CN101056624A - Controlled release pharmaceutical compositions comprising a fumaric acid ester - Google Patents

Abstract

Translated fromChinese

本发明涉及包含富马酸酯作为活性物质的控释药物组合物。这些组合物适合用于治疗例如牛皮癣或者其他过度增殖性、炎性或自身免疫性疾患，被设计成以受控方式释放富马酸，以便能够避免活性物质口服给药后在胃肠道内的局部高浓度，由此能够减少胃肠副作用。

The present invention relates to controlled release pharmaceutical compositions comprising fumarate esters as active substance. These compositions are suitable for the treatment of e.g. psoriasis or other hyperproliferative, inflammatory or autoimmune disorders and are designed to release fumaric acid in a controlled manner in order to be able to avoid localization of the active substance in the gastrointestinal tract following oral administration. High concentration, thereby reducing gastrointestinal side effects.

Description

Translated fromChinese

包含富马酸酯的控释药物组合物Controlled release pharmaceutical composition comprising fumarate

发明领域field of invention

本发明涉及包含富马酸酯作为活性物质的控释药物组合物。这些组合物适合用于治疗例如牛皮癣或者其他过度增殖性、炎性或自身免疫性疾患，被设计成以受控方式释放富马酸，以便能够避免活性物质口服给药后在胃肠道内的局部高浓度，由此能够减少胃肠副作用。The present invention relates to controlled release pharmaceutical compositions comprising fumarate esters as active substance. These compositions are suitable for the treatment of e.g. psoriasis or other hyperproliferative, inflammatory or autoimmune disorders and are designed to release fumaric acid in a controlled manner in order to be able to avoid localization of the active substance in the gastrointestinal tract following oral administration. High concentration, thereby reducing gastrointestinal side effects.

发明背景Background of the invention

富马酸酯、即富马酸二甲酯与富马酸氢乙酯的组合已经用于治疗牛皮癣达很多年。该组合的市售品名为Fumaderm^。其为口用片剂的剂型，有两种不同的剂量强度可用(Fumaderm^initial和Fumaderm^)：Fumarates, the combination of dimethyl fumarate and ethyl hydrogen fumarate, have been used for many years in the treatment of psoriasis. This combination is commercially available under the name Fumaderm^(R) . It comes in the form of an oral tablet and is available in two different dosage strengths (Fumaderm^(R) initial and Fumaderm(^R )):

                      Fumaderm^  Initial  Fumaderm^Fumaderm^(R) Initial Fumaderm(^R)

富马酸二甲酯          30mg                  120mgDimethyl fumarate 30mg 120mg

富马酸氢乙酯钙盐      67mg                  87mgEthyl fumarate calcium salt 67mg 87mg

富马酸氢乙酯镁盐      5mg                   5mgEthyl magnesium hydrogen fumarate 5mg 5mg

富马酸氢乙酯锌盐      3mg                   3mgEthyl hydrogen fumarate zinc salt 3mg 3mg

这两种强度旨在应用在各自基础的剂量制度中，始于Fumaderm^initial，剂量逐步扩大，然后在例如治疗三周后转换为Fumaderm^。Fumaderm^initial和Fumaderm^都是肠溶衣片。These two strengths are intended to be used in a respective basic dosing regime, starting with Fumaderm^(R) initial, with dose escalation, and then switching to Fumaderm^(R) after, for example, three weeks of treatment. Fumaderm^(R) initial and Fumaderm^(R) are both enteric-coated tablets.

另一种市售组合物是Fumaraat120^，含有120mg富马酸二甲酯和95mg富马酸单乙酯钙(TioFarma，Oud-Beijerland，Netherlands)。在最近一份出版物中(Litjens et al.Br.J.Clin.Pharmacol.2004，vol.58：4，pp.429-432)，描述了Fumaraat120^在健康受试者中的药动学曲线。结果显示，在单次口服剂量的Fumaraat120^之后，血清富马酸单甲酯浓度上升，并且观察到可以忽略不计的富马酸二甲酯和富马酸浓度。这些结果表明，富马酸二甲酯在碱性环境中被迅速水解为富马酸单甲酯，但是根据作者的看法，在酸性环境中则不然。由于该组合物是肠溶衣型，可以设想富马酸酯的摄取主要发生在小肠中，在那里富马酸二甲酯在摄取之前由于碱性环境被水解为单酯，或者它可以在循环中由于酯酶被迅速转化。此外，该研究显示t_max和C_max受到食物的影响，也就是说伴随着食物摄取，t_max被延长(禁食条件的平均值为182min，而进食条件的平均值为361min)(禁食的滞后时间为90min，进食的滞后时间为300min)，C_max被降低(禁食：0.84mg/l，进食：0.48mg/l)。另一项利用两片Fumaderm^P forte在健康受试者中进行的研究(Reddingius W.G.Bioanalysis andPharmacokinetics of Fumarates in Humans.Dissertation ETHZurich No.12199(1997))揭示了C_max值(根据富马酸单乙酯或单甲酯测定)在1.0至2.4μg/ml范围内，t_max在4.8至6.0小时范围内。Another commercially available composition is Fumaraat 120^(R) , containing 120 mg dimethyl fumarate and 95 mg calcium monoethyl fumarate (TioFarma, Oud-Beijerland, Netherlands). In a recent publication (Litjens et al. Br. J. Clin. Pharmacol. 2004, vol. 58:4, pp. 429-432), the pharmacokinetic profile of Fumaraat120^(R) in healthy subjects was described . The results showed that after a single oral dose of Fumaraat 120^(R) , serum monomethyl fumarate concentrations rose and negligible concentrations of dimethyl fumarate and fumaric acid were observed. These results suggest that dimethyl fumarate is rapidly hydrolyzed to monomethyl fumarate in an alkaline environment but, according to the authors, not in an acidic environment. Since the composition is enteric-coated, it is conceivable that the uptake of fumarate mainly takes place in the small intestine, where dimethyl fumarate is hydrolyzed to monoesters due to the alkaline environment prior to ingestion, or it may be in the circulation are rapidly converted by esterases. In addition, the study showed that_tmax and_Cmax were affected by food, that is,_tmax was prolonged with food intake (mean of 182min in fasted conditions and 361min in fed conditions) (fasted With a lag time of 90 min and a fed lag time of 300 min), C_max was reduced (fasted: 0.84 mg/l, fed: 0.48 mg/l). Another study (Reddingius WGBioanalysis and Pharmacokinetics of Fumarates in Humans. Dissertation ETH Zurich No. 12199 (1997)) using two tablets of Fumaderm^(R) P forte in healthy subjects revealed_Cmax values (according to monoethyl fumarate or monomethyl ester assay) in the range of 1.0 to 2.4 μg/ml and t_max in the range of 4.8 to 6.0 hours.

US 6,277,882和US 6,355,676分别公开了富马酸氢烷基酯和某些富马酸单烷基酯盐的用途，用于制备治疗牛皮癣、牛皮癣性关节炎、神经皮炎和克罗恩氏局限性肠炎的微型片。US 6,509,376公开了某些富马酸二烷基酯的用途，用于制备用在移植医学或自身免疫疾病疗法中的药物制备物，为微型片或颗粒的形式。US 4,959,389公开了组合物，含有富马酸单烷基酯单独或者与富马酸二烷基酯的组合的不同盐。GB 1,153,927涉及医药组合物，包含二甲基马来酸酐和/或二甲基马来酸和/或二甲基富马酸化合物。来自BMC Dermatology，vol.2，no.5，2002的案例报道″Treatment of disseminated granuloma annularewith fumaric acid esters″涉及用富马酸酯治疗。US 6,277,882 and US 6,355,676 respectively disclose the use of hydroalkyl fumarate and certain monoalkyl fumarate salts for the preparation of psoriasis, psoriatic arthritis, neurodermatitis and Crohn's Crohn's enteritis of microchips. US 6,509,376 discloses the use of certain dialkyl fumarates for the preparation of pharmaceutical preparations for use in transplant medicine or therapy of autoimmune diseases, in the form of microtablets or granules. US 4,959,389 discloses compositions containing different salts of monoalkyl fumarates alone or in combination with dialkyl fumarates. GB 1,153,927 relates to pharmaceutical compositions comprising dimethylmaleic anhydride and/or dimethylmaleic acid and/or dimethylfumaric acid compounds. The case report "Treatment of disseminated granuloma annulare with fumaric acid esters" from BMC Dermatology, vol.2, no.5, 2002 involved treatment with fumarate.

不过，富马酸酯疗法、例如象Fumaderm^经常引起胃肠副作用，例如发胀、腹泻、上腹部绞痛、气胀和恶心。因此，需要开发包含一种或多种有治疗或预防活性的富马酸酯的组合物，它们提供改进的治疗，减少口服给药后的胃肠副作用。However, fumarate therapy, such as for example Fumaderm^(R) , often causes gastrointestinal side effects such as bloating, diarrhea, epigastric cramps, flatulence and nausea. Accordingly, there is a need to develop compositions comprising one or more therapeutically or prophylactically active fumarates which provide improved therapy with reduced gastrointestinal side effects following oral administration.

此外，目前商业上可获得的产品含有两种不同酯的组合，其中一种酯(也就是富马酸氢乙酯，它是富马酸的单乙基酯)以三种不同的盐形式存在(也就是钙盐、镁盐和锌盐)。尽管每种单个形式都可以具有其自身的治疗特性，不过如果可能的话提供更简单的产品将是有利的，目的是获得适合的治疗效果。Furthermore, currently commercially available products contain a combination of two different esters, one of which (namely ethyl hydrogen fumarate, which is the monoethyl ester of fumaric acid) exists as three different salts (i.e. calcium, magnesium and zinc salts). Although each individual form may have its own therapeutic properties, it would be advantageous if possible to provide a simpler product in order to obtain a suitable therapeutic effect.

本发明人设想，借助一种药物组合物的给药可以获得改进的治疗制度，该药物组合物被设计成以受控方式递送活性物质，也就是与商业上可获得的产品相比延长、延缓和/或延迟的方式。此外，设想利用单独的单一富马酸酯，例如二甲基富马酸，可以达到适合的治疗应答，代替使用不同富马酸酯的组合。The present inventors envisage that an improved therapeutic regime may be obtained by the administration of a pharmaceutical composition designed to deliver the active substance in a controlled manner, that is, prolonging, delaying and/or delayed manner. Furthermore, it is envisioned that a suitable therapeutic response may be achieved with a single fumarate alone, such as dimethyl fumarate, instead of using a combination of different fumarates.

附图的简要说明Brief description of the drawings

图1显示如实施例5所述制备的胶囊的体外溶解曲线实例。Figure 1 shows an example of an in vitro dissolution profile of a capsule prepared as described in Example 5.

图2显示如实施例16所述制备的片剂样品(在包肠溶衣之前)的体外溶解曲线实例。Figure 2 shows an example of the in vitro dissolution profile of a tablet sample prepared as described in Example 16 (prior to enteric coating).

图3显示如实施例17所述制备的片剂样品(在包肠溶衣之前)的体外溶解曲线实例。Figure 3 shows an example of the in vitro dissolution profile of a tablet sample prepared as described in Example 17 (prior to enteric coating).

发明内容Contents of the invention

因此，本发明涉及药物组合物，包含作为活性物质的一种或多种富马酸酯、选自富马酸的二-(C₁-C₅)烷基酯和富马酸的单-(C₁-C₅)烷基酯或者其药学上可接受的盐，它在口服给药后，与同等剂量Fumaderm^片口服给药后相比，减少GI(胃肠)副作用。Accordingly, the present invention relates to pharmaceutical compositions comprising as active substance one or more fumaric acid esters selected from di-(C₁ -C₅ )alkyl esters of fumaric acid and mono-( C₁ -C₅ ) alkyl esters or pharmaceutically acceptable salts thereof, which, after oral administration, reduce GI (gastrointestinal) side effects compared with oral administration of the same dose of Fumaderm^(R) tablets.

如上所述，本发明人设想适合于减少胃肠副作用的方式是活性物质以控释组合物的形式给药。As mentioned above, the inventors envisage that a suitable way to reduce gastrointestinal side effects is to administer the active substance in the form of a controlled release composition.

因此，本发明在另一方面涉及口用控释药物组合物，包含作为活性物质的一种或多种富马酸酯，选自富马酸的二-(C₁-C₅)烷基酯和富马酸的单-(C₁-C₅)烷基酯或者其药学上可接受的盐，其中富马酸酯在进行体外溶解试验时的释放如下，该试验在前2个小时期间采用0.1N盐酸作为溶解介质，然后以0.05M磷酸盐缓冲液pH6.5作为溶解介质：Accordingly, the present invention in a further aspect relates to a pharmaceutical composition for oral controlled release comprising as active substance one or more fumaric acid esters selected from the group consisting of di-(C₁ -C₅ )alkyl esters of fumaric acid and mono-(C₁ -C₅ ) alkyl esters of fumaric acid or pharmaceutically acceptable salts thereof, wherein the release of the fumaric acid esters during the in vitro dissolution test is as follows, which is used during the first 2 hours 0.1N hydrochloric acid as the dissolution medium, and then 0.05M phosphate buffer pH6.5 as the dissolution medium:

在试验开始后前3个小时内，该组合物所含有的富马酸酯总量至多有大约70％w/w被释放，和/或At most about 70% w/w of the total amount of fumarate contained in the composition is released within the first 3 hours after the start of the test, and/or

在试验开始后前4个小时内，富马酸酯的总量至多有大约92％w/w被释放，和/或Up to about 92% w/w of the total amount of fumarate is released within the first 4 hours after the start of the test, and/or

在试验开始后前5个小时内，富马酸酯的总量至多有大约94％w/w被释放，和/或Up to about 94% w/w of the total amount of fumarate is released within the first 5 hours after the start of the test, and/or

在试验开始后前6个小时内，该组合物所含有的富马酸酯总量至多有大约95％w/w被释放，和/或At most about 95% w/w of the total amount of fumarate contained in the composition is released within the first 6 hours after the start of the test, and/or

在试验开始后前7个小时内，该组合物所含有的富马酸酯总量至多有大约98％w/w被释放，和/或At most about 98% w/w of the total amount of fumarate contained in the composition is released within the first 7 hours after the start of the test, and/or

在试验开始后前9个小时内，该组合物所含有的富马酸酯总量至多有大约99％w/w被释放，和/或At most about 99% w/w of the total amount of fumarate contained in the composition is released within the first 9 hours after the start of the test, and/or

在试验开始后前12个小时内，该组合物所含有的富马酸酯总量至多有大约99％w/w被释放。Up to about 99% w/w of the total amount of fumarate contained in the composition is released within the first 12 hours after the start of the test.

在本文中，控释组合物是这样一种组合物，它被设计成当在可比条件下试验时(例如就体内研究而言：剂量相当，伴有或没有标准化膳食等，或者就体外研究而言：剂量相当，溶解试验装置和工作条件，例如包括所采用的溶解介质的组成、体积和温度，旋转速度等)，与商业上可获得的产品Fumaderm^相比，以延长、延缓和/或延迟的方式释放富马酸酯。As used herein, a controlled-release composition is a composition that is designed so that when tested under comparable conditions (e.g., for in vivo studies: comparable doses, with or without standardized diet, etc., or for in vitro studies) Statement: equivalent dosage, dissolution test apparatus and working conditions, for example including the composition, volume and temperature of the dissolution medium adopted, rotation speed, etc.), compared with the commercially available product Fumaderm^(R) , in order to prolong, delay and/or Release fumarate in a delayed manner.

体内释放可以如下测试，在预定时间测量血浆浓度，由此得到有关富马酸酯、或者如果相关的话其代谢产物的血浆浓度-时间曲线(例如在富马酸二甲酯的情况下，活性物质被想象为富马酸氢甲酯，也就是富马酸的单甲基酯)。此外，设想代谢已经发生在胃肠道内或者在穿过胃肠粘膜期间或者在首次通过肝循环之后。因此，当给予富马酸二甲酯时，所要在血浆中寻找的相关组分可能是富马酸的单甲基酯，而不是二甲基酯。The release in vivo can be tested by measuring the plasma concentration at predetermined times, whereby a plasma concentration-time profile of the relevant fumarate, or, if relevant, its metabolites (for example in the case of dimethyl fumarate, the active substance Think of it as methyl hydrogen fumarate, which is the monomethyl ester of fumaric acid). Furthermore, it is envisioned that metabolism already takes place in the gastrointestinal tract or during passage through the gastrointestinal mucosa or after the first pass through the hepatic circulation. Therefore, when dimethyl fumarate is administered, the relevant component to look for in plasma may be the monomethyl ester of fumarate, rather than the dimethyl ester.

也可以利用其他试验测定体内活性物质释放或者给出其量度。因而，可以使用动物(例如小鼠、大鼠、狗等)作为模型。动物接受所研究的组合物，在指定的时间之后处死动物，在血浆或特定器官中测定或者从肠内容物中提取活性成分(或其代谢产物，如果相关的话)的含量。Other tests can also be used to determine or give a measure of the active substance release in vivo. Thus, animals (eg, mice, rats, dogs, etc.) can be used as models. Animals receive the investigated compositions, sacrificed after indicated times, and the content of the active ingredient (or its metabolites, if relevant) is determined in the plasma or in specific organs or extracted from the intestinal contents.

另一项试验牵涉特定一段动物肠道的使用。将该段置于适合的溶解装置中，该装置含有两个舱(供体和受体)，被该段肠道分开，将所研究的组合物置于一个舱(供体舱)中的适合介质中。组合物将释放活性物质，随后跨越该肠段转运。因此，以适合的时间间隔测量受体舱中的活性物质(或者如果相关的话，代谢产物)浓度。Another trial involved the use of a specific section of the animal's gut. Place the segment in a suitable dissolution apparatus containing two compartments (donor and recipient), separated by the segment of intestine, and place the composition under study in a suitable medium in one compartment (donor compartment) middle. The composition will release the active substance, which is then transported across the intestinal tract. Therefore, the active substance (or if relevant, metabolite) concentration in the receptor compartment is measured at suitable time intervals.

本领域技术人员将能够根据特定组合物调整上述方法。Those skilled in the art will be able to adapt the above methods to a particular composition.

关于体外模型，有成熟的方法可用，尤其官方专著所述方法，例如美国药典(USP)或欧洲药典。本领域技术人员将知晓选择何种方法和如何选择特定条件来进行体外试验。例如，USP规定体外试验在37+/-1.0摄氏度下进行，例如37+/-0.5度。适合的溶解试验例如如实施例29关于胶囊所述，其中如美国药典所述在37℃下测定溶解曲线，使用100rpm的旋转篮，在试验的前2个小时期间采用0.1N盐酸作为溶解介质，然后在其余试验阶段以0.05M磷酸盐缓冲液pH6.5作为溶解介质，以及例如如实施例30关于片剂所述，其中如美国药典所述在37℃下测定溶解曲线，使用100rpm的桨式溶解装置，在试验的前2个小时期间采用0.1N盐酸作为溶解介质，然后在其余试验阶段以0.05M磷酸盐缓冲液pH6.5作为溶解介质。For in vitro models, well-established methods are available, especially those described in official monographs, such as the United States Pharmacopoeia (USP) or the European Pharmacopoeia. Those skilled in the art will know which method to choose and how to choose specific conditions for in vitro testing. For example, USP specifies that in vitro tests are performed at 37+/-1.0 degrees Celsius, eg 37+/-0.5 degrees. A suitable dissolution test is e.g. as described in Example 29 for capsules, wherein the dissolution profile is determined as described in the USP at 37°C, using a rotating basket at 100 rpm, using 0.1 N hydrochloric acid as the dissolution medium during the first 2 hours of the test, 0.05 M phosphate buffer pH 6.5 was then used as dissolution medium during the remaining test period and as described for example in Example 30 for tablets, wherein the dissolution profile was determined at 37°C as described in the USP using a 100 rpm paddle The dissolution apparatus used 0.1N hydrochloric acid as the dissolution medium during the first 2 hours of the test, and then 0.05M phosphate buffer pH 6.5 as the dissolution medium during the rest of the test period.

如上所述，活性物质的体内释放比商业上可获得的Fumaderm^组合物延长、延缓和/或延迟了。本文中，术语“延长”旨在表明在比Fumaderm^更长的时间期间释放活性物质，例如时间比Fumaderm^长至少1.2倍，例如至少1.5倍、至少2倍、至少3倍、至少4倍或至少5倍。因而，例如如果Fumaderm^片在适合的试验开始后3个小时释放100％富马酸二甲酯，那么根据本发明的组合物在适合的试验开始后至少3.6个小时释放100％富马酸二甲酯。As mentioned above, the in vivo release of the active substance is prolonged, delayed and/or delayed compared to commercially available Fumaderm^(R) compositions. Herein, the term "prolonged" is intended to indicate that the active substance is released over a longer period of time than Fumaderm(^R ), for example at least 1.2 times longer than Fumaderm(^R ), such as at least 1.5 times, at least 2 times, at least 3 times, at least 4 times or At least 5 times. Thus, for example, if Fumaderm^(R) tablets release 100% dimethyl fumarate 3 hours after the start of a suitable test, the composition according to the invention releases 100% dimethyl fumarate at least 3.6 hours after the start of a suitable test. methyl ester.

本文中，术语“延迟”旨在表明活性物质的释放开始于比Fumaderm^更晚的时间点(例如30min或更晚，例如45min或更晚、1小时或更晚或者1.5小时或更晚)，作为替代选择，前2个小时期间的初始释放大大少于Fumaderm^(也就是少于Fumaderm^的80％w/w，例如少于70％w/w、少于60％w/w或少于50％)。Herein, the term "delayed" is intended to indicate that the release of the active substance begins at a later point in time than Fumaderm⁽ R) (for example 30 min or later, for example 45 min or later, 1 hour or later or 1.5 hours or later), Alternatively, the initial release during the first 2 hours is substantially less than Fumaderm^(R) (that is, less than 80% w/w of^Fumaderm(R) , such as less than 70% w/w, less than 60% w/w or less than 50%).

本发明所用的胃肠(GI)副作用可以包括但不限于腹泻、胃痛、胃疼痛、腹部疼痛、腹部绞痛、恶心、气胀、里急后重、鼓胀、排便频率增加、发胀感和上腹部绞痛。Gastrointestinal (GI) side effects as used in the present invention may include, but are not limited to, diarrhea, stomach pain, stomach pain, abdominal pain, abdominal cramping, nausea, flatulence, tenesmus, bloating, increased frequency of bowel movements, feeling of fullness, and upper abdominal cramps .

本文重，GI副作用减少旨在表示与Fumaderm^给药后所观察到的GI副作用相比，根据本发明的组合物给药在接受治疗的患者群中降低严重性和/或发生率。按照这种定义，GI副作用的减少因而可以被解释为任意上述GI副作用的发生有实质性减少，例如发生减少了至少10％，或者更优选减少了至少20％，或者进而更优选减少了30％以上。GI副作用的减少也可以被表示为任意上述GI副作用的严重性有实质性减轻，例如腹泻、胃痛、胃疼痛、腹部疼痛、腹部绞痛、恶心、气胀、里急后重、鼓胀、排便频率增加、发胀感或上腹部绞痛的严重性和/或频率的减低。可以在临床试用环境中监测上述GI副作用的减少，比较根据本发明的组合物给药与Fumaderm^或安慰剂。在安慰剂对照的试用情况下，接受根据本发明的组合物的患者与安慰剂组比较GI副作用发生率，Fumaderm^与安慰剂比较历史试用，再比较二者(例如参见Altmeyer et al，J.Am.Acad.Dermatol.1994；完整参照：Altmeyer PJ et al，Antipsoriatic effect of fumaric acidderivatives.Results of amulticenter double-blind study in 100patients.J.Am.Acad.Dermatol.1994；30：977-81)。通常，在这样一种研究中包括牛皮癣患者，通常超过10％的体表面积将被牛皮癣感染(严重牛皮癣)。不过，也可以包括体表面积被感染2至10％的患者(中度牛皮癣)。也可以基于牛皮癣面积严重指数(PASI)选择患者。通常，包括PASI在一定范围内的患者，例如10与40之间，或者例如12与30之间，或者例如15与25之间。可以包括任意类型牛皮癣患者(慢性斑型、疹性滴状型、脓疱型、牛皮癣性红皮病或掌趾型)，但是在有些情况下仅包括慢性斑型患者。每一治疗组(根据本发明的组合物和Fumaderm^或安慰剂)大约15至20名患者在多数情况下是足够的，但是更优选地在每一研究分支中包括大约30至50名患者。总研究周期可以短达一天至一周，但是更优选地研究将进行8周至12周或者长达16周。副作用可以例如被评估为在每组中所报告的某种副作用总次数(与多少患者体验该副作用无关)，或者副作用可以被评估为体验某种副作用达一定次数的患者人数，例如在研究期间至少一次或至少两次或至少三次。此外，在研究中可以监测副作用的严重性，或者为了定性为副作用可能需要一定严重性的副作用。适宜于评估副作用严重性的方式是肉眼类似(VAS)评价。Herein, reduction of GI side effects is intended to mean that the administration of the composition according to the invention reduces the severity and/or incidence in the treated patient population compared to the GI side effects observed after administration of Fumaderm^(R ). According to this definition, a reduction in GI side effects may thus be interpreted as a substantial reduction in the occurrence of any of the above GI side effects, such as a reduction in the occurrence of at least 10%, or more preferably a reduction of at least 20%, or even more preferably a reduction of 30% above. A reduction in GI side effects can also be expressed as a substantial reduction in the severity of any of the above GI side effects, such as diarrhea, stomach pain, stomach pain, abdominal pain, abdominal cramping, nausea, gas, tenesmus, bloating, increased bowel frequency, diarrhea Reduction in the severity and/or frequency of bloating or upper abdominal cramps. The reduction of the aforementioned GI side effects can be monitored in a clinical trial setting, comparing administration of the composition according to the invention with Fumaderm^(R) or placebo. In the case of a placebo-controlled trial, patients receiving a composition according to the invention were compared with the placebo group for the incidence of GI side effects, Fumaderm^(R) versus placebo for historical trials, and both (see for example Altmeyer et al, J. Am. Acad. Dermatol. 1994; full reference: Altmeyer PJ et al, Antipsoriatic effect of fumaric acid derivatives. Results of multicenter double-blind study in 100 patients. J. Am. Acad. Dermatol. 1994; 30: 977-81). Typically, psoriasis patients are included in such a study, usually more than 10% of the body surface area will be infected with psoriasis (severe psoriasis). However, patients with 2 to 10% of the body surface area infected (moderate psoriasis) can also be included. Patients can also be selected based on the Psoriasis Area Severity Index (PASI). Typically, patients with a PASI within a certain range, such as between 10 and 40, or such as between 12 and 30, or such as between 15 and 25 are included. Patients with any type of psoriasis (chronic plaque, eruptive guttate, pustular, psoriatic erythroderma, or palmar toe) could be included, but in some cases only patients with chronic plaque were included. About 15 to 20 patients per treatment group (composition according to the invention and Fumaderm^(R) or placebo) is sufficient in most cases, but more preferably about 30 to 50 patients are included in each study arm. The total study period can be as short as one day to one week, but more preferably the study will run for 8 to 12 weeks or as long as 16 weeks. Side effects can be assessed, for example, as the total number of times a certain side effect was reported in each group (independent of how many patients experienced it), or side effects can be assessed as the number of patients who experienced a certain side effect a certain number of times, such as at least Once or at least twice or at least three times. In addition, the severity of side effects may be monitored during the study, or side effects of a certain severity may be required in order to qualify as side effects. A suitable means for assessing the severity of side effects is the visual analogue (VAS) assessment.

活性物质active substance

本发明组合物中的活性物质是任意富马酸酯。在一种发明实施方式中，富马酸酯优选地选自由富马酸二甲酯、富马酸二乙酯、富马酸二丙酯、富马酸二丁酯、富马酸二戊酯、富马酸甲基乙基酯、富马酸甲基丙基酯、富马酸甲基丁基酯、富马酸甲基戊基酯、富马酸单甲基酯、富马酸单乙基酯、富马酸单丙基酯、富马酸单丁基酯和富马酸单戊基酯组成的组，包括其药学上可接受的盐。The active substance in the compositions of the present invention is any fumarate. In one embodiment of the invention, fumarate is preferably selected from dimethyl fumarate, diethyl fumarate, dipropyl fumarate, dibutyl fumarate, dipentyl fumarate , methyl ethyl fumarate, methyl propyl fumarate, methyl butyl fumarate, methyl pentyl fumarate, monomethyl fumarate, monoethyl fumarate The group consisting of propyl fumarate, monopropyl fumarate, monobutyl fumarate and monoamyl fumarate, including pharmaceutically acceptable salts thereof.

在特定的发明实施方式中，富马酸酯是富马酸的单-(C₁-C₅)烷基酯，以药学上可接受的盐形式存在。适合的盐例如是金属盐，例如选自碱金属盐和碱土金属盐的盐，包括钠、钾、钙、镁或锌盐。In a particular embodiment of the invention, the fumarate is a mono-(C₁ -C₅ )alkyl fumaric acid ester in the form of a pharmaceutically acceptable salt. Suitable salts are, for example, metal salts, for example selected from alkali metal salts and alkaline earth metal salts, including sodium, potassium, calcium, magnesium or zinc salts.

术语(C₁-C₅)烷基表示分支或未分支的烷基，具有一至五个(含)碳原子，例如甲基、乙基、1-丙基、2-丙基、1-丁基、2-丁基、2-甲基-2-丙基、2-甲基-1-丙基和戊基。The term (C₁ -C₅ )alkyl denotes a branched or unbranched alkyl group having one to five carbon atoms (inclusive), for example methyl, ethyl, 1-propyl, 2-propyl, 1-butyl , 2-butyl, 2-methyl-2-propyl, 2-methyl-1-propyl and pentyl.

在另一种实施方式中，根据本发明的组合物包含富马酸二甲酯作为活性物质。In another embodiment, the composition according to the invention comprises dimethyl fumarate as active substance.

在另一实施方式中，根据本发明的组合物包含富马酸单甲基酯作为活性物质，可选地为药学上可接受的盐形式，例如它的钠、钾、钙、镁和/或锌盐。In another embodiment, the composition according to the invention comprises monomethyl fumarate as active substance, optionally in the form of a pharmaceutically acceptable salt, such as its sodium, potassium, calcium, magnesium and/or zinc salt.

在另一种实施方式中，根据本发明的组合物本质上由作为活性物质的富马酸二甲酯组成。In another embodiment, the composition according to the invention consists essentially of dimethyl fumarate as active substance.

在另一种实施方式中，根据本发明的组合物由作为活性物质的富马酸二甲酯组成。In another embodiment, the composition according to the invention consists of dimethyl fumarate as active substance.

在另一实施方式中，根据本发明的组合物本质上由作为活性物质的富马酸单甲酯组成，可选地为药学上可接受的盐，例如它的钠、钾、钙、镁和/或锌盐。In another embodiment, the composition according to the invention consists essentially of monomethyl fumarate as active substance, optionally a pharmaceutically acceptable salt such as its sodium, potassium, calcium, magnesium and / or zinc salts.

在另一实施方式中，根据本发明的组合物由作为活性物质的富马酸单甲酯组成，可选地为药学上可接受的盐，例如它的钠、钾、钙、镁和/或锌盐。In another embodiment, the composition according to the invention consists of monomethyl fumarate as active substance, optionally a pharmaceutically acceptable salt, such as its sodium, potassium, calcium, magnesium and/or zinc salt.

在另一实施方式中，根据本发明的组合物包含富马酸二甲酯和富马酸单甲酯(可选地为药学上可接受的盐，例如它的钠、钾、钙、镁和/或锌盐)作为活性物质，其重量比在约1∶10与约10∶1之间。In another embodiment, the composition according to the invention comprises dimethyl fumarate and monomethyl fumarate (optionally pharmaceutically acceptable salts such as its sodium, potassium, calcium, magnesium and /or zinc salt) as active substance in a weight ratio between about 1:10 and about 10:1.

在另一实施方式中，根据本发明的组合物本质上由作为活性物质的富马酸二甲酯和富马酸单甲酯(可选地为药学上可接受的盐，例如它的钠、钾、钙、镁和/或锌盐)组成，其重量比在约1∶10与约10∶1之间。In another embodiment, the composition according to the present invention consists essentially of dimethyl fumarate and monomethyl fumarate (optionally pharmaceutically acceptable salts such as its sodium, potassium, calcium, magnesium and/or zinc salts) in a weight ratio between about 1:10 and about 10:1.

在另一实施方式中，根据本发明的组合物由作为活性物质的富马酸二甲酯和富马酸单甲酯(可选地为药学上可接受的盐，例如它的钠、钾、钙、镁和/或锌盐)组成，其重量比在约1∶10与约10∶1之间。In another embodiment, the composition according to the present invention consists of dimethyl fumarate and monomethyl fumarate (optionally pharmaceutically acceptable salts such as its sodium, potassium, calcium, magnesium and/or zinc salts) in a weight ratio between about 1:10 and about 10:1.

美容和/或药物组合物Cosmetic and/or pharmaceutical compositions

本发明所解决的问题涉及在富马酸酯口服给药后出现胃肠副作用。通过延长和/或延迟活性物质从组合物中释放，可以想象活性物质在胃肠道特定部位的局部浓度减少了(与Fumaderm^相比)，进而引起胃肠副作用的减少。因此，如上所定义的能够延长和/或延缓富马酸酯释放的组合物落入本发明的范围。The problem addressed by the present invention relates to the occurrence of gastrointestinal side effects following oral administration of fumaric acid esters. By prolonging and/or delaying the release of the active substance from the composition, it is conceivable that the local concentration of the active substance in a specific part of the gastrointestinal tract is reduced (compared to Fumaderm^(R )), leading to a reduction in gastrointestinal side effects. Accordingly, compositions as defined above capable of prolonging and/or delaying the release of fumarate esters fall within the scope of the present invention.

这类组合物是技术人员熟知的，例如包括扩散控制性药物递送系统、渗透压控制性药物递送系统、可侵蚀性药物递送系统等。而且，有药业公司基于特定技术(例如上述)能够提供特定的组合物，具有特定的活性物质释放特征。因此，本领域技术人员一旦认识到关于确切药物物质的特定需求，将知晓如何得到适合的产品。举例而言，Eurand是这类提供技术方案的公司之一，目的是得到控释药物组合物，含有特定的活性物质，具有关于活性物质从组合物中释放的特定要求(例如参见http://www.eurand.com)。另一家公司是MacroMed，Inc.，它已经开发了一项牵涉所谓SQZgel^TM的技术(http://macromed.com，SQZgel^TM的作用机理是合并有外部包衣的pH-敏感性聚合物混合物。在胃的酸性环境中，该聚合物吸取水分和溶胀，包埋药物。一旦进入pH更高的肠道，该聚合物缓慢萎缩，或者以“dialed-in”速率压缩，以持续方式释放活性组合物)，或者Egaleta/s，它拥有一项特定的挤出类技术(http://www.egalet.com，Egalet^技术的关键要素是生物可降解的包衣和基质，包含活性药物，它是表面可侵蚀的、疏水性的，由PEG-硬脂酸酯组成。Egalet^技术之一是2K Egalet^恒定释放系统，它是由包衣和基质组成的2-组分生产模型。药物均匀分布于Egalet^基质，随时间恒定释放。本文也关注如下技术，例如Eurand的技术Diffucaps(将活性药物层压到中性核上，例如糖球、晶体或颗粒，继之以速率-控制性功能性膜，创建药物释放曲线。Diffucaps/Surecaps珠粒的尺寸较小，直径大约1mm或以下。通过向硬明胶胶囊结合不同药物释放曲线的珠粒，能够达到组合释放曲线)、Diffutabs(Diffutab技术结合了亲水性聚合物的掺合物，它通过基质片的扩散和侵蚀控制药物释放)、Minitabs(EurandMinitabs是微小(2mm×2mm)的片剂，含有控制药物释放速率的凝胶-生成性赋形剂。可以加入附加的膜，以进一步控制释放速率)、Orbexa(这种技术利用限定类造粒挤出和球体化工艺生产受控大小和密度的珠粒。所得珠粒能够包以释放速率控制膜，以进一步控制释放速率，并且可以填充到胶囊中或者以药囊形式提供)和SDS(Eurand的SDS技术使用功能性聚合物或者功能性聚合物与特定添加剂的组合，例如复合聚合材料，以沿着肠道递送药物至最佳吸收部位。为此，Eurand首先生产多微粒剂型，例如Diffucaps或Eurand Minitabs，它们结合有活性药物。然后将这些剂型包以pH依赖性/独立性聚合膜，将递送药物至所需部位。然后将它们填充到硬明胶胶囊中)。Such compositions are well known to the skilled artisan and include, for example, diffusion-controlled drug delivery systems, osmolarity-controlled drug delivery systems, erodible drug delivery systems, and the like. Moreover, there are pharmaceutical companies that are able to provide specific compositions based on specific technologies (such as those mentioned above), with specific release characteristics of the active substance. Thus, once a person skilled in the art recognizes the specific requirements regarding the exact drug substance, he will know how to obtain a suitable product. For example, Eurand is one of such companies offering technical solutions for the purpose of obtaining controlled release pharmaceutical compositions, containing specific active substances, with specific requirements regarding the release of active substances from the composition (see for examplehttp:// www.eurand.com ). Another company is MacroMed, Inc., which has developed a technology involving the so-called SQZgel^™ (http://macromed.com)^, the mechanism of action of which is a pH-sensitive polymer mixture incorporating an external coating. In the acidic environment of the stomach, the polymer absorbs water and swells, entrapping the drug. Once in the higher pH intestine, the polymer slowly shrinks, or compresses at a "dialed-in" rate, releasing the active combination in a sustained manner material), or Egaleta/s, which has a specific extrusion-like technology (http://www.egalet.com , the key element of the Egalet^® technology is the biodegradable coating and matrix, containing the active drug, which Is surface erodible, hydrophobic, composed of PEG-stearate. One of the Egalet^(R) technologies is the 2K Egalet^(R) constant release system, which is a 2-component production model consisting of coating and matrix. Drug uniformity Distributed in Egalet^(R) matrix, constant release over time. This article also focuses on technologies such as Eurand's technology Diffucaps (lamination of active drug onto neutral cores, such as sugar spheres, crystals or granules, followed by rate-controlled functional Diffutabs/Surecaps beads are small in size, about 1mm or less in diameter. Combination release profiles can be achieved by combining beads with different drug release profiles into hard gelatin capsules), Diffutabs (Diffutab technology combined blends of hydrophilic polymers that control drug release through diffusion and erosion of the matrix tablet), Minitabs (Eurand Minitabs are tiny (2mm x 2mm) tablets containing gel-forming excipients that control the rate of drug release. Additional membranes can be added to further control the release rate), Orbexa (this technology utilizes a defined granulation-like extrusion and spheroidization process to produce beads of controlled size and density. The resulting beads can be packaged with a release rate Control membranes to further control the release rate and can be filled into capsules or provided in sachet form) and SDS (Eurand's SDS technology uses functional polymers or a combination of functional polymers with specific additives, such as composite polymeric materials, to deliver the drug along the intestinal tract to the site of optimal absorption. To this end, Eurand first produces multiparticulate dosage forms, such as Diffucaps or Eurand Minitabs, which incorporate the active drug. These dosage forms are then coated with a pH-dependent/independent polymeric membrane, will deliver the drug to the desired site. They are then filled into hard gelatin capsules).

另一种用于配制根据本发明的组合物的技术是所谓的MeltDose^技术，如WO03/004001所述(参见http://www.lifecyclepharma.com。MeltDose^牵涉将经过增溶的单个分子配制成片剂。通过配制单个的分子，消除了低水溶性药物口服吸收的主要限制，能够实现优异的生物利用度)。通过采用这种技术，有可能得到适合于加工成各种药物剂型的微粒材料，例如颗粒或片剂的形式。此外，该技术适合使用，因为有可能得到适合的活性物质释放曲线，例如本文所述那些释放曲线。在一种实施方式中，适合使用的颗粒可以具有大于2000μm的平均粒径。在另一种实施方式中，适合使用的颗粒可以具有约0.01μm至约250μm的平均粒径。Another technology for formulating the compositions according to the invention is the so-called MeltDose^(R) technology, as described in WO03/004001 (seehttp://www.lifecyclepharma.com . MeltDose^(R) involves the formulation of solubilized individual molecules Tablets. By formulating individual molecules, the major limitation of oral absorption of drugs with low water solubility is eliminated, enabling excellent bioavailability). By employing this technique, it is possible to obtain particulate materials suitable for processing into various pharmaceutical dosage forms, for example in the form of granules or tablets. Furthermore, this technique is suitable for use, since it is possible to obtain suitable active substance release profiles, such as those described herein. In one embodiment, particles suitable for use may have an average particle size greater than 2000 μm. In another embodiment, particles suitable for use may have an average particle size of from about 0.01 μm to about 250 μm.

另一种特别适合用在本文中的制剂原理是在亲脂性环境中配制，例如软明胶胶囊。这种制剂原理的一种适合实例是来自Scherer的Vegicaps Soft(基于角叉菜胶和淀粉的软胶囊技术，尽管是100％植物来源的，仍然提供传统软明胶胶囊的所有关键属性。它们包括柔软和柔韧的剂型，容易吞咽)(进一步的信息参见http://www.rpscherer.de/page.php？pageID＝94)。Another formulation principle that is particularly suitable for use herein is formulation in a lipophilic environment, such as soft gelatin capsules. A suitable example of this formulation principle is Vegicaps Soft from Scherer (soft capsule technology based on carrageenan and starch which, despite being 100% vegetable derived, still provides all the key attributes of traditional soft gelatin capsules. They include soft and flexible dosage form, easy to swallow) (for further information seehttp://www.rpscherer.de/page.php?pageID=94 ).

另一适合的制剂的特定实例包含活性物质与维生素E浓缩物一起在软或硬明胶胶囊中的制剂。这种制剂的改进形式是商品环孢菌素Neoral^的基础，除了环孢菌素以外还尤其含有玉米油-单-二-三甘油酯、聚氧40氢化蓖麻油NF、DL-α-生育酚USP(维生素E家族的一部分)、明胶NF、甘油、氧化铁黑、丙二醇USP、二氧化钛USP、胭脂红和酒精。Another specific example of a suitable formulation comprises the formulation of the active substance in soft or hard gelatin capsules together with vitamin E concentrate. A modified form of this formulation is the basis of the commercial cyclosporine Neoral^(R) , which contains, in addition to cyclosporin, inter alia corn oil-mono-di-triglycerides, polyoxygen 40 hydrogenated castor oil NF, DL-α-tocopheryl Phenol USP (part of the Vitamin E family), Gelatin NF, Glycerin, Black Iron Oxide, Propylene Glycol USP, Titanium Dioxide USP, Carmine and Alcohol.

另一适合的制剂的特定实例包含活性物质与乙醇、生育酚乙二醇1000琥珀酸酯(TPGS)、玉米油和蜡在软或硬明胶胶囊中的制剂。这种产品可以是半固体或固体剂型。这种制剂的释放速率依赖于肠中脂酶的降解作用。Another specific example of a suitable formulation comprises the formulation of the active substance with ethanol, tocopheryl glycol 1000 succinate (TPGS), corn oil and wax in soft or hard gelatin capsules. This product can be in semi-solid or solid dosage form. The release rate of this formulation is dependent on the degradation by lipases in the intestine.

另一适合的制剂实例包含活性物质与乙醇、生育酚乙二醇1000琥珀酸酯(TPGS)、玉米油和聚乙二醇化甘油酯(例如Gelucire)在软或硬明胶胶囊中的制剂。这种产品可以是半固体或固体剂型。这种制剂的释放速率依赖于肠中脂酶的降解作用。Another example of a suitable formulation comprises the active substance in soft or hard gelatin capsules with ethanol, tocopheryl glycol 1000 succinate (TPGS), corn oil and polyethylene glycolated glycerides (eg Gelucire). This product can be in semi-solid or solid dosage form. The release rate of this formulation is dependent on the degradation by lipases in the intestine.

另一适合的制剂实例是口服脉冲剂量药物递送系统。这种剂型可以被视为Schering Repetab片剂的改进形式。一部分本发明组合物被放置在片芯中。Another example of a suitable formulation is an oral pulse dose drug delivery system. This dosage form can be considered an improved form of Schering Repetab tablets. A portion of the composition of the invention is placed in the tablet core.

片芯例如可以由常规湿法造粒或连续造粒制成，例如挤出继之以颗粒压制成片。然后利用适当的技术包衣，优选空气悬浮，使用肠溶衣聚合物，例如Eudragits。Tablet cores can be made, for example, by conventional wet or continuous granulation, eg extrusion followed by compression of the granules to form tablets. It is then coated using an appropriate technique, preferably air suspension, using an enteric coating polymer such as Eudragits.

第一释放剂量被压在片芯上，或者被空气悬浮包以肠溶衣或者包在肠溶衣上。在一种发明实施方式中，第一释放剂量被空气悬浮包以肠溶衣。在另一发明实施方式中，第一释放剂量被压在片芯上，目的是避免根据本发明的组合物在肠溶衣降解之前释放，这类降解通常发生在比胃室更高的pH值下；也就是说，肠溶衣的降解通常发生在通过胃室之后。The first release dose is compressed onto a tablet core, either air-suspended or enteric-coated. In one embodiment of the invention, the first release dose is air-suspension coated with an enteric coating. In another embodiment of the invention, the first release dose is compressed on the tablet core in order to avoid the release of the composition according to the invention before the degradation of the enteric coating, which usually occurs at a higher pH than the gastric chamber down; that is, degradation of enteric coatings usually occurs after passage through the gastric chamber.

另一适合的制剂实例是口服持续药物递送系统。一部分本发明组合物被放置在片芯中。Another example of a suitable formulation is an oral sustained drug delivery system. A portion of the composition of the invention is placed in the tablet core.

片芯例如可以由常规湿法造粒或连续造粒制成，例如挤出继之以颗粒压制成片。然后利用适当的技术包衣，优选空气悬浮，使用乙基纤维素和亲水性赋形剂，例如羟丙基纤维素(HPC)。Tablet cores can be made, for example, by conventional wet or continuous granulation, eg extrusion followed by compression of the granules to form tablets. It is then coated using an appropriate technique, preferably air suspension, using ethylcellulose and a hydrophilic excipient such as hydroxypropylcellulose (HPC).

第一释放剂量被压在片芯上，或者被空气悬浮包以肠溶衣或者包在肠溶衣上。在优选的发明实施方式中，第一释放剂量被空气悬浮包以肠溶衣。在另一发明实施方式中，第一释放剂量被压在片芯上，目的是避免根据本发明的组合物在肠溶衣降解之前释放，这类降解通常发生在比胃室更高的pH值下；也就是说，肠溶衣的降解通常发生在通过胃室之后。The first release dose is compressed onto a tablet core, either air-suspended or enteric-coated. In a preferred embodiment of the invention, the first release dose is air-suspension coated with an enteric coating. In another embodiment of the invention, the first release dose is compressed on the tablet core in order to avoid the release of the composition according to the invention before the degradation of the enteric coating, which usually occurs at a higher pH than the gastric chamber down; that is, degradation of enteric coatings usually occurs after passage through the gastric chamber.

另一适合的制剂实例是经由晶体工程得到的，例如WO03/080034所述，引用在此作为参考。Another example of a suitable formulation is obtained via crystal engineering, eg as described in WO03/080034, incorporated herein by reference.

因此，在另一种实施方式中，本发明组合物包含具有亲水性表面的微晶形式活性物质。此外，在另一种发明实施方式中，微晶是直接膜包衣的，目的是实现持续释放制剂。Thus, in another embodiment, the compositions of the present invention comprise the active substance in microcrystalline form having a hydrophilic surface. Furthermore, in another embodiment of the invention, the microcrystals are directly film coated in order to achieve a sustained release formulation.

另一适合的制剂的特定实例包含根据本发明的组合物与真环糊精和环糊精衍生物(例如烷基-和羟基烷基-衍生物或磺基丁基-衍生物)的配合物。配合物是按照熟知的方法实现的。设想这样一种配合物引起根据本发明的组合物与配位化合之前相比具有更高的溶解度和更高的溶解速率。此外，设想这样一种配合物引起根据本发明的组合物与配位化合之前相比具有更高的生物利用度。Another specific example of a suitable formulation comprises complexes of the composition according to the invention with true cyclodextrins and cyclodextrin derivatives, such as alkyl- and hydroxyalkyl-derivatives or sulfobutyl-derivatives . The complexes are achieved according to well-known methods. It is envisaged that such a complex leads to a higher solubility and a higher dissolution rate of the composition according to the invention than before the complexation. Furthermore, it is envisaged that such a complex leads to a higher bioavailability of the composition according to the invention than before the complexation.

在特定的实施方式中，本发明涉及控释药物组合物，它可以被每日给药一次、两次或多次，例如每日一次或两次或三次。此外，组合物可以被设计成相对独立于pH地释放富马酸酯，也就是说释放不依赖于胃肠道中的pH。这类组合物的实例例如是固体剂型形式的组合物(例如片剂、胶囊、颗粒、珠粒等)，它们包有控释包衣。适合于控释包衣的材料例如是纤维素和纤维素衍生物，包括甲基纤维素、乙基纤维素和乙酸纤维素，或者聚(乙烯-共-乙酸乙烯酯)、聚(氯乙烯)。In a particular embodiment, the invention relates to controlled release pharmaceutical compositions, which may be administered once, twice or more times per day, for example once or twice or three times per day. Furthermore, the composition can be designed to release the fumarate relatively independently of pH, that is, the release is not dependent on the pH in the gastrointestinal tract. Examples of such compositions are, for example, compositions in solid dosage form (eg tablets, capsules, granules, beads, etc.), which are coated with a release-controlling coating. Materials suitable for controlled release coatings are, for example, cellulose and cellulose derivatives including methylcellulose, ethylcellulose and cellulose acetate, or poly(ethylene-co-vinyl acetate), poly(vinyl chloride) .

富马酸酯从包有扩散控制膜的组合物中释放通常分三个步骤发生：The release of fumarate from a composition coated with a diffusion controlling membrane usually occurs in three steps:

i)首先，(来自GI道的)水从周围环境扩散进入剂型，i) First, water (from the GI tract) diffuses from the surrounding environment into the dosage form,

ii)其次，至少一些存在于剂型中的富马酸酯被水的作用溶解，ii) secondly, at least some of the fumarate present in the dosage form is dissolved by the action of water,

iii)已溶解的富马酸酯从剂型中扩散出来，进入周围环境(也就是GI道)。iii) The dissolved fumarate diffuses out of the dosage form into the surrounding environment (ie GI tract).

其他实例例如包括基质片或者含有大量各自为基质系统形式的单元的剂型。活性物质被包埋在基质中，基质例如含有纤维素和纤维素衍生物，包括微晶纤维素、羟丙基甲基纤维素、羟丙基纤维素和甲基纤维素，聚维酮、聚(氧乙烯)(PEO)、聚乙二醇(PEG)、聚(乙烯醇)(PVA)、黄原胶、角叉菜胶和其他合成材料。可以向基质组合物加入在正常情况下用作药学上可接受的赋形剂或添加剂的物质。Other examples include, for example, matrix tablets or dosage forms comprising a plurality of units each in the form of a matrix system. The active substance is embedded in a matrix containing, for example, cellulose and cellulose derivatives, including microcrystalline cellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose and methylcellulose, povidone, polyvinylcellulose (ethylene oxide) (PEO), polyethylene glycol (PEG), poly(vinyl alcohol) (PVA), xanthan gum, carrageenan, and other synthetic materials. Substances normally used as pharmaceutically acceptable excipients or additives may be added to the matrix composition.

其他适合的组合物实例例如是水凝胶，也就是整体(monolithic)系统，其中活性物质被包埋在水可溶胀性网络聚合物中。适合使用的材料例如包括亲水性乙烯基与丙烯酸聚合物，多糖、象藻酸盐，和聚(氧乙烯)。Other examples of suitable compositions are eg hydrogels, ie monolithic systems in which the active substance is embedded in a water-swellable network polymer. Materials suitable for use include, for example, hydrophilic vinyl and acrylic polymers, polysaccharides, like alginates, and poly(oxyethylene).

在特定的实施方式中，根据本发明的组合物具有富马酸酯的pH控制性释放(也称为pH依赖性释放)。在正常情况下，释放被设计成只有少量(如果有的话)富马酸酯在胃(pH至多约3)中被释放，而富马酸酯在肠(pH变为约6-7)中被释放。通过为本发明组合物提供肠溶衣(全部组合物，或者如果组合物是多微粒组合物的单个单元)，或者通过提供借助pH-依赖性渗透机理或采用适合的酶释放富马酸的组合物，可以获得这样一种pH控制性释放。In a particular embodiment, the composition according to the invention has a pH-controlled release (also called pH-dependent release) of the fumaric acid ester. Under normal conditions, the release is designed so that only a small amount, if any, of the fumarate is released in the stomach (pH up to about 3) and the fumarate in the intestine (pH changes to about 6-7) released. By providing the compositions of the invention with an enteric coating (the entire composition, or if the composition is a single unit of a multiparticulate composition), or by providing a combination of fumaric acid release via a pH-dependent osmotic mechanism or using a suitable enzyme substances, such a pH-controlled release can be obtained.

适合用作肠溶衣材料的物质实例包括聚丙烯酰胺；邻苯二酸酯衍生物，例如碳水化合物的酸式邻苯二酸酯、乙酸直链淀粉邻苯二酸酯、乙酸纤维素邻苯二酸酯、其他纤维素酯邻苯二酸酯、纤维素醚邻苯二酸酯、羟丙基纤维素邻苯二酸酯、羟丙基乙基纤维素邻苯二酸酯、羟丙基甲基纤维素邻苯二酸酯、甲基纤维素邻苯二酸酯、聚乙酸乙烯酯邻苯二酸酯；聚丙烯酸异丁烯酸共聚物；虫胶；乙酸乙烯酯和巴豆酸共聚物等。Examples of substances suitable for use as enteric coating materials include polyacrylamides; phthalate derivatives such as acid phthalates of carbohydrates, acetate amylose phthalate, cellulose acetate phthalate Diesters, Other Cellulose Esters Phthalates, Cellulose Ether Phthalates, Hydroxypropyl Cellulose Phthalate, Hydroxypropyl Ethyl Cellulose Phthalate, Hydroxypropyl Cellulose Phthalate Methylcellulose phthalate, methylcellulose phthalate, polyvinyl acetate phthalate; polyacrylic acid methacrylate copolymer; shellac; vinyl acetate and crotonic acid copolymer, etc.

上述具有pH独立性释放的组合物也可以被配制成例如通过为组合物提供外层肠溶衣来释放富马酸酯。The above pH-independent release compositions may also be formulated to release fumarate, for example by providing the composition with an outer enteric coating.

此外，可以以这样一种方式配制组合物，以获得富马酸酯释放的初始延迟。例如通过选择以时间-控制性方式降解(例如侵蚀)的最外层包衣，可以获得这样一种延迟，并且仅当这种最外层包衣被侵蚀掉时，富马酸酯的释放才开始。Furthermore, the composition can be formulated in such a way as to obtain an initial delay in the release of the fumarate. Such a delay can be obtained, for example, by selecting an outermost coating that degrades (e.g., erodes) in a time-controlled manner, and only when this outermost coating is eroded away does the fumarate release occur. start.

下面给出各种根据本发明的组合物的说明，它们被设计成获得适合的富马酸酯释放。基于上述说明和药物控释领域内的手册，本领域技术人员将知晓如何选择不同的制剂原理，目的是达到所需的释放特性。A description is given below of various compositions according to the invention, which are designed to obtain a suitable fumarate release. Based on the above descriptions and handbooks in the field of drug controlled release, those skilled in the art will know how to choose different formulation principles in order to achieve the desired release characteristics.

被设计成每日给药两次或多次的组合物Compositions designed to be administered two or more times daily

pH独立性释放pH independent release

下面给出特定实施方式的说明，其中富马酸酯独立于pH地被释放，并且其中释放模式适合于每日给药两次或多次的组合物。适合的制剂原理实例例如是带有扩散包衣、例如控释扩散包衣的组合物、基质微粒或基质片、水凝胶、脉冲剂量药物递送系统、与维生素E浓缩物或乙醇、TPGS、玉米油和蜡等的共同制剂，包括任意上述制剂原理。A description is given below of specific embodiments wherein the fumarate is released independently of pH and wherein the release profile is suitable for compositions that are administered two or more times per day. Examples of suitable formulation principles are e.g. compositions with diffusion coatings, e.g. controlled release diffusion coatings, matrix particles or matrix tablets, hydrogels, pulsatile drug delivery systems, with vitamin E concentrate or ethanol, TPGS, corn Co-formulations of oils and waxes, etc., including any of the above formulation principles.

因此，本发明在一方面涉及口用控释药物组合物，包含作为活性物质的一种或多种富马酸酯，选自富马酸的二-(C₁-C₅)烷基酯和富马酸的单-(C₁-C₅)烷基酯或者其药学上可接受的盐，其中富马酸酯在进行采用水作为溶解介质的体外溶解试验时的释放如下：Accordingly, the present invention relates in one aspect to a pharmaceutical composition for oral controlled release comprising as active substance one or more fumaric acid esters selected from the group consisting of di-(C₁ -C₅ )alkyl esters of fumaric acid and A mono-(C₁ -C₅ ) alkyl ester of fumaric acid or a pharmaceutically acceptable salt thereof, wherein the release of the fumaric acid ester in an in vitro dissolution test using water as the dissolution medium is as follows:

在试验开始后前6个小时内，该组合物所含有的富马酸酯总量至多有大约60％w/w被释放，例如大约30％至大约60％w/w、大约40％至大约55％w/w或者大约50％w/w，和/或Within the first 6 hours after the start of the test, at most about 60% w/w of the total amount of fumarate contained in the composition is released, such as about 30% to about 60% w/w, about 40% to about 55% w/w or about 50% w/w, and/or

在试验开始后前9个小时内，该组合物所含有的富马酸酯总量至多有大约85％w/w被释放，例如大约50％至大约85％w/w、大约60％至大约80％w/w或者大约75％w/w，和/或Within the first 9 hours after the start of the test, at most about 85% w/w of the total amount of fumarate contained in the composition is released, such as about 50% to about 85% w/w, about 60% to about 80% w/w or about 75% w/w, and/or

在试验开始后前12个小时内，该组合物所含有的富马酸酯总量至少有大约80％w/w被释放，例如大约80％w/w或以上、大约85％w/w或以上、大约90％w/w或以上或者大约95％w/w或以上，和/或Within the first 12 hours after the start of the test, at least about 80% w/w of the total amount of fumarate contained in the composition is released, such as about 80% w/w or more, about 85% w/w or More than, about 90% w/w or more, or about 95% w/w or more, and/or

组合物所含有的富马酸酯总量在试验开始后前12个小时内被释放。The total amount of fumarate contained in the composition is released within the first 12 hours after the start of the test.

pH控制性释放pH controlled release

下面给出特定实施方式的说明，其中富马酸酯依赖于pH地被释放，并且其中释放模式适合于每日给药两次或多次的组合物。适合的制剂原理实例例如是带有肠溶衣或者Zentner等(US 6,537,584)和Bae(US 5,484,610)所述类型水凝胶的组合物，引用在此作为参考。其他适合的制剂原理实例例如是带有扩散包衣、例如控释扩散包衣的组合物、基质微粒或基质片、水凝胶、脉冲剂量药物递送系统、与维生素E浓缩物或乙醇、TPGS、玉米油和蜡等的共同制剂，包括任意上述制剂原理，可选地带有肠溶衣。A description is given below of specific embodiments in which the fumarate is released in a pH-dependent manner and in which the release profile is suitable for compositions that are administered two or more times per day. Examples of suitable formulation principles are eg compositions with enteric coatings or hydrogels of the type described by Zentner et al. (US 6,537,584) and Bae (US 5,484,610), incorporated herein by reference. Examples of other suitable formulation principles are e.g. compositions with diffusion coatings, such as controlled release diffusion coatings, matrix particles or matrix tablets, hydrogels, pulsatile drug delivery systems, with vitamin E concentrate or ethanol, TPGS, Co-formulations of corn oil and waxes etc., including any of the above formulation principles, optionally with an enteric coating.

因此，本发明在一方面涉及口用控释药物组合物，包含作为活性物质的一种或多种富马酸酯，选自富马酸的二-(C₁-C₅)烷基酯和富马酸的单-(C₁-C₅)烷基酯或者其药学上可接受的盐，其中富马酸酯在进行体外溶解试验时的释放如下，该试验在前2个小时期间采用0.1N盐酸作为溶解介质，然后以0.05M磷酸盐缓冲液pH6.5或6.8作为溶解介质：Accordingly, the present invention relates in one aspect to a pharmaceutical composition for oral controlled release comprising as active substance one or more fumaric acid esters selected from the group consisting of di-(C₁ -C₅ )alkyl esters of fumaric acid and Mono-(C₁ -C₅ ) alkyl esters of fumaric acid or pharmaceutically acceptable salts thereof, wherein the release of fumaric acid esters in an in vitro dissolution test using a 0.1 N hydrochloric acid as the dissolution medium, and then 0.05M phosphate buffer pH6.5 or 6.8 as the dissolution medium:

在试验开始后前2个小时内，富马酸酯的总量至少有大约1％w/w被释放，例如至少大约2％w/w、至少大约3％w/w或者大约5％w/w，和/或Within the first 2 hours after the start of the test, at least about 1% w/w of the total amount of fumarate is released, such as at least about 2% w/w, at least about 3% w/w or about 5% w/ w, and/or

在试验开始后前3个小时内，富马酸酯的总量至多有大约35％w/w被释放，例如大约15％至大约35％w/w、大约20％至大约30％w/w或者大约25％w/w，和/或Up to about 35% w/w of the total amount of fumarate is released, such as about 15% to about 35% w/w, about 20% to about 30% w/w, within the first 3 hours after the start of the test or about 25% w/w, and/or

在试验开始后前3个小时内，富马酸酯的总量有大约10％至大约70％w/w、大约10％至大约65％w/w、大约10％至大约60％w/w、大约15％至大约50％w/w、大约15％至大约35％w/w、大约20％至大约30％w/w或者大约20％w/w或大约25％w/w被释放，和/或The total amount of fumarate is about 10% to about 70% w/w, about 10% to about 65% w/w, about 10% to about 60% w/w within the first 3 hours after the start of the test , about 15% to about 50% w/w, about 15% to about 35% w/w, about 20% to about 30% w/w or about 20% w/w or about 25% w/w are released, and / or

在试验开始后前4个小时内，富马酸酯的总量至多有大约92％w/w被释放，例如大约10％至大约92％w/w、大约20％至大约85％w/w、大约20％至大约80％w/w、大约20％至大约70％w/w、大约25％至大约60％w/w、大约25％至大约55％w/w、大约30％至大约50％w/w或者大约35％w/w或大约40％w/w或大约45％w/w，和/或Up to about 92% w/w of the total amount of fumarate is released, such as about 10% to about 92% w/w, about 20% to about 85% w/w, within the first 4 hours after the start of the test , about 20% to about 80% w/w, about 20% to about 70% w/w, about 25% to about 60% w/w, about 25% to about 55% w/w, about 30% to about 50% w/w or about 35% w/w or about 40% w/w or about 45% w/w, and/or

在试验开始后前5个小时内，富马酸酯的总量至多有大约94％w/w被释放，例如大约15％至大约94％w/w、大约25％至大约90％w/w、大约30％至大约85％w/w、大约35％至大约80％w/w、大约35％至大约75％w/w、大约40％至大约70％w/w、大约45％至大约70％w/w、大约55％至大约70％w/w、大约60％至大约70％w/w或者大约45％w/w或大约50％w/w或大约55％w/w或大约60％w/w或大约65％w/w，和/或Up to about 94% w/w of the total amount of fumarate is released, such as about 15% to about 94% w/w, about 25% to about 90% w/w, within the first 5 hours after the start of the test , about 30% to about 85% w/w, about 35% to about 80% w/w, about 35% to about 75% w/w, about 40% to about 70% w/w, about 45% to about 70% w/w, about 55% to about 70% w/w, about 60% to about 70% w/w, or about 45% w/w, or about 50% w/w, or about 55% w/w, or about 60% w/w or about 65% w/w, and/or

在试验开始后前6个小时内，该组合物所含有的富马酸酯总量至多有大约60％w/w被释放，例如大约30％至大约60％w/w、大约40％至大约55％w/w或者大约50％w/w，和/或Within the first 6 hours after the start of the test, at most about 60% w/w of the total amount of fumarate contained in the composition is released, such as about 30% to about 60% w/w, about 40% to about 55% w/w or about 50% w/w, and/or

在试验开始后前6个小时内，该组合物所含有的富马酸酯总量至多有大约95％w/w被释放，例如大约35％至大约95％w/w、大约40％至大约90％w/w、大约45％至大约85％w/w、大约50％至大约85％w/w、大约55％至大约85％w/w、大约60％至大约85％w/w、大约65％至大约85％w/w、大约70％至大约85％w/w、大约75％至大约85％w/w或者大约65％w/w或大约70％w/w或大约75％w/w或大约80％w/w，和/或Within the first 6 hours after the start of the test, at most about 95% w/w of the total amount of fumarate contained in the composition is released, such as from about 35% to about 95% w/w, from about 40% to about 90% w/w, about 45% to about 85% w/w, about 50% to about 85% w/w, about 55% to about 85% w/w, about 60% to about 85% w/w, about 65% to about 85% w/w, about 70% to about 85% w/w, about 75% to about 85% w/w, or about 65% w/w or about 70% w/w or about 75% w/w or about 80% w/w, and/or

在试验开始后前7个小时内，该组合物所含有的富马酸酯总量至多有大约98％w/w被释放，例如大约45％至大约98％w/w、大约50％至大约98％w/w、大约55％至大约98％w/w、大约60％至大约98％w/w、大约65％至大约98％w/w、大约70％至大约98％w/w、大约75％至大约95％w/w、大约80％至大约95％w/w、大约85％至大约95％w/w或者大约75％w/w或大约80％w/w或大约85％w/w或大约90％w/w，和/或Within the first 7 hours after the start of the test, at most about 98% w/w of the total amount of fumarate contained in the composition is released, such as about 45% to about 98% w/w, about 50% to about 98% w/w, about 55% to about 98% w/w, about 60% to about 98% w/w, about 65% to about 98% w/w, about 70% to about 98% w/w, about 75% to about 95% w/w, about 80% to about 95% w/w, about 85% to about 95% w/w, or about 75% w/w or about 80% w/w or about 85% w/w or about 90% w/w, and/or

在试验开始后前9个小时内，该组合物所含有的富马酸酯总量至多有大约85％w/w被释放，例如大约50％至大约85％w/w、大约60％至大约80％w/w或者大约75％w/w，和/或Within the first 9 hours after the start of the test, at most about 85% w/w of the total amount of fumarate contained in the composition is released, such as about 50% to about 85% w/w, about 60% to about 80% w/w or about 75% w/w, and/or

在试验开始后前9个小时内，该组合物所含有的富马酸酯总量至多有大约99％w/w被释放，例如大约60％至大约99％w/w、大约70％至大约99％w/w、大约80％至大约99％w/w、大约90％至大约99％w/w或者大约95％w/w。Within the first 9 hours after the start of the test, at most about 99% w/w of the total amount of fumarate contained in the composition is released, such as from about 60% to about 99% w/w, from about 70% to about 99% w/w, about 80% to about 99% w/w, about 90% to about 99% w/w, or about 95% w/w.

本发明在另一方面提供口用控释药物组合物，包含作为活性物质的一种或多种富马酸酯，选自富马酸的二-(C₁-C₅)烷基酯和富马酸的单-(C₁-C₅)烷基酯或者其药学上可接受的盐，其特征在于它由控释剂型组成，当按照USP在前2个小时期间在0.1N盐酸中测量，然后在0.05M磷酸盐缓冲液pH6.5或6.8中测量体外溶解曲线时，该剂型历经预定时间释放富马酸的二-(C₁-C₅)烷基酯和/或单-(C₁-C₅)烷基酯或其药学上可接受的盐，In another aspect the present invention provides a controlled release pharmaceutical composition for oral use comprising as active substance one or more fumaric acid esters selected from the group consisting of di-(C₁ -C₅ )alkyl fumaric acid esters and fumaric acid Mono-(C₁ -C₅ )alkyl esters of malic acid or pharmaceutically acceptable salts thereof, characterized in that it consists of a controlled release dosage form when measured in 0.1N hydrochloric acid during the first 2 hours according to USP, The dosage form then releases di-(C₁ -C₅ )alkyl esters of fumaric acid and/or mono-(C₁ -C₅ ) alkyl esters or pharmaceutically acceptable salts thereof,

其中组合物所含有的富马酸酯总量至多有5％w/w在试验开始后前2个小时内被释放，和/或wherein at most 5% w/w of the total amount of fumarate contained in the composition is released within the first 2 hours after the start of the test, and/or

其中组合物所含有的富马酸酯总量有大约20％至大约75％w/w在试验开始后前3个小时内被释放，和/或wherein about 20% to about 75% w/w of the total amount of fumarate contained in the composition is released within the first 3 hours after the start of the test, and/or

其中组合物所含有的富马酸酯总量有大约50％至大约90％w/w在试验开始后前4个小时内被释放，和/或wherein about 50% to about 90% w/w of the total amount of fumarate contained in the composition is released within the first 4 hours after the start of the test, and/or

其中组合物所含有的富马酸酯总量有大约60％至大约90％w/w在试验开始后前5个小时内被释放，和/或wherein about 60% to about 90% w/w of the total amount of fumarate contained in the composition is released within the first 5 hours after the start of the test, and/or

其中组合物所含有的富马酸酯总量有大约70％至大约95％w/w在试验开始后前6个小时内被释放，和/或wherein about 70% to about 95% w/w of the total amount of fumarate contained in the composition is released within the first 6 hours after the start of the test, and/or

其中组合物所含有的富马酸酯总量有大约75％至大约97％w/w在试验开始后前7个小时内被释放。From about 75% to about 97% w/w of the total amount of fumarate contained in the composition is released within the first 7 hours after initiation of the test.

本发明在另一方面提供口用控释药物组合物，包含作为活性物质的一种或多种富马酸酯，选自富马酸的二-(C₁-C₅)烷基酯和富马酸的单-(C₁-C₅)烷基酯或者其药学上可接受的盐，其特征在于它由控释剂型组成，当按照USP在前2个小时期间在0.1N盐酸中测量，然后在0.05M磷酸盐缓冲液pH6.5或6.8中测量体外溶解曲线时，该剂型历经预定时间释放富马酸的二-(C₁-C₅)烷基酯和/或单-(C₁-C₅)烷基酯或其药学上可接受的盐，其中组合物所含有的富马酸酯总量至多有5％w/w在试验开始后前2个小时内被释放，其中组合物所含有的富马酸酯总量有大约20％至大约75％w/w在试验开始后前3个小时内被释放，其中组合物所含有的富马酸酯总量有大约50％至大约90％w/w在试验开始后前4个小时内被释放，其中组合物所含有的富马酸酯总量有大约60％至大约90％w/w在试验开始后前5个小时内被释放，其中组合物所含有的富马酸酯总量有大约70％至大约95％w/w在试验开始后前6个小时内被释放，其中组合物所含有的富马酸酯总量有大约75％至大约97％w/w在试验开始后前7个小时内被释放，并且其中组合物所含有的富马酸酯总量至少有85％w/w在试验开始后前8个小时内被释放。In another aspect the present invention provides a controlled release pharmaceutical composition for oral use comprising as active substance one or more fumaric acid esters selected from the group consisting of di-(C₁ -C₅ )alkyl fumaric acid esters and fumaric acid Mono-(C₁ -C₅ )alkyl esters of malic acid or pharmaceutically acceptable salts thereof, characterized in that it consists of a controlled release dosage form when measured in 0.1N hydrochloric acid during the first 2 hours according to USP, The dosage form then releases di-(C₁ -C₅ )alkyl esters of fumaric acid and/or mono-(C₁ -C₅ ) Alkyl ester or a pharmaceutically acceptable salt thereof, wherein at most 5% w/w of the total amount of fumarate contained in the composition is released within the first 2 hours after the start of the test, wherein the composition About 20% to about 75% w/w of the total amount of fumarate contained is released within the first 3 hours after the start of the test, wherein the total amount of fumarate contained in the composition is about 50% to about 90% w/w is released within the first 4 hours after the start of the test, wherein about 60% to about 90% of the total amount of fumarate contained in the composition is released within the first 5 hours after the start of the test. Release, wherein about 70% to about 95% w/w of the total amount of fumarate contained in the composition is released within the first 6 hours after the start of the test, wherein the total amount of fumarate contained in the composition has About 75% to about 97% w/w is released within the first 7 hours after the start of the test, and wherein the composition contains at least 85% w/w of the total amount of fumarate in the first 8 hours after the start of the test was released within.

本发明在另一方面提供控释药物组合物，包含作为活性物质的一种或多种富马酸酯，选自富马酸的二-(C₁-C₅)烷基酯和富马酸的单-(C₁-C₅)烷基酯或者其药学上可接受的盐，其特征在于它由控释剂型组成，当按照USP在前2个小时期间在0.1N盐酸中测量，然后在0.05M磷酸盐缓冲液pH6.5或6.8中测量体外溶解曲线时，该剂型历经预定时间释放富马酸的二-(C₁-C₅)烷基酯和/或单-(C₁-C₅)烷基酯或其药学上可接受的盐，In another aspect the present invention provides controlled release pharmaceutical compositions comprising as active substance one or more fumaric acid esters selected from the group consisting of di-(C₁ -C₅ )alkyl esters of fumaric acid and fumaric acid Mono-(C₁ -C₅ ) alkyl esters or pharmaceutically acceptable salts thereof, characterized in that it consists of a controlled release dosage form when measured in 0.1N hydrochloric acid during the first 2 hours according to USP, then in The dosage form releases di-(C₁ -C₅ )alkyl esters of fumaric acid and/or mono-(C₁ -C₅ ) an alkyl ester or a pharmaceutically acceptable salt thereof,

其中组合物所含有的富马酸酯总量至多有5％w/w在试验开始后前2个小时内被释放，和/或wherein at most 5% w/w of the total amount of fumarate contained in the composition is released within the first 2 hours after the start of the test, and/or

其中组合物所含有的富马酸酯总量有大约20％至大约50％w/w在试验开始后前3个小时内被释放，和/或wherein about 20% to about 50% w/w of the total amount of fumarate contained in the composition is released within the first 3 hours after the start of the test, and/or

其中组合物所含有的富马酸酯总量有大约45％至大约70％w/w在试验开始后前4个小时内被释放，和/或wherein about 45% to about 70% w/w of the total amount of fumarate contained in the composition is released within the first 4 hours after the start of the test, and/or

其中组合物所含有的富马酸酯总量有大约65％至大约85％w/w在试验开始后前5个小时内被释放，和/或wherein about 65% to about 85% w/w of the total amount of fumarate contained in the composition is released within the first 5 hours after the start of the test, and/or

其中组合物所含有的富马酸酯总量有大约75％至大约90％w/w在试验开始后前6个小时内被释放。From about 75% to about 90% w/w of the total amount of fumarate contained in the composition is released within the first 6 hours after initiation of the test.

本发明在另一方面提供控释药物组合物，包含作为活性物质的一种或多种富马酸酯，选自富马酸的二-(C₁-C₅)烷基酯和富马酸的单-(C₁-C₅)烷基酯或者其药学上可接受的盐，其特征在于它由控释剂型组成，当按照USP在前2个小时期间在0.1N盐酸中测量，然后在0.05M磷酸盐缓冲液pH6.5或6.8中测量体外溶解曲线时，该剂型历经预定时间释放富马酸的二-(C₁-C₅)烷基酯和/或单-(C₁-C₅)烷基酯或其药学上可接受的盐，其中组合物所含有的富马酸酯总量至多有5％w/w在试验开始后前2个小时内被释放，其中组合物所含有的富马酸酯总量有大约20％至大约50％w/w在试验开始后前3个小时内被释放，其中组合物所含有的富马酸酯总量有大约45％至大约70％w/w在试验开始后前4个小时内被释放，其中组合物所含有的富马酸酯总量有大约65％至大约85％w/w在试验开始后前5个小时内被释放，其中组合物所含有的富马酸酯总量有大约75％至大约90％w/w在试验开始后前6个小时内被释放，并且其中组合物所含有的富马酸酯总量至少有80％w/w在试验开始后前7个小时内被释放。In another aspect the present invention provides controlled release pharmaceutical compositions comprising as active substance one or more fumaric acid esters selected from the group consisting of di-(C₁ -C₅ )alkyl esters of fumaric acid and fumaric acid Mono-(C₁ -C₅ ) alkyl esters or pharmaceutically acceptable salts thereof, characterized in that it consists of a controlled release dosage form when measured in 0.1N hydrochloric acid during the first 2 hours according to USP, then in The dosage form releases di-(C₁ -C₅ )alkyl esters of fumaric acid and/or mono-(C₁ -C₅ ) Alkyl esters or pharmaceutically acceptable salts thereof, wherein at most 5% w/w of the total amount of fumarate contained in the composition is released within the first 2 hours after the start of the test, wherein the composition contains The total amount of fumarate has about 20% to about 50% w/w to be released within the first 3 hours after the start of the test, wherein the total amount of fumarate contained in the composition has about 45% to about 70% w/w is released within the first 4 hours after the start of the test, wherein about 65% to about 85% of the total amount of fumarate contained in the composition is released within the first 5 hours after the start of the test, wherein about 75% to about 90% w/w of the total amount of fumarate contained in the composition is released within the first 6 hours after the start of the test, and wherein the total amount of fumarate contained in the composition is at least 80% w/w was released within the first 7 hours after the start of the test.

本发明在另一方面提供控释药物组合物，包含作为活性物质的一种或多种富马酸酯，选自富马酸的二-(C₁-C₅)烷基酯和富马酸的单-(C₁-C₅)烷基酯或者其药学上可接受的盐，其特征在于它由控释剂型组成，当按照USP在前2个小时期间在0.1N盐酸中测量，然后在0.05M磷酸盐缓冲液pH6.5或6.8中测量体外溶解曲线时，该剂型历经预定时间释放富马酸的二-(C₁-C₅)烷基酯和/或单-(C₁-C₅)烷基酯或其药学上可接受的盐，In another aspect the present invention provides controlled release pharmaceutical compositions comprising as active substance one or more fumaric acid esters selected from the group consisting of di-(C₁ -C₅ )alkyl esters of fumaric acid and fumaric acid Mono-(C₁ -C₅ ) alkyl esters or pharmaceutically acceptable salts thereof, characterized in that it consists of a controlled release dosage form when measured in 0.1N hydrochloric acid during the first 2 hours according to USP, then in The dosage form releases di-(C₁ -C₅ )alkyl esters of fumaric acid and/or mono-(C₁ -C₅ ) an alkyl ester or a pharmaceutically acceptable salt thereof,

其中组合物所含有的富马酸酯总量至多有5％w/w在试验开始后前2个小时内被释放，和/或wherein at most 5% w/w of the total amount of fumarate contained in the composition is released within the first 2 hours after the start of the test, and/or

其中组合物所含有的富马酸酯总量有大约50％至大约75％w/w在试验开始后前3个小时内被释放，和/或wherein about 50% to about 75% w/w of the total amount of fumarate contained in the composition is released within the first 3 hours after the start of the test, and/or

其中组合物所含有的富马酸酯总量有大约70％至大约90％w/w在试验开始后前4个小时内被释放，和/或wherein about 70% to about 90% w/w of the total amount of fumarate contained in the composition is released within the first 4 hours after the start of the test, and/or

其中组合物所含有的富马酸酯总量有大约80％至大约90％w/w在试验开始后前5个小时内被释放。From about 80% to about 90% w/w of the total amount of fumarate contained in the composition is released within the first 5 hours after initiation of the test.

本发明在另一方面提供控释药物组合物，包含作为活性物质的一种或多种富马酸酯，选自富马酸的二-(C₁-C₅)烷基酯和富马酸的单-(C₁-C₅)烷基酯或者其药学上可接受的盐，其特征在于它由控释剂型组成，当按照USP在前2个小时期间在0.1N盐酸中测量，然后在0.05M磷酸盐缓冲液pH6.5或6.8中测量体外溶解曲线时，该剂型历经预定时间释放富马酸的二-(C₁-C₅)烷基酯和/或单-(C₁-C₅)烷基酯或其药学上可接受的盐，其中组合物所含有的富马酸酯总量至多有5％w/w在试验开始后前2个小时内被释放，其中组合物所含有的富马酸酯总量有大约50％至大约75％w/w在试验开始后前3个小时内被释放，其中组合物所含有的富马酸酯总量有大约70％至大约90％w/w在试验开始后前4个小时内被释放，其中组合物所含有的富马酸酯总量有大约80％至大约90％w/w在试验开始后前5个小时内被释放，并且其中组合物所含有的富马酸酯总量至少有大约90％w/w在试验开始后前6个小时内被释放。In another aspect the present invention provides controlled release pharmaceutical compositions comprising as active substance one or more fumaric acid esters selected from the group consisting of di-(C₁ -C₅ )alkyl esters of fumaric acid and fumaric acid Mono-(C₁ -C₅ ) alkyl esters or pharmaceutically acceptable salts thereof, characterized in that it consists of a controlled release dosage form when measured in 0.1N hydrochloric acid during the first 2 hours according to USP, then in The dosage form releases di-(C₁ -C₅ )alkyl esters of fumaric acid and/or mono-(C₁ -C₅ ) Alkyl esters or pharmaceutically acceptable salts thereof, wherein at most 5% w/w of the total amount of fumarate contained in the composition is released within the first 2 hours after the start of the test, wherein the composition contains About 50% to about 75% w/w of the total amount of fumarate is released within the first 3 hours after the start of the test, wherein the composition contains about 70% to about 90% of the total amount of fumarate w/w is released within the first 4 hours after the start of the test, wherein about 80% to about 90% w/w of the total amount of fumarate contained in the composition is released within the first 5 hours after the start of the test, And wherein at least about 90% w/w of the total amount of fumarate contained in the composition is released within the first 6 hours after the start of the test.

随逐渐变换的pH的释放(“半数变化”法)Release with gradually changing pH ("half change" method)

下面给出特定实施方式的说明，其中富马酸酯依赖于pH地被释放，并且其中释放模式适合于每日给药两次或多次的组合物。适合的制剂原理实例例如是带有肠溶衣或者Zentner等(US 6,537,584)和Bae(US 5,484,610)所述类型水凝胶的组合物，引用在此作为参考。其他适合的制剂原理实例例如是带有扩散包衣、例如控释扩散包衣的组合物、基质微粒或基质片、水凝胶、脉冲剂量药物递送系统、与维生素E浓缩物或乙醇、TPGS、玉米油和蜡等的共同制剂，包括任意上述制剂原理，可选地带有肠溶衣。A description is given below of specific embodiments in which the fumarate is released in a pH-dependent manner and in which the release profile is suitable for compositions that are administered two or more times per day. Examples of suitable formulation principles are eg compositions with enteric coatings or hydrogels of the type described by Zentner et al. (US 6,537,584) and Bae (US 5,484,610), incorporated herein by reference. Examples of other suitable formulation principles are e.g. compositions with diffusion coatings, such as controlled release diffusion coatings, matrix particles or matrix tablets, hydrogels, pulsatile drug delivery systems, with vitamin E concentrate or ethanol, TPGS, Co-formulations of corn oil and waxes etc., including any of the above formulation principles, optionally with an enteric coating.

“半数变化”法是为肠溶衣或持续释放制备物而特别开发的。这种方法涵盖每小时用等份中性溶解介质代替一半溶解介质(以模拟从十二指肠到回肠pH值轻微变换的GI通道)。该方法如下表所述：   开始后的时间(小时)   模拟胃液/模拟肠液的比例(％)     pH值   0-1   100/0     1.3   1-2   50/50     2.4   2-3   25/75     6.2   3-4   12.5/87.5     6.8   4-5   6.25/93.75     7.1   5-6   ～3/97     7.2   6-7   ～1/99     7.3   7-8   ～0/100     7.3The "half change" method was developed especially for enteric coated or sustained release preparations. This method involves replacing half of the lysis medium with an equal portion of neutral lysis medium every hour (to simulate the GI passage with a slight shift in pH from the duodenum to the ileum). The method is described in the following table: time since start (hours) Ratio of simulated gastric juice/simulated intestinal juice (%) pH value 0-1 100/0 1.3 1-2 50/50 2.4 2-3 25/75 6.2 3-4 12.5/87.5 6.8 4-5 6.25/93.75 7.1 5-6 ~3/97 7.2 6-7 ~1/99 7.3 7-8 ~0/100 7.3

模拟胃液的组成例如可以参见美国药典(USP)2005：The composition of simulated gastric juice can be found, for example, in United States Pharmacopoeia (USP) 2005:

将2.0g NaCl和3.2g来自猪胃粘膜、活性为800至2500单位每mg蛋白质的纯化胃蛋白酶溶于7.0mL盐酸和足量水，至1000mL。所得试验溶液具有大约1.2的pH。Dissolve 2.0 g of NaCl and 3.2 g of purified pepsin from porcine gastric mucosa with an activity of 800 to 2500 units per mg protein in 7.0 mL of hydrochloric acid and sufficient water to 1000 mL. The resulting test solution had a pH of approximately 1.2.

另一种模拟胃液的组成参见German E DIN 19738(DeutscheIndustrie Norm)：The composition of another simulated gastric juice can be found in German E DIN 19738 (Deutsche Industrie Norm):

100mL合成/模拟胃液含有290mg NaCl、70mg KCl、27mg KH₂PO₄和足量HCl，以调节pH至2.0。另外，它含有100mg胃蛋白酶和300mg粘蛋白。100 mL of synthetic/simulated gastric juice contained 290 mg NaCl, 70 mg KCl,₂₇ mg_KH2PO4 and sufficient HCl to adjust the pH to 2.0. Plus, it contains 100mg of pepsin and 300mg of mucin.

模拟肠液的组成例如可以参见美国药典(USP)2005：The composition of simulated intestinal fluid can be found, for example, in United States Pharmacopoeia (USP) 2005:

将6.8g磷酸二氢钾溶于250mL水。混合，加入77mL 0.2N氢氧化钠和500mL水。加入10.0g胰酶，混合该溶液，加入0.2N氢氧化钠或0.2N盐酸调节pH为6.8±0.1。将所得溶液用水稀释至1000mL。Dissolve 6.8g of potassium dihydrogen phosphate in 250mL of water. Mix and add 77 mL of 0.2N sodium hydroxide and 500 mL of water. Add 10.0 g of trypsin, mix the solution, add 0.2N sodium hydroxide or 0.2N hydrochloric acid to adjust the pH to 6.8±0.1. The resulting solution was diluted to 1000 mL with water.

另一种模拟肠液的组成参见German E DIN 19738(DeutscheIndustrie Norm)：The composition of another simulated intestinal fluid can be found in German E DIN 19738 (Deutsche Industrie Norm):

100mL合成/模拟肠液含有30mg KCl、50mg CaCl₂、20mg MgCl₂和足量NaHCO₃，以调节pH至7.5。此外，它含有30mg胰蛋白酶、900mg胰酶、900mg冻干胆汁和30mg尿素。100 mL of synthetic/simulated intestinal fluid contained 30 mg KCl, 50 mg CaCl₂ , 20 mg MgCl₂ and sufficient NaHCO₃ to adjust the pH to 7.5. In addition, it contains 30mg trypsin, 900mg trypsin, 900mg freeze-dried bile and 30mg urea.

在本发明的优选实施方式中，“半数变化”法是利用如USP 2005所定义的模拟胃液和模拟肠液进行的。In a preferred embodiment of the present invention, the "half change" method is performed using simulated gastric fluid and simulated intestinal fluid as defined in USP 2005.

在本发明的另一种实施方式中，“半数变化”法是利用如USP 2005所定义的模拟胃液和模拟肠液进行的，但是没有蛋白质(也就是在模拟胃液中没有胃蛋白酶，在模拟肠液中没有胰酶)。In another embodiment of the present invention, the "half change" method is carried out using simulated gastric fluid and simulated intestinal fluid as defined in USP 2005, but without protein (i.e. no pepsin in simulated gastric fluid, no pepsin in simulated intestinal fluid) without trypsin).

因此，本发明在一方面涉及口用控释药物组合物，包含作为活性物质的一种或多种富马酸酯，选自富马酸的二-(C₁-C₅)烷基酯和富马酸的单-(C₁-C₅)烷基酯或者其药学上可接受的盐，其中富马酸酯在按照“半数变化”法进行体外溶解试验时的释放如下：Accordingly, the present invention relates in one aspect to a pharmaceutical composition for oral controlled release comprising as active substance one or more fumaric acid esters selected from the group consisting of di-(C₁ -C₅ )alkyl esters of fumaric acid and Mono-(C₁ -C₅ ) alkyl esters of fumaric acid or pharmaceutically acceptable salts thereof, wherein the release of fumaric acid esters in an in vitro dissolution test according to the "half change" method is as follows:

在试验开始后前3个小时内，富马酸酯的总量有大约20％至大约40％w/w、大约20％至大约35％w/w或者大约30％w/w被释放，和/或About 20% to about 40% w/w, about 20% to about 35% w/w, or about 30% w/w of the total amount of fumarate is released within the first 3 hours after the start of the test, and /or

在试验开始后前3个小时内，富马酸酯的总量至少有大约12％w/w被释放，例如大约12％至大约50％w/w、大约15％至大约45％w/w、大约20％至大约40％w/w、大约20％至大约35％w/w、大约22％至大约35％w/w或者大约25％w/w或大约30％w/w，和/或During the first 3 hours after the start of the test, at least about 12% w/w of the total amount of fumarate is released, such as about 12% to about 50% w/w, about 15% to about 45% w/w , about 20% to about 40% w/w, about 20% to about 35% w/w, about 22% to about 35% w/w, or about 25% w/w or about 30% w/w, and/ or

在试验开始后前4个小时内，富马酸酯的总量有大约25％至大约40％w/w、大约30％至大约40％w/w或者大约40％w/w被释放，和/或About 25% to about 40% w/w, about 30% to about 40% w/w, or about 40% w/w of the total amount of fumarate is released within the first 4 hours after the start of the test, and /or

在试验开始后前4个小时内，富马酸酯的总量至少有大约76％w/w被释放，例如大约76％至大约95％w/w、大约80％至大约90％w/w或者大约80％w/w或大约85％w/w，和/或During the first 4 hours after the start of the test, at least about 76% w/w of the total amount of fumarate is released, such as about 76% to about 95% w/w, about 80% to about 90% w/w or about 80% w/w or about 85% w/w, and/or

在试验开始后前4个小时内，富马酸酯的总量至多有大约40％w/w被释放，例如大约10％至大约40％w/w、大约15％至大约35％w/w、大约20％至大约30％w/w或者大约25％w/w或大约30％w/w，和/或Up to about 40% w/w of the total amount of fumarate is released, such as about 10% to about 40% w/w, about 15% to about 35% w/w, within the first 4 hours after the start of the test , about 20% to about 30% w/w or about 25% w/w or about 30% w/w, and/or

在试验开始后前6个小时内，该组合物所含有的富马酸酯总量至少有大约81％w/w被释放，例如大约81％至大约96％w/w、大约85％至大约95％w/w、大约85％至大约90％w/w或者大约80％w/w或大约85％w/w或大约90％w/w，和/或Within the first 6 hours after the start of the test, at least about 81% w/w of the total amount of fumarate contained in the composition is released, such as from about 81% to about 96% w/w, from about 85% to about 95% w/w, about 85% to about 90% w/w or about 80% w/w or about 85% w/w or about 90% w/w, and/or

在试验开始后前6个小时内，该组合物所含有的富马酸酯总量至多有大约50％w/w被释放，例如大约20％至大约50％w/w、大约25％至大约45％w/w、大约30％至大约45％w/w或者大约40％w/w或大约45％w/w，和/或Within the first 6 hours after the start of the test, at most about 50% w/w of the total amount of fumarate contained in the composition is released, such as about 20% to about 50% w/w, about 25% to about 45% w/w, about 30% to about 45% w/w or about 40% w/w or about 45% w/w, and/or

在试验开始后前7个小时内，该组合物所含有的富马酸酯总量至少有大约82％w/w被释放，例如大约82％至大约99％w/w、大约85％至大约99％w/w、大约85％至大约95％w/w或者大约90％w/w，和/或Within the first 7 hours after the start of the test, at least about 82% w/w of the total amount of fumarate contained in the composition is released, such as about 82% to about 99% w/w, about 85% to about 99% w/w, about 85% to about 95% w/w, or about 90% w/w, and/or

在试验开始后前7个小时内，该组合物所含有的富马酸酯总量至多有大约65％w/w被释放，例如大约25％至大约65％w/w、大约30％至大约65％w/w、大约35％至大约60％w/w、大约40％至大约60％w/w、大约50％至大约60％w/w或者大约55％w/w或大约60％w/w，和/或Within the first 7 hours after the start of the test, at most about 65% w/w of the total amount of fumarate contained in the composition is released, such as about 25% to about 65% w/w, about 30% to about 65% w/w, about 35% to about 60% w/w, about 40% to about 60% w/w, about 50% to about 60% w/w, or about 55% w/w or about 60% w /w, and/or

在试验开始后前8个小时内，该组合物所含有的富马酸酯总量至多有大约85％w/w被释放，例如大约50％至大约85％w/w、大约60％至大约80％w/w或者大约75％w/w，和/或Within the first 8 hours after the start of the test, at most about 85% w/w of the total amount of fumarate contained in the composition is released, such as about 50% to about 85% w/w, about 60% to about 80% w/w or about 75% w/w, and/or

在试验开始后前8个小时内，该组合物所含有的富马酸酯总量至多有大约92％w/w被释放，例如大约30％至大约92％w/w、大约35％至大约90％w/w、大约40％至大约85％w/w、大约45％至大约80％w/w、大约50％至大约75％w/w、大约55％至大约75％w/w、大约60％至大约75％w/w或者大约65％w/w或大约70％w/w，和/或Within the first 8 hours after the start of the test, at most about 92% w/w of the total amount of fumarate contained in the composition is released, such as from about 30% to about 92% w/w, from about 35% to about 90% w/w, about 40% to about 85% w/w, about 45% to about 80% w/w, about 50% to about 75% w/w, about 55% to about 75% w/w, about 60% to about 75% w/w or about 65% w/w or about 70% w/w, and/or

在试验开始后前12个小时内，该组合物所含有的富马酸酯总量至少有大约80％w/w被释放，例如大约80％w/w或以上、大约85％w/w或以上、大约90％w/w或以上或者大约95％w/w或以上。Within the first 12 hours after the start of the test, at least about 80% w/w of the total amount of fumarate contained in the composition is released, such as about 80% w/w or more, about 85% w/w or More than, about 90% w/w or more or about 95% w/w or more.

缓慢释放slow release

下面给出特定实施方式的说明，其中富马酸酯以缓慢或延迟的方式被释放，其中释放模式适合于每日给药两次或多次的组合物。适合的制剂原理实例是任意上述那些。A description is given below of specific embodiments wherein the fumarate is released in a slow or delayed manner, wherein the release profile is suitable for two or more daily administration of the composition. Examples of suitable formulation principles are any of those mentioned above.

因此，本发明在一方面涉及口用控释药物组合物，包含作为活性物质的一种或多种富马酸酯，选自富马酸的二-(C₁-C₅)烷基酯和富马酸的单-(C₁-C₅)烷基酯或者其药学上可接受的盐，其中富马酸酯在进行采用水作为溶解介质的体外溶解试验时的释放如下：Accordingly, the present invention relates in one aspect to a pharmaceutical composition for oral controlled release comprising as active substance one or more fumaric acid esters selected from the group consisting of di-(C₁ -C₅ )alkyl esters of fumaric acid and A mono-(C₁ -C₅ ) alkyl ester of fumaric acid or a pharmaceutically acceptable salt thereof, wherein the release of the fumaric acid ester in an in vitro dissolution test using water as the dissolution medium is as follows:

在试验开始后前6个小时内，该组合物所含有的富马酸酯总量至多有大约35％w/w被释放，例如大约15％至大约35％w/w、大约20％至大约30％w/w或者大约25％w/w，和/或Within the first 6 hours after the start of the test, at most about 35% w/w of the total amount of fumarate contained in the composition is released, such as about 15% to about 35% w/w, about 20% to about 30% w/w or about 25% w/w, and/or

在试验开始后前8个小时内，该组合物所含有的富马酸酯总量至多有大约60％w/w被释放，例如大约30％至大约60％w/w、大约40％至大约55％w/w或者大约50％w/w，和/或Within the first 8 hours after the start of the test, at most about 60% w/w of the total amount of fumarate contained in the composition is released, such as about 30% to about 60% w/w, about 40% to about 55% w/w or about 50% w/w, and/or

在试验开始后前10个小时内，该组合物所含有的富马酸酯总量至多有大约85％w/w被释放，例如大约50％至大约85％w/w、大约60％至大约80％w/w或者大约75％w/w，和/或Within the first 10 hours after the start of the test, at most about 85% w/w of the total amount of fumarate contained in the composition is released, such as about 50% to about 85% w/w, about 60% to about 80% w/w or about 75% w/w, and/or

在试验开始后前12个小时内，该组合物所含有的富马酸酯总量至少有大约80％w/w被释放，例如大约80％w/w或以上、大约85％w/w或以上、大约90％w/w或以上或者大约95％w/w或以上。Within the first 12 hours after the start of the test, at least about 80% w/w of the total amount of fumarate contained in the composition is released, such as about 80% w/w or more, about 85% w/w or More than, about 90% w/w or more or about 95% w/w or more.

被设计成每日给药一次的组合物Compositions designed for once-daily administration

pH独立性释放pH independent release

下面给出特定实施方式的说明，其中富马酸酯独立于pH地被释放，并且其中释放模式适合于每日给药一次的组合物。适合的制剂原理实例例如是带有扩散包衣、例如控释扩散包衣的组合物、基质微粒或基质片、水凝胶、脉冲剂量药物递送系统、与维生素E浓缩物或乙醇、TPGS、玉米油和蜡等的共同制剂，包括任意上述制剂原理。A description is given below of specific embodiments in which the fumarate is released independently of pH and in which the release profile is suitable for a once-daily dosing composition. Examples of suitable formulation principles are e.g. compositions with diffusion coatings, e.g. controlled release diffusion coatings, matrix particles or matrix tablets, hydrogels, pulsatile drug delivery systems, with vitamin E concentrate or ethanol, TPGS, corn Co-formulations of oils and waxes, etc., including any of the above formulation principles.

因此，本发明在一方面涉及口用控释药物组合物，包含作为活性物质的一种或多种富马酸酯，选自富马酸的二-(C₁-C₅)烷基酯和富马酸的单-(C₁-C₅)烷基酯或者其药学上可接受的盐，其中富马酸酯在进行采用水作为溶解介质的体外溶解试验时的释放如下：Accordingly, the present invention relates in one aspect to a pharmaceutical composition for oral controlled release comprising as active substance one or more fumaric acid esters selected from the group consisting of di-(C₁ -C₅ )alkyl esters of fumaric acid and A mono-(C₁ -C₅ ) alkyl ester of fumaric acid or a pharmaceutically acceptable salt thereof, wherein the release of the fumaric acid ester in an in vitro dissolution test using water as the dissolution medium is as follows:

在试验开始后前9个小时内，该组合物所含有的富马酸酯总量至多有大约60％w/w被释放，例如大约30％至大约60％w/w、大约40％至大约55％w/w或者大约50％w/w，和/或Within the first 9 hours after the start of the test, at most about 60% w/w of the total amount of fumarate contained in the composition is released, such as about 30% to about 60% w/w, about 40% to about 55% w/w or about 50% w/w, and/or

在试验开始后前13.5个小时内，该组合物所含有的富马酸酯总量至多有大约85％w/w被释放，例如大约50％至大约85％w/w、大约60％至大约80％w/w或者大约75％w/w，和/或Within the first 13.5 hours after the start of the test, at most about 85% w/w of the total amount of fumarate contained in the composition is released, such as about 50% to about 85% w/w, about 60% to about 80% w/w or about 75% w/w, and/or

在试验开始后前18个小时内，该组合物所含有的富马酸酯总量至少有大约80％w/w被释放，例如大约80％w/w或以上、大约85％w/w或以上、大约90％w/w或以上或者大约95％w/w或以上，和/或Within the first 18 hours after the start of the test, at least about 80% w/w of the total amount of fumarate contained in the composition is released, such as about 80% w/w or more, about 85% w/w or More than, about 90% w/w or more, or about 95% w/w or more, and/or

组合物所含有的富马酸酯总量在试验开始后前18个小时内被释放。The total amount of fumarate contained in the composition was released within the first 18 hours after the start of the test.

pH控制性释放pH controlled release

下面给出特定实施方式的说明，其中富马酸酯依赖于pH地被释放，并且其中释放模式适合于每日给药一次的组合物。适合的制剂原理实例例如是带有肠溶衣或者Zentner等(US 6,537,584)和Bae(US5,484,610)所述类型水凝胶的组合物。其他适合的制剂原理实例例如是带有扩散包衣、例如控释扩散包衣的组合物、基质微粒或基质片、水凝胶、脉冲剂量药物递送系统、与维生素E浓缩物或乙醇、TPGS、玉米油和蜡等的共同制剂，包括任意上述制剂原理，可选地带有肠溶衣。A description is given below of specific embodiments wherein the fumarate is released in a pH-dependent manner and wherein the release profile is suitable for a once-daily dosing composition. Examples of suitable formulation principles are eg compositions with enteric coatings or hydrogels of the type described by Zentner et al. (US 6,537,584) and Bae (US 5,484,610). Examples of other suitable formulation principles are e.g. compositions with diffusion coatings, such as controlled release diffusion coatings, matrix particles or matrix tablets, hydrogels, pulsatile drug delivery systems, with vitamin E concentrate or ethanol, TPGS, Co-formulations of corn oil and waxes etc., including any of the above formulation principles, optionally with an enteric coating.

因此，本发明在一方面涉及口用控释药物组合物，包含作为活性物质的一种或多种富马酸酯，选自富马酸的二-(C₁-C₅)烷基酯和富马酸的单-(C₁-C₅)烷基酯或者其药学上可接受的盐，其中富马酸酯在进行体外溶解试验时的释放如下，该试验在前2个小时期间采用0.1N盐酸作为溶解介质，然后以0.05M磷酸盐缓冲液pH6.5或6.8作为溶解介质：Accordingly, the present invention relates in one aspect to a pharmaceutical composition for oral controlled release comprising as active substance one or more fumaric acid esters selected from the group consisting of di-(C₁ -C₅ )alkyl esters of fumaric acid and Mono-(C₁ -C₅ ) alkyl esters of fumaric acid or pharmaceutically acceptable salts thereof, wherein the release of fumaric acid esters in an in vitro dissolution test using a 0.1 N hydrochloric acid as the dissolution medium, and then 0.05M phosphate buffer pH6.5 or 6.8 as the dissolution medium:

在试验开始后前2个小时内，富马酸酯的总量至少有大约1％w/w被释放，例如至少大约2％w/w、至少大约3％w/w或者大约5％w/w，和/或Within the first 2 hours after the start of the test, at least about 1% w/w of the total amount of fumarate is released, such as at least about 2% w/w, at least about 3% w/w or about 5% w/ w, and/or

在试验开始后前4个小时内，富马酸酯的总量至多有大约90％w/w被释放，例如大约5％至大约90％w/w、大约5％至大约85％w/w、大约10％至大约80％w/w、大约10％至大约70％w/w、大约10％至大约65％w/w、大约10％至大约60％w/w、大约15％至大约50％w/w、大约15％至大约35％w/w、大约20％至大约30％w/w或者大约20％w/w或大约25％w/w，和/或Up to about 90% w/w of the total amount of fumarate is released within the first 4 hours after the start of the test, for example about 5% to about 90% w/w, about 5% to about 85% w/w , about 10% to about 80% w/w, about 10% to about 70% w/w, about 10% to about 65% w/w, about 10% to about 60% w/w, about 15% to about 50% w/w, about 15% to about 35% w/w, about 20% to about 30% w/w or about 20% w/w or about 25% w/w, and/or

在试验开始后前4.5个小时内，富马酸酯的总量至多有大约35％w/w被释放，例如大约15％至大约35％w/w、大约20％至大约30％w/w或者大约25％w/w，和/或Up to about 35% w/w of the total amount of fumarate is released within the first 4.5 hours after the start of the test, for example about 15% to about 35% w/w, about 20% to about 30% w/w or about 25% w/w, and/or

在试验开始后前5个小时内，富马酸酯的总量至多有大约92％w/w被释放，例如大约10％至大约92％w/w、大约20％至大约85％w/w、大约20％至大约80％w/w、大约20％至大约70％w/w、大约25％至大约60％w/w、大约25％至大约55％w/w、大约30％至大约50％w/w或者大约35％w/w或大约40％w/w或大约45％w/w，和/或Up to about 92% w/w of the total amount of fumarate is released, for example about 10% to about 92% w/w, about 20% to about 85% w/w, within the first 5 hours after the start of the test , about 20% to about 80% w/w, about 20% to about 70% w/w, about 25% to about 60% w/w, about 25% to about 55% w/w, about 30% to about 50% w/w or about 35% w/w or about 40% w/w or about 45% w/w, and/or

在试验开始后前6个小时内，富马酸酯的总量至多有大约94％w/w被释放，例如大约15％至大约94％w/w、大约25％至大约90％w/w、大约30％至大约85％w/w、大约35％至大约80％w/w、大约35％至大约75％w/w、大约40％至大约70％w/w、大约45％至大约70％w/w、大约55％至大约70％w/w、大约60％至大约70％w/w或者大约45％w/w或大约50％w/w或大约55％w/w或大约60％w/w或大约65％w/w，和/或Up to about 94% w/w of the total amount of fumarate is released, such as about 15% to about 94% w/w, about 25% to about 90% w/w, within the first 6 hours after the start of the test , about 30% to about 85% w/w, about 35% to about 80% w/w, about 35% to about 75% w/w, about 40% to about 70% w/w, about 45% to about 70% w/w, about 55% to about 70% w/w, about 60% to about 70% w/w, or about 45% w/w, or about 50% w/w, or about 55% w/w, or about 60% w/w or about 65% w/w, and/or

在试验开始后前7个小时内，该组合物所含有的富马酸酯总量至多有大约95％w/w被释放，例如大约35％至大约95％w/w、大约40％至大约90％w/w、大约45％至大约85％w/w、大约50％至大约85％w/w、大约55％至大约85％w/w、大约60％至大约85％w/w、大约65％至大约85％w/w、大约70％至大约85％w/w、大约75％至大约85％w/w或者大约65％w/w或大约70％w/w或大约75％w/w或大约80％w/w，和/或Within the first 7 hours after the start of the test, at most about 95% w/w of the total amount of fumarate contained in the composition is released, such as from about 35% to about 95% w/w, from about 40% to about 90% w/w, about 45% to about 85% w/w, about 50% to about 85% w/w, about 55% to about 85% w/w, about 60% to about 85% w/w, about 65% to about 85% w/w, about 70% to about 85% w/w, about 75% to about 85% w/w, or about 65% w/w or about 70% w/w or about 75% w/w or about 80% w/w, and/or

在试验开始后前9个小时内，该组合物所含有的富马酸酯总量至多有大约98％w/w被释放，例如大约45％至大约98％w/w、大约50％至大约98％w/w、大约55％至大约98％w/w、大约60％至大约98％w/w、大约65％至大约98％w/w、大约70％至大约98％w/w、大约75％至大约95％w/w、大约80％至大约95％w/w、大约85％至大约95％w/w或者大约75％w/w或大约80％w/w或大约85％w/w或大约90％w/w，和/或Within the first 9 hours after the start of the test, at most about 98% w/w of the total amount of fumarate contained in the composition is released, such as about 45% to about 98% w/w, about 50% to about 98% w/w, about 55% to about 98% w/w, about 60% to about 98% w/w, about 65% to about 98% w/w, about 70% to about 98% w/w, about 75% to about 95% w/w, about 80% to about 95% w/w, about 85% to about 95% w/w, or about 75% w/w or about 80% w/w or about 85% w/w or about 90% w/w, and/or

在试验开始后前9个小时内，该组合物所含有的富马酸酯总量至多有大约60％w/w被释放，例如大约30％至大约60％w/w、大约40％至大约55％w/w或者大约50％w/w，和/或Within the first 9 hours after the start of the test, at most about 60% w/w of the total amount of fumarate contained in the composition is released, such as about 30% to about 60% w/w, about 40% to about 55% w/w or about 50% w/w, and/or

在试验开始后前12个小时内，该组合物所含有的富马酸酯总量至多有大约99％w/w被释放，例如大约60％至大约99％w/w、大约70％至大约99％w/w、大约80％至大约99％w/w、大约90％至大约99％w/w或者大约95％w/w，和/或Within the first 12 hours after the start of the test, at most about 99% w/w of the total amount of fumarate contained in the composition is released, such as from about 60% to about 99% w/w, from about 70% to about 99% w/w, about 80% to about 99% w/w, about 90% to about 99% w/w, or about 95% w/w, and/or

在试验开始后前13.5个小时内，该组合物所含有的富马酸酯总量至多有大约85％w/w被释放，例如大约50％至大约85％w/w、大约60％至大约80％w/w或者大约75％w/w。Within the first 13.5 hours after the start of the test, at most about 85% w/w of the total amount of fumarate contained in the composition is released, such as about 50% to about 85% w/w, about 60% to about 80% w/w or about 75% w/w.

随逐渐变换的pH的释放(“半数变化”法)Release with gradually changing pH ("half change" method)

下面给出特定实施方式的说明，其中富马酸酯依赖于pH地被释放，并且其中释放模式适合于每日给药一次的组合物。适合的制剂原理实例例如是带有肠溶衣或者Zentner等(US 6,537,584)和Bae(US5,484,610)所述类型水凝胶的组合物，引用在此作为参考。其他适合的制剂原理实例例如是带有扩散包衣、例如控释扩散包衣的组合物、基质微粒或基质片、水凝胶、脉冲剂量药物递送系统、与维生素E浓缩物或乙醇、TPGS、玉米油和蜡等的共同制剂，包括任意上述制剂原理，可选地带有肠溶衣。A description is given below of specific embodiments wherein the fumarate is released in a pH-dependent manner and wherein the release profile is suitable for a once-daily dosing composition. Examples of suitable formulation principles are eg compositions with enteric coatings or hydrogels of the type described by Zentner et al. (US 6,537,584) and Bae (US 5,484,610), incorporated herein by reference. Examples of other suitable formulation principles are e.g. compositions with diffusion coatings, such as controlled release diffusion coatings, matrix particles or matrix tablets, hydrogels, pulsatile drug delivery systems, with vitamin E concentrate or ethanol, TPGS, Co-formulations of corn oil and waxes etc., including any of the above formulation principles, optionally with an enteric coating.

因此，本发明在一方面涉及口用控释药物组合物，包含作为活性物质的一种或多种富马酸酯，选自富马酸的二-(C₁-C₅)烷基酯和富马酸的单-(C₁-C₅)烷基酯或者其药学上可接受的盐，其中富马酸酯在按照“半数变化”法进行体外溶解试验时的释放如下：Accordingly, the present invention relates in one aspect to a pharmaceutical composition for oral controlled release comprising as active substance one or more fumaric acid esters selected from the group consisting of di-(C₁ -C₅ )alkyl esters of fumaric acid and Mono-(C₁ -C₅ ) alkyl esters of fumaric acid or pharmaceutically acceptable salts thereof, wherein the release of fumaric acid esters in an in vitro dissolution test according to the "half change" method is as follows:

在试验开始后前3个小时内，富马酸酯的总量至少有大约12％w/w被释放，例如大约12％至大约60％w/w、大约15％至大约50％w/w、大约20％至大约40％w/w、大约20％至大约35％w/w或者大约25％w/w或大约30％w/w，和/或During the first 3 hours after the start of the test, at least about 12% w/w of the total amount of fumarate is released, such as about 12% to about 60% w/w, about 15% to about 50% w/w , about 20% to about 40% w/w, about 20% to about 35% w/w or about 25% w/w or about 30% w/w, and/or

在试验开始后前4个小时内，富马酸酯的总量至多有大约35％w/w被释放，例如大约15％至大约35％w/w、大约20％至大约30％w/w或者大约25％w/w，和/或Up to about 35% w/w of the total amount of fumarate is released, such as about 15% to about 35% w/w, about 20% to about 30% w/w, within the first 4 hours after the start of the test or about 25% w/w, and/or

在试验开始后前5个小时内，富马酸酯的总量至多有大约45％w/w被释放，例如大约10％至大约45％w/w、大约15％至大约40％w/w、大约15％至大约35％w/w、大约20％至大约30％w/w或者大约25％w/w或大约30％w/w，和/或Up to about 45% w/w of the total amount of fumarate is released, for example about 10% to about 45% w/w, about 15% to about 40% w/w, within the first 5 hours after the start of the test , about 15% to about 35% w/w, about 20% to about 30% w/w, or about 25% w/w or about 30% w/w, and/or

在试验开始后前7个小时内，富马酸酯的总量至多有大约65％w/w被释放，例如大约20％至大约65％w/w、大约20％至大约60％w/w、大约20％至大约50％w/w、大约25％至大约45％w/w、大约30％至大约45％w/w或者大约40％w/w或大约45％w/w，和/或During the first 7 hours after the start of the test, up to about 65% w/w of the total amount of fumarate is released, such as about 20% to about 65% w/w, about 20% to about 60% w/w , about 20% to about 50% w/w, about 25% to about 45% w/w, about 30% to about 45% w/w, or about 40% w/w or about 45% w/w, and/ or

在试验开始后前8个小时内，该组合物所含有的富马酸酯总量至多有大约92％w/w被释放，例如大约25％至大约92％w/w、大约25％至大约90％w/w、大约30％至大约80％w/w、大约35％至大约70％w/w、大约40％至大约65％w/w、大约45％至大约60％w/w、大约50％至大约60％w/w或者大约55％w/w或大约60％w/w，和/或Within the first 8 hours after the start of the test, at most about 92% w/w of the total amount of fumarate contained in the composition is released, such as from about 25% to about 92% w/w, from about 25% to about 90% w/w, about 30% to about 80% w/w, about 35% to about 70% w/w, about 40% to about 65% w/w, about 45% to about 60% w/w, about 50% to about 60% w/w or about 55% w/w or about 60% w/w, and/or

在试验开始后前8个小时内，该组合物所含有的富马酸酯总量至多有大约60％w/w被释放，例如大约30％至大约60％w/w、大约40％至大约55％w/w或者大约50％w/w，和/或Within the first 8 hours after the start of the test, at most about 60% w/w of the total amount of fumarate contained in the composition is released, such as about 30% to about 60% w/w, about 40% to about 55% w/w or about 50% w/w, and/or

在试验开始后前12个小时内，该组合物所含有的富马酸酯总量至多有大约99％w/w被释放，例如大约30％至大约99％w/w、大约30％至大约95％w/w、大约35％至大约90％w/w、大约40％至大约85％w/w、大约45％至大约80％w/w、大约50％至大约75％w/w、大约55％至大约75％w/w、大约60％至大约75％w/w或者大约65％w/w或大约70％w/w，和/或Within the first 12 hours after the start of the test, at most about 99% w/w of the total amount of fumarate contained in the composition is released, such as from about 30% to about 99% w/w, from about 30% to about 95% w/w, about 35% to about 90% w/w, about 40% to about 85% w/w, about 45% to about 80% w/w, about 50% to about 75% w/w, about 55% to about 75% w/w, about 60% to about 75% w/w or about 65% w/w or about 70% w/w, and/or

在试验开始后前12.5个小时内，该组合物所含有的富马酸酯总量至多有大约85％w/w被释放，例如大约50％至大约85％w/w、大约60％至大约80％w/w或者大约75％w/w，和/或Within the first 12.5 hours after the start of the test, at most about 85% w/w of the total amount of fumarate contained in the composition is released, such as about 50% to about 85% w/w, about 60% to about 80% w/w or about 75% w/w, and/or

在试验开始后前18个小时内，该组合物所含有的富马酸酯总量至少有大约80％w/w被释放，例如大约80％w/w或以上、大约85％w/w或以上、大约90％w/w或以上或者大约95％w/w或以上。Within the first 18 hours after the start of the test, at least about 80% w/w of the total amount of fumarate contained in the composition is released, such as about 80% w/w or more, about 85% w/w or More than, about 90% w/w or more or about 95% w/w or more.

缓慢释放slow release

下面给出特定实施方式的说明，其中富马酸酯以缓慢或延迟的方式被释放，其中释放模式适合于每日给药一次的组合物。适合的制剂原理实例是任意上述那些。A description is given below of specific embodiments wherein the fumarate is released in a slow or delayed manner, wherein the release profile is suitable for a once-daily administration composition. Examples of suitable formulation principles are any of those mentioned above.

因此，本发明在一方面涉及口用控释药物组合物，包含作为活性物质的一种或多种富马酸酯，选自富马酸的二-(C₁-C₅)烷基酯和富马酸的单-(C₁-C₅)烷基酯或者其药学上可接受的盐，其中富马酸酯在进行采用水作为溶解介质的体外溶解试验时的释放如下：Accordingly, the present invention relates in one aspect to a pharmaceutical composition for oral controlled release comprising as active substance one or more fumaric acid esters selected from the group consisting of di-(C₁ -C₅ )alkyl esters of fumaric acid and A mono-(C₁ -C₅ ) alkyl ester of fumaric acid or a pharmaceutically acceptable salt thereof, wherein the release of the fumaric acid ester in an in vitro dissolution test using water as the dissolution medium is as follows:

在试验开始后前7个小时内，该组合物所含有的富马酸酯总量至多有大约35％w/w被释放，例如大约15％至大约35％w/w、大约20％至大约30％w/w或者大约25％w/w，和/或Within the first 7 hours after the start of the test, at most about 35% w/w of the total amount of fumarate contained in the composition is released, such as about 15% to about 35% w/w, about 20% to about 30% w/w or about 25% w/w, and/or

在试验开始后前11个小时内，该组合物所含有的富马酸酯总量至多有大约60％w/w被释放，例如大约30％至大约60％w/w、大约40％至大约55％w/w或者大约50％w/w，和/或Within the first 11 hours after the start of the test, at most about 60% w/w of the total amount of fumarate contained in the composition is released, such as about 30% to about 60% w/w, about 40% to about 55% w/w or about 50% w/w, and/or

在试验开始后前14个小时内，该组合物所含有的富马酸酯总量至多有大约85％w/w被释放，例如大约50％至大约85％w/w、大约60％至大约80％w/w或者大约75％w/w，和/或Within the first 14 hours after the start of the test, at most about 85% w/w of the total amount of fumarate contained in the composition is released, such as about 50% to about 85% w/w, about 60% to about 80% w/w or about 75% w/w, and/or

在试验开始后前18个小时内，该组合物所含有的富马酸酯总量至少有大约80％w/w被释放，例如大约80％w/w或以上、大约85％w/w或以上、大约90％w/w或以上或者大约95％w/w或以上。Within the first 18 hours after the start of the test, at least about 80% w/w of the total amount of fumarate contained in the composition is released, such as about 80% w/w or more, about 85% w/w or More than, about 90% w/w or more or about 95% w/w or more.

通常，如上所述，根据本发明的组合物被设计成以延长方式递送活性物质(也就是富马酸的单烷基酯，它继而被代谢为富马酸，随后进行迅速消除过程)。除了本文所述体外释放模式的特征以外，这样一种延长释放也反映在临床研究后所得药动学参数中。因此，设想富马酸的单烷基酯(在所给予的二烷基酯的水解或代谢之后出现在血浆中)的C_max与以前文献所述处于相同的数量级，只要给予相似或相等的剂量(也就是说富马酸单甲酯的C_max在大约0.4至大约2.0mg/L的范围内，相当于120至240mg富马酸二甲酯的口服剂量)。不过，为了避免多次频繁的每日给药(2-4片，每日1-3次)，有意延长时间，其中浓度在治疗窗内。因此，设想W₅₀(也就是其中血浆浓度为C_max的50％或以上的时间)比市售治疗延长了至少10％，例如至少20％、至少30％、至少40％或至少50％。适合的W₅₀相信是至少2小时，例如在大约2至大约15小时或者大约2.5至大约10小时或者大约3至大约8小时的范围内。Generally, as mentioned above, the compositions according to the invention are designed to deliver the active substance (ie the monoalkyl ester of fumaric acid, which is then metabolized to fumaric acid followed by a rapid elimination process) in a prolonged manner. Such a prolonged release is also reflected in the pharmacokinetic parameters obtained after clinical studies, in addition to the in vitro release profile characteristics described herein. Therefore, it is envisaged that the_Cmax of the monoalkyl esters of fumaric acid (which appear in the plasma following hydrolysis or metabolism of the administered dialkyl esters) is of the same order of magnitude as previously reported, provided similar or equivalent doses are administered (That is, the_Cmax of monomethyl fumarate is in the range of about 0.4 to about 2.0 mg/L, corresponding to an oral dose of 120 to 240 mg of dimethyl fumarate). However, in order to avoid multiple frequent daily dosing (2-4 tablets, 1-3 times a day), the duration is intentionally prolonged, wherein the concentration is within the therapeutic window. Thus, it is envisioned that_W50 (ie the time during which the plasma concentration is 50% or above_Cmax ) is prolonged by at least 10%, such as at least 20%, at least 30%, at least 40% or at least 50% over marketed treatments. A suitable_W50 is believed to be at least 2 hours, for example in the range of about 2 to about 15 hours or about 2.5 to about 10 hours or about 3 to about 8 hours.

此外，设想根据本发明的控释组合物可以减少血浆曲线的个体间和/或个体内差异，减少对于组合物是否与食物一起服用的依赖性(当给予药物组合物伴有或没有食物摄取时，减少富马酸单甲酯血浆浓度曲线的差异)。因此，根据本发明的控释组合物可以减少服药的频率和/或减少平均总每日剂量，和/或与Fumaderm^相比增加在相同总每日剂量下的活性物质功效。Furthermore, it is envisaged that the controlled-release composition according to the present invention can reduce the inter- and/or intra-individual variability of the plasma profile, reducing the dependence on whether the composition is taken with food (when the pharmaceutical composition is administered with or without food intake). , reducing the difference in plasma concentration curves of monomethyl fumarate). Thus, the controlled-release compositions according to the invention allow to reduce the frequency of dosing and/or to reduce the average total daily dose, and/or to increase the efficacy of the active substance at the same total daily dose compared to Fumaderm^(R) .

不同的动力学模型可以应用于解释药物释放动力学，例如；零级(1)、一级(2)、平方根(Higuchi方程)。Different kinetic models can be applied to explain drug release kinetics, eg; zero order (1), first order (2), square root (Higuchi equation).

1：M_t＝M₀+k₀*t1: M_t =M₀ +k₀ *t

2：lnM_t＝lnM+k₁*t2: lnM_t = lnM+k₁ *t

3：M_t＝M₀+k_H*t^1/23: M_t =M₀ +k_H *t^1/2

在这些方程中，M_t是在任意指定时间点所释放的药物的累积量，M₀是药物组合物中所结合的活性物质的剂量，k₀、k₁和k_H分别是零级、一级和Higuchi方程的速率常数。In these equations, M_t is the cumulative amount of drug released at any given point in time, M₀ is the dose of active substance incorporated in the pharmaceutical composition, k₀ , k₁ and k_H are the zero order, one order and rate constants for the Higuchi equation.

本发明在一方面涉及零级溶解释放曲线。另一方面涉及一级溶解释放曲线。另一方面涉及平方根(Higuchi方程)溶解释放曲线。In one aspect the invention relates to zero order dissolution release profiles. Another aspect involves a first order dissolution release profile. Another aspect involves the square root (Higuchi equation) dissolution release curve.

本发明在一方面提供控释药物组合物，包含作为活性物质的10至90重量％的一种或多种富马酸酯，选自富马酸的二-(C₁-C₅)烷基酯和富马酸的单-(C₁-C₅)烷基酯或者其药学上可接受的盐，2至40重量％的药学上可接受的聚合物，和1至40重量％的亲水性赋形剂，可选地和药学上可接受的赋形剂或添加剂。In one aspect the present invention provides a controlled release pharmaceutical composition comprising asactive substance 10 to 90% by weight of one or more fumaric acid esters selected from di-(C₁ -C₅ )alkyl fumaric acid Esters and mono-(C₁ -C₅ ) alkyl esters of fumaric acid or pharmaceutically acceptable salts thereof, 2 to 40% by weight of pharmaceutically acceptable polymers, and 1 to 40% by weight of hydrophilic Sexual excipients, optionally with pharmaceutically acceptable excipients or additives.

本发明在另一方面提供控释药物组合物，包含作为活性物质的40至60重量％的一种或多种富马酸酯，选自富马酸的二-(C₁-C₅)烷基酯和富马酸的单-(C₁-C₅)烷基酯或者其药学上可接受的盐，15至25重量％的药学上可接受的聚合物，和2至15重量％的亲水性赋形剂，可选地和药学上可接受的赋形剂或添加剂。In another aspect the present invention provides controlled release pharmaceutical compositions comprising asactive substance 40 to 60% by weight of one or more fumaric acid esters selected from di-(C₁ -C₅ )alkanes of fumaric acid mono-(C₁ -C₅ ) alkyl ester of fumaric acid or a pharmaceutically acceptable salt thereof, 15 to 25% by weight of a pharmaceutically acceptable polymer, and 2 to 15% by weight of Aqueous excipients, optionally with pharmaceutically acceptable excipients or additives.

本发明在另一方面提供控释药物组合物，包含作为活性物质的65至80重量％的一种或多种富马酸酯，选自富马酸的二-(C₁-C₅)烷基酯和富马酸的单-(C₁-C₅)烷基酯或者其药学上可接受的盐，10至25重量％的药学上可接受的聚合物，和2至15重量％的亲水性赋形剂，可选地和药学上可接受的赋形剂或添加剂。In another aspect the present invention provides controlled release pharmaceutical compositions comprising as active substance 65 to 80% by weight of one or more fumaric acid esters selected from di-(C₁ -C₅ )alkanes of fumaric acid mono-(C₁ -C₅ ) alkyl ester of fumaric acid or a pharmaceutically acceptable salt thereof, 10 to 25% by weight of a pharmaceutically acceptable polymer, and 2 to 15% by weight of Aqueous excipients, optionally with pharmaceutically acceptable excipients or additives.

“药学上可接受的聚合物”的实例包含但不限于乙基纤维素或者异丁烯酸/丙烯酸共聚物，例如异丁烯酸铵共聚物A型和B型或者异丁烯酸共聚物A和B。Examples of "pharmaceutically acceptable polymers" include, but are not limited to, ethylcellulose or methacrylic acid/acrylic acid copolymers, such as ammonium methacrylate copolymers types A and B or methacrylic acid copolymers A and B.

“亲水性赋形剂”的实例包含但不限于聚乙二醇(PEG)、聚维酮、羟丙基纤维素(HPC)、羟乙基淀粉(HES)或羟丙基甲基纤维素(HPMC)或者具有相似性质的材料，或者它们的组合。Examples of "hydrophilic excipients" include, but are not limited to, polyethylene glycol (PEG), povidone, hydroxypropylcellulose (HPC), hydroxyethylstarch (HES), or hydroxypropylmethylcellulose (HPMC) or materials with similar properties, or combinations thereof.

本发明在另一方面提供控释药物组合物，其中该药学上可接受的聚合物是乙基纤维素。In another aspect the invention provides a controlled release pharmaceutical composition wherein the pharmaceutically acceptable polymer is ethylcellulose.

本发明在另一方面提供控释药物组合物，其中该亲水性赋形剂是羟丙基纤维素。In another aspect the invention provides a controlled release pharmaceutical composition wherein the hydrophilic excipient is hydroxypropylcellulose.

本发明在另一方面提供控释药物组合物，其中该亲水性赋形剂是聚乙二醇。In another aspect the invention provides a controlled release pharmaceutical composition wherein the hydrophilic excipient is polyethylene glycol.

本发明在另一方面提供控释药物组合物，包含作为活性物质的10至90重量％的一种或多种富马酸酯，选自富马酸的二-(C₁-C₅)烷基酯和富马酸的单-(C₁-C₅)烷基酯或者其药学上可接受的盐，和2至40重量％的异丁烯酸共聚物A和B，重量比在1∶9与9∶1之间，可选地和药学上可接受的赋形剂或添加剂。In another aspect the present invention provides controlled release pharmaceutical compositions comprising asactive substance 10 to 90% by weight of one or more fumaric acid esters selected from di-(C₁ -C₅ )alkanes of fumaric acid mono-(C₁ -C₅ ) alkyl esters of fumaric acid or pharmaceutically acceptable salts thereof, and 2 to 40% by weight of methacrylic acid copolymers A and B, in a weight ratio of 1:9 and Between 9:1, optionally with pharmaceutically acceptable excipients or additives.

本发明在另一方面提供控释药物组合物，包含50至90重量％的一种或多种富马酸酯、选自富马酸的二-(C₁-C₅)烷基酯和富马酸的单-(C₁-C₅)烷基酯或者其药学上可接受的盐。In another aspect the present invention provides controlled release pharmaceutical compositions comprising 50 to 90% by weight of one or more fumaric acid esters selected from di-(C₁ -C₅ )alkyl esters of fumaric acid and fumaric acid Mono-(C₁ -C₅ )alkyl esters of maleic acid or pharmaceutically acceptable salts thereof.

下面描述各种控释制剂，它们不限制本发明的范围，仅供阐述发明(所有浓度都基于最终的片剂)：Various controlled release formulations are described below, which do not limit the scope of the invention, but merely illustrate the invention (all concentrations are based on the final tablet):

1)颗粒剂1) Granules

颗粒剂可以如下制备，混合和/或造粒活性物质，浓度大约10至大约90％，尤其大约50至大约70％，与造粒赋形剂，例如药学上可接受的聚合物，例如乙基纤维素，例如Ethocel^NF premium，或者异丁烯酸/丙烯酸共聚物，例如异丁烯酸铵共聚物A型和B型(重量比为1∶9至9∶1)或异丁烯酸共聚物A和B(重量比为1∶9至9∶1)，所结合的浓度在大约2至大约40％之间。可以结合有亲水性赋形剂，例如聚乙二醇(PEG)、聚维酮、羟丙基纤维素(HPC)、羟乙基淀粉(HES)或羟丙基甲基纤维素(HPMC)，浓度大约1至大约40％，和/或药学上可接受的表面活性剂，HLB值在8以上，浓度大约0.01至大约3％。Granules can be prepared by mixing and/or granulating the active substance at a concentration of about 10 to about 90%, especially about 50 to about 70%, with a granulation excipient, such as a pharmaceutically acceptable polymer, such as ethyl Cellulose, for example Ethocel^(R) NF premium, or methacrylate/acrylic acid copolymers, for example ammonium methacrylate copolymers type A and type B (1:9 to 9:1 by weight) or methacrylate copolymers A and B (by weight ratio of 1:9 to 9:1), the combined concentration is between about 2 and about 40%. Can incorporate hydrophilic excipients such as polyethylene glycol (PEG), povidone, hydroxypropylcellulose (HPC), hydroxyethylstarch (HES) or hydroxypropylmethylcellulose (HPMC) , at a concentration of about 1 to about 40%, and/or a pharmaceutically acceptable surfactant, with an HLB value above 8, at a concentration of about 0.01 to about 3%.

2)微晶制剂2) Microcrystalline preparations

在任意适合于重结晶的有机溶剂中进行结晶，例如异丙醇，适当的温度例如在+70℃与-20℃之间。可以使用适当浓度的水胶体(例如HPMC)或表面活性剂(例如聚山梨醇酯)，以操控晶体在重结晶期间的生长。可以使用任意造粒/包衣赋形剂，例如药学上可接受的聚合物，例如乙基纤维素，浓度大约10至大约50％，尤其大约20至大约35％，聚异丁烯酸酯，例如异丁烯酸铵共聚物A型和B型或者异丁烯酸共聚物A和B。作为亲水性赋形剂，可以提到例如PEG 400。Crystallization is carried out in any organic solvent suitable for recrystallization, such as isopropanol, at a suitable temperature, eg, between +70°C and -20°C. Appropriate concentrations of hydrocolloids (such as HPMC) or surfactants (such as polysorbates) can be used to manipulate crystal growth during recrystallization. Any granulation/coating excipients may be used, for example pharmaceutically acceptable polymers such as ethyl cellulose at a concentration of about 10 to about 50%, especially about 20 to about 35%, polymethacrylates such as isobutylene Ammonium acid copolymer type A and B or methacrylic acid copolymer A and B. As hydrophilic excipient, mention may be made, for example, ofPEG 400.

3)胶囊剂和药囊剂3) Capsules and sachets

可以向胶囊(例如明胶、HPMC或淀粉衍生物的胶囊)或药囊填充包衣微晶或包衣颗粒，如果必要的话还有适量的填充赋形剂，例如糖醇，例如甘露糖醇，和/或助流剂。Capsules (e.g. of gelatin, HPMC or starch derivatives) or sachets may be filled with coated microcrystals or coated granules, if necessary with appropriate filling excipients, such as sugar alcohols, such as mannitol, and / or glidants.

4)片剂4) Tablets

片剂可以基于微晶或颗粒剂。在大规模生产片剂时，尤其在旋转机上，可能需要另外的赋形剂，以增加流动能力或者改进压片行为。作为填充与粘合赋形剂，如果需要的话，可以提到例如微晶纤维素，例如Avicel^102，和纤维素，浓度大约1至大约60％，经过喷雾干燥或造粒的结晶性乳糖一水合物，例如Tablettose^，以及无水乳糖一水合物，浓度大约5至大约60％，糖醇，例如山梨糖醇和甘露糖醇，浓度大约0至大约40％，和改性淀粉，浓度大约0至大约40％。此外，可以加入崩解剂，例如淀粉和淀粉衍生物，例如淀粉乙醇酸钠(浓度大约0.2至大约10％)，交联聚维酮(浓度大约0.2至大约10％)，羧甲基纤维素钠(浓度大约0.1至大约10％)，助流剂，例如胶体无水与含水二氧化硅(浓度大约0.2至大约4％)，和润滑剂，例如硬脂酸镁、山萮酸钙和花生酸钙(浓度大约0.2至大约3％)或硬脂酰富马酸钠(浓度大约1至大约8％)。Tablets may be based on microcrystalline or granules. When manufacturing tablets on a large scale, especially on rotary machines, additional excipients may be required to increase flow capacity or to improve tableting behaviour. As filling and binding excipients, mention may be made, if desired, for example of microcrystalline cellulose, such as Avicel^(R) 102, and cellulose, in a concentration of about 1 to about 60%, spray-dried or granulated crystalline lactose- Hydrates, such as Tablettose^(R) , and anhydrous lactose monohydrate at a concentration of about 5 to about 60%, sugar alcohols, such as sorbitol and mannitol, at a concentration of about 0 to about 40%, and modified starches at a concentration of about 0 to about 40%. In addition, disintegrants, such as starch and starch derivatives, such as sodium starch glycolate (concentration of about 0.2 to about 10%), crospovidone (concentration of about 0.2 to about 10%), carboxymethylcellulose, etc., may be added. Sodium (in concentrations of about 0.1 to about 10%), glidants such as colloidal anhydrous and hydrous silicon dioxide (in concentrations of about 0.2 to about 4%), and lubricants such as magnesium stearate, calcium behenate, and peanuts calcium phosphate (concentration of about 0.2 to about 3%) or sodium stearyl fumarate (concentration of about 1 to about 8%).

剂量dose

除了提供具有不同富马酸含量的组合物以外，本发明还提供例如含有两个或多个容器的药盒，例如容纳有包括各种富马酸含量的组合物。这类药盒适合用在需要随时间增加剂量的情形中。下面给出常规的剂量规格：     周     晨     午     晚     强度     1     1     -     -     A     2     1     -     1     A     3     1     -     1     B     4     1     -     -     B     5     1     -     1     B     6     1     1     1     B     7     2     1     1     B     8     2     1     2     B     9     2     2     2     BIn addition to providing compositions having varying levels of fumaric acid, the present invention also provides, for example, kits comprising two or more containers, eg containing compositions comprising various levels of fumaric acid. Such kits are suitable for use where it is desired to increase the dosage over time. The usual dosage specifications are given below: week morning noon Night strength 1 1 - -A 2 1 - 1 A 3 1 - 1 B 4 1 - - B 5 1 - 1 B 6 1 1 1 B 7 2 1 1B 8 2 1 2B 9 2 2 2 B

A相当于低强度，例如大约30mg富马酸二甲酯(或者相应有效剂量的另一种富马酸酯)。A corresponds to a low strength, eg, about 30 mg dimethyl fumarate (or a corresponding effective dose of another fumarate).

B相当于高强度，例如大约120mg富马酸二甲酯(或者相应有效剂量的另一种富马酸酯)。B corresponds to high strength, eg about 120 mg dimethyl fumarate (or a corresponding effective dose of another fumarate).

本发明在一方面提供控释药物组合物，其中一种或多种富马酸酯、选自富马酸的二-(C₁-C₅)烷基酯和富马酸的单-(C₁-C₅)烷基酯或者其药学上可接受的盐在剂型中的量为90mg至360mg活性物质，例如90、120、180、240或360mg活性物质。在本发明的另一方面，活性物质的量为120、180或240mg活性物质。在本发明的另一方面，活性物质的量为180或360mg。In one aspect the present invention provides controlled release pharmaceutical compositions wherein one or more fumaric acid esters are selected from di-(C₁ -C₅ )alkyl esters of fumaric acid and mono-(C The amount of₁ -C₅ ) alkyl esters or pharmaceutically acceptable salts thereof in the dosage form is 90 mg to 360 mg active substance, for example 90, 120, 180, 240 or 360 mg active substance. In another aspect of the invention, the amount of active substance is 120, 180 or 240 mg active substance. In another aspect of the invention, the amount of active substance is 180 or 360 mg.

根据本发明的控释药物组合物给药治疗患者的每日剂量依赖于一些因素，其中非限制性地包括体重、年龄和所要治疗的病症或疾病的病因，医师有能力确定之。在本发明的一个方面，每日剂量可以是例如240至360mg活性物质，分一至三次给予，另一方面360至480mg活性物质，分一至三次给予，另一方面480至600mg活性物质，分一至三次给予，另一方面600至720mg活性物质，分一至三次给予，另一方面720至840mg活性物质，分一至三次给予，另一方面840至960mg活性物质，分一至三次给予，另一方面960至1080mg活性物质，分一至三次给予。The daily dosage for administration of the controlled release pharmaceutical composition according to the invention to treat a patient depends on factors including, but not limited to, body weight, age and etiology of the condition or disease to be treated, as determined by the physician. In one aspect of the invention, the daily dosage may be, for example, 240 to 360 mg of active substance administered in one to three divided doses, 360 to 480 mg of active substance administered in one to three divided doses on the other hand, and 480 to 600 mg of active substance administered in one to three divided doses in another aspect Administration, on theother hand 600 to 720 mg of active substance in one to three doses, on the other hand 720 to 840 mg of active substance in one to three doses, on the other hand 840 to 960 mg of active substance in one to three doses, on the other hand 960 to 1080 mg Active substance, administered in one to three divided doses.

在本发明的一个方面，控释药物组合物是胶囊的形式。In one aspect of the invention, the controlled release pharmaceutical composition is in the form of a capsule.

本发明在另一方面提供片剂形式的控释药物组合物，例如形状使其容易和适宜为患者所吞咽的片剂，例如圆形或棒样形状，没有任何尖锐的边缘。In another aspect the present invention provides controlled release pharmaceutical compositions in the form of tablets, for example shaped such that they are easily and conveniently swallowed by a patient, for example round or stick-like in shape, without any sharp edges.

本发明在另一方面提供片剂形式的药物组合物，它被设计成分为两个或多个部分。In another aspect the invention provides a pharmaceutical composition in the form of a tablet, which is divided into two or more parts.

根据本发明的组合物可以与膳食一起或者在膳食前后给药，例如在膳食之前至少大约30分钟直至膳食之后大约2小时，或者在全天内任意特定时间点给予组合物。Compositions according to the invention may be administered with or around a meal, for example at least about 30 minutes before and up to about 2 hours after a meal, or at any particular point throughout the day.

在一种实施方式中，在就寝时给予总每日剂量，例如在就寝之前至多或大约30分钟、在就寝之前至多或大约60分钟、在就寝之前至多或大约90分钟、在就寝之前至多或大约120分钟或者在就寝之前至多或大约180分钟。In one embodiment, the total daily dose is administered at bedtime, e.g., at most or about 30 minutes before bedtime, at most or about 60 minutes before bedtime, at most or about 90 minutes before bedtime, at most or about 120 minutes or up to or about 180 minutes before bedtime.

根据本发明的组合物和药盒被设想成适合用于治疗一种或多种下列病症：Compositions and kits according to the invention are contemplated as being suitable for use in the treatment of one or more of the following conditions:

a.牛皮癣a. Psoriasis

b.牛皮癣性关节炎b. Psoriatic arthritis

c.神经皮炎c. Neurodermatitis

d.炎性肠疾病，例如d. Inflammatory bowel disease, eg

i.克罗恩氏病i. Crohn's disease

ii.溃疡性结肠炎ii. Ulcerative colitis

e.自身免疫疾病：e. Autoimmune diseases:

i.多关节炎i. Polyarthritis

ii.多发性硬化(MS)ii. Multiple Sclerosis (MS)

iii.青少年发作的糖尿病iii. Juvenile-onset diabetes

iv.桥本氏甲状腺炎iv. Hashimoto's thyroiditis

v.格雷夫氏病v. Graves' disease

vi.SLE(系统性红斑狼疮)vi.SLE (systemic lupus erythematosus)

vii.斯耶格伦氏综合征vii. Sjogren's syndrome

viii.恶性贫血viii. Pernicious anemia

ix.慢性活动型(狼疮样)肝炎ix. Chronic active (lupus-like) hepatitis

x.类风湿性关节炎(RA)x. Rheumatoid arthritis (RA)

xi.视神经炎xi. Optic neuritis

而且，根据本发明的新颖组合物或药盒可以用于治疗Furthermore, the novel compositions or kits according to the invention can be used for the treatment of

1.疼痛，例如神经根疼痛、与神经根病有关的疼痛、神经病疼痛或坐骨神经/坐骨疼痛1. Pain, such as radicular pain, pain associated with radiculopathy, neuropathic pain, or sciatic nerve/sciatic pain

2.器官移植(排斥的预防)2. Organ transplantation (prevention of rejection)

3.肉样瘤病3. Sarcoidosis

4.脂性渐进性坏死4. Fatty progressive necrosis

5.环形肉芽肿5. Granuloma annulare

牛皮癣已被提出可能与如下疾病有关：克罗恩氏病(Najarian DJ，Gottlieb AB，Connections between psoriasis and Crohn′s disease.J Am Acad Dermatol.2003 Jun；48(6)：805-21)、腹腔疾病(OjettiV et al，High prevalence of celiac disease in psoriasis.Am JGastroenterol.2003 Nov；98(11)：2574-5)、精神或心理疾病(例如抑郁或生活危机)(Gupta MA，Gupta AK，Psychiatric andpsychological co-morbidity in patients with dermatologicdisorders：epidemiology and management.Am J Clin Dermatol.2003；4(12)：833-42.and Mallbris L et al，Psoriasis phenotypeat disease onset：clinical characterization of 400 adult cases.J Invest Dermatol.2005 Mar；124(3)：499-504)、超重、糖尿病、酒精的过量消费/酒精中毒以及牛皮癣性关节炎。Psoriasis has been proposed to be associated with Crohn's disease (Najarian DJ, Gottlieb AB, Connections between psoriasis and Crohn's disease. J Am Acad Dermatol. 2003 Jun; 48(6): 805-21), celiac Disease (OjettiV et al, High prevalence of celiac disease in psoriasis. Am J Gastroenterol. 2003 Nov; 98(11): 2574-5), mental or psychological illness (eg depression or life crisis) (Gupta MA, Gupta AK, Psychiatric andpsychological co-morbidity in patients with dermatologic disorders: epidemiology and management. Am J Clin Dermatol. 2003; 4(12): 833-42. and Mallbris L et al, Psoriasis phenotypeat disease onset: clinical characterization of 400 adult Invasions. J 2005 Mar;124(3):499-504), overweight, diabetes, excessive alcohol consumption/alcoholism, and psoriatic arthritis.

本发明因而在一方面涉及治疗牛皮癣、牛皮癣性关节炎、神经皮炎、炎性肠疾病(例如克罗恩氏病和溃疡性结肠炎)、自身免疫疾病(例如多关节炎、多发性硬化(MS)、青少年发作的糖尿病、桥本氏甲状腺炎、格雷夫氏病、SLE(系统性红斑狼疮)、斯耶格伦氏综合征、恶性贫血、慢性活动型(狼疮样)肝炎、类风湿性关节炎(RA)和视神经炎)、疼痛(例如神经根疼痛、与神经根病有关的疼痛、神经病疼痛或坐骨神经/坐骨疼痛)、器官移植(排斥的预防)、肉样瘤病、脂性渐进性坏死或环形肉芽肿的方法，该方法包含对有需要的患者口服给予有效剂量的根据本发明的控释药物组合物。The present invention thus relates in one aspect to the treatment of psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), autoimmune disease (such as polyarthritis, multiple sclerosis (MS ), juvenile-onset diabetes, Hashimoto's thyroiditis, Graves' disease, SLE (systemic lupus erythematosus), Sjogren's syndrome, pernicious anemia, chronic active (lupus-like) hepatitis, rheumatoid arthritis neuritis (RA) and optic neuritis), pain (eg, radicular pain, pain associated with radiculopathy, neuropathic pain, or sciatic nerve/sciatic pain), organ transplantation (prevention of rejection), sarcoidosis, liponecrosis or a method for granuloma annulare, the method comprising orally administering an effective dose of the controlled-release pharmaceutical composition according to the present invention to a patient in need thereof.

本发明在另一方面涉及根据本发明的控释药物组合物制备药品的用途，该药品用于治疗牛皮癣、牛皮癣性关节炎、神经皮炎、炎性肠疾病(例如克罗恩氏病和溃疡性结肠炎)、自身免疫疾病(例如多关节炎、多发性硬化(MS)、青少年发作的糖尿病、桥本氏甲状腺炎、格雷夫氏病、SLE(系统性红斑狼疮)、斯耶格伦氏综合征、恶性贫血、慢性活动型(狼疮样)肝炎、类风湿性关节炎(RA)和视神经炎)、疼痛(例如神经根疼痛、与神经根病有关的疼痛、神经病疼痛或坐骨神经/坐骨疼痛)、器官移植(排斥的预防)、肉样瘤病、脂性渐进性坏死或环形肉芽肿。In another aspect, the present invention relates to the use of the controlled-release pharmaceutical composition according to the present invention for the preparation of a medicament for the treatment of psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel diseases (such as Crohn's disease and ulcerative colitis). colitis), autoimmune diseases (eg, polyarthritis, multiple sclerosis (MS), juvenile-onset diabetes, Hashimoto's thyroiditis, Graves' disease, SLE (systemic lupus erythematosus), Sjogren's syndrome pernicious anemia, chronic active (lupus-like) hepatitis, rheumatoid arthritis (RA), and optic neuritis), pain (eg, radicular pain, pain associated with radiculopathy, neuropathic pain, or sciatic nerve/sciatic pain) , organ transplantation (prevention of rejection), sarcoidosis, lipogenic necrosis or granuloma annulare.

此外，本发明也涉及用根据本发明的组合物或药盒治疗患有上述病症之一的个体，更具体为牛皮癣或牛皮癣性关节炎，所述个体进一步接受如下治疗：Furthermore, the present invention also relates to the treatment of an individual suffering from one of the aforementioned disorders, more particularly psoriasis or psoriatic arthritis, with a composition or a kit according to the invention, said individual being further treated by:

a)局部抗牛皮癣药，例如1)维生素D或其衍生物(骨钙三醇、骨钙三烯)，2)皮质甾类，例如倍他米松、去羟米松、氟轻松、莫美他松、氢醋丙氢可的松、氟替卡松、氯倍他索、氯倍他松、丁酸氢化可的松、地奈德、曲安西龙或氢化可的松，3)tazaroten，4)ditranol，5)他克莫司(FK-506)，和其他钙神经素抑制剂，例如pimecrolimus，或者6)任意1-5的组合，和/或a) Topical antipsoriatic agents such as 1) vitamin D or its derivatives (calcitriol, osteocalctriene), 2) corticosteroids such as betamethasone, deoxymethasone, fluocinolone, mometasone , hydrocortisone, fluticasone, clobetasol, clobetasone, hydrocortisone butyrate, desonide, triamcinolone or hydrocortisone, 3) tazaroten, 4) ditranol, 5 ) tacrolimus (FK-506), and other calcineurin inhibitors, such as pimecrolimus, or 6) any combination of 1-5, and/or

b)口服抗牛皮癣药，例如1)口服类视黄酸，例如阿维A或阿维A酯，组合或不组合有PUVA，2)环孢菌素和其他钙神经素抑制剂，例如ISA247、他克莫司和pimecrolimus，3)甲氨蝶呤，4)羟基脲，5)硫唑嘌呤，6)柳氮磺胺吡啶，7)富马酸酯衍生物，例如Fumaderm^或BG-12，8)罗格列酮(Avandia)和其他过氧化物酶体增殖物-活化-γ(PPARγ)激动剂或调控剂，例如吡格列酮、farglitazar、GW1929、GW7845、MC-555、MBX-102/MBX-10、MBX-1828、MBX-2044、CLX-0921、R-483、reglitazar、naveglitazar(LY-519818/LY-818)、netoglitazone(MCC-555)、CS-7017、曲格列酮、西格列酮、tesaglitazar、isaglitazone、balaglitazone、muraglitazar、TAK-654、LBM642、DRF4158、EML4156、T-174、TY-51501、TY-12780、VDO-52或AMG-131(T131)，或者任意1-8的组合，和/或b) Oral antipsoriatic agents such as 1) oral retinoids such as acitretin or acitretin with or without PUVA, 2) cyclosporine and other calcineurin inhibitors such as ISA247, Tacrolimus and pimecrolimus, 3) methotrexate, 4) hydroxyurea, 5) azathioprine, 6) sulfasalazine, 7) fumarate derivatives such as Fumaderm^(R) or BG-12,8 ) rosiglitazone (Avandia) and other peroxisome proliferator-activated-gamma (PPARγ) agonists or modulators, such as pioglitazone, farglitazar, GW1929, GW7845, MC-555, MBX-102/MBX-10 , MBX-1828, MBX-2044, CLX-0921, R-483, reglitazar, naveglitazar (LY-519818/LY-818), netoglitazone (MCC-555), CS-7017, troglitazone, siglitazone , tesaglitazar, isaglitazone, balaglitazone, muraglitazar, TAK-654, LBM642, DRF4158, EML4156, T-174, TY-51501, TY-12780, VDO-52 or AMG-131 (T131), or any combination of 1-8, and / or

c)肠胃外给药的抗牛皮癣药，例如1)alefacept(Amevive)，2)etanercept(Enbrel)，3)efalizumab(Raptiva)，4)onercept，5)adalimumab(Humira)，或者任意1-5的组合，和/或c) Antipsoriatic drugs for parenteral administration, such as 1) alefacept (Amevive), 2) etanercept (Enbrel), 3) efalizumab (Raptiva), 4) onercept, 5) adalimumab (Humira), or any of 1-5 combination, and/or

d)在上节c)下没有提到的TNF-α抑制剂(例如CDP 870或infliximab(Remicade))，经由肠内或肠胃外途径给药，和/或d) TNF-α inhibitors not mentioned under section c) above (eg CDP 870 or infliximab (Remicade)), administered via enteral or parenteral routes, and/or

e)tisocalicitrate和/或NCX 1022和/或IDEC-131和/或MEDI-507，和/或e) tisocalicitrate and/or NCX 1022 and/or IDEC-131 and/or MEDI-507, and/or

f)NSAID或者COX或LOX抑制剂，例如COX-2抑制剂或COX/5-LOX抑制剂，和/或f) NSAIDs or COX or LOX inhibitors, such as COX-2 inhibitors or COX/5-LOX inhibitors, and/or

g)抗糖尿病或抗肥胖药，例如双胍，例如甲福明、甲福明XR；磺酰脲，例如氯磺丙脲、格列吡嗪、格列齐特、格列本脲/优降糖或glimepiride；Glucovance(甲福明+格列本脲)；Metaglip(格列吡嗪+甲福明)；过氧化物酶体增殖物-活化-γ(PPARγ)激动剂或调控剂，例如罗格列酮(Avandia)、吡格列酮、farglitazar、GW1929、GW7845、MC-555、MBX-102/MBX-10、MBX-1828、MBX-2044、CLX-0921、R-483、reglitazar、naveglitazar(LY-519818/LY-818)、netoglitazone(MCC-555)、CS-7017、曲格列酮、西格列酮、tesaglitazar、isaglitazone、balaglitazone、muraglitazar、TAK-654、LBM642、DRF4158、EML4156、T-174、TY-51501、TY-12780、VDO-52或AMG-131(T131)；Avandamet(罗格列酮+甲福明)；Actos(吡格列酮+甲福明)；Avandaryl(马来酸罗格列酮+glimepiride)；苯并咪唑，例如FK-614；CS-917；TA-1095；ONO-5129；TAK-559；TAK-677/AJ-9667；d-苯丙氨酸诱导剂，例如senaglinide；c-3347；NBI-6024；ingliforib；BVT3498；LY929；SGLT2抑制剂；CS011；BIM51077；R1438；R1439；R1440；R1498；R1499；AVE0847；AVE2268；AVE5688；AVE8134；TA-6666；AZD6370；SSR162369；TLK-17411；NN2501；MK431；KGA-2727；MK-767；CS-872；β-3受体拮抗剂，例如N-5984；α-糖苷酶抑制剂，例如阿卡波糖、伏格列波糖或米格列醇；glinitide/meglitinide类似物或氨甲酰基甲基bensoeicacid衍生物，例如米格列奈、瑞格列奈或纳格列奈；DPP-IV抑制剂，例如LAF237(vildagliptin)、DPP728、P93/01、P32/98、PT-630或saxagliptin；GLP-1或GLP-1类似物，例如exenatide、Exenatide-LAR、liraglutide(NN2211)、ZP10/AVE0010、LY307161、betatropin、CJC-1131、GTP-010、SUN E7001或AZM134；pramlinitideacetate；胰岛素或胰岛素类似物，例如Humalog(insulin lispro)、Humulin、Novolin、Novolog/NovoRapid(insulin aspart)、Apidra(insulin glulisine)、Lantus(insulin glargine)、Exubera、Levemir/NN 304(insulin detemir)、AERx/NN 1998、Insuman、Pulmonary insulin或NN344；西布曲明或其他血清素和去甲肾上腺素突触前再摄取阻滞剂；奥利司他和其他GI脂酶抑制剂；β3-肾上腺素能受体激动剂；解偶联蛋白；PPARγ(过氧化酶体增殖物-活化受体γ)的(特异性)拮抗剂；胰岛素促分泌剂；rimonabant和其他CB1内类大麻碱受体拮抗剂；安非他酮；topiramate；苗条蛋白激动剂；睫状神经营养因子；人生长激素片段177-191的肽类似物；缩胆囊素-A受体激动剂；黑皮质素-3激动剂；去甲肾上腺素能药，例如芬特明、安非拉酮、苯甲曲嗪或苄非他明；，或者任意上述抗糖尿病或抗肥胖药的组合，和/或g) Antidiabetic or antiobesity agents such as biguanides such as metformin, metformin XR; sulfonylureas such as chlorpropamide, glipizide, gliclazide, glibenclamide/glyburide or glimepiride; Glucovance (metformin + glibenclamide); Metaglip (glipizide + metformin); peroxisome proliferator-activated-gamma (PPARγ) agonists or modulators such as Rog Avandia, pioglitazone, farglitazar, GW1929, GW7845, MC-555, MBX-102/MBX-10, MBX-1828, MBX-2044, CLX-0921, R-483, reglitazar, naveglitazar (LY-519818/ LY-818), netoglitazone (MCC-555), CS-7017, troglitazone, siglitazone, tesaglitazar, isaglitazone, balaglitazone, muraglitazar, TAK-654, LBM642, DRF4158, EML4156, T-174, TY- 51501, TY-12780, VDO-52, or AMG-131 (T131); Avandamet (rosiglitazone + metformin); Actos (pioglitazone + metformin); Avandaryl (rosiglitazone maleate + glimepiride) ; benzimidazoles such as FK-614; CS-917; TA-1095; ONO-5129; TAK-559; TAK-677/AJ-9667; d-phenylalanine inducers such as senaglinide; c-3347; NBI-6024; ingliforib; BVT3498; LY929; SGLT2 inhibitor; CS011; BIM51077; R1438; R1439; R1440; R1498; R1499; AVE0847; AVE2268; AVE5688; MK431; KGA-2727; MK-767; CS-872; beta-3 receptor antagonists, such as N-5984; alpha-glucosidase inhibitors, such as acarbose, voglibose, or miglitol ; glinitide/meglitinide analogs or carbamoylmethyl bensoeicacid derivatives such as mitiglinide, repaglinide or nateglinide; DPP-IV inhibitors such as LAF237 (vildagliptin), DPP728, P93/01, P32/98, PT-630, or saxagliptin; GLP-1 or GLP-1 analogs such as exenatide, Exenatide-LAR, liraglutide (NN2211), ZP10/AVE0010, LY307161, betatropin, CJC-1131, GTP-010, SUN E7001 or AZM134; pramlinitideacetate; insulin or insulin analogs such as Humalog (insulin lispro), Humulin, Novolin, Novolog/NovoRapid (insulin aspart), Apidra (insulin glulisine), Lantus (insulin glargine), Exubera, Levemir/NN 304 (insulin detemir), AERx/NN 1998, Insuman, Pulmonary insulin, or NN344; sibutramine or other serotonin and norepinephrine presynaptic reuptake blockers; orlistat and other GI lipase inhibitors; beta3 - Adrenergic receptor agonists; uncoupling proteins; (specific) antagonists of PPARγ (peroxisome proliferator-activated receptor gamma); insulin secretagogues; rimonabant and other CB1 endocannabinoid receptors body antagonist; bupropion; topiramate; leptin agonist; ciliary neurotrophic factor; peptide analogue of human growth hormone fragment 177-191; cholecystokinin-A receptor agonist; melanocortin-3 agonist a noradrenergic agent such as phentermine, difepramone, phenmetrazine, or benzfetamine; or a combination of any of the foregoing antidiabetic or antiobesity agents, and/or

h)潜在可用于治疗精神作用物质滥用、例如酒精滥用的药物，例如纳曲酮、acamprosate、disulphiram或Vivitrex(纳曲酮长效注射剂)，和/或h) Drugs potentially useful in the treatment of psychoactive substance abuse, such as alcohol abuse, such as naltrexone, acamprosate, disulphiram or Vivitrex (naltrexone long-acting injection), and/or

i)潜在可用于治疗克罗恩氏病的药物，例如i) Drugs potentially useful in the treatment of Crohn's disease, such as

1.5-ASA化合物，例如柳氮磺胺吡啶、口服5-ASA制剂或直肠5-ASA制剂，1. 5-ASA compounds such as sulfasalazine, oral 5-ASA preparations or rectal 5-ASA preparations,

2.糖皮质甾类，例如全身作用性甾类(例如布地奈德或泼尼松龙)或局部作用性甾类(例如布地奈德)，2. Glucocorticosteroids, such as systemically acting steroids (such as budesonide or prednisolone) or locally acting steroids (such as budesonide),

3.抗生素，例如甲硝唑或喹诺酮(例如环丙沙星、氧氟沙星、诺氟沙星、左氟沙星或moxifloxacine)，3. Antibiotics such as metronidazole or quinolones (such as ciprofloxacin, ofloxacin, norfloxacin, levofloxacin, or moxifloxacine),

4.免疫抑制剂，例如硫唑嘌呤、6-巯基嘌呤或甲氨蝶呤，4. Immunosuppressants such as azathioprine, 6-mercaptopurine or methotrexate,

5.营养疗法，例如元素或聚合物配方或者前-与促-抗生素，5. Nutritional therapy, such as elemental or polymeric formulations or pro- and pro-antibiotics,

6.生物疗法，例如TNF-α抑制剂，例如infliximab、adalimumab、CDP870、CDP571、etanercept或onercept，6. Biological therapy, such as TNF-α inhibitors, such as infliximab, adalimumab, CDP870, CDP571, etanercept or oneercept,

7.对症药物，例如抗腹泻药或抗痉挛药。7. Symptomatic drugs, such as antidiarrheal drugs or antispasmodics.

适合的NSAID实例是吡罗昔康、双氯芬酸、nabumetone、丙酸类(包括萘普生、氟比洛芬、非诺洛芬、酮洛芬和布洛芬)、fenamates(包括霉酚酸)、对乙酰氨基酚、消炎痛、舒林酸、美罗昔康、阿扎丙宗、吡唑酮类(包括保泰松)、水杨酸盐(包括阿司匹林)。Examples of suitable NSAIDs are piroxicam, diclofenac, nabumetone, propionates (including naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen), fenamates (including mycophenolic acid), acetaminophen Phenol, indomethacin, sulindac, meloxicam, azapropazone, pyrazolones (including phenylbutazone), salicylates (including aspirin).

适合的COX-2抑制剂实例是rofecoxib(Vioxx)、valdecoxib(Bextra)、celecoxib(Celebrex)、etoricoxib(Arcoxia)、lumiracoxib(Prexige)、parecoxib(Dynastat)、deracoxib(Deram)、tiracoxib、美罗昔康、尼美舒利、(1，1-二甲基庚基)-6a，7，10，10a-四氢-1-羟基-6，6-二甲基-6H-二苯并[b，d]吡喃羧酸(CT-3)、2(5H)-呋喃酮、5，5-二甲基(1-甲基乙氧基)[4-(甲基磺酰基)苯基]-(DFP)；Carprofen(RIMADYL)、(乙酰氧基)-苯甲酸3-[(硝酰基)甲基]苯基酯(NCX4016)、P54(CAS Reg.No.130996 0)、2，6-双(1，1-二甲基乙基)[(E)-(2-乙基-1，1-二氧代亚异噻唑烷基)甲基]苯酚(S-2474)、5(R)-硫代磺酰胺-3(2H)-苯并呋喃酮(SVT-2016)和N-[3-(甲酰氨基)氧代苯氧基-4H-苯并吡喃基]甲磺酰胺(″T-614″)；或者其药学上可接受的盐。Examples of suitable COX-2 inhibitors are rofecoxib (Vioxx), valdecoxib (Bextra), celecoxib (Celebrex), etoricoxib (Arcoxia), lumiracoxib (Prexige), parecoxib (Dynastat), deracoxib (Deram), tiracoxib, meloxicam, Mesulide, (1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyridine Carboxylic acid (CT-3), 2(5H)-furanone, 5,5-dimethyl(1-methylethoxy)[4-(methylsulfonyl)phenyl]-(DFP); Carprofen (RIMADYL), (acetoxy)-benzoic acid 3-[(nitroxyl)methyl]phenyl ester (NCX4016), P54 (CAS Reg.No.130996 0), 2,6-bis(1,1 -Dimethylethyl)[(E)-(2-Ethyl-1,1-dioxoisothiazolidinyl)methyl]phenol (S-2474), 5(R)-thiosulfonamide -3(2H)-benzofuranone (SVT-2016) and N-[3-(formylamino)oxyphenoxy-4H-benzopyranyl]methanesulfonamide ("T-614") ; or a pharmaceutically acceptable salt thereof.

适合的COX/5-LOX抑制剂实例是licofelone(ML-3000或[2，2-二甲基-6-(4-氯苯基)-7-苯基-2，3-二氢-1H-吡嗪-5-基]乙酸)，二叔丁基苯酚类，例如(E)-(5)-(3，5-二叔丁基-4-羟基亚苄基)-2-乙基-1，2-异噻唑烷-1，1-二氧化物(S-2474)，darbufelone或tebufelone和药学活性代谢产物，以及衍生物，例如二氢-二甲基-苯并呋喃和PGV-20229，二氢-二甲基-苯并呋喃，噻吩类化合物，例如RWJ-63556，N-羟基-N-甲基-4-(2，3-双-(4-甲氧基苯基)-噻吩-5-基)-丁酰胺(S19812)，甲氧基四氢吡喃衍生物，氧合呫吨酮类，例如1，3，6，7-四羟基呫吨酮(norathyriol)-吡唑硫代氨基甲酸酯，吡唑类，例如含有phenidone的化合物的改性形式或三氟苯取代的吡唑啉衍生物BW-755C，tepoxaline和衍生物，和二叔丁基嘧啶类。Examples of suitable COX/5-LOX inhibitors are licofelone (ML-3000 or [2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H- pyrazin-5-yl]acetic acid), di-tert-butylphenols such as (E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-1 , 2-isothiazolidine-1,1-dioxide (S-2474), darbufelone or tebufelone and pharmaceutically active metabolites, and derivatives such as dihydro-dimethyl-benzofuran and PGV-20229, di Hydrogen-dimethyl-benzofuran, thiophenes, such as RWJ-63556, N-hydroxy-N-methyl-4-(2,3-bis-(4-methoxyphenyl)-thiophene-5 -yl)-butanamide (S19812), methoxytetrahydropyran derivatives, oxyxanthones, such as 1,3,6,7-tetrahydroxyxanthone (norathyriol)-pyrazolethioamino Formic esters, pyrazoles, such as modified forms of phenidone-containing compounds or trifluorobenzene-substituted pyrazoline derivatives BW-755C, tepoxaline and derivatives, and di-tert-butylpyrimidines.

设想这类组合疗法与未用根据本发明的组合物或药盒治疗的个体相比，提高所述个体的治疗应答和/或增加适宜性。It is envisaged that such combination therapy improves the therapeutic response and/or increases suitability in an individual compared to an individual not treated with a composition or kit according to the invention.

本发明在另一方面涉及减少与口服治疗任意上述病症a-e和1-5有关的副作用的方法，在该方法中使用治疗所述病症的活性药物成分，组合有一种或多种下列成分：In another aspect the present invention relates to a method of reducing side effects associated with the oral treatment of any of the above conditions a-e and 1-5 using an active pharmaceutical ingredient for the treatment of said condition in combination with one or more of the following:

a)抗酸剂，例如1)氢氧化镁，2)三硅酸镁，3)氢氧化铝凝胶，4)碳酸氢钠，5)magaldrat，或者任意1-5的组合，和/或a) antacids such as 1) magnesium hydroxide, 2) magnesium trisilicate, 3) aluminum hydroxide gel, 4) sodium bicarbonate, 5) magaldrat, or any combination of 1-5, and/or

b)组胺H-2拮抗剂，例如1)西米替丁，2)雷尼替丁，3)尼扎替丁，4)法莫替丁，5)罗沙替丁，6)拉伏替丁，或者任意1-6的组合，和/或b) Histamine H-2 antagonists such as 1) cimetidine, 2) ranitidine, 3) nizatidine, 4) famotidine, 5) roxatidine, 6) laval Tidine, or any combination of 1-6, and/or

c)细胞保护剂，例如1)硫糖铝，2)tripotassiumdictitratobismuthate，3)卡贝索酮，4)前列腺素E-2类似物，例如misoprostol，5)ecabet，6)西曲酸酯HCl，7)teprenone，8)troxipide，9)盐酸双环胺，10)sofalcon，或者任意1-10的组合，和/或c) Cytoprotectants such as 1) sucralfate, 2) tripotassium dictitratobismuthate, 3) cabexolone, 4) prostaglandin E-2 analogs such as misoprostol, 5) ecabet, 6) cetraxate HCl, 7 ) teprenone, 8) troxipide, 9) dicyclomine hydrochloride, 10) sofalcon, or any combination of 1-10, and/or

d)质子泵抑制剂(PPI)，例如1)奥美拉唑，2)esomeprazole，3)兰索拉唑，4)pantoprazole，5)拉贝拉唑，6)CS-526/R-105266，7)AZD 0865，8)soraprazan，或者任意1-8的组合，和/或d) Proton pump inhibitors (PPI), such as 1) omeprazole, 2) esomeprazole, 3) lansoprazole, 4) pantoprazole, 5) labetrazole, 6) CS-526/R-105266, 7) AZD 0865, 8) soraprazan, or any combination of 1-8, and/or

e)NSAID或者COX或LOX抑制剂，例如COX-2抑制剂或COX/5-LOX抑制剂，和/或e) NSAIDs or COX or LOX inhibitors, such as COX-2 inhibitors or COX/5-LOX inhibitors, and/or

f)己酮可可碱，例如剂量范围为400至800mg/天。f) Pentoxifylline, for example in a dosage range of 400 to 800 mg/day.

在特定的实施方式中，活性物质是含有富马酸酯的化合物。确切而言，含有富马酸酯的化合物是任何和全部在Fumaderm^或Fumaraat^或Panaclar^(BG-12)或者在如US 6,277,882、US 6,355,676或US6,509,376所述或根据本发明的制剂中所含有的盐。可以在根据本发明的制剂或者任意Fumaderm^或Fumaraat^或Panaclar^制剂或者如US 6,277,882、US 6,355,676或US 6,509,376所述制剂中提供活性药物成分。In a particular embodiment, the active substance is a fumarate-containing compound. Precisely, compounds containing fumarate are any and all compounds present in Fumaderm^(R) or Fumaraat^(R) or Panaclar^(R) (BG-12) or in formulations as described in US 6,277,882, US 6,355,676 or US 6,509,376 or according to the invention Contains salt. The active pharmaceutical ingredient may be provided in a formulation according to the invention or in any of the Fumaderm^(R) or Fumaraat^(R) or Panaclar^(R) formulations or formulations as described in US 6,277,882, US 6,355,676 or US 6,509,376.

不言而喻，本发明不限于所描述的确切实施方式，它们当然可以各不相同。也不言而喻，本文所用术语仅仅出于描述确切实施方式的目的，不打算限制，本发明的范围仅受权利要求书的限制。若提供数值的范围，不言而喻在该范围上下限之间的每个中间值和其他所规定的或者在所规定的范围内的中间值都涵盖在本发明内，距离下限的十分之一单位，上下文另有明确指令除外。这些更小范围的上下限可以独立地被包括在更小的范围内，也涵盖在本发明内，受限于所规定的范围内任意具体排除的限制。若所规定的范围包括一个或两个限度，排除这些限度之一或之二的范围也包括在本发明内。除非另有限定，本文所用所有科技术语都具有本发明所属领域普通技术人员所普遍理解的含义。尽管在本发明的实践或试验时也可以使用任意与本文所述那些相似或等价的方法和材料，不过描述优选的方法和材料。本文提到的所有出版物都引用在此作为参考，以公开和描述关于这些出版物所引用的方法和/或材料。必须注意，本文和权利要求书所用的单数形式“一种”、“一个”和“该”包括复数指示物，上下文另有明确指令除外。本文所讨论的专利和出版物仅供在本申请提交日之前的公开。本文不被解释为由于在先发明而允许本发明没有资格先行于这类专利或出版物。进而，所提供的公布日期可能不同于实际的公布日期，它们可能需要独立地确认。正如将为本领域技术人员在阅读本文之后所显而易见的，本文所描述和阐述的每种个别实施方式具有离散的组分和特性，它们可以容易地与任意其他若干实施方式的特性分开或者组合，而不背离本发明的范围或精神。本文所示附图不必按比例绘制，为清楚起见放大了一些组分和特性。It goes without saying that the invention is not limited to the exact embodiments described, which may, of course, differ from each other. It is also to be understood that the terminology used herein is for the purpose of describing precise embodiments only and is not intended to be limiting, the scope of the present invention being limited only by the claims. Where a range of values is provided, it is understood that every intervening value between the upper and lower limits of that range and other intermediate values stated or within a stated range is encompassed within the invention, up to tenths of the lower limit A unit, unless the context clearly dictates otherwise. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those limits are also included in the invention. Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by those of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in respect of which the publications are cited. It must be noted that as used herein and in the claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The patents and publications discussed herein refer only to their disclosure prior to the filing date of this application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such patents or publications by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed. As will be apparent to those skilled in the art after reading this document, each individual embodiment described and illustrated herein has discrete components and characteristics that can be readily separated or combined with characteristics of any of the other several embodiments, without departing from the scope or spirit of the invention. The drawings shown herein are not necessarily drawn to scale, with some components and features exaggerated for clarity.

尽管出于清楚理解的目的已经借助举例说明详细描述了上述发明，不过鉴于本发明的教导将为本领域普通技术人员所显而易见的是，可以进行某些变化和修改，而不背离权利要求书的精神或范围。Although the foregoing invention has been described in detail by way of illustration for purposes of clarity of understanding, it will be apparent to those of ordinary skill in the art in view of the teachings of the invention that certain changes and modifications can be made without departing from the teachings of the claims spirit or range.

实施例Example

实施例1Example 1

片剂的制备Tablet preparation

将200g颗粒与150g微晶纤维素(例如Avicel^102)、97.5g乳糖(例如Tablettose^)、10g羧甲基纤维素钠(例如Ac-Di-Sol^)和25g淀粉混合30min。然后加入10g硬脂酸镁和7.5g无定形二氧化硅(例如Aerosil^200)，将粉末混合物混合5min。200 g of granules are mixed with 150 g microcrystalline cellulose (eg Avicel^(R) 102), 97.5 g lactose (eg Tablettose^(R )), 10 g sodium carboxymethylcellulose (eg Ac-Di-Sol^(R )) and 25 g starch for 30 min. Then 10 g of magnesium stearate and 7.5 g of amorphous silicon dioxide (eg Aerosil^(R) 200) are added and the powder mixture is mixed for 5 min.

在压片设备中将这种粉末混合物压制成片(片径10mm，表面积大约280-300mm²)。在盘式包衣或流化床包衣过程中包以肠溶衣，如实施例4所述。This powder mixture was compressed into tablets (tablet diameter 10 mm, surface area approximately 280-300 mm² ) in a tableting machine. Enteric coating was applied during pan coating or fluidized bed coating, as described in Example 4.

实施例2Example 2

片剂的制备Tablet preparation

将200g微晶与150g微晶纤维素(例如Avicel^102)、130g乳糖(例如Tablettose^)、10g羧甲基纤维素钠(例如Ac-Di-Sol^)和25mg淀粉混合30min。然后加入10g硬脂酸镁和7.5g无定形二氧化硅，将粉末混合物混合5min。在压片设备中将这种粉末混合物压制成片(片径10mm，表面积大约280-300mm²)。在盘式包衣或流化床包衣过程中包以肠溶衣，如实施例4所述。200 g microcrystalline are mixed with 150 g microcrystalline cellulose (eg Avicel^(R) 102), 130 g lactose (eg Tablettose^(R )), 10 g sodium carboxymethylcellulose (eg Ac-Di-Sol^(R )) and 25 mg starch for 30 min. Then 10 g of magnesium stearate and 7.5 g of amorphous silicon dioxide were added and the powder mixture was mixed for 5 min. This powder mixture was compressed into tablets (tablet diameter 10 mm, surface area approximately 280-300 mm² ) in a tableting machine. Enteric coating was applied during pan coating or fluidized bed coating, as described in Example 4.

实施例3Example 3

胶囊剂的制备Preparation of capsules

将颗粒或微晶填充在HPMC胶囊中，如下所述包以肠溶衣。在盘式包衣机中，向胶囊上喷以Eudragit^L30D-55，干燥温度60℃至80℃，用量20mg聚合材料每mm²。加入适量色素和滑石。The granules or microcrystals were filled into HPMC capsules and enteric coated as described below. The capsules were sprayed with Eudragit^(R) L30D-55 in a pan coater at a drying temperature of 60°C to 80°C in an amount of 20 mg of polymeric material per mm² . Add appropriate amount of coloring and talc.

实施例4Example 4

片剂包肠溶衣Tablets with enteric coating

在盘式包衣机中，向药片上喷以Eudragit^L30D-55，干燥温度60℃至80℃，用量6mg聚合材料每mm²。加入适量色素和滑石。The tablets were sprayed with Eudragit^(R) L30D-55 in a pan coater at a drying temperature of 60°C to 80°C at a rate of 6 mg of polymeric material per mm² . Add appropriate amount of coloring and talc.

实施例5Example 5

胶囊剂的制备Preparation of capsules

将如实施例15所述制备的156mg微晶填充在0号硬明胶胶囊中。将胶囊浸入5％HPMCP(Pharmacoat HP50^)的丙酮溶液中，每侧胶囊四次，包以肠溶衣。156 mg of microcrystals prepared as described in Example 15 are filled intosize 0 hard gelatin capsules. The capsules were dipped into a solution of 5% HPMCP (Pharmacoat HP50^(R )) in acetone four times on each side of the capsule and coated with an enteric coating.

实施例6Example 6

颗粒的制备Granule preparation

在造粒过程中，将50g富马酸二甲酯(下称DMF)与溶于10ml乙醇96％的1g乙基纤维素(例如Ethocel^NF premium)混合，通过1.0mm筛，在50℃至60℃下干燥30min。利用实施例1和3所述过程将这些颗粒制成片剂和胶囊剂。During the granulation process, 50 g of dimethyl fumarate (hereinafter referred to as DMF) was mixed with 1 g of ethyl cellulose (such as Ethocel^® NF premium) dissolved in 10 ml of ethanol 96%, passed through a 1.0 mm sieve, and heated at 50 ° C to Dry at 60°C for 30 minutes. These granules were formulated into tablets and capsules using the procedure described in Examples 1 and 3.

实施例7Example 7

颗粒的制备Granule preparation

在造粒过程中，将50g DMF与溶于10ml乙醇96％的1g聚乙酸乙烯酯(PVA)(例如Kollicoat^SR30)混合，通过1.00mm筛，在50℃至60℃下干燥30min。During granulation, 50 g DMF was mixed with 1 g polyvinyl acetate (PVA) (eg Kollicoat^(R) SR30) dissolved in 10 ml ethanol 96%, passed through a 1.00 mm sieve and dried at 50°C to 60°C for 30 min.

实施例8Example 8

颗粒的制备Granule preparation

在造粒过程中，将50g DMF与15g粉碎的Eudragit^RL100混合。加入适量2-丙醇和通过1.00mm筛后，在60℃下干燥颗粒。利用实施例1和3所述过程将这些颗粒制成片剂或胶囊剂。During granulation, 50 g of DMF were mixed with 15 g of pulverized Eudragit^(R) RL100. After adding an appropriate amount of 2-propanol and passing through a 1.00 mm sieve, the granules were dried at 60°C. These granules were formed into tablets or capsules using the procedure described in Examples 1 and 3.

实施例9Example 9

包衣颗粒的制备Preparation of coated granules

在造粒过程中，将50g DMF直接与5g Eudragit^RL30D混合，过筛(1.00mm)，在80℃下干燥。过筛后，在流化床包衣机(Mini-Glatt)中用15g Eudragit^RL30D/RS30D的1∶1混合物包衣。可以利用实施例1和3所述过程将这些包衣颗粒制成片剂或胶囊剂。During granulation, 50 g of DMF was directly mixed with 5 g of Eudragit(^R) RL30D, sieved (1.00 mm) and dried at 80°C. After sieving, it was coated with 15 g of a 1:1 mixture of Eudragit^(R) RL30D/RS30D in a fluid bed coater (Mini-Glatt). These coated granules can be formed into tablets or capsules using the procedure described in Examples 1 and 3.

实施例10Example 10

包衣颗粒的制备Preparation of coated granules

在造粒过程中，将50g DMF与溶于适量乙醇96％的20％乙基纤维素(例如Ethocel^NF premium)混合。向造粒液体加入15％聚乙二醇6000。使混合物通过1.00mm筛，在50℃至60℃下干燥30min。过筛后，在流化床包衣机(Mini-Glatt)中用乙基纤维素与聚乙二醇6000的2∶1混合物包衣，用量为20mg每mm²颗粒表面积。可以利用实施例1和3所述过程将这些颗粒制成片剂或胶囊剂。During granulation, 50 g of DMF are mixed with 20% ethylcellulose (eg Ethocel^(R) NF premium) dissolved in qs. ethanol 96%. Add 15% polyethylene glycol 6000 to the granulation liquid. The mixture was passed through a 1.00 mm sieve and dried at 50°C to 60°C for 30 min. After sieving, they were coated in a fluid bed coater (Mini-Glatt) with a 2:1 mixture of ethylcellulose and polyethylene glycol 6000 at a rate of 20 mg per^mm2 of particle surface area. These granules can be formulated into tablets or capsules using the procedure described in Examples 1 and 3.

实施例11Example 11

包衣颗粒的制备Preparation of coated granules

在造粒过程中，将50g DMF与溶于适量乙醇96％的10％乙基纤维素(例如Ethocel^NF premium)混合。向造粒液体加入6％聚维酮(例如Kollidon^25)。使混合物通过1.00mm筛，在50℃至60℃下干燥30min。过筛后，在流化床包衣机(Mini-Glatt)中用乙基纤维素与聚维酮的3∶2混合物包衣，用量为20mg每mm²颗粒表面积。During granulation, 50 g of DMF are mixed with 10% ethylcellulose (eg Ethocel^(R) NF premium) dissolved in qs. ethanol 96%. 6% povidone (eg Kollidon^(R) 25) is added to the granulation liquid. The mixture was passed through a 1.00 mm sieve and dried at 50°C to 60°C for 30 min. After sieving, they were coated in a fluid bed coater (Mini-Glatt) with a 3:2 mixture of ethylcellulose and povidone at a rate of 20 mg per^mm2 of particle surface area.

可以利用实施例1和3所述过程将这些颗粒制成片剂或胶囊剂。These granules can be formulated into tablets or capsules using the procedure described in Examples 1 and 3.

实施例12Example 12

包衣颗粒的制备Preparation of coated granules

在造粒过程中，将50g DMF与溶于适量乙醇96％的10％乙基纤维素(例如Ethocel^NF premium)混合。向造粒液体加入5％羟丙基纤维素(HPC)(例如Klucel^)。使混合物通过1.00mm筛，在50℃至60℃下干燥30min。过筛后，在流化床包衣机(Mini-Glatt)中用乙基纤维素与HPC的2∶1混合物包衣，用量为20mg每mm²颗粒表面积。During granulation, 50 g of DMF are mixed with 10% ethylcellulose (eg Ethocel^(R) NF premium) dissolved in qs. ethanol 96%. 5% Hydroxypropylcellulose (HPC) (eg Klucel^(R) ) is added to the granulation liquid. The mixture was passed through a 1.00 mm sieve and dried at 50°C to 60°C for 30 min. After sieving, they were coated in a fluid bed coater (Mini-Glatt) with a 2:1 mixture of ethylcellulose and HPC at a rate of 20 mg per^mm2 of particle surface area.

可以利用实施例1和3所述过程将这些颗粒制成片剂或胶囊剂。These granules can be formulated into tablets or capsules using the procedure described in Examples 1 and 3.

实施例13Example 13

包衣颗粒的制备Preparation of coated granules

在造粒过程中，将50g DMF直接与适量Eudragit^NE30D的水分散体混合，过筛(1.00mm)，在80℃下干燥。过筛后，在流化床包衣机(Mini-Glatt)中用15g Eudragit^RL30D/RS30D的1∶1混合物包衣。可以利用实施例1和3所述过程将包衣颗粒制成片剂和胶囊剂。During granulation, 50 g of DMF was directly mixed with an appropriate amount of Eudragit^(R) NE30D aqueous dispersion, sieved (1.00 mm), and dried at 80°C. After sieving, it was coated with 15 g of a 1:1 mixture of Eudragit^(R) RL30D/RS30D in a fluid bed coater (Mini-Glatt). The coated granules can be formed into tablets and capsules using the procedure described in Examples 1 and 3.

实施例14Example 14

包衣颗粒的制备Preparation of coated granules

在造粒过程中，将50g DMF直接与适量Eudragit^RL30D的水分散体混合，过筛(1.00mm)，在80℃下干燥。过筛后，在流化床包衣机(Mini-Glatt)中用Eudragit^NE30D包衣。可以利用实施例1和3所述过程将包衣颗粒制成片剂和胶囊剂。During granulation, 50 g of DMF was directly mixed with an appropriate amount of Eudragit^(R) RL30D aqueous dispersion, sieved (1.00 mm), and dried at 80°C. After sieving, it was coated with Eudragit^(R) NE30D in a fluid bed coater (Mini-Glatt). The coated granules can be formed into tablets and capsules using the procedure described in Examples 1 and 3.

实施例15Example 15

包衣微晶的制备Preparation of coated microcrystals

在60℃下制备50g DMF在300ml 2-丙醇中的饱和溶液，在磁搅拌下缓慢冷却。滤出所沉淀的晶体，在50℃下干燥。使晶体过筛，使用315-710μm级分在盘式包衣机或流化床包衣机(Mini-Glatt)中进行包衣过程。在60℃下向粉末表面喷以12g乙基纤维素(例如Ethocel^NF premium)与3g聚乙二醇400在500g乙醇中的包衣溶液。干燥后，使包衣晶体通过1.00mm筛。可以利用实施例2和3所述过程将包衣DMF晶体制成片剂和胶囊剂。A saturated solution of 50 g DMF in 300 ml 2-propanol was prepared at 60°C and cooled slowly under magnetic stirring. The precipitated crystals were filtered off and dried at 50°C. The crystals were sieved and the 315-710 μm fraction was used for the coating process in a pan coater or fluid bed coater (Mini-Glatt). A coating solution of 12 g of ethylcellulose (eg Ethocel^(R) NF premium) and 3 g ofpolyethylene glycol 400 in 500 g of ethanol is sprayed onto the surface of the powder at 60°C. After drying, the coated crystals were passed through a 1.00 mm sieve. The process described in Examples 2 and 3 can be used to form coated DMF crystals into tablets and capsules.

实施例16Example 16

片剂的制备Tablet preparation

在造粒过程中，将50g DMF与12g乙基纤维素(例如Ethocel^NFpremium)和3g聚乙二醇400的150ml乙醇96％溶液混合，通过1.0mm筛，在50℃至60℃下干燥30min，再次通过1.0mm筛。如下制备安慰颗粒：将Tablettose^和Avicel^102等份混合，用2％聚维酮(例如Kollidon^25)的水(q.s.)溶液造粒，通过1.0mm筛，在50℃至60℃下干燥30min，再次通过1.0mm筛。将60份DMF-颗粒与38份安慰-颗粒在Turbula Shaker混合机中混合30分钟。加入一份Aerosil^200和一份硬脂酸镁，再次混合5分钟。将掺合物压制成片，直径10mm，片重大约260mg，硬度大约50N。利用实施例4所述过程包以肠溶衣。During granulation, 50 g of DMF was mixed with 12 g of ethylcellulose (e.g. Ethocel^(R) NF premium) and 3 g ofpolyethylene glycol 400 in 150 ml of ethanol 96%, passed through a 1.0 mm sieve and dried at 50°C to 60°C for 30 min , again through a 1.0mm sieve. Placebo granules are prepared by mixing equal portions of Tablettose^(R) and Avicel(^R) 102, granulating with a 2% solution of povidone (eg Kollidon(^R) 25) in water (qs), passing through a 1.0 mm sieve, and drying at 50°C to 60°C After 30 minutes, pass through a 1.0mm sieve again. 60 parts of DMF-granules and 38 parts of placebo-granules were mixed in a Turbula Shaker mixer for 30 minutes. Add onepart Aerosil^(R) 200 and one part magnesium stearate and mix for an additional 5 minutes. The blend was compressed into tablets with a diameter of 10 mm, a tablet weight of approximately 260 mg, and a hardness of approximately 50N. The process described in Example 4 was used for enteric coating.

实施例17Example 17

片剂的制备Tablet preparation

在造粒过程中，将50g DMF与12g乙基纤维素(例如Ethocel^NFpremium)和3g聚乙二醇400的150ml乙醇96％溶液混合，通过1.0mm筛，在50℃至60℃下干燥30min，再次通过1.0mm筛。如下制备安慰颗粒：将Tablettose^和Avicel^102等份混合，用2％聚维酮(例如Kollidon^25)的水(q.s.)溶液造粒，通过1.0mm筛，在50℃至60℃下干燥30min，再次通过1.0mm筛。将60份DMF-颗粒与37份安慰-颗粒在Turbula Shaker混合机中混合30分钟。加入一份羧甲基纤维素(例如Ac-Di-Sol^)、一份Aerosil^200和一份硬脂酸镁，再次混合该掺合物5分钟。将掺合物压制成片，直径10mm，片重大约260mg，硬度大约50N。利用实施例4所述过程包以肠溶衣。During granulation, 50 g of DMF was mixed with 12 g of ethylcellulose (e.g. Ethocel^(R) NF premium) and 3 g ofpolyethylene glycol 400 in 150 ml of ethanol 96%, passed through a 1.0 mm sieve and dried at 50°C to 60°C for 30 min , again through a 1.0mm sieve. Placebo granules are prepared by mixing equal portions of Tablettose^(R) and Avicel(^R) 102, granulating with a 2% solution of povidone (eg Kollidon(^R) 25) in water (qs), passing through a 1.0 mm sieve, and drying at 50°C to 60°C After 30 minutes, pass through a 1.0mm sieve again. 60 parts of DMF-granules and 37 parts of placebo-granules were mixed in a Turbula Shaker mixer for 30 minutes. Add one part carboxymethylcellulose (eg, Ac-Di-Sol^(R ), onepart Aerosil^(R) 200, and one part magnesium stearate and mix the blend again for 5 minutes. The blend was compressed into tablets with a diameter of 10 mm, a tablet weight of approximately 260 mg, and a hardness of approximately 50N. Use the process described in Example 4 to enteric coat.

实施例18Example 18

包衣微晶的制备Preparation of coated microcrystals

在60℃下制备50g DMF在300ml 2-丙醇中的饱和溶液，在磁搅拌下缓慢冷却。滤出所沉淀的晶体，在50℃下干燥。使晶体过筛，使用315-710μm级分在盘式包衣机或流化床包衣机(Mini-Glatt)中进行包衣过程。在60℃下向晶体表面喷以12g乙基纤维素(例如Ethocel^NF premium)与3g聚维酮(PVP)在500g乙醇中的包衣溶液。干燥后，使包衣晶体通过1.00mm筛。可以利用实施例2和3所述过程将包衣DMF晶体制成片剂和胶囊剂。A saturated solution of 50 g DMF in 300 ml 2-propanol was prepared at 60°C and cooled slowly under magnetic stirring. The precipitated crystals were filtered off and dried at 50°C. The crystals were sieved and the 315-710 μm fraction was used for the coating process in a pan coater or fluid bed coater (Mini-Glatt). A coating solution of 12 g of ethylcellulose (eg Ethocel^(R) NF premium) and 3 g of povidone (PVP) in 500 g of ethanol is sprayed onto the crystal surface at 60°C. After drying, the coated crystals were passed through a 1.00 mm sieve. The process described in Examples 2 and 3 can be used to form coated DMF crystals into tablets and capsules.

实施例19Example 19

包衣微晶的制备Preparation of coated microcrystals

在60℃下制备50g DMF在300ml 2-丙醇中的饱和溶液，在磁搅拌下缓慢冷却。滤出所沉淀的晶体，在50℃下干燥。使晶体过筛，使用315-710μm级分在盘式包衣机或流化床包衣机(Mini-Glatt)中进行包衣过程。在60℃下向粉末表面喷以12g乙基纤维素(例如Ethocel^NF premium)与3g羟丙基纤维素(HPC)在500g乙醇中的包衣溶液。干燥后，使包衣晶体通过1.00mm筛。可以利用实施例2和3所述过程将包衣DMF晶体制成片剂和胶囊剂。A saturated solution of 50 g DMF in 300 ml 2-propanol was prepared at 60°C and cooled slowly under magnetic stirring. The precipitated crystals were filtered off and dried at 50°C. The crystals were sieved and the 315-710 μm fraction was used for the coating process in a pan coater or fluid bed coater (Mini-Glatt). A coating solution of 12 g of ethylcellulose (eg Ethocel^(R) NF premium) and 3 g of hydroxypropylcellulose (HPC) in 500 g of ethanol is sprayed onto the surface of the powder at 60°C. After drying, the coated crystals were passed through a 1.00 mm sieve. The process described in Examples 2 and 3 can be used to form coated DMF crystals into tablets and capsules.

实施例20Example 20

微晶的制备Preparation of microcrystals

如实施例15所述制备DMF-晶体，但是在晶体的沉淀之前直接向2-丙醇加入2％乙基纤维素，相对于晶体的质量而言。DMF-crystals were prepared as described in Example 15, but 2% ethylcellulose was added to 2-propanol directly before the precipitation of the crystals, relative to the mass of the crystals.

实施例21Example 21

包衣微晶的制备Preparation of coated microcrystals

如实施例15所述制备50g DMF晶体，在流化床包衣机(Mini-Glatt)中用Eudragit^RL30D/RS30D的1∶1混合物的20g水分散体包衣，温度80℃。利用实施例2和3所述过程将这些包衣DMF晶体制成片剂和胶囊剂。50 g of DMF crystals were prepared as described in Example 15 and coated with 20 g of an aqueous dispersion of a 1:1 mixture of Eudragit^(R) RL30D/RS30D in a fluid bed coater (Mini-Glatt) at 80°C. These coated DMF crystals were formed into tablets and capsules using the procedure described in Examples 2 and 3.

实施例22Example 22

片剂的制备Tablet preparation

如实施例15所述制备DMF晶体，直接与25％固体Eudragit^RSPO/RL PO 1∶2混合，如实施例2所述制成片剂。DMF crystals were prepared as described in Example 15, mixed directly with 25% solids Eudragit^(R) RSPO/RL PO 1:2 and tableted as described in Example 2.

实施例23Example 23

包衣微晶的制备Preparation of coated microcrystals

如实施例15所述制备DMF晶体，在流化床包衣机(Mini-Glatt)中用5％(相对于晶体质量而言)聚乙酸乙烯酯(例如Kollicoat^SR30D)的水分散体包衣。利用实施例2和3所述过程将这些包衣DMF晶体制成片剂和胶囊剂。DMF crystals were prepared as described in Example 15, coated in a fluid bed coater (Mini-Glatt) with an aqueous dispersion of 5% (relative to the crystal mass) polyvinyl acetate (e.g. Kollicoat^(R) SR30D) . These coated DMF crystals were formed into tablets and capsules using the procedure described in Examples 2 and 3.

实施例24Example 24

颗粒的制备Granule preparation

在造粒过程中，将50g DMF与溶于适量乙醇96％的15％乙基纤维素(例如Ethocel^NF premium)混合。向造粒液体加入10％聚乙二醇6000。使混合物通过1.00mm筛，在50℃至60℃下干燥30min。可以利用实施例1和3所述过程将这些颗粒制成片剂或胶囊剂。During granulation, 50 g of DMF are mixed with 15% ethylcellulose (eg Ethocel^(R) NF premium) dissolved in qs ethanol 96%. Add 10% polyethylene glycol 6000 to the granulation liquid. The mixture was passed through a 1.00 mm sieve and dried at 50°C to 60°C for 30 min. These granules can be formulated into tablets or capsules using the procedure described in Examples 1 and 3.

实施例25Example 25

颗粒的制备Granule preparation

在造粒过程中，将50g富马酸二乙酯(DEF)与溶于适量乙醇96％的15％乙基纤维素(例如Ethocel^NF premium)混合。向造粒液体加入10％聚乙二醇6000。使混合物通过1.00mm筛，在50℃至60℃下干燥30min。可以利用实施例1和3所述过程将这些颗粒制成片剂或胶囊剂。During granulation, 50 g of diethyl fumarate (DEF) are mixed with 15% ethylcellulose (eg Ethocel^(R) NF premium) dissolved in 96% ethanol qs. Add 10% polyethylene glycol 6000 to the granulation liquid. The mixture was passed through a 1.00 mm sieve and dried at 50°C to 60°C for 30 min. These granules can be formulated into tablets or capsules using the procedure described in Examples 1 and 3.

实施例26Example 26

片剂的制备Tablet preparation

如实施例24所述制备颗粒，但是加入10％聚维酮(例如Kollidon^25)代替PEG 6000。可以利用实施例1和3所述过程将这种混合物制成片剂或胶囊剂。Granules were prepared as described in Example 24, but with the addition of 10% povidone (eg Kollidon^(R) 25) instead of PEG 6000. This mixture can be formulated into tablets or capsules using the procedure described in Examples 1 and 3.

实施例27Example 27

片剂的制备Tablet preparation

如实施例24所述制备颗粒，但是加入10％羟丙基甲基纤维素代替PEG6000。可以利用实施例1和3所述过程将这种混合物制成片剂或胶囊剂。Granules were prepared as described in Example 24, but with the addition of 10% hydroxypropylmethylcellulose instead of PEG6000. This mixture can be formulated into tablets or capsules using the procedure described in Examples 1 and 3.

实施例28Example 28

如实施例15所述制备50g DMF晶体，在流化床包衣机(Mini-Glatt)中用Eudragit^RL30D/RS30D的1∶1混合物的20g水分散体包衣，温度80℃。如下所述在盘式包衣机中向包衣晶体包以肠溶衣。向包衣晶体喷以Eudragit^L30D-55，干燥温度60℃至80℃，用量为6mg聚合材料每mm²。50 g of DMF crystals were prepared as described in Example 15 and coated with 20 g of an aqueous dispersion of a 1:1 mixture of Eudragit^(R) RL30D/RS30D in a fluid bed coater (Mini-Glatt) at 80°C. Enteric coating was applied to the coated crystals in a pan coater as described below. Eudragit^(R) L30D-55 was sprayed onto the coated crystals at a drying temperature of 60°C to 80°C in an amount of 6 mg of polymeric material per mm² .

将这些双重包衣DMF晶体填充在硬明胶或软明胶胶囊中，或者利用实施例2所述过程制成片剂。These double-coated DMF crystals were filled into hard or soft gelatin capsules, or made into tablets using the procedure described in Example 2.

实施例29Example 29

片剂的制备Tablet preparation

在造粒过程中，将50g DMF与12g乙基纤维素(例如Ethocel^NFpremium)和3g羟丙基纤维素(例如Klucel^)的150ml乙醇96％溶液混合，通过1.0mm筛，在50℃至60℃下干燥30min，再次通过1.0mm筛。将Tablettose^和Avicel^102等份混合，用2％聚维酮(例如Kollidon^25)的水(q.s.)溶液造粒。将60份DMF-颗粒与38份安慰-颗粒在Turbula Shaker混合机中混合30分钟。加入一份Aerosil^200和一份硬脂酸镁，再次混合5分钟。将掺合物压制成片，直径10mm，片重大约260mg，硬度大约50N。利用实施例4所述过程包以肠溶衣。During granulation, 50 g of DMF was mixed with 12 g of ethylcellulose (e.g. Ethocel^(R) NFpremium) and 3 g of hydroxypropylcellulose (e.g. Klucel^(R) ) in 150 ml of ethanol 96% solution, passed through a 1.0 mm sieve at 50° C. to Dry at 60°C for 30 minutes, and pass through a 1.0mm sieve again. Tablettose^(R) and Avicel^(R) 102 are mixed in equal parts and granulated with a 2% solution of povidone (eg Kollidon^(R) 25) in water (qs). 60 parts of DMF-granules and 38 parts of placebo-granules were mixed in a Turbula Shaker mixer for 30 minutes. Add onepart Aerosil^(R) 200 and one part magnesium stearate and mix for an additional 5 minutes. The blend was compressed into tablets with a diameter of 10 mm, a tablet weight of approximately 260 mg, and a hardness of approximately 50N. The process described in Example 4 was used for enteric coating.

实施例30Example 30

胶囊剂的pH控制性释放溶解曲线的测定Determination of pH Controlled Release Dissolution Curve of Capsules

如美国药典所述测定溶解曲线，使用旋转篮，6支所谓的Levy-glasses容器，容量1升，和6只篮子搅拌元件，由电动机驱动(100rpm)。向Levy-glasses容器灌注0.1N HCl(水浴温度为37℃+/-0.5℃)，向篮子放入胶囊。2小时后，从容器中除去酸，用溶解介质(USP磷酸盐缓冲液pH6.5)代替，测试另外6小时。在用USP缓冲液代替溶解介质后，在0、60和120分钟后从酸介质中取样(5ml)，在30、60、90、120、180、240、300和360分钟后从缓冲液介质中取样。在每次取样后不用缓冲溶液代替所抽取的量，而是在计算所释放的DMF量时考虑缓冲液的损失。借助HPLC(Kontron XXX)测定DMF的量，使用Merck LiChroCART RP8 5μM，20cm柱，温度25℃。移动相由乙腈与0.0725mol/l NaH₂PO₄*H₂O-缓冲液的混合物(35∶65)组成，用磷酸调节至pH3.2。UV检测器的设置为波长230nm，流速1.0ml每分钟。大约5min的保留时间后，DMF峰是可检测的。The dissolution curve was determined as described in the US Pharmacopoeia using a rotating basket, 6 so-called Levy-glasses containers with a capacity of 1 liter, and 6 basket stirring elements driven by an electric motor (100 rpm). Fill the Levy-glasses container with 0.1N HCl (water bath temperature is 37°C +/- 0.5°C), and put the capsules into the basket. After 2 hours, the acid was removed from the vessel, replaced with dissolution medium (USP phosphate buffer pH 6.5), and tested for an additional 6 hours. After replacing the dissolution medium with USP buffer, samples (5 ml) were taken from the acid medium after 0, 60 and 120 minutes and from the buffer medium after 30, 60, 90, 120, 180, 240, 300 and 360 minutes sampling. Instead of replacing the withdrawn volume with buffer solution after each sampling, buffer loss was taken into account when calculating the amount of DMF released. The amount of DMF was determined by means of HPLC (Kontron XXX) using a Merck LiChroCART RP8 5 μM, 20 cm column, temperature 25°C. The mobile phase consisted of a mixture of acetonitrile and 0.0725 mol/l NaH₂ PO₄ *H₂ O-buffer (35:65), adjusted to pH 3.2 with phosphoric acid. The UV detector was set at a wavelength of 230 nm and a flow rate of 1.0 ml per minute. After a retention time of approximately 5 min, the DMF peak was detectable.

实施例31Example 31

非肠溶衣片的pH控制性释放溶解曲线的测定Determination of pH Controlled Release Dissolution Profile of Non-enteric Coated Tablets

如下测定溶解曲线，使用6支所谓的Levy-glasses容器，容量1升，和6只桨作为搅拌元件，由电动机驱动。桨的转速为100rpm。向Levy-glasses容器灌注USP磷酸盐缓冲液pH6.5(水浴温度为37℃+/-0.5℃)，向Levy-glasses容器放入药片。在用USP缓冲液代替溶解介质后，在0、30、60、90、120、180、240、300和360分钟后从缓冲液介质中取样(5ml)。在每次取样后不用缓冲溶液代替所抽取的量，而是在计算所释放的DMF量时考虑缓冲液的损失。借助HPLC(Kontron XXX)测定DMF的量，使用Merck LiChroCART RP8 5μM，20cm柱，温度25℃。移动相由乙腈与0.0725mol/l NaH₂PO₄*H₂O-缓冲液的混合物(35∶65)组成，用磷酸调节至pH3.2。UV检测器的设置为波长230nm，流速1.0ml每分钟。大约5min的保留时间后，DMF峰是可检测的。The dissolution curves were determined as follows, using 6 so-called Levy-glasses containers, with a capacity of 1 liter, and 6 paddles as stirring elements, driven by electric motors. The rotational speed of the paddles was 100 rpm. Fill the Levy-glasses container with USP phosphate buffer pH6.5 (water bath temperature is 37°C+/-0.5°C), and put the tablets into the Levy-glasses container. After replacing the dissolution medium with USP buffer, samples (5 ml) were taken from the buffer medium after 0, 30, 60, 90, 120, 180, 240, 300 and 360 minutes. Instead of replacing the withdrawn volume with buffer solution after each sampling, buffer loss was taken into account when calculating the amount of DMF released. The amount of DMF was determined by means of HPLC (Kontron XXX) using a Merck LiChroCART RP8 5 μM, 20 cm column, temperature 25°C. The mobile phase consisted of a mixture of acetonitrile and 0.0725 mol/l NaH₂ PO₄ *H₂ O-buffer (35:65), adjusted to pH 3.2 with phosphoric acid. The UV detector was set at a wavelength of 230 nm and a flow rate of 1.0 ml per minute. After a retention time of approximately 5 min, the DMF peak was detectable.

实施例32Example 32

如实施例5所述制备胶囊剂，如实施例30所述测定溶解曲线。溶解曲线如图1所示。Capsules were prepared as described in Example 5 and the dissolution profile determined as described in Example 30. The dissolution curve is shown in Figure 1.

实施例33Example 33

如实施例16所述制备片剂(在包以肠溶衣之前)，如实施例31所述测定溶解曲线。溶解曲线如图2所示。Tablets were prepared as described in Example 16 (prior to enteric coating) and the dissolution profile determined as described in Example 31. The dissolution curve is shown in Figure 2.

实施例34Example 34

如实施例17所述制备片剂(在包以肠溶衣之前)，如实施例31所述测定溶解曲线。溶解曲线如图3所示。Tablets were prepared as described in Example 17 (prior to enteric coating) and the dissolution profile determined as described in Example 31. The dissolution curve is shown in Figure 3.

Claims (45)

1, pharmaceutical composition comprises one or more fumarates as active substance, is selected from two of fumaric acid-(C₁-C₅) the list-(C of Arrcostab and fumaric acid₁-C₅) Arrcostab or its pharmaceutically acceptable salt, it is behind oral administration, with Isodose Fumaderm^Compare behind the sheet oral administration, reduce the GI side effect.

2, according to the pharmaceutical composition of claim 1, be the form of controlled release composition.

3, mouthful use controlled release pharmaceutical compositions, comprise one or more fumarates, be selected from two of fumaric acid-(C as active substance₁-C₅) the list-(C of Arrcostab and fumaric acid₁-C₅) Arrcostab or its pharmaceutically acceptable salt, wherein the release of fumarate when carrying out extracorporeal dissoluting test is as follows, this test pro-adopts 0.1N hydrochloric acid as dissolve medium during 2 hours, then with 0.05M phosphate buffer pH 6.5 as dissolve medium:

In preceding 3 hours, the fumarate total amount that said composition contained has about 70%w/w to be released at the most after on-test.

4, mouthful use controlled release pharmaceutical compositions, comprise one or more fumarates, be selected from two of fumaric acid-(C as active substance₁-C₅) the list-(C of Arrcostab and fumaric acid₁-C₅) Arrcostab or its pharmaceutically acceptable salt, wherein the release of fumarate when carrying out extracorporeal dissoluting test is as follows, this test pro-adopts 0.1N hydrochloric acid as dissolve medium during 2 hours, then with 0.05M phosphate buffer pH 6.5 as dissolve medium:

In preceding 4 hours, the total amount of fumarate has about 92%w/w to be released at the most after on-test.

5, according to the controlled release composition of claim 3, wherein the release of fumarate is as follows:

In preceding 4 hours, the total amount of fumarate has about 92%w/w to be released at the most after on-test.

6, the controlled release composition any according to claim 3-5, wherein the release of fumarate is as follows:

In preceding 5 hours, the total amount of fumarate has about 94%w/w to be released at the most after on-test.

7, the controlled release composition any according to claim 3-6, wherein the release of fumarate is as follows:

In preceding 6 hours, the fumarate total amount that said composition contained has about 95%w/w to be released at the most after on-test.

8, the controlled release composition any according to claim 3-7, wherein the release of fumarate is as follows:

In preceding 7 hours, the fumarate total amount that said composition contained has about 98%w/w to be released at the most after on-test.

9, the controlled release composition any according to claim 3-8, wherein the release of fumarate is as follows:

In preceding 9 hours, the fumarate total amount that said composition contained has about 99%w/w to be released at the most after on-test.

10, the controlled release composition any according to claim 3-9, wherein the release of fumarate is as follows:

In preceding 12 hours, the fumarate total amount that said composition contained has about 99%w/w to be released at the most after on-test.

11, according to any one controlled release pharmaceutical compositions of claim formerly, wherein this release has zero level, one-level or square root (Higuchi equation) kinetics release profiles.

12, according to the controlled release pharmaceutical compositions of claim 11, wherein this release has square root (Higuchi equation) kinetics release profiles.

13, the controlled release composition any according to claim 3-12, it is behind oral administration, with Isodose Fumaderm^Compare behind the sheet oral administration, reduce the GI side effect.

14, controlled release pharmaceutical compositions comprises one or more fumarates as 10 to 90 weight % of active substance, is selected from two of fumaric acid-(C₁-C₅) the list-(C of Arrcostab and fumaric acid₁-C₅) Arrcostab or its pharmaceutically acceptable salt, the pharmaceutically acceptable polymer of 2 to 40 weight % and the hydrophilic excipient of 1 to 40 weight % are alternatively with pharmaceutically acceptable excipient or additive.

15,, comprise one or more fumarates, be selected from two of fumaric acid-(C as 40 to 60 weight % of active substance according to the controlled release pharmaceutical compositions of claim 14₁-C₅) the list-(C of Arrcostab and fumaric acid₁-C₅) Arrcostab or its pharmaceutically acceptable salt, the pharmaceutically acceptable polymer of 15 to 25 weight % and the hydrophilic excipient of 2 to 15 weight % are alternatively with pharmaceutically acceptable excipient or additive.

16,, comprise one or more fumarates, be selected from two of fumaric acid-(C as 65 to 80 weight % of active substance according to the controlled release pharmaceutical compositions of claim 14₁-C₅) the list-(C of Arrcostab and fumaric acid₁-C₅) Arrcostab or its pharmaceutically acceptable salt, the pharmaceutically acceptable polymer of 10 to 25 weight % and the hydrophilic excipient of 2 to 15 weight % are alternatively with pharmaceutically acceptable excipient or additive.

17, the controlled release pharmaceutical compositions any according to claim 14-16, wherein this pharmaceutically acceptable polymer is an ethyl cellulose.

18, the controlled release pharmaceutical compositions any according to claim 14-17, wherein this hydrophilic excipient is a Polyethylene Glycol.

19, the controlled release pharmaceutical compositions any according to claim 14-17, wherein this hydrophilic excipient is a hydroxypropyl cellulose.

20, controlled release pharmaceutical compositions comprises one or more fumarates as 10 to 90 weight % of active substance, is selected from two of fumaric acid-(C₁-C₅) the list-(C of Arrcostab and fumaric acid₁-C₅) methacrylic acid copolymer A and the B of Arrcostab or its pharmaceutically acceptable salt and 2 to 40 weight %, weight ratio is between 1: 9 and 9: 1, alternatively with pharmaceutically acceptable excipient or additive.

21, according to claim 14 and any one controlled release pharmaceutical compositions of 16-20, comprise 50 to 90 weight % one or more fumarates, be selected from two of fumaric acid-(C₁-C₅) the list-(C of Arrcostab and fumaric acid₁-C₅) Arrcostab or its pharmaceutically acceptable salt.

22, the controlled release pharmaceutical compositions any according to claim 14-21 has the solubility curve any according to claim 3-13.

23, according to any one controlled release pharmaceutical compositions of claim formerly, wherein this fumarate is selected from the group of being made up of dimethyl fumarate, DEF, fumaric acid dipropyl, dibutyl fumarate, fumaric acid diamyl ester, fumaric acid Methylethyl ester, fumaric acid methyl-propyl ester, fumaric acid methyl butyl ester, fumaric acid methyl amyl ester, fumaric acid monomethyl ester, fumaric acid list ethyl ester, fumaric acid list propyl diester, fumaric acid monobutyl ester and fumaric acid list amyl group ester, comprises its pharmaceutically acceptable salt.

24, according to any one controlled release pharmaceutical compositions of claim formerly, wherein this fumarate is the list-(C of fumaric acid₁-C₅) Arrcostab, exist with the pharmaceutically acceptable salt form.

25, according to the controlled release composition of claim 24, wherein this salt is slaine, for example is selected from the salt of alkali metal salt and alkali salt

26, according to claim 24 or 25 any one controlled release compositions, wherein this salt is sodium, potassium, calcium, magnesium or zinc salt.

27, according to any one controlled release pharmaceutical compositions of claim formerly, comprise dimethyl fumarate as active substance.

28, according to any one controlled release pharmaceutical compositions of claim formerly, comprise monomethyl fumarate as active substance.

29, according to the controlled release pharmaceutical compositions of claim 28, wherein monomethyl fumarate exists with the form of its sodium, potassium, calcium, magnesium and/or zinc salt.

30,, be used for being administered once every day, twice or three times according to any one controlled release composition of claim formerly.

31,, be used for being administered once every day according to the controlled release composition of claim 30.

32,, be used for being administered twice every day according to the controlled release composition of claim 30.

33, according to any one controlled release pharmaceutical compositions of claim formerly, wherein one or more fumarates, be selected from two of fumaric acid-(C₁-C₅) the list-(C of Arrcostab and fumaric acid₁-C₅) Arrcostab or the amount of its pharmaceutically acceptable salt in dosage form be 90mg to 360mg active substance.

34, according to the controlled release pharmaceutical compositions of claim 33, wherein the amount in dosage form is 90,120,180,240 or the 360mg active substance.

35, according to the controlled release pharmaceutical compositions of claim 33, wherein the amount in dosage form is the 120mg active substance.

36, according to the controlled release pharmaceutical compositions of claim 33, wherein the amount in dosage form is the 180mg active substance.

37, according to the controlled release pharmaceutical compositions of claim 33, wherein the amount in dosage form is the 240mg active substance.

38, according to the controlled release pharmaceutical compositions of claim 33, wherein the amount in dosage form is the 360mg active substance.

39, according to any one controlled release pharmaceutical compositions of claim formerly, be the form of tablet.

40, according to the controlled release pharmaceutical compositions of claim 39, wherein the shape of this tablet makes it easily and be suitably the patient and swallow.

41, the controlled release pharmaceutical compositions any according to claim 39-40, wherein this tablet is circular or excellent sample shape, without any sharp-pointed edge.

42, the controlled release pharmaceutical compositions any according to claim 39-41, wherein this tablet is designed to be divided into two or more parts.

43, the controlled release pharmaceutical compositions any according to claim 1-38 is the form of capsule.

44, the treatment psoriasis, arthritic psoriasis, neural dermatitis, inflammatory bowel (for example Crohn disease and ulcerative colitis), autoimmune disease (polyarthritis for example, multiple sclerosis (MS), the diabetes of teenager outbreak, struma lymphomatosa, the Ge Leifushi disease, SLE (systemic lupus erythematosus (sle)), siogren's syndrome, pernicious anemia, chronic active type (lupoid acne) hepatitis, rheumatoid arthritis (RA) and optic neuritis), pain (nerve root pain for example, the pain relevant with radiculopathy, neuropathy pain or sciatic nerve/ischium pain), organ transplantation (prevention of repulsion), sarcoidosis, the method of necrobiosis lipoidica or granuloma annulare, this method comprise the pharmaceutical composition any according to claim 1-43 to patient's orally give effective dose that needs are arranged.

45, according to the purposes of any one the preparation of pharmaceutical compositions medicine of claim 1-43, this medicine is used for the treatment of psoriasis, arthritic psoriasis, neural dermatitis, inflammatory bowel (for example Crohn disease and ulcerative colitis), autoimmune disease (polyarthritis for example, multiple sclerosis (MS), the diabetes of teenager outbreak, struma lymphomatosa, the Ge Leifushi disease, SLE (systemic lupus erythematosus (sle)), siogren's syndrome, pernicious anemia, chronic active type (lupoid acne) hepatitis, rheumatoid arthritis (RA) and optic neuritis), pain (nerve root pain for example, the pain relevant with radiculopathy, neuropathy pain or sciatic nerve/ischium pain), organ transplantation (prevention of repulsion), sarcoidosis, necrobiosis lipoidica or granuloma annulare.

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