CN111511222A - 用于钙补充的组合物 - Google Patents
用于钙补充的组合物 Download PDFInfo
- Publication number
- CN111511222A CN111511222A CN201880064639.2A CN201880064639A CN111511222A CN 111511222 A CN111511222 A CN 111511222A CN 201880064639 A CN201880064639 A CN 201880064639A CN 111511222 A CN111511222 A CN 111511222A
- Authority
- CN
- China
- Prior art keywords
- formulation
- aqueous suspension
- calcium
- lactic acid
- suspension according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 64
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 title claims abstract description 49
- 239000011575 calcium Substances 0.000 title claims abstract description 49
- 229910052791 calcium Inorganic materials 0.000 title claims abstract description 49
- 230000009469 supplementation Effects 0.000 title claims abstract description 20
- 238000009472 formulation Methods 0.000 claims abstract description 58
- 239000007900 aqueous suspension Substances 0.000 claims abstract description 56
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 claims abstract description 41
- 239000001354 calcium citrate Substances 0.000 claims abstract description 40
- 235000013337 tricalcium citrate Nutrition 0.000 claims abstract description 40
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 82
- 239000004310 lactic acid Substances 0.000 claims description 41
- 235000014655 lactic acid Nutrition 0.000 claims description 41
- 239000000725 suspension Substances 0.000 claims description 22
- 239000000230 xanthan gum Substances 0.000 claims description 21
- 235000010493 xanthan gum Nutrition 0.000 claims description 21
- 229920001285 xanthan gum Polymers 0.000 claims description 21
- 229940082509 xanthan gum Drugs 0.000 claims description 21
- TUMCWFMHZOUPDA-UHFFFAOYSA-N 2-ethylsulfanyl-1,3-benzothiazol-6-amine Chemical group C1=C(N)C=C2SC(SCC)=NC2=C1 TUMCWFMHZOUPDA-UHFFFAOYSA-N 0.000 claims description 11
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 239000004376 Sucralose Substances 0.000 claims description 9
- 235000019408 sucralose Nutrition 0.000 claims description 9
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 9
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 7
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- 208000001132 Osteoporosis Diseases 0.000 claims description 3
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- 208000019902 chronic diarrheal disease Diseases 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
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- 150000001875 compounds Chemical class 0.000 claims 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 20
- 238000002360 preparation method Methods 0.000 description 11
- 229910000019 calcium carbonate Inorganic materials 0.000 description 10
- 230000037406 food intake Effects 0.000 description 9
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical group [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 7
- 239000007958 cherry flavor Substances 0.000 description 7
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
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- 208000002310 Achlorhydria Diseases 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 2
- 239000001639 calcium acetate Substances 0.000 description 2
- 235000011092 calcium acetate Nutrition 0.000 description 2
- 229960005147 calcium acetate Drugs 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 229940069978 calcium supplement Drugs 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000007938 effervescent tablet Substances 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
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- 239000004615 ingredient Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
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- 238000004062 sedimentation Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- MIDXCONKKJTLDX-UHFFFAOYSA-N 3,5-dimethylcyclopentane-1,2-dione Chemical compound CC1CC(C)C(=O)C1=O MIDXCONKKJTLDX-UHFFFAOYSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 208000010444 Acidosis Diseases 0.000 description 1
- 241000167854 Bourreria succulenta Species 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 235000016623 Fragaria vesca Nutrition 0.000 description 1
- 240000009088 Fragaria x ananassa Species 0.000 description 1
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 1
- 229940122957 Histamine H2 receptor antagonist Drugs 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 206010025476 Malabsorption Diseases 0.000 description 1
- 208000004155 Malabsorption Syndromes Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000007950 acidosis Effects 0.000 description 1
- 208000026545 acidosis disease Diseases 0.000 description 1
- 230000009056 active transport Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037180 bone health Effects 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 235000013736 caramel Nutrition 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 230000002612 cardiopulmonary effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
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- 201000006370 kidney failure Diseases 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
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- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
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Classifications
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Abstract
本发明涉及包含柠檬酸钙的呈水性悬浮液形式的制剂。所述制剂表现出优异的稳定性和依从性,并且在需要这样的钙补充的受试者的钙补充中找到用途。
Description
发明领域
本发明涉及一种包含柠檬酸钙的水性悬浮液制剂(aqueous suspensionformulation),该水性悬浮液制剂可以用于需要钙补充的受试者的钙补充。
所述组合物的使用预防并且阻碍与骨量丢失(bone mass loss)相关的疾病的发作,所述疾病例如骨质疏松症和骨折。
技术现状
钙是人类有机体内最丰富的矿物质之一,是骨骼和牙齿的主要成分,并且在多种生理系统中起着重要作用。由于我们的身体不产生矿物质,因此它的含量完全依赖于它通过饮食或补充的外部摄入。
因此,它的正确摄入对于儿童牙齿的发育以及对于贯穿人类的整个寿命的骨骼健康是至关重要的。事实上,我们体内的钙的水平还是在老年受试者的骨质疏松症的发展中涉及的主要因素之一,鉴于平均人口寿命的延长,尤其是在较发达国家,老年受试者代表人口的越来越大的部分。
例如,1994年,在美国,国家健康研究所(National Health Institute)(NIH)共识发展小组(Consensus Development Panel)回顾了钙的推荐日摄入量,其取决于年龄被确定为在每天800mg和1500mg之间。
随着时间的推移,已经开发了许多钙补充剂和药物的制剂,以允许正确的补充来满足其要求。
国际市场上最普遍的产品是基于碳酸钙的产品,其主要呈片剂的形式,以多种剂量,主要是500mg和1000mg。
虽然这些产品显然满足了对于钙补充的需求,但另一方面,它们没有免除副作用。正如目前为止在文献中所熟知的,事实上,碳酸钙的长期摄入通常与肾结石(kidneystone)(肾结石(nephrolithiasis))的发作有关。
事实上,到目前为止,由该领域运营的公司所进行的许多药物开发尝试旨在研究替代碳酸钙的钙盐,其在消化道中是容易地可吸收的,更具生物利用性,并且因此能够更有效地提供期望的钙剂量,同时抑制钙肾结石。
随着时间的推移,已经考虑了多种钙盐(磷酸盐、柠檬酸盐、氯化物、醋酸盐、乳酸盐、葡萄糖酸乳酸盐(gluconolactate)等),取决于其分子量,它们中的每一种都提供不同量的钙,并且具有其自身的溶解度,在经过负责吸收的肠道期间,该溶解度决定了其生物利用度。
这些中的一种,例如氯化钙,是具有高溶解度的盐,目前专门在心肺紧急的情况下通过静脉注射途径使用;它作为钙补充剂的口服摄入,尤其是对于长的时间段,将是不可能的,因为它将引起整个消化道的粘膜的刺激,将使患者处于血液和尿液中酸中毒的危险中,并且将需要持续监测患者中二氧化碳和氯的水平。
可选择地,使用磷酸钙,一种同样不溶且具有与碳酸钙完全可比较的40%的钙含量的盐,在制剂和临床方面,相对于碳酸盐都没有任何特别的优势,尤其是不可用于患有胃酸缺乏症的受试者(例如老年人),他们代表最需要补充的人群部分,对于这些人群部分,这种盐的临床功效似乎甚至低于碳酸盐的临床功效。
代替地,由于醋酸钙对磷酸根离子的螯合性质,这使得醋酸钙成为在严重肾功能不全的情况下的首选药物,在临床实践中已经是已知的并被使用的醋酸钙的潜在用途在允许正确补充钙所需的剂量下将是不可能的,因为它将放大其慢性摄入的典型副作用,例如腹痛、便秘或腹泻。
近年来已经被特别研究的另外的盐是柠檬酸钙,其被证明被考虑是碳酸钙的有效替代品。
这种盐实际上表现出高的生物利用度,甚至是磷酸钙的生物利用度的约两倍,并且比碳酸钙的生物利用度高约20%-30%。这种较大的生物利用度似乎取决于在肠水平上涉及的不同吸收机制:当呈离子化形式时,钙通过主动输送在肠水平被吸收,并且当钙呈与柠檬酸根离子的络合物形式时,钙通过经由细胞旁途径(paracellular pathway)的被动扩散在肠水平被吸收。
它还是被完美耐受的,并且因此可用于患有胃酸缺乏症的受试者,因此它适合于广大老年患者部分(elderly patients segment)、患有炎症性肠病的受试者、患有吸收障碍的受试者、用H2-阻断剂或质子泵抑制剂治疗的受试者,并且与碳酸钙相比,它与肾结石(肾结石)的发展的非常降低的风险相关,是柠檬酸盐离子结晶抑制剂。
此外,由于它可以在一天中的任何时间、在存在食物和不存在食物两者的情况下自由服用,因此它给含有它的药物产品或整合剂(integrator)提供了广泛的使用灵活性。
因此,如果人们想要制备用于钙补充的药物产品或补充剂,柠檬酸钙似乎代表了当今最有效的治疗替代物,并且与碳酸钙相比具有更少的副作用。
然而,从配制的角度来看,柠檬酸钙的使用由于多种原因而远远不是简单的。
首先,柠檬酸钙分子仅含有约21%的钙(例如,与碳酸钙的分子中的40%相比),因此,在药物产品或片剂补充剂的制备期间,为了施用相等剂量的钙,典型地每单位剂量500mg或1000mg,必须获得按比例高得多的单剂量的体积和重量,这实际上使得不可能制备具有这样的剂量的片剂。事实上,这样的片剂更易碎、更脆、更难以机械加工并且因此更难以生产,并且在任何情况下,如果与它们的生产相关的技术问题被克服,将获得非常大的片剂,患者尤其是老人和儿童难以吞咽。
到达市场上的、仅基于柠檬酸钙的很少的制剂实际上具有比推荐的剂量低得多的剂量,典型地每单位剂量约200mg的钙,并且涉及差的依从性,需要患者每天服用3-5片才能达到推荐的日剂量。
然而,在施用呈柠檬酸钙形式的钙的尝试中,随着时间的推移,已经研究和开发了呈可溶解的粉末形式(例如,泡腾粉剂或片剂)的制剂,其在摄入时通过溶解在一定体积的水中,典型地每剂不少于150ml-200ml。
这些制剂通常含有碳酸钙或其他钙盐,以及其混合物,和柠檬酸或柠檬酸与其他有机酸(诸如例如酒石酸或苹果酸)的混合物,它们有利于钙在溶液中的溶解,并且因此允许部分或全部转化成易于吸收的(assimilable)可溶性柠檬酸钙。
实际上,这种类型的药物制品在患者依从性方面仍具有缺点,因为它们在摄入时需要水的可获得性,而患者并不总是随身携带水,并且在任何情况下都将被迫寻找水;需要摄入不少于150ml-200ml的体积的制品,即不是所有患者都喜欢喝的相当大量的液体;以及在制品中存在的钙盐需要几分钟才完全溶解并且仍然易于再沉淀的事实。
这些证据和限制明显地影响了患者服用制品的舒适性和愉快性,从而降低了依从性。
作为实例,在专利文献US 5,759,575中,报告了对随时间所研究的解决方案尝试的广泛回顾,以解决与钙盐的差的溶解性、其再沉淀的趋势以及所制备的粉剂和泡腾片剂常常难以机械加工的事实相关的问题。
因此,本发明的目的是提供一种不产生上述缺点的包含柠檬酸钙的制剂。
特别地,本发明的目的是提供一种包含柠檬酸钙的制剂,该制剂可以在任何情况下容易地服用,而不需要找到在其中进行其溶解的溶液。
因此,本发明的目的是提供一种包含柠檬酸钙的制剂,该制剂可以是即用型的,易于由老年患者和儿科患者两者服用。
因此,本发明的最终目的是提供一种包含柠檬酸钙的即用型制剂,其可以容易地被任何年龄和身体状况的患者服用,以便确保所推荐的每日钙摄入量,从而预防并且阻碍与骨量丢失相关的疾病的发作,所述疾病例如骨质疏松症和骨折。
发明概述
本发明人已经惊奇地发现,本发明的目的可以通过制备包含柠檬酸钙、黄原胶和乳酸的呈水性悬浮液形式的制剂来实现。
发明详述
因此,本发明涉及一种呈水性悬浮液形式的制剂,包含柠檬酸钙、黄原胶和乳酸。
出于本发明的目的,术语“柠檬酸钙”意图指的是在钙离子和柠檬酸根离子之间可获得的任何盐形式,甚至是水合形式,以及其任何无定形或多晶型形式。
优选地,所述柠檬酸钙是柠檬酸钙四水合物。
本发明的呈水性悬浮液形式的制剂包含柠檬酸钙,该柠檬酸钙处于以钙表示的一浓度,所述浓度在从20mg至100mg每1ml悬浮液的范围内,优选地在从40mg至70mg每1ml悬浮液的范围内,更优选地约50mg每1ml悬浮液。
本发明的呈水性悬浮液形式的所述制剂包含黄原胶,相对于最终制剂的重量,所述黄原胶是以以下的百分比浓度(w/w),所述百分比浓度(w/w)在从0.3%至5%(w/w)的范围内,优选地从0.4%至2%(w/w),更优选地约0.45%(w/w)。
本发明的呈水性悬浮液形式的所述制剂包含乳酸,相对于最终制剂的重量,所述乳酸是以以下的百分比浓度(w/w),所述百分比浓度(w/w)在从0.1%至0.5%(w/w)的范围内,优选地从0.25%至0.35%(w/w),更优选地约0.27%(w/w)。
优选地,所述乳酸是呈包含按重量计80%乳酸的水溶液形式的乳酸。
如从后面的实验部分将明显的,本发明人惊奇地发现,通过在黄原胶和乳酸的存在下将柠檬酸钙盐悬浮在水溶液中,获得了随时间稳定的即用型悬浮液。
本发明是令人惊讶的,因为为了获得稳定的柠檬酸钙悬浮液,对许多类型的增溶剂、络合剂、增粘剂和助溶剂单独地以及作为其混合物进行了测试,但是在大多数情况下,即使在获得了最初的悬浮液的情况下,它们已经在几个小时内或者最多几天内,很快地趋于沉降,产生了不可溶的“饼”。
代替地,黄原胶作为增粘剂、增稠剂和稳定剂与柠檬酸钙在乳酸的存在下的特定组合令人惊讶地使制备不经历沉积的、具有令人愉快的感官特性的稳定的悬浮液成为可能。
本发明的水性悬浮液制剂还可以有利地被制备为单位剂量。
呈单位剂量形式的本发明的所述水性悬浮液包含以下量的柠檬酸钙,所述量对应于在从200mg至1500mg的范围内、优选地从400mg至1200mg的范围内、还更优选地500mg或1000mg的钙的单位剂量。
呈单位剂量的本发明的所述水性悬浮液包含以下量的黄原胶,所述量在从30mg至200mg的范围内,优选地从45mg至150mg,还更优选地约50mg或约100mg。
呈单位剂量形式的本发明的所述水性悬浮液包含以下量的乳酸,优选地呈包含按重量计80%乳酸的水溶液形式的乳酸,所述量在从15mg至80mg的范围内,优选地从25mg至65mg,还更优选地约30mg或约60mg。
呈单位剂量形式的本发明的所述水性悬浮液具有一总体积,所述总体积在从5ml至30ml的范围内,优选地从8ml至25ml,还更优选地约10ml或约20ml。
包含柠檬酸钙、黄原胶和乳酸、也是呈单位剂量形式的本发明的水性悬浮液制剂可以另外包含可用于其制备的任何药物赋形剂,诸如例如甜味剂、增溶剂、pH调节剂、稳定剂、防腐剂、调味剂。
优选地,本发明的水性悬浮液包含甜味剂,还更优选地,所述甜味剂是三氯蔗糖。
优选地,本发明的水性悬浮液包含防腐剂,还更优选地,所述防腐剂是山梨酸钾。
为了隐藏这些制剂的典型的“像白垩的”味道,本发明的水性悬浮液还可以容易地被调味,以便获得更可口并且更容易被患者,尤其是被儿科患者服用的悬浮液。
可以使用的典型香料是,例如,焦糖布丁香料(creme caramel flavor)、橙子香料、樱桃香料、草莓香料、柠檬香料。
因此,优选地,本发明的水性悬浮液还包含香料,更优选地,所述香料是樱桃香料。
因此,在本发明的优选实施方案中,本发明涉及包含柠檬酸钙四水合物、黄原胶、乳酸、三氯蔗糖、山梨酸钾和樱桃香料的水性悬浮液制剂,所述乳酸优选地是呈包含按重量计80%乳酸的水溶液形式的乳酸。
特别地,本发明的水性悬浮液允许以容易地可吸收的柠檬酸钙的形式,通过摄入通常在从5ml至15ml的范围内、优选地约10ml的减少体积的制品来施用500mg钙的单位剂量。
由本发明的水性悬浮液提供的通过单次摄入提供500mg钙的单位剂量的可能性还允许在每天仅两次摄入的情况下达到科学界和医学界推荐的每日钙剂量。
此外,由水性悬浮液提供的在如此小的体积中提供500mg钙的单位剂量的可能性使得其摄入即使是由吞咽困难的受试者也容易且愉快。
因此,本发明的呈水性悬浮液形式的制剂可以容易地由老年患者和儿科患者服用。
因此,本发明的呈水性悬浮液形式的制剂可以有效地用于需要钙补充的受试者的钙补充,因此,例如,用于预防和治疗由骨量丢失表征的疾病,例如骨质疏松症、骨折、慢性腹泻综合征、高血压、结肠癌。
此外,本发明的水性悬浮液,其被填充到柔性容器中,诸如例如柔韧性包装(cheerpack)或棒状包装(stick pack),优选地棒状包装,使得患者可以在一天中的任何时间或任何地点摄入,因为这些容器体积不大且易于运输,它们还可以被穿在衣服内,例如简单地在口袋内。
因此,本发明还涉及一种单剂量容器,优选地柔性的,还更优选地棒状包装,其包含呈水性悬浮液形式的药物制品或营养补充剂,所述药物制品或营养补充剂包含柠檬酸钙、黄原胶和乳酸。
优选地,所述柠檬酸钙是柠檬酸钙四水合物。
优选地,所述乳酸是呈包含按重量计80%乳酸的水溶液形式的乳酸。
因此,在本发明的另外的实施方案中,本发明涉及包含水性悬浮液的单剂量棒状包装,所述水性悬浮液包含柠檬酸钙、黄原胶、乳酸、三氯蔗糖、山梨酸钾和樱桃香料,所述柠檬酸钙优选地是柠檬酸钙四水合物,所述乳酸优选地呈包含按重量计80%乳酸的水溶液形式。
优选地,所述单剂量棒状包装包含约10ml的水性悬浮液,所述水性悬浮液包含以等效于约500mg钙的单位剂量的量的柠檬酸钙四水合物、黄原胶、乳酸(优选地80%乳酸)、三氯蔗糖、山梨酸钾和樱桃香料。
还更优选地,包含约10ml的本发明的水性悬浮液的所述单剂量棒状包装包含以等效于约500mg钙的单位剂量的量的柠檬酸钙四水合物、约50mg的黄原胶、约30mg的80%乳酸、约2mg的三氯蔗糖、约22mg的山梨酸钾和约9mg的樱桃香料。
如从后面的实验部分还将明显的,在乳酸的存在下包含与柠檬酸钙组合的黄原胶的、本发明的呈水性悬浮液形式的制剂被证明是特别稳定的,即使当使用高剂量的柠檬酸钙和小的悬浮液体积时。因此,本发明的制剂的结果是有利于被需要钙补充的任何类型的患者,特别是老年患者和儿科患者容易地服用。
应当理解,对于包含上文描述的柠檬酸钙的水性悬浮液制剂被认为优选的和有利的所有方面都应当同样被认为对于包含所述制剂的单剂量容器及其在治疗需要钙补充的患者中的相应用途也是优选的和有利的。
本发明的实施方案的实施例在下文作为非限制性实例被提供。
实验部分
实施例1
为了获得稳定的悬浮液,通过在具有增溶性质、稳定化性质和增粘性质的多种赋形剂的存在下将柠檬酸钙四水合物分散在去离子水中来制备多种溶液。
在下文的表1中,报告了几十种测试的制剂中的一些示例性制剂,特别地报告了通过在去离子水中混合以表中所示的重量比例的多种成分而获得的A-H制剂。
一旦制备了多种水性悬浮液,就进行它们随时间的观察,以验证它们的稳定性,并且因此验证沉积现象的潜在发生。
如在相同的表1中所报告的,对应于每种制剂,在制备时(时间点t=0)、在从制备后24小时(时间点t=24小时)以及最后在从制备后48小时(时间点t=48小时)记录悬浮液的外观和行为。
由于或多或少的快速沉积物形成现象(饼),不再可再悬浮,A-F悬浮液被证明是完全不能令人满意的。
只有包含黄原胶和乳酸两者作为稳定剂、增粘剂、悬浮剂和/或增溶剂的G-H制剂才允许获得即使在其制备后48小时仍保持流体的悬浮液,所述乳酸特别是包含按重量计80%乳酸的水溶液。
实施例2
鉴于在实施例1的G制剂和H制剂的情况下获得的优异的结果,制备了一批约11kg的悬浮液I,所述悬浮液I通过将下表2中所列的成分以特定的重量比例混合而获得。
表2.
特别地,最初在合适的混合器中,将指定量的三氯蔗糖和山梨酸钾溶解在水中;然后在剧烈搅拌下向所述溶液中添加柠檬酸钙四水合物,之后仍然在搅拌下分批添加黄原胶。最后,用乳酸酸化悬浮液,并且然后通过添加樱桃香料完成制备。
如此获得的悬浮液是完全稳定的,即使是在制备若干天后,具有优异的感官特性,并且还适合于儿科施用。
实施例3
实施例2的批量柠檬酸钙水性悬浮液制剂I被用于制备单剂量棒状包装容器。
然后,使用棒状灌装机(stick filling machine)将悬浮液定量给料到目标柔性棒状包装容器中,以便将约10ml悬浮液填充到每个单剂量容器中。
因此,如此制成的每个单剂量容器包含约10ml的对应于约500mg钙的单位剂量的柠檬酸钙四水合物水性悬浮液、约50mg的黄原胶、约30mg的80%乳酸(即呈包含按重量计80%乳酸的水溶液形式)、约2mg的三氯蔗糖、约22mg的山梨酸钾和约9mg的樱桃香料。
实施例4
测试了以实施例3的棒状包装形式包装的实施例2的水性悬浮液制剂I的稳定性,使代表性数量的所述棒状包装经历稳定性测试,特别是在以下条件下:
(a)长期:约25℃的温度和约60%的相对湿度;
(b)中间:约30℃的温度和约65%的相对湿度;
(c)加速:约40℃的温度和约75%的相对湿度。
因此,进行持续的分析检查以便验证样品随时间的稳定性,特别是在稳定性测试开始之前以及在上文指定的温度和湿度条件下调节1个月、3个月和6个月之后确定pH和钙测定值。
在所有测试的稳定性条件(a)、(b)和(c)中,初始等于约4.4的pH值对于整个观察期始终保持在规格所允许的范围内,即始终在被包括在4.3和4.5之间的范围内。
在整个观察期期间,初始等于约500mg每棒状包装的钙测定从未超过允许的变化规格。
因此,包含在棒状包装中的悬浮液I即使在其制备后6个月仍保持绝对稳定,甚至当被置于特别有强力(stressful)的条件例如条件(b)和条件(c)下时。
因此,棒状包装被证明是安全的形式,易于生产和销售,适合于确保需要钙补充的患者的高度依从性,这是由于其轻便和易于运输,打开的简单(simplicity of openness),在一天的任何时间摄入的即时性,由于减少的体积的摄入的快速性,不需要另外的分散装置的摄入的实用性(例如在目前市场上的颗粒剂或粉剂的情况下),以及由于香料的存在的令人愉快的摄入;作为整体,使如此配制的产品对于所有类型的患者,尤其是最困难的患者(例如老年患者和儿童患者)成为高度可接受的补充剂的特性。
因此,明显的是,在乳酸的存在下,优选地在包含按重量计80%乳酸的水溶液的存在下,包含与柠檬酸钙组合的黄原胶的本发明的呈水性悬浮液形式的制剂被证明是令人惊讶地稳定的,还使用了高剂量的柠檬酸钙和小体积的悬浮液,甚至在非常长的观察时间后以及在特别有强力的储存条件下,从而代表了一种用于向需要钙补充的患者施用呈易于生物利用的形式的钙(例如柠檬酸钙)以预防或阻碍与骨量丢失相关的疾病例如骨质疏松症和骨折的理想的解决方案。
Claims (21)
1.一种呈水性悬浮液形式的制剂,包含柠檬酸钙、黄原胶和乳酸。
2.根据权利要求1所述的呈水性悬浮液形式的制剂,其中柠檬酸钙是柠檬酸钙四水合物。
3.根据权利要求1或2所述的呈水性悬浮液形式的制剂,其中乳酸是80%乳酸。
4.根据权利要求1至3中任一项所述的呈水性悬浮液形式的制剂,其中柠檬酸钙是以关于钙表示的一浓度,所述浓度在从25mg至100mg每1ml悬浮液的范围内,优选地约50mg每1ml悬浮液。
5.根据权利要求1至4中任一项所述的呈水性悬浮液形式的制剂,其中,相对于所述制剂的总重量,黄原胶是以以下的百分比浓度(w/w),所述百分比浓度(w/w)在从0.3%至5%(w/w)的范围内,优选地从0.4%至2%(w/w),更优选地约0.45%(w/w)。
6.根据权利要求1至5中任一项所述的呈水性悬浮液形式的制剂,其中,相对于所述制剂的总重量,乳酸,优选地呈包含按重量计80%乳酸的水溶液形式的乳酸,是以以下的百分比浓度(w/w),所述百分比浓度(w/w)在从0.1%至0.5%(w/w)的范围内,优选地从0.25%至0.35%(w/w),更优选地约0.27%(w/w)。
7.根据权利要求1至6中任一项所述的呈水性悬浮液形式的制剂,其中所述水性悬浮液呈单位剂量形式。
8.根据权利要求7所述的呈水性悬浮液形式的制剂,其中呈单位剂量形式的所述水性悬浮液包含以下量的柠檬酸钙,所述量对应于在从200mg至1500mg的范围内、优选地从400mg至1200mg的钙的单位剂量。
9.根据权利要求8所述的呈水性悬浮液形式的制剂,其中呈单位剂量形式的所述水性悬浮液包含以下量的柠檬酸钙,所述量对应于约500mg或约1000mg的钙的单位剂量。
10.根据权利要求7至9中任一项所述的呈水性悬浮液形式的制剂,其中所述黄原胶是以按重量计在从30mg至200mg的范围内,优选地从45mg至150mg的量,还更优选地是以约50mg或约100mg的量。
11.根据权利要求7至10中任一项所述的呈水性悬浮液形式的制剂,其中乳酸,优选地呈包含按重量计80%乳酸的水溶液形式的乳酸,是以在从15mg至80mg的范围内,优选地从25mg至65mg的量,还更优选地是以约30mg或约60mg的量。
12.根据权利要求7至11中任一项所述的呈水性悬浮液形式的制剂,其中所述水性悬浮液的总体积在从5ml至30ml的范围内,优选地从8ml至25ml,还更优选地为约10ml或约20ml。
13.根据权利要求7至12中任一项所述的呈水性悬浮液形式的制剂,包含以下量的柠檬酸钙,所述量对应于在约10ml的总体积中500mg的钙的单位剂量。
14.根据权利要求1至13中任一项所述的呈水性悬浮液形式的制剂,还包含三氯蔗糖。
15.一种单剂量柔性容器,包含单位剂量的药物制品或营养补充剂,所述药物制品或营养补充剂包含根据权利要求1至14中任一项所述的制剂。
16.根据权利要求15所述的容器,其中所述柔性容器是柔韧性包装或棒状包装,优选地棒状包装。
17.根据权利要求15或16所述的容器,包含约10ml的水性悬浮液,所述水性悬浮液包含以等效于约500mg钙的单位剂量的量的柠檬酸钙四水合物、约50mg的黄原胶、约30mg的呈包含按重量计80%乳酸的化合物形式的乳酸。
18.根据权利要求17所述的容器,还包含三氯蔗糖。
19.根据权利要求1至14中任一项所述的呈水性悬浮液形式的制剂或根据权利要求15至18中任一项所述的容器,用于在治疗需要钙补充的受试者中使用。
20.根据权利要求19所述的用于使用的制剂或用于使用的容器,其中需要钙补充的所述受试者是老年患者或儿科患者。
21.根据权利要求19所述的用于使用的制剂或用于使用的容器,其中需要钙补充的所述受试者是受与骨量丢失相关的疾病影响的患者,所述疾病优选地选自由以下组成的组:骨质疏松症、骨折、慢性腹泻综合征、高血压、结肠癌。
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CY1124633T1 (el) | 2022-07-22 |
PL3678497T3 (pl) | 2022-01-31 |
EA202090654A1 (ru) | 2020-06-24 |
WO2019048532A1 (en) | 2019-03-14 |
EP3678497B1 (en) | 2021-07-21 |
CN111511222B (zh) | 2023-05-30 |
BR112020004453B1 (pt) | 2023-11-14 |
BR112020004453A2 (pt) | 2020-09-15 |
ES2894115T3 (es) | 2022-02-11 |
MX2020002545A (es) | 2020-10-01 |
SA520411478B1 (ar) | 2022-08-04 |
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