CN1245158C - 片剂组合物 - Google Patents
片剂组合物 Download PDFInfo
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- CN1245158C CN1245158C CNB971811407A CN97181140A CN1245158C CN 1245158 C CN1245158 C CN 1245158C CN B971811407 A CNB971811407 A CN B971811407A CN 97181140 A CN97181140 A CN 97181140A CN 1245158 C CN1245158 C CN 1245158C
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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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- A—HUMAN NECESSITIES
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- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
揭示含有N-(反式-4-异丙基环己烷羰基)-D-苯基丙氨酸及低取代度羟丙基纤维素的片剂组合物。此片剂组合物为通过投予后,在胃中迅速崩解,而可不受饮食影响地抑制服用此药的糖尿病患者的饭后血糖的上升。
Description
技术领域
本发明涉及控制糖尿病患者血糖值所使用的片剂组合物。
发明背景
已知下述式:
所示的N-(反式-4-异丙基环己烷羰基)-D-苯基丙氨酸(以下,称为化合物〔1〕)经口用药时,显示出优异的降低血糖效果,可用于作为糖尿病治疗药剂(特公平4-15221号公报,以下称“J.P.KOKOKU”)。
然而,已知于抑制饭后血糖上升的目的下,于饭前或饭后经口服用化合物〔1〕时,令其生物利用率降低。
发明内容
本发明目的是提供表现血糖降低作用且持续有效时间短的片剂组合物,并且不受饮食影响地快速地被吸收,以及不破坏其中化合物〔1〕的基本性能。
本发明为关于含有化合物〔1〕作为活性成分,和低取代度羟丙基纤维素作为崩解剂的片剂组合物。
本发明还涉及于含有上述化合物及低取代度羟丙基纤维素,加上赋形剂较佳为含有乳糖的赋形剂的片剂组合物。
本发明还涉及再含有羟丙基纤维素作为粘合剂的前述片剂组合物。
此类组成的片剂组合物可通过服药后,在胃中迅速崩解,而可不受饮食影响地被吸收,以防止糖尿病患者饭后血糖上升。
图面的简单说明
图1示出绝食下服药的病人血浆中化合物〔1〕的浓度。
图2示出饭前服药的病人血浆中化合物〔1〕的浓度。
实施发明的最佳形态
本发明的片剂组合物中的活性化合物为前述式所示的N-(反式-4-异丙基环己烷羰基)-D-苯基丙氨酸〔化合物1〕。化合物〔1〕的制造方法为如J.P.KOKOKU平4-15221号公报等所记载,例如可通过令4-异丙基环己烷羧酸和D-苯基丙氨酸或其酯使用活性酯法予以缩合而取得。其稳定结晶的制造方法为如未审特开(以后称“J.P.KOKAI”)平5-208943号所记载,例如化合物〔1〕可通过从乙醇,丙酮等的水混合溶剂中,于不低于10℃结晶化而取得。
本发明的片剂组合物中的化合物〔1〕配入量,-般为5~50重量%,较佳为10~40重量%,再佳为20~30重量%。
本发明的片剂组合物中,被使用作为崩解剂的低取代度羟丙基纤维素,为令纤维素的吡喃糖环的部分羟基,以氧化丙烯予以醚化得到的纤维素的羟丙基醚。定量测定低取代度羟丙基纤维素的干燥物质时,为含有5.0~16.0重量%羟丙氧基的化合物(参照日本药典第13版D-885~D-888及美国药典第23版第2253~2254页)。该低取代度羟丙基纤维素的例可列举例如信越化学工业(株)制低取代度羟丙基纤维素L-HPC(LH-11,LH-20,LH-21,LH-22,LH-30,LH-31和LH-32)等。
低取代度羟丙基纤维素的配合量,以5~50重量%为较佳,更佳为5~40重量%,再佳为10~40重量%,最佳为20~40重量%。
于使用羧甲基纤维素纳,羧甲基纤维素钙及交联羧甲基纤维素钠等的情形中,因于保存中发生着色而为不佳。虽然玉米淀粉,羧甲基淀粉钠,结晶纤维素及部分预胶凝化淀粉等于单独使用的情形中因崩解性较差而为不佳,但若与低取代度羟丙基纤维素组合使用则可改善其崩解性。
于本发明的片剂组合物中,除了上述的必须成分可再配合乳糖,淀粉,结晶纤维素,磷酸氢钙,轻质无水硅酸,氧化钛,偏硅酸铝镁作为赋形剂,其中亦以乳糖为较佳,因其易与化合物〔1〕产生配合。赋形剂的配合量可为片剂组合物中的平衡部分,以10~90重量%为较佳,更佳为20~80重量%,再佳为30~60重量%。
此外,再配入0.1-5重量%,较佳为0.5~2重量%的羟丙基纤维素作为粘合剂,可使制造过程的造粒变易。此处所使用的羟丙基纤维素不同于上述的低取代度羟丙基纤维素,测定羟丙基纤维素干燥物质时,羟丙氧基占53.4~77.5重量%(参照日本药典第13版D-880~D-885及美国药典第23版第2253页)。此类羟丙基纤维素为以日本曹达(株)HPC-L,L(微粉)等型式易于取得。
于本发明的片剂组合物中,上述成分以外的通常片剂组合物中所使用的添加剂,可在不损害本发明效果的范围内使用。此类添加剂可列举结晶纤维素,磷酸氢钙,淀粉,轻质无水硅酸,氧化钛,偏硅酸铝镁,聚乙二醇等的赋形剂,淀粉,结晶纤维素,羟丙基淀粉和部分预胶凝化淀粉等崩解剂,明胶,阿拉伯胶,乙基纤维素,聚乙烯醇等的粘合剂,硬脂酸,硬脂酸镁,硬脂酸钙,滑石,氢化油等的润滑剂,羟丙基甲基纤维素,羟丙基纤维素,甲基纤维素,乙基纤维素,羟丙基甲基纤维素酞酸酯,聚乙烯醇缩醛二乙胺基醋酸酯,甲基丙烯酸胺烷基酯共聚物,聚乙烯醋酸酯酞酸酯等的涂层剂,焦油色素,氧化钛等的着色剂,柠檬酸,己二酸,抗坏血酸,薄荷醇等的矫味矫臭剂,单硬脂酸甘油酯,聚山梨酸酯类,月桂基硫酸钠,蔗糖脂肪酸酯等的表面活性剂等。
本发明的片剂组合物可依据一般的湿式造粒法予以制造。即,将上述成分充分混合后,使用亦可含有乙醇或异丙醇等低级醇的水进行造粒,干燥,视需要将颗粒减小后,通过压片机进行压片。再视需要亦可予以涂层。
以下,以实施例具体说明本发明。
实施例1
秤量表1所示的各成分,除了硬脂酸镁以外,将各成分以搅拌制粒机混合10分钟。其次添加可制得粒径100~500μm颗粒左右的纯水(15~75重量份),并进行搅拌制粒10分钟。将所有的颗粒以压碎机予以压碎,并干燥。于所得的干燥颗粒中加入硬脂酸镁,并以V型混合机混合2分钟,并压片作成直径7mm,厚度3mm,重量100毫克的片剂。所得片剂于水中的崩散时间为依据日本药典崩散试验法进行试验。尚,使用信越化学工业(株)制L-HPC(LH-31)〔羟丙氧基10~12.9重量%,平均粒径30μm以下〕作为低取代度羟丙基纤维素。结果示于表1。
表1
比较品 | 本发明品 | |||||||||
1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | |
化合物〔1〕乳糖玉米淀粉羧甲基淀粉钠部分预胶凝化淀粉结晶纤维素低取代度羟丙基纤维素硬脂酸镁 | 25741 | 25492051 | 254410201 | 255410101 | 2564101 | 2554201 | 254420101 | 254410201 | 2534101010101 | 254410201 |
崩散时间(分) | >30 | >30 | >30 | >30 | 11 | 0.8 | 3.1 | 3.1 | 3.0 | 3.8 |
由表1可知,使用低取代度羟丙基纤维素作为崩解剂制得的片剂,为比使用其他崩散剂的片剂更快速地崩散。
实施例2
将化合物〔1〕250克,乳糖530克及低取代度羟丙基纤维素〔信越化学工业(株)制LH-31,羟丙氧基10.0~13.0重量%,平均粒径30μm以下〕200克,于搅拌混合制粒机中充分搅拌后,加入溶解于500克纯水中的羟丙其纤维素〔日本曹达(株)制HPC-L〕10克并进行搅拌制粒。将所得的颗粒弄碎并进行干燥后,添加硬脂酸镁10克并压片,取得直径7mm,厚度3.7mm,重量120毫克,含有30毫克化合物〔1〕的片剂。将此片剂以羟丙基甲基纤维素8克,聚乙二醇60001.5克,滑石2.4克,氧化钛0.5克及纯水87.6克所组成的涂层液予以喷雾,取得包衣片。
比较例1
将化合物〔1〕250克,乳糖440克,玉米淀粉100克及结晶纤维素200克,于搅拌混合制粒机中充分搅拌后,加入溶解于360克纯水中的羟丙其纤维素〔日本曹达(株)制HPC-L〕30克并进行搅拌制粒。将所得的颗粒弄碎并进行干燥后,添加硬脂酸镁10克并压片,取得直径7mm,厚度3.7mm,重量120毫克,含有30毫克化合物〔1〕的片剂。将此片剂以羟丙基甲基纤维素8克,聚乙二醇60001.5克,滑石2.4克,氧化钛0.5克及纯水87.6克所组成的涂层液予以喷雾,取得包衣片。
对于实施例2及比较例1所得的各片剂,评价食物对经口吸收性的影响。对照群为使用将化合物〔1〕30毫克及乳糖70毫克充填至硬明胶3号胶囊中的胶囊剂。将片剂或胶囊剂经口投药至小猎犬(n=8),并于5分钟后令其取用食物。于投药后0,15,30,45,60,90,120,180,240,360及480分钟采血,并以HPLC测定血浆中化合物〔1〕的浓度,算出最高血中浓度到达时间(Tmax),最高血中浓度(Cmax)及血中浓度曲线下面积(AUC)。为了比较,对于在绝食时投予各片剂或胶囊剂的情况亦同样地处理进行试验。结果示于表2,图1及图2。
表2
Cmax(μg/ml) | Tmax(分) | AUC(μg·min/ml) | ||
实施例2的片剂 | 饭前投予 | 6.6±3.3 | 68±30 | 1218±278 |
绝食时投予 | 9.7±2.6 | 47±36 | 1635±526 | |
比较例1的片剂 | 饭前投予 | 3.5±0.9 | 131±96 | 1018±200 |
绝食时投予 | 7.5±3.3 | 64±41 | 1462±542 | |
胶囊剂 | 饭前投予 | 3.1±1.1 | 226±145 | 738±210 |
绝食时投予 | 9.5±2.3 | 38±36 | 1445±453 |
(平均值±标准偏差,n=8)
如表2及图1所示,于绝食时投予的情形中,本发明的片剂组合物与比较例1的片剂组合物及胶囊剂相比较,显示出同等或稍优的吸收性。相对地,于假定实际使用的饭前投予的情形中,则如图2所示,以比较例1的片剂组合物或胶囊剂用于对照例1,其化合物〔1〕的吸收差,而不实用,但相反地,本发明的片剂组合物为不受到食物影响地迅速地被吸收,可抑制糖尿病患者饭后血糖的上升。
实施例3
将化合物〔1〕330克,乳糖450克及低聚代度羟丙基纤维素〔信越化学工业(株)制LH-31〕200克于搅拌混合制粒机中充分搅拌后,加入溶解于500克纯水中的羟丙基纤维素〔日本曹达(株)制HPC-L〕10克并进行搅拌制粒。将所得的颗粒弄碎并进行干燥后,添加硬脂酸镁10克并压片,取得直径7mm,厚度3.7mm,重量121毫克,含有40毫克化合物〔1〕的片剂。将此片剂以羟丙基甲基纤维素8克,聚乙二醇6000 1.5克,滑石2.4克,氧化钛0.5克及纯水87.6克所组成的涂层液予以喷雾,取得包衣片。
对于所得的包衣片,与前述同样评价食物对经口吸收性的影响,结果绝食时投予或饭前投予的情况均与实施例2的包衣片同样地显示出较比较例1的片剂或胶囊剂更优异的吸收性,特别可作为抑制糖尿病患者饭后血糖上升的物质。
实施例4
将化合物〔1〕125克,乳糖655克及低取代度羟丙基纤维素〔信越化学工业(株)制LH-31〕200克于搅拌混合制粒机中充分搅拌后,加入溶解于500克纯水中的羟丙基纤维素〔日本曹达(株)制HPC-L〕10克并进行搅拌制粒。将所得的颗粒弄碎并进行干燥后,添加硬脂酸镁10克并压片,取得直径7mm,厚度3.7mm,重量120毫克,含有15毫克化合物〔1〕的片剂。将此片剂以羟丙基甲基纤维素8克,聚乙二醇6000 1.5克,滑石2.4克,氧化钛0.5克及纯水87.6克所组成的涂层液予以喷雾,取得包衣片。
对于所得的包衣片,与前述同样评价食物对经口吸收性的影响,结果绝食时投予或饭前投予的情况均与实施例2的包衣片同样地显示出较比较例1的片剂或胶囊剂更优异的吸收性,特别可作为抑制糖尿病患者饭后血糖上升的物质。
实施例5
将化合物〔1〕250克,乳糖430克,结晶纤维素100克及低取代度羟丙基纤维素〔信越化学工业(株)制LH-31〕200克于搅拌混合制粒机中充分搅拌后,加入溶解于570克纯水中的羟丙基纤维素〔日本曹达(株)制HPC-L〕10克并进行搅拌制粒。将所得的颗粒弄碎并进行干燥后,添加硬脂酸镁10克并压片,取得直径7mm,厚度3.7mm,重量120毫克,含有30毫克化合物〔1〕的片剂。将此片剂以羟丙基甲基纤维素8克,聚乙二醇6000 1.5克,滑石2.4克,氧化钛0.5克及纯水87.6克所组成的涂层液予以喷雾,取得包衣片。
对于所得的包衣片,与前述同样评价食物对经口吸收性的影响,结果绝食时投予或饭前投予的情况均与实施例2的包衣片同样地显示出较比较例1的片剂或胶囊剂更优异的吸收性,特别可作为抑制糖尿病患者饭后血糖上升的物质。
实施例6
将化合物〔1〕250克,乳糖320克,玉米淀粉100克,结晶纤维素100克,部分预胶凝化淀粉100克及低取代度羟丙基纤维素〔信越化学工业(株)制LH-31〕100克于搅拌混合制粒机中充分搅拌后,加入溶解于450克纯水中的羟丙基纤维素〔日本曹达(株)制HPC-L〕10克并进行搅拌制粒。将所得的颗粒弄碎并进行干燥后,添加硬脂酸镁10克并压片,取得直径7mm,厚度3.7mm,重量100毫克,含有30毫克化合物〔1〕的片剂。将此片剂以羟丙基甲基纤维素8克,聚乙二醇6000 1.5克,滑石2.4克,氧化钛0.5克及纯水87.6克所组成的涂层液予以喷雾,取得包衣片。
对于所得的包衣片,与前述同样评价食物对经口吸收性的影响,结果绝食时投予或饭前投予的情况均与实施例2的包衣片同样地显示出较比较例1的片剂或胶囊剂更优异的吸收性,特别可作为抑制糖尿病患者饭后血糖上升的物质。
实施例7
将化合物〔1〕250克,乳糖430克,羧甲基淀粉钠100克及低取代度羟丙基纤维素〔信越化学工业(株)制LH-31〕200克于搅拌混合制粒机中充分搅拌后,加入溶解于640克纯水中的羟丙基纤维素〔日本曹达(株)制HPC-L〕10克并进行搅拌制粒。将所得的颗粒弄碎并进行干燥后,添加硬脂酸镁10克并压片,取得直径7mm,厚度3.7mm,重量120毫克,含有30毫克化合物〔1〕的片剂。将此片剂以羟丙基甲基纤维素8克,聚乙二醇6000 1.5克,滑石2.4克,氧化钛0.5克及纯水87.6克所组成的涂层液予以喷雾,取得包衣片。
对于所得的包衣片,与前述同样评价食物对经口吸收性的影响,结果绝食时投予或饭前投予的情况均与实施例2的包衣片同样地显示出较比较例1的片剂或胶囊剂更优异的吸收性,特别可作为抑制糖尿病患者饭后血糖上升的物质。
以上,如所详述,若依据本发明,则可提供不受饮食影响,且快速地被吸收的表现出降低血糖作用的N-(反式-4-异丙基环己烷羰基)-D-苯基丙氨酸的片剂组合物。
Claims (13)
1.一种片剂组合物,其特征为含有N-(反式-4-异丙基环己烷羰基)-D-苯基丙氨酸及低取代度羟丙基纤维素。
2.如权利要求第1项所述的片剂组合物,其中低取代度羟丙基纤维素的含量为5~50重量%。
3.如权利要求第1项所述的片剂组合物,其再含有赋形剂。
4.如权利要求第3项所述的片剂组合物,其中赋形剂中的至少一种为乳糖。
5.如权利要求第1项所述的片剂组合物,其再含有羟丙基纤维素。
6.如权利要求第5项所述的片剂组合物,其中羟丙基纤维素含有53.4~77.5重量%的羟丙氧基。
7.一种片剂组合物,其特征为含有5~50重量%的N-(反式-4-异丙基环己烷羰基)-D-苯基丙氨酸,5~40重量%的低取代度羟丙基纤维素及10~90重量%的赋形剂。
8.如权利要求第7项所述的片剂组合物,其中赋形剂为乳糖。
9.如权利要求第7项所述的片剂组合物,其再含有羟丙基纤维素。
10.如权利要求第9项所述的片剂组合物,其中羟丙基纤维素含有53.4~77.5重量%的羟丙氧基。
11.一种片剂组合物,其特征为含有5~50重量%的N-(反式-4-异丙基环己烷羰基)-D-苯基丙氨酸,5~40重量%的羟丙氧基量为5.0~16.0重量%的低取代度羟丙基纤维素,10~90重量%的赋形剂及0.1~5重量%的羟丙氧基量为53.4~77.5重量%的羟丙基纤维素。
12.如权利要求第11项所述的片剂组合物,其中赋形剂为乳糖。
13.一种片剂组合物,其特征为含有N-(反式-4-异丙基环己烷羰基)-D-苯基丙氨酸及选自低取代度羟丙基纤维素、羧甲基纤维素钠、羧甲基纤维素钙和交联羧甲基纤维素钠的崩解剂。
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DE69735644T2 (de) * | 1996-11-15 | 2007-05-03 | Ajinomoto Co., Inc. | Nateglinide zubereitung in tablettenform |
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ATE406885T1 (de) * | 2000-10-24 | 2008-09-15 | Ajinomoto Kk | Nateglinid enthaltende präparate |
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WO2005094812A1 (ja) * | 2004-04-01 | 2005-10-13 | Ajinomoto Co., Inc. | ナテグリニド含有製剤 |
WO2005117840A1 (en) * | 2004-05-31 | 2005-12-15 | Ranbaxy Laboratories Limited | Stable pharmaceutical compositions comprising pulverized granules of nateglinide of form b |
WO2006013444A1 (en) * | 2004-07-28 | 2006-02-09 | Ranbaxy Laboratories Limited | Preparations of stable pharmaceutical compositions of nateglinide and processes for their preparation |
MX2007001563A (es) * | 2004-08-04 | 2008-03-05 | Johnson & Johnson | Composicion para liberacion sostenida de farmaco que demuestra un patron de liberacion ascendente del orden cero, metodos para la elaboracion de dicha composicion. |
US20080038344A1 (en) * | 2004-10-01 | 2008-02-14 | Nippon Zoki Pharmaceutical Co., Ltd. | Solid Pharmaceutical Preparation |
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BRPI0719529B8 (pt) * | 2006-12-07 | 2021-05-25 | Daiichi Sankyo Co Ltd | método para produzir uma preparação sólida |
JP5289975B2 (ja) * | 2006-12-07 | 2013-09-11 | 第一三共株式会社 | マンニトール又は乳糖を含有する固形製剤 |
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JPS6354321A (ja) * | 1985-03-27 | 1988-03-08 | Ajinomoto Co Inc | 血糖降下剤 |
JP3586471B2 (ja) * | 1991-06-25 | 2004-11-10 | 三菱ウェルファーマ株式会社 | トラセミド含有医薬組成物 |
JP2508949B2 (ja) | 1991-07-30 | 1996-06-19 | 味の素株式会社 | N−(トランス−4−イソプロピルシクロヘキシルカルボニル)−d−フェニルアラニンの結晶及びその製造法 |
EP0614358A1 (en) * | 1991-11-26 | 1994-09-14 | Warner-Lambert Company | Process and composition for the development of controlled release gemfibrozil dosage form |
DE69735644T2 (de) * | 1996-11-15 | 2007-05-03 | Ajinomoto Co., Inc. | Nateglinide zubereitung in tablettenform |
-
1997
- 1997-11-14 DE DE69735644T patent/DE69735644T2/de not_active Expired - Lifetime
- 1997-11-14 WO PCT/JP1997/004152 patent/WO1998022105A1/ja active IP Right Grant
- 1997-11-14 AU AU49654/97A patent/AU718350B2/en not_active Ceased
- 1997-11-14 ES ES05014497T patent/ES2364145T3/es not_active Expired - Lifetime
- 1997-11-14 DK DK05014497.1T patent/DK1586314T3/da active
- 1997-11-14 AT AT97912459T patent/ATE322260T1/de not_active IP Right Cessation
- 1997-11-14 CA CA002271865A patent/CA2271865C/en not_active Expired - Lifetime
- 1997-11-14 EP EP05014497A patent/EP1586314B1/en not_active Expired - Lifetime
- 1997-11-14 TW TW086117009A patent/TW492878B/zh not_active IP Right Cessation
- 1997-11-14 AT AT05014497T patent/ATE503472T1/de active
- 1997-11-14 JP JP32974597A patent/JP4171091B2/ja not_active Expired - Lifetime
- 1997-11-14 PT PT97912459T patent/PT965339E/pt unknown
- 1997-11-14 PT PT05014497T patent/PT1586314E/pt unknown
- 1997-11-14 ES ES97912459T patent/ES2257772T3/es not_active Expired - Lifetime
- 1997-11-14 EP EP97912459A patent/EP0965339B1/en not_active Expired - Lifetime
- 1997-11-14 DE DE69740161T patent/DE69740161D1/de not_active Expired - Lifetime
- 1997-11-14 CN CNB971811407A patent/CN1245158C/zh not_active Expired - Lifetime
- 1997-11-14 KR KR1019997004308A patent/KR100343062B1/ko not_active IP Right Cessation
- 1997-11-14 EP EP10010714A patent/EP2277517A1/en not_active Withdrawn
-
1999
- 1999-05-14 US US09/311,060 patent/US6143323A/en not_active Expired - Lifetime
-
2000
- 2000-09-29 US US09/672,896 patent/US6296872B1/en not_active Expired - Lifetime
-
2001
- 2001-08-03 US US09/920,830 patent/US6641841B2/en not_active Expired - Lifetime
-
2003
- 2003-02-05 US US10/358,324 patent/US6844008B2/en not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
DE69740161D1 (de) | 2011-05-12 |
US6844008B2 (en) | 2005-01-18 |
EP1586314A1 (en) | 2005-10-19 |
CA2271865A1 (en) | 1998-05-28 |
JP4171091B2 (ja) | 2008-10-22 |
US20020028239A1 (en) | 2002-03-07 |
DK1586314T3 (da) | 2011-06-20 |
US6641841B2 (en) | 2003-11-04 |
PT965339E (pt) | 2006-06-30 |
AU4965497A (en) | 1998-06-10 |
PT1586314E (pt) | 2011-07-01 |
ATE322260T1 (de) | 2006-04-15 |
CN1242704A (zh) | 2000-01-26 |
EP0965339B1 (en) | 2006-04-05 |
CA2271865C (en) | 2003-10-14 |
DE69735644T2 (de) | 2007-05-03 |
US6143323A (en) | 2000-11-07 |
ATE503472T1 (de) | 2011-04-15 |
EP1586314B1 (en) | 2011-03-30 |
KR100343062B1 (ko) | 2002-07-02 |
TW492878B (en) | 2002-07-01 |
ES2257772T3 (es) | 2006-08-01 |
EP2277517A1 (en) | 2011-01-26 |
EP0965339A1 (en) | 1999-12-22 |
EP0965339A4 (en) | 2003-04-23 |
JPH10194969A (ja) | 1998-07-28 |
DE69735644D1 (de) | 2006-05-18 |
US20030147951A1 (en) | 2003-08-07 |
AU718350B2 (en) | 2000-04-13 |
KR20000053312A (ko) | 2000-08-25 |
ES2364145T3 (es) | 2011-08-25 |
WO1998022105A1 (fr) | 1998-05-28 |
US6296872B1 (en) | 2001-10-02 |
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