Suitable for producing the drug forms according to the invention are, inter alia, conventional tableting processes, for example processes in which the individual phases in each case are compressed together in the form of granules or pellets. In these 25 cases, the individual phases with their different release characteristics are ret~ine~ It is possible in this way to obtain monolayer or multilayer tablets.
The drug forms according to the invention are preferably produced 30 by a melt extrusion process, in which case the active ingredients are mixed with the ancillary substances in the melt and extruded through one or more dies or breaker plates, and then the still the ~plastic materials are subjected to shaping. This process is preferably carried out in the absence of solvents. Particularly 35 suitable for producing open or closed l~in~ted tablets is the coextrusion process in which the compositions int~n~e~ for the individual phases are melted and extruded separately, after which the still plastic strands, ribbons or layers are brought together and shaped. A coextrusion process of this type is described, for 40 example, in DE 195 39 361. Alternatively, it is also possible to produce multilayer tablets by combining melts in an injection molding process, applying successive layers in the mold, or by 2-component injection molding.
45 Production preferably takes place in twin-screw extruders with or without kneading disks.
= CA 0222962l l998-03-ll BASF ~ktiengesellschaft 960833 O.Z. 0050/47837 It is furthermore possible to incorporate one of the phases in solid form into the other phase in the form of a melt or a still plastic material. ~he precondition for this is that the solid phase does not dissolve in the melt, which can be achieved by 5 suitable choice of the ancillary substance, or by one matrix being coated or dusted with powder before incorporation into the other.
Solid, at least two-phase drug forms which can be produced by the lO process according to the invention are, in particular, tablets, preferably oblong tablets, coated tablets, pastilles or pelle1s.
The drug forms can also be provided with a taste-masking coatLng.
The opioid drug forms obtained according to the invention 15 display, because they are composed of a rapid-release phase and at least one slow-release phase, release kinetics which are particularly desirable for strong analgesics. Forms of this type can be produced particularly straightforwardly and reliably by the process according to the invention.
A~; ni ~tration of the dosage forms according to the invention achieves not only a rapid onset of the analgesic effect but also a long-lasting pain control. It was surprising that plasma le~els in the pain-relevant range could be achieved even after 5 h.
In the case of tramadol, blood plasma levels of 90 - 200 mg~ml, preferably lO0 - 180 mg/ml, particularly preferably llO -165 mg/ml, are achieved 5 hours after a single ~l~nin;~tration under fasting conditions.
The compositions mentioned in the following Examples are preferably coextruded in a Werner ~ Pfleiderer ZSK 30 twin-screw extruder with an output of 2 kg/hour in each case. The shaping of the still plastic extrudate takes place as described in EP-A 240 35 906 by calendering.
Formulation l:
Extruder l:
l kg of a mixture of 40% by weight of tramadol HCl, 15% by weight of ethylcellulose (Ethocel NlO0), 35% by weight of isomalt, 7% by weight of polyvinylpyrrolidone K30 and 3% by weight of hydrogenated castor oil (Cutina HR) were mixed in a twin-screw 45 extruder.
BASF AktiengesellscAao~t2962l 9998-o3-11 O.Z. 0050/47837 Section t~reratures: 44, 80, 121, 99, 92, 82 ~C
Die: 80 ~C
Extruder 2:
1 kg of a mixture of 35% by weight of tramadol HCl, 34~ by weight of hydroxypropylmethylcellulose (Methocel RlOOM) and 31% by weight of hydroxypropylcellulose (Klucel EF) were mixed in twin-screw extruder.
Section temr~ratures: 44, 80, 121, 99, 92, 8Z~C
Die: 80 ~C
The drug forms displayed the following in vitro release.
Time in minutes % by weight of active ingredient relea$ed 71.9 120 81.9 180 87.9 300 95.6 360 97.0 480 98.0 3 Example 2:
Extruder 1:
1 kg of a mixture of 40% by weight of tramadol HCl, 15% by weight of ethylcellulose, 35% by weight of isomalt, 7~ by weight of polyvinylpyrrolidone K30 and 3% by weight of hydrogenated castor oil were mixed in a twin-screw extruder.
Section t~ _~ratures 44, 80, 121, 99, 92, 82 ~C
Die: 80~C
Extruder 2:
. ., 1 kg of a mixture of 52% by weight of tramadol HCl, 36~ by weigllt of hydroxypropylmethylce~lulose and 12% by weight of hydroxypropylcellulose were mixed in a twin-screw extruder.
BASF Aktiengesellschaft 960833 O.Z. 0050/47837 Section temperatures: 43, 78, 123, 124, 131, 131 ~C
Die: 131~C
The tablets displayed the following in vitro release:
Time in minutes% by weight of active ingredient 58.5 120 70.4 180 81.3 240 88.8 300 93.8 360 96.2 480 97,5 20 The release rate was measured by the Ph.Eur. paddle method in 0.1 N HCl at 100 rpm und 37 ~C with UV detection at 270 nm.
-
Opioid drug forms disclosed to date release the active ingredient 15 either with no delay or with classical slowing of release. Such forms with classical slowing of release have either a coating which acts to slow release or contain a homogeneous phase of the active ingredient in an ancillary substance matrix. One-stage release profiles are accordingly achieved. However, the 20 disadvantage of classical slowing of release is that release o~
the active ingredient starts relatively slowly, which also results in delayed onset of the analgesic effect. Another disadvantage of slowing release by means of a coating is that dose dumping may occur if the coating is damaged by the - 25 peristalsis in the digestive tract. This may result in an init:ial dose so large as to be outside the therapeutic range.
Thus, EP-A 271 193 describes hydromorphone formulations for A~; n; stration twice a day which contain the active ingredient in 30 a matrix and with which up to 42.5% by weight of the active ingredient are released after one hour. Formulations of this t~rpe consist of a homogeneous phase.
EP-A 543 541 describes preparations of the active ingredient 35 flutamide which have a rapid release phase as outer shell and a core which has a release-slowing coating.
It is an object of the present invention to find drug forms which permit both a rapid rise in level of the active ingredient for 40 rapidly ~;m; n; ~hing severe pain and a slow release for pro~onged pain control.
we have found that this object is achieved by dosage forms which display at least biphasic release of the active ingredient. The 45 solid, at least two-phase drug forms for oral ~m; n; ~tration, where each phase comprises at least one opioid analgesic, show an in vitro release rate measured by the Ph.Eur. p~l~ method of ~CA 0222962l l998-03-ll ~ BASF Aktiengesellschaft 960833 O.Z. 0050/47837 more than 50% of the active ingredient after one hour. Preferred drug forms have a release rate of from 55 up to 80% after one hour, up to 85% a~ter two hours, 60 to 95% after four hours and from 65 to l00~ after eight hours. Particularly preferred release 5 rates are from 56 to 70% in the first hour. The drug forms are particularly in~en~ed for Al' ; n; ctration twice a day. Unless otherwise mentioned, the in vitro release rates are det~r~;ned by the Ph. Eur. paddle method at l00 rpm in 0.l N HCl at 37~C with W
detection at 270 nm.
Opioid analgesics for the purpose of this invention are:
morphine, codeine, ethylmorphine, dihydrocodeine, hydLc -rphone, oxycodone, hydroco~one, thebacon, levorphanol, pethidine, 15 ketobe~i~e, levomethadone, normethadone, fenpipramide, dextromoramide, clofenadol, pentazocine, tili~;ne~ naloxone, piritramide, fentanyl, nefopam, tramadol and buprenorphine or their physiologically tolerated salts.
20 Preferred opioids are:
codeine, dihydrocodeine, hydrocodone, hydromorphone, morphine, dihydromorphine, oxymorphone, tramadol or mixtures thereof.
Very particularly preferred opioids are selected from the group 25 of hydromorphone, morphine, tramadol or their physiologically tolerated salts.
The claimed drug forms comprise therapeutically effective amoun1s of the opioid active ingredients. In the case of tramadol, 50 -30 l000 mg of tramadol hydrochloride are employed per drug form,preferably l00 to 600 mg. This preferably comprises 5 - 50~ by weight in the IR phase and 50 - 95% by weight in the SR phase.
In the case of morphine or its physiologically tolerated salts 35 such as morphine sulfate or morphine hydrochloride, l0 mg, 30 mg, 60 mg, l00 mg, 200 mg or 500 mg of active ingredient are employe per drug form, preferably comprising l - 20% by weight in the I~.
phase and 80 - 99% by weight in the SR phase.
40 In the case of hydromorphone, the drug forms comprise l - 150 mg, preferably 2 - 60 mg, in particular 2 - 30 mg, preferably comprising l - 15% by weight in the IR phase and 85 - 99% by weight in the SR phase.
45 The drug forms consist of at least two phases, each phase comprising at least one opioid in a matrix. The opioids can be identical or different. The various phases each display a BASF Aktiengesellschaft 960833 O.Z. 0050/47837 different release profile, one phase being rapid release (IR
phase; instant release) and intended to achieve a rapid onset of the analgesic effect, while the other phase shows slow release (SR phase, sustained release), in order to achieve an additi~
5 prolonged effect.
The control of release can in each case be achieved by the composition of the matrix of the individual phases. This matrix can consist of low molecular weight ancillary substAnc~s and~or 10 polymeric binders. The release is not controlled by a release-slowing coating.
Rapid release matrices may, for example, be obt~;n~ by the following compositions of ancillary substances:
a) suitable polymeric binders are synthetic or semisynthetic polymers such as water-soluble homo- or copolymers of N-vinylpyrrolidone (NVP) with Fikentscher K values up to 30, with preferred comonomers being vinyl esters, especially vinyl acetate, also hydroxyalkylcelluloses such as hydroxypropylcellulose, alkylcelluloses such as ethylcellulose, as well as polyethylene glycols, preferably those having molecular weights of from 1000 to 20000. Also suitable are methacrylic acid copolymers (Eudragit types) 03 polyvinyl alcohol. Also suitable as binders are natural polymers such as starch or else starch derivatives such as hydroxyethyl starch, oxidized starches or pregelatini~e~
starches.
30 b) suitable bulking agents are sugars, for example lactose, glucose or sucrose, sugar alcohols such as maltitol, mannitol, sorbitol, xylitol and isomalt, also degraded starches such as dextrins, especially maltodextrin. Also suitable are microcrystalline cellulose or inorganic salts such as calcium phosphate, dicalcium phosphate or sodium chlorider and, where appropriate, also alkali metal carbonates such as Na2CO3.
c) suitable disintegrants are sodium starch glycolate, crosslinked polyvinylpyrrolidone, crosslinked carboxymethylcellulose, bentonites, alginates or croscarmellose.
. ., BA~F Aktiengesellschaft 960833 O.Z. 0050~47837 d) suitable water-soluble wetting agents or water-soluble surfactants are sodium lauryl sulfate, sorbitan fatty acid esters, salts of bile acids and similar phAr~ceu~ic~lly acceptable surface-active substances.
e) further phA ~eutical additives such as colors and~or - flavors.
The various components can be employed in the matrix in the lO following amounts:
a) 0 - 80% by weight b) 0 - 99% by weight c) 1 - 8% by weight 15 d) 0.1 - ~0% by weight e) 0.1 - 5~ by weight The stated amounts are based on the total amount of the ancillary substances ~a) to (e), with the amounts of a) and b) being chosen ~ 20 in each case so that the total amount of 100% by weight results.
The slow-release phase may comprise the following ingredients:
Suitable polymeric binders are:
A) soluble homo- and copolymers of NVP with K values from 10 l:o 100, preferred comonomers being vinyl esters such as vinyl propionate or, in particular, vinyl acetate, also polyvinyl alcohol, polyvinyl acetate, partially hydrolyzed polyvinyl acetate, s) alkylcelluloses such as methylcellulose or ethylce~tllo~e, hydroxyalkylcelluloses such as hydroxypropylcellulose, hydroxyethylcellulose, and hydroxypropylmethylcellulose, furthermore cellulose esters such as cellulose acetate, cellulose acetate propionate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate phthalate and uncrosslinked carboxymethylcellulose, C) methacrylic acid copolymers, with ethyl acrylate being preferred as comonomer, A~;noAlkyl methacrylate copolymers.
It is also possible to employ mixtures of polymers A), B) and/or 45 C), for example mixtures of 0 - 90% by weight of A), 10 - 70% by weight of B) and 0 - 20% by weight of C).
' BASF A~tiengesellschaft 960833 O.Z. 0050/47837 Each of the phases may furthermore contain additional pharmaceutical ancillary substances such as lubricants, fl~vor improvers, emulsifiers etc.
5 The drug forms may also comprise more than two opioid-cont~ining phases when a more pronounced gradation of the slow release is to be achieved. The drug forms may furthermore additionally contain nonopioid-cont~in;ng phases which may comprise other analgesics such as nonsteroidal antiinflammatory analgesics.
The drug forms according to the invention are preferably in the form of open multilayer tablets in which each phase forms a layer. The drug forms may also be in the form of closed 1~ in~ted tablets in which the rapid release phase forms the outer coati~g 15 while the core is formed by one or more slow-release phases.
Suitable multiphase drug forms are also inlay tablets (bull-eye tablets) or multiparticulate forms in which individual granule:~, pellets or other particles which correspond to the slow-release phase are incorporated into a rapid-release phase.
Suitable for producing the drug forms according to the invention are, inter alia, conventional tableting processes, for example processes in which the individual phases in each case are compressed together in the form of granules or pellets. In these 25 cases, the individual phases with their different release characteristics are ret~ine~ It is possible in this way to obtain monolayer or multilayer tablets.
The drug forms according to the invention are preferably produced 30 by a melt extrusion process, in which case the active ingredients are mixed with the ancillary substances in the melt and extruded through one or more dies or breaker plates, and then the still the ~plastic materials are subjected to shaping. This process is preferably carried out in the absence of solvents. Particularly 35 suitable for producing open or closed l~in~ted tablets is the coextrusion process in which the compositions int~n~e~ for the individual phases are melted and extruded separately, after which the still plastic strands, ribbons or layers are brought together and shaped. A coextrusion process of this type is described, for 40 example, in DE 195 39 361. Alternatively, it is also possible to produce multilayer tablets by combining melts in an injection molding process, applying successive layers in the mold, or by 2-component injection molding.
45 Production preferably takes place in twin-screw extruders with or without kneading disks.
= CA 0222962l l998-03-ll BASF ~ktiengesellschaft 960833 O.Z. 0050/47837 It is furthermore possible to incorporate one of the phases in solid form into the other phase in the form of a melt or a still plastic material. ~he precondition for this is that the solid phase does not dissolve in the melt, which can be achieved by 5 suitable choice of the ancillary substance, or by one matrix being coated or dusted with powder before incorporation into the other.
Solid, at least two-phase drug forms which can be produced by the lO process according to the invention are, in particular, tablets, preferably oblong tablets, coated tablets, pastilles or pelle1s.
The drug forms can also be provided with a taste-masking coatLng.
The opioid drug forms obtained according to the invention 15 display, because they are composed of a rapid-release phase and at least one slow-release phase, release kinetics which are particularly desirable for strong analgesics. Forms of this type can be produced particularly straightforwardly and reliably by the process according to the invention.
A~; ni ~tration of the dosage forms according to the invention achieves not only a rapid onset of the analgesic effect but also a long-lasting pain control. It was surprising that plasma le~els in the pain-relevant range could be achieved even after 5 h.
In the case of tramadol, blood plasma levels of 90 - 200 mg~ml, preferably lO0 - 180 mg/ml, particularly preferably llO -165 mg/ml, are achieved 5 hours after a single ~l~nin;~tration under fasting conditions.
The compositions mentioned in the following Examples are preferably coextruded in a Werner ~ Pfleiderer ZSK 30 twin-screw extruder with an output of 2 kg/hour in each case. The shaping of the still plastic extrudate takes place as described in EP-A 240 35 906 by calendering.
Formulation l:
Extruder l:
l kg of a mixture of 40% by weight of tramadol HCl, 15% by weight of ethylcellulose (Ethocel NlO0), 35% by weight of isomalt, 7% by weight of polyvinylpyrrolidone K30 and 3% by weight of hydrogenated castor oil (Cutina HR) were mixed in a twin-screw 45 extruder.
BASF AktiengesellscAao~t2962l 9998-o3-11 O.Z. 0050/47837 Section t~reratures: 44, 80, 121, 99, 92, 82 ~C
Die: 80 ~C
Extruder 2:
1 kg of a mixture of 35% by weight of tramadol HCl, 34~ by weight of hydroxypropylmethylcellulose (Methocel RlOOM) and 31% by weight of hydroxypropylcellulose (Klucel EF) were mixed in twin-screw extruder.
Section temr~ratures: 44, 80, 121, 99, 92, 8Z~C
Die: 80 ~C
The drug forms displayed the following in vitro release.
Time in minutes % by weight of active ingredient relea$ed 71.9 120 81.9 180 87.9 300 95.6 360 97.0 480 98.0 3 Example 2:
Extruder 1:
1 kg of a mixture of 40% by weight of tramadol HCl, 15% by weight of ethylcellulose, 35% by weight of isomalt, 7~ by weight of polyvinylpyrrolidone K30 and 3% by weight of hydrogenated castor oil were mixed in a twin-screw extruder.
Section t~ _~ratures 44, 80, 121, 99, 92, 82 ~C
Die: 80~C
Extruder 2:
. ., 1 kg of a mixture of 52% by weight of tramadol HCl, 36~ by weigllt of hydroxypropylmethylce~lulose and 12% by weight of hydroxypropylcellulose were mixed in a twin-screw extruder.
BASF Aktiengesellschaft 960833 O.Z. 0050/47837 Section temperatures: 43, 78, 123, 124, 131, 131 ~C
Die: 131~C
The tablets displayed the following in vitro release:
Time in minutes% by weight of active ingredient 58.5 120 70.4 180 81.3 240 88.8 300 93.8 360 96.2 480 97,5 20 The release rate was measured by the Ph.Eur. paddle method in 0.1 N HCl at 100 rpm und 37 ~C with UV detection at 270 nm.
-
Claims (5)
1. A solid, at least two-phase formulation of at least one opioid analgesic in a matrix, where each of the two phases contains at least one opioid with an in vitro release rate by the Ph.Eur. paddle method of more than 50% by weight of active ingredient after one hour.
2. A formulation as claimed in claim 1, having a release rate of 55-80% by weight of active ingredient after one hour, 58-85% by weight after two hours, 60-95% by weight after four hours and 65-100% by weight after eight hours.
3. A formulation as claimed in claim 1, comprising a rapid-release phase and a slow-release phase.
4. A formulation as claimed in claim 1, comprising as opioid hydromorphone, morphine, tramadol or their physiologically tolerated salts.
5. A process for producing a formulation as claimed in any of claims 1 to 4, which comprises the ingredients of each of the phases being separately melted in an extruder, coextruded and shaped to drug forms.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1997110008 DE19710008A1 (en) | 1997-03-12 | 1997-03-12 | Solid, at least two-phase formulations of a sustained-release opioid analgesic |
| DE19710008.2 | 1997-03-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2229621A1 true CA2229621A1 (en) | 1998-09-12 |
Family
ID=7822982
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2229621 Abandoned CA2229621A1 (en) | 1997-03-12 | 1998-03-11 | Solid, at least two-phase formulations of an opioid analgesic with delayed release |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0864325A3 (en) |
| JP (1) | JPH10251149A (en) |
| CA (1) | CA2229621A1 (en) |
| DE (1) | DE19710008A1 (en) |
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|---|---|---|---|---|
| ATE107857T1 (en) * | 1986-06-10 | 1994-07-15 | Euro Celtique Sa | COMPOSITION WITH CONTROLLED RELEASE OF DIHYDROCODEINE. |
| GB8626098D0 (en) * | 1986-10-31 | 1986-12-03 | Euro Celtique Sa | Controlled release hydromorphone composition |
| US5162117A (en) * | 1991-11-22 | 1992-11-10 | Schering Corporation | Controlled release flutamide composition |
| US5266331A (en) * | 1991-11-27 | 1993-11-30 | Euroceltique, S.A. | Controlled release oxycodone compositions |
| IL109460A (en) * | 1993-05-10 | 1998-03-10 | Euro Celtique Sa | Controlled release formulation comprising tramadol |
| US6159501A (en) * | 1996-03-08 | 2000-12-12 | Nycomed Danmark A/S | Modified release multiple-units dosage composition for release of opioid compounds |
-
1997
- 1997-03-12 DE DE1997110008 patent/DE19710008A1/en not_active Withdrawn
-
1998
- 1998-03-06 EP EP98104001A patent/EP0864325A3/en not_active Withdrawn
- 1998-03-11 CA CA 2229621 patent/CA2229621A1/en not_active Abandoned
- 1998-03-12 JP JP6096198A patent/JPH10251149A/en not_active Withdrawn
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Also Published As
| Publication number | Publication date |
|---|---|
| DE19710008A1 (en) | 1998-09-17 |
| JPH10251149A (en) | 1998-09-22 |
| EP0864325A3 (en) | 1998-12-30 |
| EP0864325A2 (en) | 1998-09-16 |
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