CA2359381A1 - Medicament forms having controlled release and containing active substances which easily dissolve in water - Google Patents
Medicament forms having controlled release and containing active substances which easily dissolve in water Download PDFInfo
- Publication number
- CA2359381A1 CA2359381A1 CA002359381A CA2359381A CA2359381A1 CA 2359381 A1 CA2359381 A1 CA 2359381A1 CA 002359381 A CA002359381 A CA 002359381A CA 2359381 A CA2359381 A CA 2359381A CA 2359381 A1 CA2359381 A1 CA 2359381A1
- Authority
- CA
- Canada
- Prior art keywords
- drug form
- controlled release
- active ingredient
- water
- active substances
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to a medicament form containing an active substance with a water-solubility, according to USP, ranging from 23 to 30 in a matrix that is based on acrylate polymers, whereby the medicament form can be obtained by melt extrusion.
Description
MEDICAMENT FORMS HAVING CONTROLLED RELEASE AND CONTAINING
ACTIVE SUBSTANCES WHICH EASILY DISSOLVE IN WATER
The present invention relates to drug forms with controlled release comprising active ingredients with a water solubility as defined in USP of up to 30 in a matrix based on acrylate polymers, which are obtained by melt extrusion.
It is generally known that controlled release, in particular slow linear release, is problematic in the case of active ingredients with good water solubility. In particular, slow release of metoprolol tartrate is difficult by conventional means.
EP-A 240 904 discloses that it is possible to produce drug forms by melt extrusion.
It is an object of the present invention to find drug forms which make controlled release possible for active ingredients with good water solubility.
We have found that this object is achieved by tie drug forms defined at the outset.
Active ingredients with good water solubility-according to the invention are those having a water solubility as defined in USP
23 of from l to 10 (freely soluble) -or 10 to 30.-(soluble), preferably less than 1 (very soluble). Th~2 numbers relate to the number of parts of solvent required per part of substance to be dissolved.
Preferred active ingredients are metoprolol and its salts;
particularly preferably metoprolol tartrate.
The active ingredients are homogeneously dispersed or dissolved in the form pf a solid solution in a matrix based on acrylate polymers during the melt extrusion. The active ingredient is preferably present in the matrix in X-ray amorphous form. It is particularly' preferred for solid solutions of the active ingredient to be obtained.
Particularly suitable acrylate polymers are swellable polymers of la the Eudragit~ type. Examples of suitable polymers are methacrylic acid copolymers (Eudragit L types) such as 1:1 methacrylic acid/ethyl acrylate copolymers M 250,000, 1:1 methacrylic acid/methyl methacrylate copolymers M 135,000, 1:2 methacrylic acid/methyl methacrylate copolymers M 135,000 or Knoll AG 990049 O.Z. 0480/01206 D8 dimethylaminoethyl methacrylate copolymers (Eudragit E) such as poly(1:2 butyl methacrylate/2-dimethylaminoethyl methacrylate) Mt 150,000. The methacrylic ester copolymers which swell pH-independently (Eudragit NE) are preferred, such as 2:1 ethyl acrylate/methyl methacrylate copolymer M 800,000, particularly preferably 2:1 methyl methacrylate/ethyl acrylate copolymer with 5 or 10% trimethylammoniomethyl methacrylate chloride (Eudragit RS and RL types)M 150,000.
It is also possible to use mixtures of said polymers.
The amounts of active ingredient and acrylate polymers are chosen so that the drug forms comprise from 1 to 50% by weight, preferably 10 to 30% by weight, of active ingredient.
Particularly suitable formulations are those comprising from 1 to 80, preferably 10 to 40, % by weight of Eudragit RL and from 1 to 50, preferably 5 to 20, % by weight of Eudragit RS.
The matrix may additionally comprise further polymers, for w a0 example homo- or copolymers of N=yinylpyrrolidone such as .... , povidone or copovidone 6:4 or, preferably, cellulose ethers such as hydroxypropylmethylcellulose, ethylcellulose or . .
hydroxypropylcellulose.
Tt is also possible to add other conventional pharmaceutical ancillary substances for additional slowing of release. These include, in particular, water-repellent ancillary substances such 'as lipids or salts thereof, for e:eample stearic acid, palmitic acid, hydrogenated ricinoleic acid or the like, preferably magnesium stearate.
The preparations may additionally contain other conventional pharmaceutical ancillary substances in the amounts customary for this purpose, for example stabilizers, antioxidants, colorings, flavorings or bulking agents, such as highly disperse silica, or lubricants.
The preparations according to the invention are produced by mixing the components with use of shear forces and input of thermal energy. The mixing preferably takes place in a single screw or multiscrew extruder, particularly preferably a twin screw extruder. Input of thermal energy produces a melt of the components of the mixture. This normally takes place by heating the extruder jacket to temperatures in the range from 50 to 180, preferably 80 to 130°C. The active ingredient can be mixed with the other components before or after the melting of the polymeric Knoll AG 990049 O.Z. 0480/01206 D8 binder. The melts are solvent-free. This means that no water or organic solvent is added.
The molten mixture of the components is conveyed by the screw movement toward the extruder outlet, which preferably consists of a die. After extrusion through the die, the still plastic composition is shaped to suitable drug forms.
Suitable drug forms are preferably tablets, in particular bolus tablets, lenticular tablets or oblong tablets.
Tablets are preferably produced by the process described in EP-A 240 906, by passing the still plastic extrudate between two rolls driven in opposite directions with mutually opposing depressions in the surface of the rolls. It is also possible, by appropriate choice of the shape of these depressions, to obtain tablets with scores. Granules or pellets can be obtained by cold cut or, preferably, by hot cut.
The drug forms can additionally be provided with coatings.~known per se and having no effect on the release characteristics.
It is surprisingly possible by the combination according to .the invention of melt extrusion with an appropriate formulation based on acrylate polymers to produce drug forms with controlled release even for active ingredients with good water solubility.
It was. in particular not to be expected that-siow-release metoprolol tartrate preparations which, in terms of their release, are bioequivalent to the metoprolol succinate-containing marketed product Beloc-ZOK~ can be obtained in a simple manner by melt extrusion with an appropriate formula..
Examples The tablets were produced by extruding the mixtures listed in the following table in a corotating twin screw extruder of the Werner & Pfleiderer ZKS-40 type and subsequent calendering to oblong tablets weighing 500 mg by the process described in EP-A 240 906.
Extruder temperature profile:
Feed section: 20 to 25~C, section 1: 80~C, section 2: 110~C, section 3: 110~C, section 4: 130~C, die: 130~C. The speed of rotation was 110 rpm; the output was 15 kg/h. The tablets were then coated with an amount of 15 mg per tablet. Composition of the coating:
,, Kaoll AG 990049 O.Z. 0480/01206 D~
ACTIVE SUBSTANCES WHICH EASILY DISSOLVE IN WATER
The present invention relates to drug forms with controlled release comprising active ingredients with a water solubility as defined in USP of up to 30 in a matrix based on acrylate polymers, which are obtained by melt extrusion.
It is generally known that controlled release, in particular slow linear release, is problematic in the case of active ingredients with good water solubility. In particular, slow release of metoprolol tartrate is difficult by conventional means.
EP-A 240 904 discloses that it is possible to produce drug forms by melt extrusion.
It is an object of the present invention to find drug forms which make controlled release possible for active ingredients with good water solubility.
We have found that this object is achieved by tie drug forms defined at the outset.
Active ingredients with good water solubility-according to the invention are those having a water solubility as defined in USP
23 of from l to 10 (freely soluble) -or 10 to 30.-(soluble), preferably less than 1 (very soluble). Th~2 numbers relate to the number of parts of solvent required per part of substance to be dissolved.
Preferred active ingredients are metoprolol and its salts;
particularly preferably metoprolol tartrate.
The active ingredients are homogeneously dispersed or dissolved in the form pf a solid solution in a matrix based on acrylate polymers during the melt extrusion. The active ingredient is preferably present in the matrix in X-ray amorphous form. It is particularly' preferred for solid solutions of the active ingredient to be obtained.
Particularly suitable acrylate polymers are swellable polymers of la the Eudragit~ type. Examples of suitable polymers are methacrylic acid copolymers (Eudragit L types) such as 1:1 methacrylic acid/ethyl acrylate copolymers M 250,000, 1:1 methacrylic acid/methyl methacrylate copolymers M 135,000, 1:2 methacrylic acid/methyl methacrylate copolymers M 135,000 or Knoll AG 990049 O.Z. 0480/01206 D8 dimethylaminoethyl methacrylate copolymers (Eudragit E) such as poly(1:2 butyl methacrylate/2-dimethylaminoethyl methacrylate) Mt 150,000. The methacrylic ester copolymers which swell pH-independently (Eudragit NE) are preferred, such as 2:1 ethyl acrylate/methyl methacrylate copolymer M 800,000, particularly preferably 2:1 methyl methacrylate/ethyl acrylate copolymer with 5 or 10% trimethylammoniomethyl methacrylate chloride (Eudragit RS and RL types)M 150,000.
It is also possible to use mixtures of said polymers.
The amounts of active ingredient and acrylate polymers are chosen so that the drug forms comprise from 1 to 50% by weight, preferably 10 to 30% by weight, of active ingredient.
Particularly suitable formulations are those comprising from 1 to 80, preferably 10 to 40, % by weight of Eudragit RL and from 1 to 50, preferably 5 to 20, % by weight of Eudragit RS.
The matrix may additionally comprise further polymers, for w a0 example homo- or copolymers of N=yinylpyrrolidone such as .... , povidone or copovidone 6:4 or, preferably, cellulose ethers such as hydroxypropylmethylcellulose, ethylcellulose or . .
hydroxypropylcellulose.
Tt is also possible to add other conventional pharmaceutical ancillary substances for additional slowing of release. These include, in particular, water-repellent ancillary substances such 'as lipids or salts thereof, for e:eample stearic acid, palmitic acid, hydrogenated ricinoleic acid or the like, preferably magnesium stearate.
The preparations may additionally contain other conventional pharmaceutical ancillary substances in the amounts customary for this purpose, for example stabilizers, antioxidants, colorings, flavorings or bulking agents, such as highly disperse silica, or lubricants.
The preparations according to the invention are produced by mixing the components with use of shear forces and input of thermal energy. The mixing preferably takes place in a single screw or multiscrew extruder, particularly preferably a twin screw extruder. Input of thermal energy produces a melt of the components of the mixture. This normally takes place by heating the extruder jacket to temperatures in the range from 50 to 180, preferably 80 to 130°C. The active ingredient can be mixed with the other components before or after the melting of the polymeric Knoll AG 990049 O.Z. 0480/01206 D8 binder. The melts are solvent-free. This means that no water or organic solvent is added.
The molten mixture of the components is conveyed by the screw movement toward the extruder outlet, which preferably consists of a die. After extrusion through the die, the still plastic composition is shaped to suitable drug forms.
Suitable drug forms are preferably tablets, in particular bolus tablets, lenticular tablets or oblong tablets.
Tablets are preferably produced by the process described in EP-A 240 906, by passing the still plastic extrudate between two rolls driven in opposite directions with mutually opposing depressions in the surface of the rolls. It is also possible, by appropriate choice of the shape of these depressions, to obtain tablets with scores. Granules or pellets can be obtained by cold cut or, preferably, by hot cut.
The drug forms can additionally be provided with coatings.~known per se and having no effect on the release characteristics.
It is surprisingly possible by the combination according to .the invention of melt extrusion with an appropriate formulation based on acrylate polymers to produce drug forms with controlled release even for active ingredients with good water solubility.
It was. in particular not to be expected that-siow-release metoprolol tartrate preparations which, in terms of their release, are bioequivalent to the metoprolol succinate-containing marketed product Beloc-ZOK~ can be obtained in a simple manner by melt extrusion with an appropriate formula..
Examples The tablets were produced by extruding the mixtures listed in the following table in a corotating twin screw extruder of the Werner & Pfleiderer ZKS-40 type and subsequent calendering to oblong tablets weighing 500 mg by the process described in EP-A 240 906.
Extruder temperature profile:
Feed section: 20 to 25~C, section 1: 80~C, section 2: 110~C, section 3: 110~C, section 4: 130~C, die: 130~C. The speed of rotation was 110 rpm; the output was 15 kg/h. The tablets were then coated with an amount of 15 mg per tablet. Composition of the coating:
,, Kaoll AG 990049 O.Z. 0480/01206 D~
Hydroxypropylmethylcellulose 2920 6cp 58.04 Talc 4.10 Polyethylene glycol 400 9.00 Titanium dioxide 15.43 Hydroxypropylmethylcellulose l5cp 5.76 Hydroxypropylcellulose 5.76 Polyethylene glycol 6000 1.61 Highly disperse silica 0.15 Sodium docusate 0.15 The in vitro release was determined in accordance with USP 23 in a paddle apparatus at 100 rpm in simulated intestinal fluid at pH
6.8, no-change, 24 h.
ao : ...:
a5 . Kaoll AG 990049 O.Z. 0480/01206 DE
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~ ~
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, J-1~ ~i r1 ~ iJ U1 ''I
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Kaoll AG 990049 O.Z. 0480/01206 DE
Figure 1 shows the in vitro release from a tablet of Example 11 (n=6) compared with the marketed product Beloc-ZOK Retard (95 mg of metoprolol succinate).
A tablet of Example 11 was administered as a single dose to eight healthy male volunteers in the fasting state. Beloc-ZOR (with the same amount of free metoprolol base) was administered as reference substance under the same conditions. Figure 2 shows the geometric mean plasma concentration. The squares indicate the extrudate form according to the invention, and the diamonds indicate the reference substance.
ao
6.8, no-change, 24 h.
ao : ...:
a5 . Kaoll AG 990049 O.Z. 0480/01206 DE
M O O ~ O
* lp O O M O
M W O v-I tf1tn e~rl d~ N rl tp O O O O
* d~ O O O O N
N 00 C1 O rl O
e-1M rl d~ d~
O O OO O
O M e-110O N
'~O O O00 N M eiM
t0 d~ O O O
O d~ 111 O O O O
00 N O rI G~
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d~ O O O
eh u1 O O O M
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M M N
l0 d~ O O O
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W
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M M N
10 ~ D O
eIW I1 O O
W
M d~ N
W O t0OD O
w ~ d~ M rl O
00 O O r1 M erN
10 cp O
~ ll1 O ~W
O
~
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d,.. . . . . ~w . lfl O rl 1t1 OD
~ rl d~ N
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M
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ri d~ W r~
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~ ~
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, J-1~ ~i r1 ~ iJ U1 ''I
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r 1 N
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Ql ~ C
r -r T ~ ~ r ~ f-~ U
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N U ' ~ U
rtt tTb~ ?t -II ~ rlrou b ~C !
r L~ cdIdO r-I O ~ 'dO ~dW x .Y., i-l U ~ ~ ' O 1-i11~..,~ ~1 ~ ,?~riO 00U!
~ rl r-I
~ roro~ ~~ ro ~a .~ro~ -~~
~
~ a ~a~-~ ~, o ~ o -~~ a~
-~, v o ~ w w;~x x w w ~nA H x*
~n U ro ~ N
Kaoll AG 990049 O.Z. 0480/01206 DE
Figure 1 shows the in vitro release from a tablet of Example 11 (n=6) compared with the marketed product Beloc-ZOK Retard (95 mg of metoprolol succinate).
A tablet of Example 11 was administered as a single dose to eight healthy male volunteers in the fasting state. Beloc-ZOR (with the same amount of free metoprolol base) was administered as reference substance under the same conditions. Figure 2 shows the geometric mean plasma concentration. The squares indicate the extrudate form according to the invention, and the diamonds indicate the reference substance.
ao
Claims (8)
1. A drug form comprising an active ingredient with a water solubility as defined in USP 23 of up to 30 in a matrix based on acrylate polymers, the drug form being obtained by melt extrusion.
2. A drug form as claimed in claim 1, in which the active ingredient is in amorphous form.
3. A drug form as claimed in claim 1 or 2, comprising a methacrylic acid copolymer as matrix polymer.
4. A drug form as claimed in any of claims 1 to 3, comprising a methacrylic ester copolymer as matrix polymer.
5. A drug form as claimed in any of claims 1 to 4, comprising a combination of a methacrylic acid copolymer and a methacrylic ester copolymer.
6. A drug form as claimed in any of claims 1 to 5, comprising:
metoprolol tartrate as active ingredient.
metoprolol tartrate as active ingredient.
7. A process for producing a drug form as claimed in any of claims 1 to 6, which comprises a mixture of active ingredient and matrix polymer being subjected to melt extrusion and shaping.
8. A process as claimed in claim 7, wherein the shaping takes place by calendering.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19901040.4 | 1999-01-14 | ||
| DE19901040A DE19901040A1 (en) | 1999-01-14 | 1999-01-14 | Controlled release dosage forms containing active ingredients which are readily soluble in water |
| PCT/EP2000/000053 WO2000041481A2 (en) | 1999-01-14 | 2000-01-07 | Medicament forms having controlled release and containing active substances which easily dissolve in water |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2359381A1 true CA2359381A1 (en) | 2000-07-20 |
Family
ID=7894143
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002359381A Abandoned CA2359381A1 (en) | 1999-01-14 | 2000-01-07 | Medicament forms having controlled release and containing active substances which easily dissolve in water |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1140030A2 (en) |
| JP (1) | JP2002534443A (en) |
| CA (1) | CA2359381A1 (en) |
| DE (1) | DE19901040A1 (en) |
| WO (1) | WO2000041481A2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8481565B2 (en) | 2004-12-27 | 2013-07-09 | Eisai R&D Management Co., Ltd. | Method for stabilizing anti-dementia drug |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2818552B1 (en) * | 2000-12-26 | 2003-02-07 | Servier Lab | SOLID THERMOFORMABLE PHARMACEUTICAL COMPOSITIONS FOR THE CONTROLLED RELEASE OF IVABRADINE |
| JP2009523833A (en) * | 2006-01-21 | 2009-06-25 | アボット ゲーエムベーハー ウント カンパニー カーゲー | Formulations and methods for drug delivery |
| US20080069871A1 (en) * | 2006-07-21 | 2008-03-20 | Vaughn Jason M | Hydrophobic abuse deterrent delivery system |
| US9226907B2 (en) | 2008-02-01 | 2016-01-05 | Abbvie Inc. | Extended release hydrocodone acetaminophen and related methods and uses thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3830353A1 (en) * | 1988-09-07 | 1990-03-15 | Basf Ag | METHOD FOR THE CONTINUOUS PRODUCTION OF SOLID PHARMACEUTICAL FORMS |
| DK0661045T3 (en) * | 1992-09-18 | 2002-10-28 | Yamanouchi Pharma Co Ltd | Delayed release hydrogel preparation |
| DE19509807A1 (en) * | 1995-03-21 | 1996-09-26 | Basf Ag | Process for the preparation of active substance preparations in the form of a solid solution of the active substance in a polymer matrix, and active substance preparations produced using this method |
-
1999
- 1999-01-14 DE DE19901040A patent/DE19901040A1/en not_active Withdrawn
-
2000
- 2000-01-07 CA CA002359381A patent/CA2359381A1/en not_active Abandoned
- 2000-01-07 JP JP2000593105A patent/JP2002534443A/en active Pending
- 2000-01-07 WO PCT/EP2000/000053 patent/WO2000041481A2/en not_active Application Discontinuation
- 2000-01-07 EP EP00904879A patent/EP1140030A2/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8481565B2 (en) | 2004-12-27 | 2013-07-09 | Eisai R&D Management Co., Ltd. | Method for stabilizing anti-dementia drug |
| US8507527B2 (en) | 2004-12-27 | 2013-08-13 | Eisai R & D Management Co., Ltd. | Method for stabilizing anti-dementia drug |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2000041481A3 (en) | 2000-09-28 |
| EP1140030A2 (en) | 2001-10-10 |
| DE19901040A1 (en) | 2000-07-20 |
| WO2000041481A2 (en) | 2000-07-20 |
| JP2002534443A (en) | 2002-10-15 |
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|---|---|---|---|
| FZDE | Dead |