CN1171587C - Gamma-contained aminobutyric acid derivatives solid compositions and preparation process thereof - Google Patents
Gamma-contained aminobutyric acid derivatives solid compositions and preparation process thereof Download PDFInfo
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- CN1171587C CN1171587C CNB998059781A CN99805978A CN1171587C CN 1171587 C CN1171587 C CN 1171587C CN B998059781 A CNB998059781 A CN B998059781A CN 99805978 A CN99805978 A CN 99805978A CN 1171587 C CN1171587 C CN 1171587C
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Abstract
The present invention provides a stabilized solid composition containing a 4-amino-3-substituted-butanoic acid derivative which can be obtained by incorporating a humectant as a stabilizer.
Description
Invention field
The present invention relates to contain 4-amino-3-replaces-the stable solid composite of butanoic acid derivative and preparation method thereof.
In addition, the invention still further relates to that the 4-amino that contains stable solid composite-3-replaces-solid pharmaceutical preparation of butanoic acid derivative and preparation method thereof.
More particularly, the present invention relates to that the 4-amino of tablet, powder, granule and capsule dosage form-3-replaces-butanoic acid derivative, comprise stable solid pharmaceutical preparation of gabapentin, pregabalin, baclofen, 3-amino methyl-4-cyclohexyl-butanoic acid, 3-amino methyl-5-cyclohexyl valeric acid, 3-amino methyl-4-phenyl-butanoic acid or 3-amino methyl-5-phenyl-pentanoic acid and preparation method thereof.
Background of invention
United States Patent (USP) 4,024,175 and 4,087, one of 544 disclose 1-(amino methyl) cyclohexyl-acetic acid with following structural formula, 4-amino-3-replacement-butanoic acid derivative, because of its structure and γ-An Jidingsuan (GABA) relevant being called as " gabapentin " (common name).
Gabapentin is easy to by the brain barrier.Therefore, this chemical compound can be used as treatment some cerebral disorders such as some type epilepsy, faint and the medicine of hypocinesis and cranium portion wound, and can be used as the medicine that improves gerontal patient's brain function.
In addition, United States Patent (USP) 5,084,479 disclose gabapentin have been used for the treatment of neurodegenerative disease such as presenile dementia, Huntington or Parkinson's disease and amyotrophic lateral sclerosis.United States Patent (USP) 5,025,035 discloses gabapentin has been used for the treatment of depression.United States Patent (USP) 5,510,381 disclose this chemical compound have been used for the treatment of the manic and existing manic affective psychosis that paralepsy is arranged again.In addition, because this chemical compound has analgesic activities, expection can be used as analgesics.In these cases, gabapentin increases greatly as the application of the therapeutic agent of above-mentioned disease or cerebral disorders such as disease and epilepsy.
As mentioned above, gabapentin is the medicine of cerebral disorders such as a kind of very effective treatment epilepsy, and its toxicity is very low.But, in order to keep expected effect, in the past usually with its with single dosage every day of 900-1800mg or in some cases with the highest 2400mg every day dosage with three dosage that separate to the administration of being grown up.Therefore, single dose should be in the scope of 300-600mg, or in some cases up to 800mg.
In addition, the difficulty that gabapentin exists is, it is the medicine of the extremely strong and mobile non-constant of a kind of bitterness, needs high dosage with the dosage form administration of powder the time.Gabapentin is owing to its unstability is difficult to make preparation, therefore, at present the gabapentin capsule that can obtain from the overseas market all be by with gabapentin and required adjuvant simply dry mixed be encapsulated in the hard capsule then and make.
But, aforesaid 300-600mg or need the capsule of large size in some cases up to the single dose of 800mg; For example, need use capsule for every content No. 0 for the 400mg capsule.Even for the adult, it also is difficult swallowing such capsule, has said nothing of the child.Although existing gabapentin capsule listing, but still need to attempt improving the compliance of gabapentin administration and degree easily, and exist needs to the pharmaceutical preparation of small size gabapentin at clinical field.
Gabapentin itself is a kind of pulverous material, its compactibility and mobile non-constant.Compression moulding commonly used in the past or granulate and pulverize (small-sizing) or fluidisation has the medicine of this powder characteristics, and need improve molded feature by excipient substance.But the multiple adjuvant that is used for compression moulding can form 4-cyclohexyl ketopyrrolidine (corresponding lactam form) with the gabapentin reaction gradually by quickening the dehydration between intramolecular amino of gabapentin and the carboxyl.When the gabapentin powder was pressed tightly more, this dehydration was carried out soon more.In addition, when production pharmaceutical preparation, make water or organic solvent that the reaction between gabapentin and the described adjuvant is further accelerated.
For the consideration of safety, commercially available gabapentin capsule has been formulated standard, when exhaustion of effect, the acceptable content of lactams should be no more than 1.0%.Therefore, when producing gabapentin pharmaceutical preparation, need stop the formation of lactams by the dehydration between inhibition gabapentin intramolecularly amino and the carboxyl.On the other hand, as discussed above, need undersized dosage form with easy-to-swallow.In these cases, people have attempted the whole bag of tricks.But these trials are not all achieved success, perhaps because be because the dosage form size of having used a large amount of adjuvants to make to obtain is bigger, or because the increase of the formation amount of lactams, perhaps two kinds of reasons have.
For structure similar with gabapentin and with gabapentin the same have in its 3-position that bigger substituent other 4-amino of structure-3-replaces-butanoic acid derivative, also observed the unstability that in the production gabapentin formulation, is run into.
For example, 4-amino-3-(right-chlorphenyl) butanoic acid of general " baclofen " by name that following structural formula is represented,
The general 5-methyl-3-amino methyl-caproic acid that be called " pregabalin " represented with following structural formula,
The same with gabapentin, also be the medicine of compactibility and mobile non-constant.Be used to pulverize or the compression moulding of fluidisation medicine or granulate and to improve by excipient substance.But the multiple adjuvant that is used for compression moulding can form 4-cyclohexyl ketopyrrolidine (corresponding lactam form) with the gabapentin reaction gradually by quickening interior amino of compound molecule and the dehydration between the carboxyl.The same with gabapentin, when chemical compound was pressed tightly more, this dehydration was carried out soon more, and made water or organic solvent that the dehydration reaction is further accelerated when production pharmaceutical preparation.We can say that the mechanism by self condensation dehydration is that the butanoic acid derivative that has the bigger substituent 4-amino of structure-3-to replace at the 3-bit strip is peculiar.
On the contrary, do not have substituent group in the 3-position or have less substituent gamma-aminobutyric acid derivative, γ-An Jidingsuan or 4-amino-3-hydroxyl-butanoic acid for example, even dehydration can not take place in 2-3 hour when remaining on dry status under 105 ℃ the temperature yet, can not observe the formation of 4-cyclohexyl ketopyrrolidine (corresponding lactam form).In other words, the substituent group in the 3-position has in the butanoic acid derivative of the 4-amino-3-replacement than macrostructure, and dehydration is easy to take place between intramolecular amino and carboxyl.
In view of the foregoing, for the butanoic acid derivative medicine that has the bigger substituent 4-amino of structure-3-to replace at the 3-bit strip, comprise gabapentin, the new pharmaceutical preparation and the production method thereof that need contain described medicine, described pharmaceutical preparation can be dosage forms such as less or fluidizing tablet of size or granule, and has with commercially available pharmaceutical preparation, comprises the commercially available suitable shelf stability of gabapentin capsule.
Summary of the invention
We have carried out conscientious research to solve the above the problems of the prior art, found that, no matter adopt which kind of compound method, all in the solid composite that contains the butanoic acid derivative that 4-amino-3-replaces that can be produced by blocking-up remaining very small amount of evaporation of water and the motion butanoic acid derivative that stops 4-amino-3-to replace, comprise gabapentin owing to preparing and depositing the caused degraded of formation lactams in the process, can add wetting agent and prevent degraded effectively as stabilizing agent, and by the solid composite of the stable butanoic acid derivative that contains 4-amino-3-replacement of described wetting agent and the solid pharmaceutical preparation such as the tablet of the described compositions of use, granules etc. have splendid shelf stability, have finished the present invention on this basis.
Detailed Description Of The Invention
The present invention relates to contain the stable solid composite of the butanoic acid derivative that 4-amino-3-replaces, said composition contains the butanoic acid derivative that 4-amino-3-of following general formula replaces; Wetting agent; As needs, also contain the auxiliary reagent that is useful on production pharmaceutical preparation;
Wherein,
R
1Be hydrogen atom, hydroxyl, methyl or ethyl;
R
2Be univalent group, it is selected from:
The straight or branched alkyl of 3-8 carbon atom;
The straight or branched alkylidene of 3-8 carbon atom;
By the straight or branched alkyl of halogen atom, trifluoromethyl, hydroxyl, alkoxyl, alkylthio group, amino, nitro, oxo group, carboxyl or the replacement of alkoxy carbonyl group list or dibasic 3-8 carbon atom;
The cycloalkyl of 3-8 carbon atom;
By the cycloalkyl of halogen atom, trifluoromethyl, hydroxyl, alkyl, alkoxyl, alkylthio group, amino, nitro, oxo group, carboxyl or the replacement of alkoxy carbonyl group list, two replacements or a trisubstituted 3-8 carbon atom;
By the formed condensed ring group of the cycloalkyl ortho-condensed of phenyl ring and 4-8 carbon atom;
By the formed condensed ring group of the cycloalkyl ortho-condensed of phenyl ring and 4-8 carbon atom, wherein said phenyl ring is replaced or three replacements by halogen atom, trifluoromethyl, hydroxyl, alkyl, alkoxyl, alkylthio group, amino, nitro, carboxyl or alkoxy carbonyl group list replacement, two;
By the cycloalkenyl group of phenyl ring and 5-8 carbon atom or the formed condensed ring group of cycloalkadienyl ortho-condensed of 5-8 carbon atom;
By the cycloalkenyl group of phenyl ring and 5-8 carbon atom or the formed condensed ring group of cycloalkadienyl ortho-condensed of 5-8 carbon atom, wherein said phenyl ring is replaced or three replacements by halogen atom, trifluoromethyl, hydroxyl, alkyl, alkoxyl, alkylthio group, amino, nitro, carboxyl or alkoxy carbonyl group list replacement, two;
The alkyl-cycloalkyl group, wherein, described cycloalkyl contain 3-8 carbon atom and with optionally by-O-,-S-or-alkylidene of 1-4 the carbon atom that SS-is interrupted links to each other;
The alkyl-cycloalkyl group, wherein said cycloalkyl contains 3-8 carbon atom, with optionally by-O-,-S-or-alkylidene of 1-4 the carbon atom that SS-is interrupted link to each other and by halogen atom, trifluoromethyl, hydroxyl, alkyl, alkoxyl, alkylthio group, amino, nitro, oxo group, carboxyl or alkoxy carbonyl group list replace, two replacements or three replacements;
The cycloalkyl of 5-8 carbon atom, methylene (CH wherein
2-) one of quilt-O-,-NH-,-S-,-SO-or-S (O)
2-replace;
The cycloalkyl of 5-8 carbon atom, methylene (CH wherein
2-) one of quilt-O-,-NH-,-S-,-SO-or-S (O)
2-replace and not superseded methylene (CH
2-) in one or two by halogen atom, trifluoromethyl, hydroxyl, alkyl, alkoxyl, alkylthio group, amino, nitro, oxo group, carboxyl or the alkoxy carbonyl group list replaces or two replace;
The cycloalkadienyl of the cycloalkenyl group of a 5-8 carbon atom or 5-8 carbon atom, the methylene (CH in wherein said cyclenes basic ring or the cyclic diolefine basic ring
2-) one of quilt-O-,-NH-,=N-,-S-,-SO-or-S (O)
2-replace;
The cycloalkadienyl of the cycloalkenyl group of a 5-8 carbon atom or 5-8 carbon atom, the methylene (CH in wherein said cyclenes basic ring or the cyclic diolefine basic ring
2-) one of quilt-O-,-NH-,=N-,-S-,-SO-or-S (O)
2-replace and not superseded methylene (CH
2-) in one or two by halogen atom, trifluoromethyl, hydroxyl, alkyl, alkoxyl, alkylthio group, amino, nitro, oxo group, carboxyl or the alkoxy carbonyl group list replaces or two replace;
By the formed condensed ring group of the cycloalkyl ortho-condensed of phenyl ring and 5-8 carbon atom, the methylene (CH of wherein said cycloalkyl
2-) one of quilt-O-,-NH-,-S-,-SO-or-S (O)
2-replace;
By the formed condensed ring group of the cycloalkyl ortho-condensed of phenyl ring and 5-8 carbon atom, the methylene (CH of wherein said cycloalkyl
2-) one of quilt-O-,-NH-,-S-,-SO-or-S (O)
2-replace, described phenyl ring is by halogen atom, trifluoromethyl, hydroxyl, alkyl, alkoxyl, alkylthio group, amino, nitro, carboxyl or the alkoxy carbonyl group list replaces or two replace;
By the cycloalkenyl group of phenyl ring and 5-8 carbon atom or the formed condensed ring group of cycloalkadienyl ortho-condensed of 5-8 carbon atom, the methylene (CH in wherein said cyclenes basic ring or the cyclic diolefine basic ring
2-) one of quilt-O-,-NH-,=N-,-S-,-SO-or-S (O)
2-replace;
By the cycloalkenyl group of phenyl ring and 5-8 carbon atom or the formed condensed ring group of cycloalkadienyl ortho-condensed of 5-8 carbon atom, the methylene (CH in wherein said cyclenes basic ring or the cyclic diolefine basic ring
2-) one of quilt-O-,-NH-,=N-,-S-,-SO-or-S (O)
2-replace, described phenyl ring is by halogen atom, trifluoromethyl, hydroxyl, alkyl, alkoxyl, alkylthio group, amino, nitro, carboxyl or the alkoxy carbonyl group list replaces or two replace;
The alkyl-cycloalkyl group, wherein, described cycloalkyl contain 5-8 carbon atom and with optionally by-O-,-S-or-alkylidene of 1-4 the carbon atom that SS-is interrupted links to each other the methylene (CH in the described cycloalkyl ring
2-) one of quilt-O-,-NH-,-S-,-SO-or-S (O)
2-replace;
The alkyl-cycloalkyl group, wherein, described cycloalkyl contain 5-8 carbon atom and with optionally by-O-,-S-or-alkylidene of 1-4 the carbon atom that SS-is interrupted links to each other the methylene (CH in the described cycloalkyl ring
2-) one of quilt-O-,-NH-,-S-,-SO-or-S (O)
2-replace and not superseded methylene (CH
2-) in one or two replaced, two replace or three replace by halogen atom, trifluoromethyl, hydroxyl, alkyl, alkoxyl, alkylthio group, amino, nitro, oxo group, carboxyl or alkoxy carbonyl group list;
Phenyl or naphthyl;
The phenyl that is replaced by methylene-dioxy;
By following substituent group singly replace, two replacements or trisubstd phenyl or naphthyl: halogen atom; Trifluoromethyl; Hydroxyl; Alkyl; Alkoxyl; Amino; Nitro; Carboxyl; Phenoxy group; The phenyl methoxyl group; Phenyl ring wherein is by the mono-substituted phenyl methoxyl group of halogen atom, trifluoromethyl, alkoxyl, amino, nitro, carboxyl or alkoxy carbonyl group; The cycloalkyl methoxyl group that in cycloalkyl ring, contains 5-8 carbon atom; The cycloalkenyl group methoxyl group that in the cyclenes basic ring, contains 5-8 carbon atom; The cycloalkadienyl methoxyl group that in the cyclic diolefine basic ring, contains 5-8 carbon atom; The cycloalkyl methoxyl group, wherein, the methylene (CH in the described cycloalkyl ring that contains 5-8 carbon atom
2-) one of quilt-O-,-NH-,-S-,-SO-or-S (O)
2-replace; The cycloalkenyl group methoxyl group, wherein, the methylene (CH in the described cyclenes basic ring that contains 5-8 carbon atom
2-) one of quilt-O-,-NH-,=N-,-S-,-SO-or-S (O)
2-replace; The cycloalkadienyl methoxyl group, wherein, the methylene (CH in the described cyclic diolefine basic ring that contains 5-8 carbon atom
2-) one of quilt-O-,-NH-,=N-,-S-,-SO-or-S (O)
2-replace; The cycloalkyl methoxyl group that contains 5-8 carbon atom in cycloalkyl ring, wherein said cycloalkyl ring is by the methylene (CH in halogen atom, trifluoromethyl, hydroxyl, alkyl, alkoxyl, amino, nitro, carboxyl or replacement of alkoxy carbonyl group list and the described cycloalkyl ring
2-) one of quilt-O-,-NH-,-S-,-SO-or-S (O)
2-replace; The cycloalkenyl group methoxyl group that contains 5-8 carbon atom in the cyclenes basic ring, wherein said cyclenes basic ring is by the methylene (CH in halogen atom, trifluoromethyl, hydroxyl, alkyl, alkoxyl, amino, nitro, oxo group, carboxyl or replacement of alkoxy carbonyl group list and the described cyclenes basic ring
2-) one of quilt-O-,-NH-,=N-,-S-,-SO-or-S (O)
2-replace; Or in the cyclic diolefine basic ring, contain the cycloalkadienyl methoxyl group of 5-8 carbon atom, wherein said cyclic diolefine basic ring replaced by halogen atom, trifluoromethyl, hydroxyl, alkyl, alkoxyl, amino, nitro, oxo group, carboxyl or alkoxy carbonyl group list and described cyclic diolefine basic ring in methylene (CH
2-) one of quilt-O-,-NH-,=N-,-S-,-SO-or-S (O)
2-replace;
Alkyl phenyl, wherein said phenyl with optionally by-O-,-S-or-alkylidene of 1-4 the carbon atom that SS-is interrupted links to each other;
Alkyl-O-,-S-or-the SS-phenyl, wherein, described phenyl by-O-,-S-or-SS-links to each other with the alkylidene of 1-4 carbon atom;
-O-,-S-or-the SS-phenyl;
Diphenyl amino;
Alkyl phenyl, wherein said phenyl with optionally by-O-,-S-or-alkylidene of 1-4 the carbon atom that SS-is interrupted link to each other and by halogen atom, trifluoromethyl, hydroxyl, alkyl, alkoxyl, amino, nitro or carboxyl list replace, two replacements or three replacements;
Alkyl-O-,-S-or-the SS-phenyl, wherein, described phenyl by-O-,-S-or-SS-link to each other with the alkylidene of 1-4 carbon atom and by halogen atom, trifluoromethyl, hydroxyl, alkyl, alkoxyl, amino, nitro or carboxyl list replace, two replacements or three replacements;
-O-,-S-or-the SS-phenyl, wherein said phenyl is replaced, two replaces or three replace by halogen atom, trifluoromethyl, hydroxyl, alkyl, alkoxyl, amino, nitro or carboxyl list; Perhaps
R
1And R
2The carbon atom that is connected with them lumps together the group that can form bivalence, and described divalent group is selected from:
The cycloalkylidene of 5-8 carbon atom;
By the cycloalkylidene of halogen atom, trifluoromethyl, hydroxyl, alkyl, alkoxyl, alkylthio group, cycloalkyl, phenyl, amino, nitro or the replacement of carboxyl list, two replacements, three replacements or a quaternary 5-8 carbon atom;
The cycloalkylidene of 5-8 carbon atom, wherein, the methylene (CH in the described cycloalkyl ring
2-) one of quilt-O-,-NH-,-S-,-SO-or-S (O)
2-replace;
The cycloalkylidene of 5-8 carbon atom, wherein, the methylene (CH in the described cycloalkyl ring
2-) one of quilt-O-,-NH-,-S-,-SO-or-S (O)
2-replace and described cycloalkyl ring in not superseded methylene (CH
2-) in one or morely replaced, two replace, three replace or four replace by halogen atom, trifluoromethyl, hydroxyl, alkyl, alkoxyl, alkylthio group, amino, nitro, oxo group, carboxyl or alkoxy carbonyl group list;
The inferior cycloalkenyl group of 5-8 carbon atom or the inferior cycloalkadienyl of 5-8 carbon atom;
Replaced or the inferior cycloalkenyl group of a quaternary 5-8 carbon atom or the inferior cycloalkadienyls of 5-8 carbon atom by halogen atom, trifluoromethyl, hydroxyl, alkyl, alkoxyl, alkylthio group, cycloalkyl, phenyl, amino, nitro, oxo group, carboxyl or the replacement of alkoxy carbonyl group list, two replacements, three;
The inferior cycloalkenyl group of 5-8 carbon atom or the inferior cycloalkadienyl of 5-8 carbon atom, wherein, the methylene (CH in described cyclenes basic ring or the cyclic diolefine basic ring
2-) one of quilt-O-,-NH-,=NH-,-S-,-SO-or-S (O)
2-replace;
The inferior cycloalkenyl group of 5-8 carbon atom or the inferior cycloalkadienyl of 5-8 carbon atom, wherein, the methylene (CH in described cyclenes basic ring or the cyclic diolefine basic ring
2-) one of quilt-O-,-NH-,=NH-,-S-,-SO-or-S (O)
2-replace and described cyclenes basic ring or cyclic diolefine basic ring in not superseded methylene (CH
2-) in one or morely replaced, two replace, three replace or four replace by halogen atom, trifluoromethyl, hydroxyl, alkyl, alkoxyl, alkylthio group, amino, nitro, oxo group, carboxyl or alkoxy carbonyl group list;
By the formed condensed ring group of the cycloalkylidene ortho-condensed of phenyl ring and 4-8 carbon atom;
By the formed condensed ring group of the cycloalkylidene ortho-condensed of phenyl ring and 4-8 carbon atom, described phenyl ring is replaced or four replacements by halogen atom, trifluoromethyl, hydroxyl, alkyl, alkoxyl, alkylthio group, amino, nitro, carboxyl or the replacement of alkoxy carbonyl group list, two replacements, three;
By the inferior cycloalkenyl group of phenyl ring and 5-8 carbon atom or the formed condensed ring group of inferior cycloalkadienyl ortho-condensed of 5-8 carbon atom;
By the inferior cycloalkenyl group of phenyl ring and 5-8 carbon atom or the formed condensed ring group of inferior cycloalkadienyl ortho-condensed of 5-8 carbon atom, described phenyl ring is replaced by halogen atom, trifluoromethyl, hydroxyl, alkyl, alkoxyl, alkylthio group, amino, nitro, carboxyl or alkoxy carbonyl group list or two replacements.
The invention still further relates to the solid composite of the butanoic acid derivative that contains 4-amino-3-replacement, described solid composite is the solid pharmaceutical preparation of tablet, powder, granule or capsule dosage form.
In addition, the invention still further relates to the method for the solid composite for preparing the butanoic acid derivative that contains 4-amino-3-replacement, this method comprises having the butanoic acid derivative of 4-amino-3-replacement of following structural formula:
(R wherein
1And R
2Mix mutually with the auxiliary reagent of production pharmaceutical preparation as defined above) with wetting agent and (if necessary).
The invention still further relates to the method for the solid composite for preparing the butanoic acid derivative that contains 4-amino-3-replacement, described solid composite is the solid pharmaceutical preparation of tablet, powder, granule or capsule dosage form.
The invention still further relates to the stable solid composite of the butanoic acid derivative that contains 4-amino-3-replacement, described compositions also contains natural amino acid.
Can comprise as chemical compound listed in following table 1 and 2 according to the butanoic acid derivative that the stable 4-amino of method of the present invention-3-replaces:
Table 1
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
Table 1 (continuing)
-R
1
-R
2
-R
1
-R
2
-H -CH＝CH-CH
3 -H -CH＝CH-CH
2-CH
2-CH
3
-H -CH＝CH-CH
2-CH
3 -H -CH＝CH-CH(CH
3)
2
-H -C(CH
3)＝CH-CH
3
-H -CH＝C(CH
3)
2
Table 2
Table 2 (continuing)
Table 2 (continuing)
Table 2 (continuing)
The invention provides to contain in production aforesaidly has very effectively antihunt means in the pharmaceutical preparation of the butanoic acid derivative that the 4-amino of large-substituent-3-replaces at its 3-bit strip, and method of the present invention is very effective in the pharmaceutical preparation of preparation example such as gabapentin, pregabalin, baclofen, 3-amino methyl-4-cyclohexyl-butanoic acid, 3-amino methyl-5-cyclohexyl valeric acid, 3-amino methyl-4-phenyl-butanoic acid, 3-amino methyl-5-phenyl-pentanoic acid etc.
Can be selected from ethylene glycol, propylene glycol, butanediol, sorbitol and glycerol and fatty acid ester thereof at the wetting agent that the present invention is used for the butanoic acid derivative combination that replaces with 4-amino-3-, these wetting agents can use separately or use with two or more any combination wherein.
The illustrative example of fatty acid glyceride comprises the glycerol low-grade fatty acid ester, for example an acetic acid glycerol, oxalic acid glycerol, triacetic acid glycerol (glycerol triacetate); The medium-chain fatty acid monoglyceride is a caproin, a caprylin, a caprin for example; The medium-chain fatty acid polyglycerin ester is as a lauric acid polyglycerin ester or a myristic acid polyglycerin ester etc.
Solid pharmaceutical preparation of the present invention can be by carrying out granulation step, encapsulation step or film-making step and (change if desired) coating steps obtains with the dosage form of routine successively, is generally the dosage form of tablet of granule, capsule, tablet or the surface coatings of powder, granule, surface coatings; Wherein, in granulation step, will join butanoic acid derivative that 4-amino-3-replaces as the adjuvant of the wetting agent of stabilizing agent and (if necessary) production pharmaceutical preparation and for example granulate by granulator in the bulk powder of gabapentin, pregabalin, baclofen etc. and with the mixture that forms; In encapsulation step, the particulate powder that forms is sealed adding to depress with capsule filling machine; In the film-making step, with the particulate powder pelleter tabletting that forms; In coating steps, particulate powder, tablet or the granule that obtains in the abovementioned steps carried out surface coatings.
In the process of above-mentioned production pharmaceutical preparation, the butanoic acid derivative that 4-amino-3-replaces such as the granulation of gabapentin can be undertaken by any method of granulating of knowing, for example, and fluidized granulation method, high-speed stirred granulation, melt granulation etc.Bonding effectively for the bulk powder that makes the butanoic acid derivative that stabilizing agent and 4-amino-3-replaces, preferably adopt the fluidized granulation method, in the method, with the bulk powder fluidisation of the described chemical compound stabilizing agent of on fluidizing powder, spraying then.In this fluidized granulation step, stabilizing agent is added with the form of its solution in water or organic solvent such as alcohol etc., thereby make a spot of stabilizing agent just can be bonded in the surface of bulk powder of the butanoic acid derivative of 4-amino-3-replacement equably.
In the granulation step of using described fluidized granulation method, granulation can add stabiliser solution by as described above and finish in the bulk powder of the butanoic acid derivative that 4-amino-3-replaces, as needs, also can add corn starch, cellulose derivative (for example hydroxypropyl cellulose), polyvinyl alcohol, polyvinylpyrrolidone (for example Kollidon-K30 or Kollidon-K25), copolyvidone (for example Kollidon-VA64) of binding agent such as solution or form of suspension etc.
Before granulation, the aforementioned stable agent solution is coated on the bulk powder of the butanoic acid derivative that 4-amino-3-replaces with other adjuvant of binding agent or production pharmaceutical preparation.In this granulation step,, also can mix other adjuvant of sweeting agent such as mannitol, sorbitol, xylitol etc. and production pharmaceutical preparation as needs.
The resulting granules sprills can directly be used as the pharmaceutical preparation of the butanoic acid derivative that 4-amino-3-replaces, and perhaps, also it can be encapsulated as the capsule that contains the butanoic acid derivative that 4-amino-3-replaces adding to depress.In addition, also it can be pressed into tablet.
More particularly, the particulate powder of the butanoic acid derivative that replaces of the 4-amino that makes of as described above-3-can be compression molded into tablet with pelleter.In this compression moulding step, must make with lubricator, as what do often in production pharmaceutical preparation.But, we find some traditional lubrication agent that is used for medicine compression moulding step may influence the butanoic acid derivative that 4-amino-3-replaces pharmaceutical preparation shelf stability and can postpone the dissolving of medicine, therefore, these lubricants are inappropriate in some cases.
But, we also find, some natural amino acid (lubricant that seldom was used as the compression moulding step in the past) can play the effect of good lubricant when derivant of the present invention such as gabapentin are compression molded into tablet as L-leucine, L-isoleucine, L-valine, D-leucine, D-isoleucine, D-valine, DL-leucine, DL-isoleucine or DL-valine or its mixture, and in the tablet that makes thus, stabilizing agent of the present invention does not all have adverse effect to shelf stability and dissolution characteristics.
Therefore, in this compression moulding step, can be with the granule that obtains and L-leucine as lubricant, the L-isoleucine, the L-valine, the D-leucine, the D-isoleucine, the D-valine, the DL-leucine, the adjuvant of DL-isoleucine or DL-valine or its mixture and (if necessary) production pharmaceutical preparation such as binding agent or disintegrating agent such as cellulose derivative (for example hydroxypropyl cellulose), crystalline cellulose, corn starch, the starch of part gel, lactose etc. or other conventional adjuvant are compression molded into tablet with the mixture that forms with suitable pelleter then with for example mixing such as V-blender of suitable blender such as dry mixed device.
As needs, particulate powder, granule or the tablet that makes can be carried out surface coatings.The surface coatings step of tablet is optional, can be optional step.For example, because gabapentin has extremely strong taste, therefore preferably gabapentin tablets is carried out surface coatings with easy-to-swallow.In the surface coatings step, can use component of polymer such as cellulose derivative for example hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC) etc., polyvinylpyrrolidone, Kollidon-VA64, Eudragits etc. are as filmogen and use mannitol, sorbitol, xylitol, aspartame etc. as sweeting agent.
As needs, also can in described filmogen, add wetting agent such as propylene glycol, glycerol, glycerol triacetate etc. and natural amino acid such as L-leucine, L-isoleucine, L-valine, L-alanine, D-leucine, D-isoleucine, D-valine, D-alanine, DL-leucine, DL-isoleucine, DL-valine, DL-alanine or glycine.In these chemical compounds, propylene glycol, glycerol and glycerol triacetate not only can play the effect of wetting agent, but also can play the effect of coating membrane plasticizer, and L-leucine, L-isoleucine, L-valine, D-leucine, D-isoleucine, D-valine, DL-leucine, DL-isoleucine and DL-valine can play the effect of the modifier of coating membrane.In addition, when the butanoic acid derivative of 4-amino-3-replacement was gabapentin, glycine, L-alanine, D-alanine and DL-alanine can play the effect of the buffer agent of gabapentin bitterness.Can with fluid bed or rotary pot the surface coatings of particulate powder, granule or tablet be coated in the surface of particulate powder, granule or tablet according to the method for knowing.
In the solid composite that contains the butanoic acid derivative that 4-amino-3-replaces of the present invention, total consumption of wetting agent can be the 0.01-25% of the butanoic acid derivative weight of 4-amino-3-replacement, when perhaps when production pharmaceutical preparation, adding adjuvant, be the 0.01-25% of the 4-amino-butanoic acid derivative of 3-replacement and the gross weight of adjuvant.Total consumption can be according to the kind of used wetting agent, contain the butanoic acid derivative that 4-amino-3-replaces the concrete dosage form of solid composite, be tablet, powder, granule or capsule, and the kind of the adjuvant that is added and consumption.Under any circumstance, wetting agent all should use with the effective dose that can keep the butanoic acid derivative of stablizing 4-amino-3-replacement by the moisture of guaranteeing pharmaceutical preparation.In addition, in many cases, the total amount of wetting agent is preferably the 0.02-20% of the butanoic acid derivative weight of 4-amino-3-replacement, when perhaps adding adjuvant when production pharmaceutical preparation, is preferably the 0.02-20% of the 4-amino-butanoic acid derivative of 3-replacement and the gross weight of adjuvant.But when sorbitol was used with other wetting agent, consumption was not subjected to the restriction of above-mentioned scope.
When the tablet of the surface coatings of preparation 4-amino-butanoic acid derivative that 3-replaces, the consumption of wetting agent is generally the 0.1-50% of coating material gross weight in the surface coatings step.
In addition, we also find, when the solid pharmaceutical preparation of preparation 4-amino-butanoic acid derivative that 3-replaces, use some natural amino acid, comprise L-leucine, L-isoleucine, L-valine, L-alanine, D-leucine, D-isoleucine, D-valine, D-alanine, DL-leucine, DL-isoleucine, DL-valine, DL-alanine and glycine replace pharmaceutical preparation produce in adjuvant commonly used, can make required pharmaceutical preparation and can not hinder moisture to keep effect as the wetting agent of stabilizing agent of the present invention.In other words, described natural amino acid can play the effect of stabilization aid.Described natural amino acid can use separately or use with two or more combining form wherein.Described natural amino acid can mix in any selectivity step of pharmaceutical auxiliary agent of preparation 4-amino-butanoic acid derivative that 3-replaces, and comprises granulation step.Total consumption of described natural amino acid is for example, in the gabapentin solid preparation, to be the 0.05-40% of gabapentin weight.
The method of aforesaid preparation 4-amino of the present invention-butanoic acid derivative solid preparation that 3-replaces comprises, for example granulation step, film-making step and (change if desired) coating steps, wherein, in granulation step, will join as the adjuvant of wetting agent (being stabilizing agent), binding agent and production pharmaceutical preparation in the bulk powder of described chemical compound and then the mixture that forms be granulated with granulator; In the film-making step, additive such as lubricant are joined in the particulate powder of formation and then granule is used the pelleter tabletting; In coating steps, coating is carried out on the surface that obtains tablet.But, the particulate powder that is made by granulation step also can be without the film-making step and the pharmaceutical preparation of the butanoic acid derivative that directly replaces as 4-amino-3-with the dosage form of powder or granule, perhaps, the granule as described above that also granulation step can be made further carries out surface coatings.Perhaps, the granule that granulation step can be made and lubricant etc. mix and the mixture that forms are filled into capsule filling machine and prepare capsule in the snap fit capsule.In the solid preparation of the butanoic acid derivative that the 4-amino that makes-3-replaces, for example, for gabapentin formulation, gabapentin is compression or fluidizing state, thereby is easy to take to the human oral administration time.
Below will carry out more complete description to the present invention, but should not regard these embodiment as limiting the scope of the invention by embodiment.
Embodiment 1
1) preparation of gabapentin particulate powder A
With fluidized granulation machine (by FREUND Co., Ltd., SFC-Labo produces) on the bulk powder of 250g gabapentin spraying 72g water then drying obtain gabapentin particulate powder A.
2) preparation of gabapentin particulate powder B
With described fluidized granulation machine the spraying solution of 5g propylene glycol in 67g water on the bulk powder of 250g gabapentin then drying obtain gabapentin particulate powder B.
With above 1) and 2) in the gabapentin particulate powder A and the B that make under the condition described in the following table 3, deposit the content of measuring formed lactams in each particulate powder then by HPLC.
Lactams content in this embodiment and following examples is represented with the percentage by weight of gabapentin.
Table 3
The storage condition particulate powder
A B
During beginning 0.003 0.003
60 ℃/1 week (sealing) 0.017 0.011
60 ℃/2 weeks (sealing) 0.020 0.013
50 ℃/85% humidity/2 weeks (opening) 0.003 0.003
50 ℃/85% humidity/4 weeks (opening) 0.003 0.003
Last table shows, can prevent gabapentin bulk powder degrade (formation lactams) by adding propylene glycol when depositing.
Embodiment 2
1) preparation of gabapentin particulate powder C
At the spraying 72g water and the solution of 5g hydroxypropyl cellulose in 58g water of spraying thereon subsequently on the bulk powder of 250g gabapentin, drying obtains gabapentin particulate powder C then with fluidized granulation machine (by FREUND Co., Ltd., SFC-Labo production).
2) preparation of gabapentin particulate powder D
With the fluidized granulation machine (by FREUND Co.; Ltd.; SFC-Labo produces) at the solution of spraying 5g propylene glycol in 67g water on the bulk powder of 250g gabapentin and the solution of 5g hydroxypropyl cellulose in 58g water of spraying thereon subsequently, drying obtains gabapentin particulate powder D then.
3) preparation of gabapentin particulate powder E
At the solution of spraying 5g glycerol triacetate in 67g water on the bulk powder of 250g gabapentin and the solution of 5g hydroxypropyl cellulose in 58g water of spraying thereon subsequently, drying obtains gabapentin particulate powder E then with described fluidized granulation machine.
4) preparation of gabapentin particulate powder F
At spraying 2.5g propylene glycol and the solution of 2.5g glycerol triacetate in 67g water on the bulk powder of 250g gabapentin and the solution of 5g hydroxypropyl cellulose in 58g water of spraying thereon subsequently, drying obtains gabapentin particulate powder F then with described fluidized granulation machine.
With above 1)-4) in the gabapentin particulate powder C-F that makes under the condition described in the following table 4, deposit the content of measuring formed lactams in each particulate powder then by HPLC.
Table 4
The storage condition particulate powder
C D E F
During beginning 0.004 0.003 0.003 0.003
60 ℃/1 week (sealing) 0.131 0.076 0.044 0.072
60 ℃/2 weeks (sealing) 0.214 0.130 0.118 0.124
50 ℃/85% humidity/2 weeks (opening) 0.011 0.008 0.006 0.007
50 ℃/85% humidity/4 weeks (opening) 0.012 0.013 0.010 0.011
Last table shows, can prevent gabapentin bulk powder degrade (formation lactams) by adding propylene glycol or glycerol triacetate or adding above-mentioned two kinds of materials simultaneously when depositing.
Embodiment 3
1) the particulate preparation of gabapentin
With fluidized granulation machine (by FREUND Co., Ltd., SFC-Labo produces) spraying 14g copolyvidone and the solution of 14g propylene glycol in 252g water on the bulk powder of 700g gabapentin then drying obtain the gabapentin particulate powder.
2) be pressed into tablet
The dried particles that makes in the above step 1) and L-valine (particle weight 7%) mixed then being pressed into tablet with rotation pelleter (being produced by KIKUSUI SEISAKUSHO K.K.), every diameter is 9mm, and weight is 336mg.Every contains the 300mg gabapentin, and hardness is 6-10kg.
3) surface coatings of tablet
With above step 2) in the tablet that makes carry out film coating with coating solution by coating machine (by FREUND Co., Ltd., HI-COATOR HCT-30 produces) in its surface, define in the table 5 composed as follows of coating solution.
Table 5
Copolyvidone 34.0g
L-isoleucine 13.5g
Glycerol 13.5g
Propylene glycol 7.0g
Calcium stearate 7.0g
Water 432.0g
With above step 2) and 3) in the tablet (I) of the not coating that makes and film-coated tablet (II) and commercially available gabapentin capsule (III) in following table 6, deposit the content of measuring formed lactams in described tablet and the capsule then under the defined condition.
Table 6
Storage condition lactams content (%)
Gabapentin formulation
(I) (II) (III)*
During beginning 0.005 0.004 0.018
Month (sealing) 0.048 0.066 0.072 of 40 ℃/75% humidity/2
Month (sealing) 0.123 0.119 0.129 of 40 ℃/75% humidity/4
Month (sealing) 0.229 0.172 0.219 of 40 ℃/75% humidity/6
The commercially available gabapentin capsule of [notes] * makes by the dry mixed method, and every capsules contains the 300g gabapentin
Last table shows, does not observe the obvious increase of lactams content in film-coated tablet, and film-coated tablet has splendid shelf stability, and is similar to the gabapentin capsule that makes by the dry mixed method.
In addition, the film coating tablet that also as described above is made has carried out solubility test according to the dissolution test method of stipulating among the Japanese Pharmacopoeia XIII (use 900ml water and stir in 50rpm).Experimental condition and result of the test are as shown in following table 7, and numerical value wherein is the dissolved amount of representing with %.
Table 7
Dissolution time (minute) storage condition
During beginning 60 ℃/4 hours (sealing)
15 90.3 91.5
30 103.1 103.3
60 103.2 103.3
Above result of the test confirms that the gabapentin film coating tablet for preparing according to method of the present invention can be good at dissolving and have good shelf stability after dissolving in solubility test.
Embodiment 4
1) preparation of baclofen powder sample G
With the crystallization of 200mg baclofen with the 0.04ml water-wet and with mortar with mixture make particulate powder then drying obtain baclofen powder sample G.
2) preparation of baclofen powder sample H
With the crystallization of 200mg baclofen with the aqueous solution of propylene glycol moistening of 0.04ml 20% and with mortar with mixture make particulate powder then drying obtain baclofen powder sample H.
Deposit the content of measuring formed dehydration condensation in each sample then by the method for HPLC under the condition that baclofen powder sample G that as described above is made and H and undressed baclofen crystallization define in following table 8.In this embodiment, the content of dehydration condensation is represented with the percentage by weight of baclofen.
Table 8
The storage condition sample
Undressed baclofen G H
During beginning 0.10 0.10 0.10
60 ℃/1 week (sealing) 0.36 0.95 0.42
60 ℃/2 weeks (sealing) 0.57 1.26 0.61
60 ℃/3 weeks (sealing) 0.70 1.65 0.82
Last table shows, the degraded (dehydrating condensation) that the baclofen granule that water is granulated can quicken when depositing, the degraded in the time of can preventing to deposit as wetting agent by the adding propylene glycol.
Embodiment 5
1) preparation of pregabalin powder sample I
With 1g pregabalin crystallization with the 0.1ml water-wet and with mortar with mixture make particulate powder then drying obtain pregabalin powder sample I.
2) preparation of pregabalin powder sample J
With 1g pregabalin crystallization with the aqueous solution moistening of 0.1ml 1% DECAGLYCERYL MONOLAURATE (decaglyceryl monolaurate) and with mortar with mixture make particulate powder then drying obtain pregabalin powder sample J.
3) preparation of pregabalin powder sample K
With 1g pregabalin crystallization with the aqueous solution moistening of 0.1ml 10% butanediol and with mortar with mixture make particulate powder then drying obtain pregabalin powder sample K.
Deposit the content of measuring formed dehydration condensation in each sample then by the HPLC method under the condition that sample I, J that as described above is made and K and undressed pregabalin crystallization define in following table 9.In this embodiment and following embodiment 6, the content of dehydration condensation is represented with the percentage by weight of pregabalin.
Table 9
The storage condition sample
Undressed pregabalin I J K
During beginning＜0.001＜0.001＜0.001＜0.001
60 ℃/1 week (sealing) 0.001 0.009 0.001 0.001
60 ℃/2 weeks (sealing) 0.001 0.010 0.002 0.002
Last table shows, the degraded (dehydrating condensation) that the pregabalin that water is granulated can quicken when depositing, the degraded in the time of can preventing to deposit as wetting agent by adding DECAGLYCERYL MONOLAURATE or butanediol.
Embodiment 6
1) preparation of pregabalin powder sample L
With 1g pregabalin crystallization with the aqueous solution moistening of 0.1ml 10% hydroxypropyl cellulose and with mortar with mixture make particulate powder then drying obtain pregabalin powder sample L.
2) preparation of pregabalin powder sample M
With 1g pregabalin crystallization with 0.1ml contain 10% hydroxypropyl cellulose and 10% propylene glycol the aqueous solution moistening and with mortar with mixture make particulate powder then drying obtain pregabalin powder sample M.
Deposit the content of measuring formed dehydration condensation in each sample then by the HPLC method under the condition that sample L that as described above is made and M define in following table 10.
Table 10
The storage condition sample
L M
During beginning＜0.001＜0.001
60 ℃/1 week (sealing) 0.005 0.001
60 ℃/2 weeks (sealing) 0.010 0.002
60 ℃/4 weeks (sealing) 0.014 0.004
Last table shows, can prevent the degraded (dehydrating condensation) of pregabalin when depositing by adding hydroxypropyl cellulose and propylene glycol as wetting agent.
It is believed that at solid preparation, comprise that remaining excessive water is disadvantageous in the preparation of the butanoic acid derivative that 4-amino-3-replaces, because this can cause variable color, degraded, film-making difficulty etc.Outstanding feature of the present invention is, we unexpectedly find, the wetting agent that has a moisture stick effect by adding can significantly improve the stability of the solid preparation of the butanoic acid derivative that 4-amino-3-replaces, and thought in the past this will shown in produce adverse influence (referring to above description) in the preparation.Therefore, the invention provides the butanoic acid derivative of stablizing unsettled 4-amino on the pharmacopedics-3-and replacing, the method that comprises gabapentin, and illustrated the principle of this Stabilization, and for many years, this is considered to that always problem to be solved is arranged in this area.Appreciable impact of the present invention is, the wet granulation method that makes water that is widely used in the small size pharmaceutical preparation that the preparation patient is easy to take can be applied to the gabapentin of moldability extreme difference and can not cause any degraded of gabapentin.Expection the present invention is the major contribution that exploitation is contained the stabilizing pharmaceutical composition of the butanoic acid derivative that 4-amino-3-replaces.
Claims (11)
1. stable solid composite, said composition comprises:
The butanoic acid derivative that 4-amino-3-replaces;
Wetting agent; With
The dispensable auxiliary reagent that is used for production pharmaceutical preparation;
Wherein, the butanoic acid derivative that described 4-amino-3-replaces is 1-(amino methyl) cyclohexyl-acetic acid or 5-methyl-3-homoleucine or its combination, described wetting agent is one or more chemical compounds that are selected from the fatty acid ester of ethylene glycol, propylene glycol, butanediol, sorbitol and glycerol and glycerol or polyglycereol, wherein the fatty acid ester of glycerol partly has 10 or carbon atom still less
Prerequisite is that when the butanoic acid derivative of described 41 amino-3-replacement was 1-(amino methyl) cyclohexyl-acetic acid, described wetting agent was not a sorbitol.
2. the described stable solid composite of claim 1, wherein said wetting agent is an ethylene glycol.
3. the described stable solid composite of claim 1, wherein said wetting agent is a propylene glycol.
4. the described stable solid composite of claim 1, wherein said wetting agent is a butanediol.
5. the described stable solid composite of claim 1, wherein said wetting agent is the low-grade fatty acid ester of glycerol or glycerol or polyglycereol, wherein the fatty acid ester of glycerol partly has 10 or carbon atom still less.
6. claim 1,2,3,4 or 5 described stable solid composites, the total amount of wherein said wetting agent are the 0.01-25% of the weight of the butanoic acid derivative that replaces of described 4-amino-3-.
7. claim 1,2,3,4 or 5 described stable solid composites, the total amount of wherein said wetting agent are the 0.01-25% of the gross weight of the butanoic acid derivative that replaces of described 4-amino-3-and the auxiliary reagent that is used for production pharmaceutical preparation.
8. claim 1,2,3,4 or 5 described stable solid composites, said composition also comprises one or more natural amino acids.
9. the described stable solid composite of claim 8, wherein said one or more natural amino acids are L-leucine, L-isoleucine, L-valine, L-alanine, D-leucine, D-isoleucine, D-valine, D-alanine, DL-leucine, DL-isoleucine, DL-valine, DL-alanine or glycine.
10. the described stable solid composite of claim 1, wherein said stable solid composite is the pharmaceutical preparation of tablet, powder, granule or capsule formulation.
11. stablize the method for the solid composite of the butanoic acid derivative that comprises 4-amino-3-replacement, this method comprises that the butanoic acid derivative that 4-amino-3-is replaced mixes mutually with wetting agent and the dispensable auxiliary reagent that is used for production pharmaceutical preparation, the butanoic acid derivative that wherein said 4-amino-3-replaces is 1-(amino methyl) cyclohexyl-acetic acid or 5-methyl-3-homoleucine or its combination, described wetting agent is that one or more are selected from ethylene glycol, propylene glycol, butanediol, the chemical compound of the fatty acid ester of sorbitol and glycerol and glycerol or polyglycereol, wherein the fatty acid ester of glycerol partly has 10 or carbon atom still less
Prerequisite is that when the butanoic acid derivative of described 4-amino-3-replacement was 1-(amino methyl) cyclohexyl acetic acid, described wetting agent was not a sorbitol.
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| Application Number | Priority Date | Filing Date | Title |
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| JP133122/1998 | 1998-05-15 | ||
| JP13312298A JP3761324B2 (en) | 1998-05-15 | 1998-05-15 | Passenger rice transplanter |
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| CNB200410077021XA Division CN100337687C (en) | 1998-05-15 | 1999-05-10 | Gamma-aminobutyric acid derivatives containing, solid compositions and process for preparing the same |
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1998
- 1998-05-15 JP JP13312298A patent/JP3761324B2/en not_active Expired - Fee Related
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1999
- 1999-05-10 PT PT99924164T patent/PT1077691E/en unknown
- 1999-05-10 NZ NZ507162A patent/NZ507162A/en not_active IP Right Cessation
- 1999-05-10 EE EEP200000671A patent/EE05530B1/en unknown
- 1999-05-10 CN CNB998059781A patent/CN1171587C/en not_active Expired - Fee Related
- 1999-05-10 ES ES99924164T patent/ES2312208T3/en not_active Expired - Lifetime
- 1999-05-10 CA CA002325045A patent/CA2325045C/en not_active Expired - Lifetime
- 1999-05-10 IL IL13920299A patent/IL139202A0/en unknown
- 1999-05-10 EA EA200001154A patent/EA006553B1/en not_active IP Right Cessation
- 1999-05-10 GE GEAP19995678A patent/GEP20032987B/en unknown
- 1999-05-10 AT AT99924164T patent/ATE407668T1/en active
- 1999-05-10 DE DE69939532T patent/DE69939532D1/en not_active Expired - Lifetime
- 1999-05-10 DK DK99924164T patent/DK1077691T3/en active
- 1999-05-13 EG EG1999050553A patent/EG26287A/en active
- 1999-10-05 UA UA2000127205A patent/UA76398C2/en unknown
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2000
- 2000-10-23 IL IL139202A patent/IL139202A/en not_active IP Right Cessation
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| CA2325045C (en) | 2005-05-03 |
| EA200001154A1 (en) | 2001-06-25 |
| UA76398C2 (en) | 2006-08-15 |
| EA006553B1 (en) | 2006-02-24 |
| GEP20032987B (en) | 2003-06-25 |
| CY1108488T1 (en) | 2014-04-09 |
| ATE407668T1 (en) | 2008-09-15 |
| PT1077691E (en) | 2008-11-04 |
| CN1300213A (en) | 2001-06-20 |
| EE200000671A (en) | 2002-04-15 |
| DK1077691T3 (en) | 2008-10-27 |
| IL139202A0 (en) | 2001-11-25 |
| EG26287A (en) | 2013-06-12 |
| JPH11318133A (en) | 1999-11-24 |
| EE05530B1 (en) | 2012-04-16 |
| JP3761324B2 (en) | 2006-03-29 |
| DE69939532D1 (en) | 2008-10-23 |
| ES2312208T3 (en) | 2009-02-16 |
| CA2325045A1 (en) | 1999-11-25 |
| NZ507162A (en) | 2003-11-28 |
| IL139202A (en) | 2014-12-31 |
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Correction item: Priority Correct: 1998.05.15 JP 133112/1998 False: 1998.05.15 JP 133122/1998 Number: 42 Page: 411 Volume: 20 |
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Correction item: Priority Correct: 1998.05.15 JP 133112/1998 False: 1998.05.15 JP 133122/1998 Number: 42 Page: The title page Volume: 20 |
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