CN1207898A - 活化二甲硅油/无水磷酸钙组合物 - Google Patents
活化二甲硅油/无水磷酸钙组合物 Download PDFInfo
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- CN1207898A CN1207898A CN98117598A CN98117598A CN1207898A CN 1207898 A CN1207898 A CN 1207898A CN 98117598 A CN98117598 A CN 98117598A CN 98117598 A CN98117598 A CN 98117598A CN 1207898 A CN1207898 A CN 1207898A
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- Prior art keywords
- calcium phosphate
- activated
- anhydrous
- mixture
- dosage form
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Abstract
本发明涉及口服固体剂型的消泡制剂,该制剂由自由流动的颗粒状组合物制得,所述组合物含有活化二甲硅油和颗粒状无水三碱价磷酸钙或二碱价磷酸钙中的一种或两种的混合物,其中,所述混合物是粒度不大于1000微米的均匀的颗粒状组合物,该组合物适于压制成口服给药的固体剂型。
Description
本发明涉及抗胃肠气胀的固体口服药物剂型，所述剂型含有活化二甲硅油和无水三碱价或二碱价磷酸钙的混合物，本发明还涉及用于制备所述剂型的自由流动的颗粒状组合物及其生产方法。
活化二甲硅油是完全甲基化的直链硅氧烷聚合物和二氧化硅的混合物，所述硅氧烷聚合物含有用三甲基硅氧基末端封锁单元稳定的聚二甲基硅氧烷重复单元。活化二甲硅油含有90.5-99％的聚二甲基硅氧烷和4-7％的二氧化硅。活化二甲硅油中存在的聚二甲基硅氧烷实际上是分子量为14000-21000的惰性聚合物。该混合物是不溶于水的灰色透明的粘稠液体。
当口服给药时，活化二甲硅油用作气胀、功能性胃气胀和术后气胀疼痛的对症治疗的添加剂。活化二甲硅油的临床用途是基于它的消泡特性。硅氧烷消泡剂可在含水液体的表面扩展，形成一层低表面张力的膜，从而造成泡沫气泡的破裂。作为自我给药的非处方制剂，活化二甲硅油用作抗胃肠气胀的药物，用于缓解通常称为气胀的症状，包括上部胃肠道气胀、压力感、饱胀感。通常将其与其它胃肠道药物如抗酸剂、抗痉挛剂或消化酶联合使用，现有技术中公开了各种活化二甲硅油的制剂。
可将二甲硅油以液体制剂的形式口服给药，或以固体剂型如胶囊、口嚼片或口服片的形式口服给药。为了便于给药，优选口服片。相对于液体制剂，片剂的优点便于携带。相对于口嚼片，口服片的优点是易于服用并且无味。优选的口服片是薄膜包衣或明胶包衣的片剂。
以前，在制备活化二甲硅油的固体剂型时，当试图将较大量的液体活化二甲硅油掺入到用于压片的最终固体混合物中时遇到了困难。困难在于，在压片、特别是直接压片时难以达到足够的粘结力，从而使得到的片剂难以经受进一步的加工即薄膜包衣、明胶浸涂、染色、包装等。同样，还难以确保粘稠的活化二甲硅油能够均匀地分布在整个固体制剂中并在给药后迅速分散。
因此，本发明的目的是提供一种组合物及其制备方法，其中，可以将较大量的液体活化二甲硅油掺入到固体片剂中，以便通过干法混合/直接压片进行生产。
美国专利4906478公开了一种活化二甲硅油制剂，其中含有粉末化的颗粒硅酸钙和活化二甲硅油的混合物。美国专利5073384公开了含有水溶性凝胶化的麦芽糖糊精和活化二甲硅油的混合物的活化二甲硅油制剂。美国专利5458886公开了一种自由流动的颗粒状组合物，其中含有具有特定粒度和表面积的二氧化钛和活化二甲硅油。尽管这些方法在制备适于干法混合/直接压片生产过程的活化二甲硅油组合物中具有一定的优点，本发明仍提供了进一步的改进，以便提供可以方便、廉价地配制成适宜的口服片或口嚼片的组合物。
本发明涉及固体口服剂型的消泡制剂，该制剂用自由流动的颗粒状组合物制得，所述颗粒状组合物含有活化二甲硅油和颗粒状无水三碱价磷酸钙或二碱价磷酸钙中的一种或两种的混合物，其中，所述混合物是粒度不大于1000微米的均匀的颗粒状组合物，适于压制成用于口服给药的固体剂型。颗粒状无水三碱价或二碱价磷酸钙占所述混合物的约30-90％(w/w)。活化二甲硅油占所述混合物的约10-70％(w/w)。在优选的实施方案中，该混合物还含有0.5-4％(w/w)的二氧化硅或1.0-30.0％(w/w)的无水磷酸钙粉末。将自由流动的颗粒状组合物与常规的片剂粘合剂和赋形剂混合并压制成固体口服剂型。在用于压片的最终混合物中，活化二甲硅油的含量优选大于约8％并小于约20％(w/w)。
本发明另一方面提供用于压制固体口服剂型的活化二甲硅油消泡剂的自由流动颗粒状组合物的生产方法，所述方法包括，将活化二甲硅油加入到颗粒状三碱价或二碱价磷酸钙和选择性成分二氧化硅或无水磷酸钙粉末中，以形成颗粒状无水三碱价或二碱价磷酸钙、活化二甲硅油消泡剂和选择性成分二氧化硅或无水磷酸钙粉末的混合物，干法混合至均匀并剪切混合以确保形成均匀的粉末。在该方法的另一方面，将颗粒状组合物与赋形剂或其它活性成分混合并压片，以得到固体口服剂型，所述剂型优选压制成的片剂，并可将其进一步加工，用含水薄膜包衣或肠溶包衣进行包衣和/或进行明胶浸涂和染色。
与上述现有技术的组合物相比，本发明无水磷酸钙/活化二甲硅油混合物的优点在于，该混合物比含有凝胶化的麦芽糖糊精/活化二甲硅油的混合物的自由流动性更好且更稳定，从而不易从底物中分离出活化二甲硅油。与美国专利4906478中的组合物相比，其优点在于，按照美国药典标准(USP 23,1411页(活化二甲硅油片剂专题))测定时，无水磷酸钙/活化二甲硅油混合物的消泡活性明显更好。
如上所述，本发明的剂型中含有消泡剂如活化二甲硅油作为活性成分。优选该活化二甲硅油符合美国药典(USP XXII)的定义，即，是完全甲基化的直链硅氧烷聚合物和二氧化硅的混合物，所述硅氧烷聚合物含有用结构式为(-(CH3)3SiO-)的三甲基硅氧基末端封锁单元稳定的结构式为(-(CH3)2SiO-)n的重复单元。其它的有机聚硅氧烷消泡剂是本领域已知的，也可以用作本发明的活性成分。所述有机聚硅氧烷消泡剂记载于例如美国专利5458886，该文献引入本文作为参考。通常，消泡剂是粘稠的液体或糊状物质。在常温和常压下，活化二甲硅油为无色至灰色透明的粘稠油状液体，密度为0.965-0.970g/cm3，并且与水和醇不相混溶。因此，本发明提供了从所述粘稠油状液体或糊状消泡剂制备自由流动的颗粒状组合物的方法，所述颗粒状组合物适用于压制成固体口服剂型。
在所述固体口服剂型中，活化二甲硅油或其它有机聚硅氧烷消泡剂的含量应足以向患有胃肠气胀及相关症状的患者提供治疗剂量。就活化二甲硅油而言，优选的剂量范围是每剂量单位约20mg-约125mg，通常不超过500mg/天。剂量范围可随患者的年龄和体重以及症状的严重程度而变化。
三碱价或二碱价磷酸钙基本是无水的形式。无水三碱价或二碱价磷酸钙可从Rhone-Poulenc；Mendell and FMC Crop购买到。
根据本发明，将活化二甲硅油与颗粒状无水三碱价或二碱价磷酸钙混合以形成均匀的、自由流动的颗粒状组合物。通常，优选该混合物中含有与形成自由流动的颗粒状组合物相一致的成比例量的活化二甲硅油消泡剂和颗粒状无水磷酸钙。颗粒混合物组合物中各成分的比例优选为，约10-70％w/w的活化二甲硅油和约30-90％w/w的颗粒状无水三碱价或二碱价磷酸钙。将各成分混合、剪切混合并过筛，以确保自由流动的颗粒状组合物的粒度不超过约1000微米。所述颗粒状组合物还可选择性地含有一定量的二氧化硅或无水磷酸钙粉末，优选占颗粒状组合物约0.5-4％w/w的二氧化硅NF或占颗粒状组合物约1.0-30.0％w/w的的无水磷酸钙粉末。
活化二甲硅油/颗粒状无水磷酸钙混合物组合物通常通过干法混合的方法进行制备。首先将无水三碱价或二碱价磷酸钙通过干压或湿法制粒/干燥的方法制粒，优选干压的方法。然后，将活化二甲硅油加到颗粒状无水三碱价或二碱价磷酸钙的移动床上，从而使活化二甲硅油均匀分布并且颗粒状无水磷酸钙的粒度基本保持不变。通过低剪切混合器使床层保持移动。在颗粒状无水三碱价或二碱价磷酸钙床层吸附了活化二甲硅油并保持细的颗粒状组合物后，可加入二氧化硅或无水磷酸钙粉末。然后将所述颗粒过20号美国标准筛(约840微米)。
本发明的固体口服剂型可制成片剂、小胶囊(caplets)、凝胶胶囊(gelcaps)、胶囊、口嚼片、锭剂、速溶糯米纸囊剂以及其它已知可有效传递药物的形式。所述自由流动的颗粒状活化二甲硅油/无水三碱价或二碱价磷酸钙组合物可以与各种可药用赋形剂混合，所述赋形剂包括填充剂、粘合剂、甜味剂、人工甜味剂、润滑剂、助流剂。崩解剂、着色剂、吸附剂、酸化剂和矫味剂。赋形剂的选择取决于所采用的固体口服剂型(即片剂、小胶囊或胶囊)以及该剂型是口嚼制剂还是口服制剂。口服片优选通过直接压片进行制备。优选与直接压片的片剂相容的赋形剂。例如，可采用选自下表的赋形剂：
a)稀释剂如乳糖、高岭土、甘露醇、结晶山梨醇、三碱价或二碱价磷酸钙等；
b)粘合剂如糖、微晶纤维素、羧甲基纤维素、羟乙基纤维素、聚乙烯吡咯烷酮等；
c)润滑剂如硬脂酸镁、滑石、硬脂酸钙、硬脂酸锌、硬脂酸、氢化植物油、亮氨酸、甘油酯和硬脂基富马酸钠；
d)崩解剂如淀粉、交联羧甲基纤维素钠、甲基纤维素、琼脂、膨润土、藻酸、羧甲基纤维素、聚乙烯吡咯烷酮等；
e)清除剂如木炭、二氧化硅、无水磷酸钙；
f)矫味剂如甘露醇、葡萄糖、果糖、山梨醇等；和
g)着色剂。
其它适宜的赋形剂可以参见由美国药物联合会出版的药物赋形剂手册，该文献引入本文作为参考。
本发明的一般剂型可含有如下各种成分：自由流动的活化二甲硅油混合物 10％-99％三碱价磷酸钙，无水 45％-80％活化二甲硅油USP 10％-50％清除剂如二氧化硅，NF 1％-10％或无水磷酸钙粉末赋形剂 1％-90％稀释剂 0％-40％粘合剂 0％-10％润滑剂 0％-1.5％清除剂 0％-10％矫味剂/着色剂 0％-5％
优选在最终的片剂中，活化二甲硅油的含量占最终混合物的约8％-约20％w/w。可以通过本领域已知的方法生产本发明的口服剂型，例如，通过干压或湿法制粒的方法将无水三碱价或二碱价磷酸钙制粒；形成自由流动的活化二甲硅油/颗粒状无水三碱价或二碱价磷酸钙混合物；将自由流动的活化二甲硅油/颗粒状无水三碱价或二碱价磷酸钙组合物与赋形剂混合，然后通过本领域已知的方法例如直接压片、干法制粒等将组合物制成药物剂型。生产口服固体剂型的适宜方法参见由Mack Publishing Company出版的Remington’sPharmaceutical Science，第18版，该文献引入本文作为参考。生产方法优选包括如下步骤：制备上述自由流动的活化二甲硅油/颗粒状无水三碱价或二碱价磷酸钙混合物，在低剪切混合下加入粘合剂/稀释剂/崩解剂赋形剂，加入润滑剂并通过直接压片制备片剂。
随需要，药物剂型中还可含有一种或多种适于治疗胃肠疾病如胃灼热、溃疡或腹泻的其它活性成分。用于治疗胃肠疾病的适宜活性成分包括治疗胃灼热或抗溃疡的药物如硫糖铝，H2受体拮抗剂如西咪替丁、雷尼替丁、法莫替丁或尼扎替丁，质子泵抑制剂如奥美拉唑或兰索拉唑；止泻药如洛哌丁胺和地芬诺酯；胃肠动力药如西沙必利、抗酸药如氢氧化铝、碳酸镁、氢氧化镁、碳酸钙等。与活化二甲硅油联用的所述附加活性成分的量应足以向患有待治疗的胃肠疾病的患者提供治疗剂量。
提供如下实施例以进一步说明本发明：
实施例1活化二甲硅油/颗粒状无水三碱价磷酸钙混合物的制备1.将700g颗粒状磷酸钙(Tritab，Rhone-Poulenc，Shelton，Ct)加入到Kitchen Aid混合器的混合辊筒内。2.以低速进行混合的同时，在5分钟内加入200g活化二甲硅油，USP。3.继续以低速混合5分钟。4.加入2.5g二氧化硅并继续混合5分钟。
该中间体为自由流动的颗粒，不含大的聚集物。
实施例2
活化二甲硅油/颗粒状无水二碱价磷酸钙混合物的制备1.将700g颗粒状无水二碱价磷酸钙(Emcompress无水，Mendell，Paterson，NJ)加入到Kitchen Aid混合器的混合辊筒内。2.以低速进行混合的同时，在5分钟内加入200g活化二甲硅油，USP。3.继续以低速混合5分钟。4.加入7.5g二氧化硅并继续混合5分钟。
该中间体为自由流动的颗粒，不含大的聚集物。
比较例2
活化二甲硅油/颗粒状二碱价磷酸钙二水合物混合物的制备1.将700g颗粒状二碱价磷酸钙二水合物(Emcompress，Mendell，Paterson，NJ)加入到Kitchen Aid混合器的混合辊筒内。2.以低速进行混合的同时，在5分钟内加入200g活化二甲硅油，USP。3.加入30g二氧化硅并继续混合5分钟。
该中间体不是自由流动的颗粒。其中含有大量大的聚集物。
实施例3
含有活化二甲硅油/颗粒状无水三碱价磷酸钙混合物的口嚼片的制备1.将89g实施例1制得的自由流动的颗粒状中间体与98g Dextrates、7.5g颗粒状山梨醇、0.6g薄荷香精和0.5g硬脂酸混合。2.用5/8″FFBE工具将混合物压片。
片重1300mg。该药片的物理性质如下：
硬度：8-10kp脆碎度：降落100次后，小于0.1％在水中的崩解：小于1分钟消泡：5秒。
实施例4含有活化二甲硅油/颗粒状无水三碱价磷酸钙混合物的口嚼片的制备1.将1500g磷酸钙粉末以500磅/平方英寸的辊压通过辊压的方法进行干法制粒。2.将粉粒料通过带有0.093″筛的Fitz磨，刀口向前。3.将研磨后的材料过筛，收集-30至80目的部分作为产品。4.将700g压紧的磷酸钙颗粒加入到Kitchen Aid混合器的混合辊筒内。5.以低速进行混合的同时，在5分钟内加入200g活化二甲硅油，USP。6.继续以低速混合5分钟。7.加入20g磷酸钙粉末并继续混合5分钟。该中间体是自由流动的颗粒，不含大的聚集物。8.将91g上述中间体与98g Dextrates、7.5g颗粒状山梨醇、0.6g薄荷香精和0.5g硬脂酸混合。9.用5/8″FFBE工具将混合物压片。
片重1300mg。该药片的物理性质如下：
硬度：11-12kp
脆碎度：降落100次后，小于0.1％
在N/10 HCl中的崩解：小于1.5分钟
消泡：7秒。
实施例5
含有活化二甲硅油/颗粒状无水三碱价磷酸钙混合物的口嚼片的制备1.将500g磷酸钙粉末和50g预胶化淀粉在Kitchen Aid混合器中干法混合。2.连续搅拌下向混合器中缓慢加入310g纯净水。3.将湿的颗粒通过#12目筛，然后在50℃下干燥5小时。4.将干燥后的颗粒通过#18目筛，除去小于#70目的物料。5.重复步骤1-4。6.然后将700g制粒的磷酸钙/预胶化淀粉颗粒加入到Kitchen Aid混合器的混合辊筒内。7.以低速进行混合的同时，在5分钟内加入200g活化二甲硅油，USP。8.继续以低速混合5分钟。该中间体是自由流动的颗粒，不含大的聚集物。9.将89g上述中间体与98g Dextrates、7.5g颗粒状山梨醇、0.6g薄荷香精和0.5g硬脂酸混合。10.用5/8″FFBE工具将混合物压片。
片重1300mg。该药片的物理性质如下：
硬度：8-9kp
脆碎度：降落100次后，小于0.1％
在N/10 HCl中的崩解：小于1分钟
消泡：5秒。
实施例6含有活化二甲硅油/颗粒状无水三碱价磷酸钙混合物的口服薄膜包衣片的制备
第1部分)将活化二甲硅油(USP)加到颗粒状无水三碱价磷酸钙的移动床上，从而使活化二甲硅油均匀分布并且颗粒状磷酸钙的粒度基本保持不变，由此制得含有颗粒状和粉末状无水三碱价磷酸钙以及活化二甲硅油的浓缩物。通过低剪切混合器如流化床、Nauta、不带强化棒的PK、pin mixer或ribbon mixer使床层保持移动。在床层吸附了活化二甲硅油后，可加入无水三碱价磷酸钙粉末。然后将所述颗粒过20号美国标准筛(约840微米)。第2部分)根据用于压片的最终混合物的需要，可向第1部分的浓缩物中加入附加量的磷酸钙粉末并混合。第3部分)然后在低剪切混合下加入包含崩解剂的赋形剂，从而使活性成分均匀分布在限定组成范围的粘合基质中。第4部分)最后的加料步骤是加入润滑剂。第5部分)用旋转压片机将混合物压制成片。第6部分)然后将该片剂进行薄膜包衣和/进行明胶浸涂。一般薄膜包衣片的特点：硬度：6-14kp片重(片芯)：约1000mgUSP崩解时间，在水中：小于7分钟，在酸性溶媒中：小于6分钟USP消泡活性时间：9秒。
| 成分 | mg/片 |
| 第I部分-浓缩物 | |
| 三碱价磷酸钙，NF，无水，颗粒状 | 500 |
| 活化二甲硅油，USP | 125 |
| 三碱价磷酸钙，NF，无水，粉末 | 25 |
| 第II部分-清除剂 | |
| 三碱价磷酸钙，NF，无水，粉末 | 20 |
| 第III部分-赋形剂/粘合剂系统 | |
| 二碱价磷酸钙，二水合物，USP | 105.75 |
| 微晶纤维素，NF(MCC) | 53 |
| 结晶山梨醇，NF | 70 |
| 交联羧甲基纤维素钠，NF | 30 |
| 第IV部分-润滑剂 | |
| 硬脂酸镁，NF | 0.5 |
Claims (12)
1、消泡剂活化二甲硅油的口服固体剂型的制剂，该制剂由自由流动的颗粒状组合物制得，所述颗粒状组合物含有a)活化二甲硅油和b)颗粒状无水三碱价或二碱价磷酸钙或其混合物的混合物；其中，活化二甲硅油/磷酸钙混合物是粒度不大于1000微米的均匀的颗粒状组合物。
2、权利要求1的口服固体剂型，其中所述剂型为单位剂量的压制口服片或口嚼片、或小胶囊、凝胶胶囊、胶囊、锭剂或速溶糯米纸囊剂的形式。
3、权利要求1的口服固体剂型，除所述自由流动的颗粒状组合物外还含有一种或多种赋形剂。
4、权利要求3的口服固体剂型，其中所述赋形剂选自一种或多种填充剂、粘合剂、甜味剂、人工甜味剂、润滑剂、助流剂、崩解剂、着色剂、吸附剂、酸化剂和矫味剂。
5、权利要求1的口服固体剂型，其中活化二甲硅油的含量为约8％—约20％w/w。
6、权利要求5的口服固体剂型，除所述活化二甲硅油和颗粒状无水三碱价或二碱价磷酸钙的自由流动的颗粒状组合物外，还含有结晶山梨醇、微晶纤维素和无水三碱价或二碱价磷酸钙作为赋形剂。
7、权利要求1的口服固体剂型，还含有一种或多种适于治疗胃肠疾病的其它活性成分。
8、权利要求7的口服固体剂型，其中所述的其它活性成分选自如下的一种或多种成分：H2受体拮抗剂、质子泵抑制剂、止泻药、胃肠动力药和抗酸药。
9、自由流动的颗粒状组合物，该组合物含有a)活化二甲硅油和b)颗粒状无水三碱价或二碱价磷酸钙或其混合物的混合物；其中，活化二甲硅油/磷酸钙混合物是粒度不大于1000微米的均匀的颗粒状组合物。
10、权利要求9的自由流动的颗粒状组合物，其中，颗粒状混合物组合物中各成分的比例为，约10-70％w/w的活化二甲硅油和约30-90％w/w的颗粒状无水三碱价或二碱价磷酸钙。
11、权利要求9的自由流动的颗粒状组合物，还含有含量为占颗粒状组合物约0.5-4％w/w的二氧化硅或占颗粒状组合物约1-30％ w/w的无水磷酸钙粉末。
12、用于压制固体口服剂型的活化二甲硅油消泡剂的自由流动颗粒状组合物的生产方法，所述方法包括，将活化二甲硅油加入到颗粒状无水三碱价或二碱价磷酸钙和选择性成分二氧化硅或无水磷酸钙粉末中，以形成颗粒状无水三碱价和/或二碱价磷酸钙、活化二甲硅油消泡剂和选择性的清除剂如二氧化硅或无水磷酸钙粉末的混合物，干法混合至均匀并剪切混合，以确保形成均匀的、自由流动的颗粒状组合物。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/896,189 US6103260A (en) | 1997-07-17 | 1997-07-17 | Simethicone/anhydrous calcium phosphate compositions |
| US896,189 | 1997-07-17 | ||
| US896189 | 2001-06-29 |
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| CN1207898A true CN1207898A (zh) | 1999-02-17 |
| CN1267106C CN1267106C (zh) | 2006-08-02 |
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| CNB981175988A Expired - Lifetime CN1267106C (zh) | 1997-07-17 | 1998-07-17 | 活化二甲硅油/无水磷酸钙组合物 |
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| EP (1) | EP0891776B1 (zh) |
| JP (1) | JPH1192387A (zh) |
| KR (1) | KR100549355B1 (zh) |
| CN (1) | CN1267106C (zh) |
| AR (1) | AR013227A1 (zh) |
| AT (1) | ATE259236T1 (zh) |
| AU (1) | AU727271B2 (zh) |
| BR (1) | BR9802487B1 (zh) |
| CZ (1) | CZ294084B6 (zh) |
| DE (1) | DE69821553T2 (zh) |
| DK (1) | DK0891776T3 (zh) |
| ES (1) | ES2216244T3 (zh) |
| HU (1) | HUP9801615A3 (zh) |
| NZ (1) | NZ330915A (zh) |
| PL (1) | PL189988B1 (zh) |
| PT (1) | PT891776E (zh) |
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| JP6491669B2 (ja) * | 2014-02-05 | 2019-03-27 | メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． | Ｃｇｒｐ活性化合物の錠剤製剤 |
| WO2016114734A1 (en) | 2015-01-16 | 2016-07-21 | Biofarma Ilaç Sanayi Ve Ticaret A. Ş. | Pharmaceutical formulation of trimebutine maleate and simethicone comprising acidifying agent |
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| MX2016016587A (es) * | 2016-12-14 | 2018-06-13 | Rhein Siegfried Sa De Cv | Composicion mejorada de lansoprazol y simeticona y procesos para prepararla. |
| US10493026B2 (en) | 2017-03-20 | 2019-12-03 | Johnson & Johnson Consumer Inc. | Process for making tablet using radiofrequency and lossy coated particles |
| CA3062146A1 (en) | 2017-05-22 | 2018-11-29 | Johnson & Johnson Consumer Inc. | Lozenge dosage form |
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| EP3687502B1 (en) * | 2017-09-29 | 2023-06-07 | Johnson & Johnson Consumer Inc. | Solid simethicone particles and dosage form thereof |
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| USRE25205E (en) * | 1960-10-10 | 1962-07-24 | Silicone composition for the relief of | |
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| US4396604A (en) * | 1982-05-17 | 1983-08-02 | Norcliff Thayer, Inc. | Simethicone antacid lozenge |
| US4557916A (en) * | 1984-10-22 | 1985-12-10 | J. M. Huber Corporation | Synthetic calcium silicates and methods of preparation |
| US4867989A (en) * | 1986-09-09 | 1989-09-19 | Warner-Lambert Company | Chewing gum mineral supplement |
| US4906478A (en) * | 1988-12-12 | 1990-03-06 | Valentine Enterprises, Inc. | Simethicone/calcium silicate composition |
| US5073384A (en) * | 1989-10-19 | 1991-12-17 | Valentine Enterprises, Inc. | Maltodextrin/defoaming composition combinate |
| US5275822A (en) * | 1989-10-19 | 1994-01-04 | Valentine Enterprises, Inc. | Defoaming composition |
| KR920002149A (ko) * | 1990-07-03 | 1992-02-28 | 안드레아 엘. 콜비 | 비스테로이드계 소염제에 의해 유발된 위장 장애 증상을 완화시키기 위한 약제 조성물 및 이를 완화시키는 방법 |
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-
1997
- 1997-07-17 US US08/896,189 patent/US6103260A/en not_active Expired - Lifetime
-
1998
- 1998-07-07 NZ NZ330915A patent/NZ330915A/xx not_active IP Right Cessation
- 1998-07-09 AU AU75088/98A patent/AU727271B2/en not_active Ceased
- 1998-07-14 JP JP10213446A patent/JPH1192387A/ja active Pending
- 1998-07-15 CZ CZ19982221A patent/CZ294084B6/cs not_active IP Right Cessation
- 1998-07-15 PL PL98327491A patent/PL189988B1/pl unknown
- 1998-07-16 EP EP98305696A patent/EP0891776B1/en not_active Expired - Lifetime
- 1998-07-16 DK DK98305696T patent/DK0891776T3/da active
- 1998-07-16 ZA ZA9806338A patent/ZA986338B/xx unknown
- 1998-07-16 AR ARP980103484A patent/AR013227A1/es active IP Right Grant
- 1998-07-16 RU RU98114678/14A patent/RU2216317C2/ru active
- 1998-07-16 AT AT98305696T patent/ATE259236T1/de not_active IP Right Cessation
- 1998-07-16 ES ES98305696T patent/ES2216244T3/es not_active Expired - Lifetime
- 1998-07-16 PT PT98305696T patent/PT891776E/pt unknown
- 1998-07-16 KR KR1019980028787A patent/KR100549355B1/ko not_active IP Right Cessation
- 1998-07-16 HU HU9801615A patent/HUP9801615A3/hu unknown
- 1998-07-16 DE DE69821553T patent/DE69821553T2/de not_active Expired - Lifetime
- 1998-07-16 BR BRPI9802487-6A patent/BR9802487B1/pt not_active IP Right Cessation
- 1998-07-17 CN CNB981175988A patent/CN1267106C/zh not_active Expired - Lifetime
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105658088A (zh) * | 2013-08-02 | 2016-06-08 | 泰特&莱尔组分美国公司 | 甜味剂组合物 |
| US10729632B2 (en) | 2013-08-02 | 2020-08-04 | Tate & Lyle Ingredients Americas Llc | Sweetner compositions |
Also Published As
| Publication number | Publication date |
|---|---|
| HUP9801615A3 (en) | 2000-06-28 |
| DK0891776T3 (da) | 2004-05-10 |
| AU7508898A (en) | 1999-01-28 |
| PL327491A1 (en) | 1999-01-18 |
| DE69821553T2 (de) | 2004-12-23 |
| JPH1192387A (ja) | 1999-04-06 |
| CN1267106C (zh) | 2006-08-02 |
| PT891776E (pt) | 2004-05-31 |
| BR9802487B1 (pt) | 2010-05-18 |
| CZ294084B6 (cs) | 2004-10-13 |
| KR19990013918A (ko) | 1999-02-25 |
| NZ330915A (en) | 1999-06-29 |
| ATE259236T1 (de) | 2004-02-15 |
| RU2216317C2 (ru) | 2003-11-20 |
| EP0891776A1 (en) | 1999-01-20 |
| CZ222198A3 (cs) | 1999-02-17 |
| PL189988B1 (pl) | 2005-10-31 |
| DE69821553D1 (de) | 2004-03-18 |
| AU727271B2 (en) | 2000-12-07 |
| EP0891776B1 (en) | 2004-02-11 |
| BR9802487A (pt) | 1999-09-08 |
| ES2216244T3 (es) | 2004-10-16 |
| AR013227A1 (es) | 2000-12-13 |
| KR100549355B1 (ko) | 2006-04-06 |
| HUP9801615A2 (hu) | 1999-07-28 |
| US6103260A (en) | 2000-08-15 |
| ZA986338B (en) | 2000-01-17 |
| HU9801615D0 (en) | 1998-09-28 |
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