WO2016110225A1 - 一种磺酰胺类药物组合物 - Google Patents

一种磺酰胺类药物组合物 Download PDF

Info

Publication number
WO2016110225A1
WO2016110225A1 PCT/CN2016/070015 CN2016070015W WO2016110225A1 WO 2016110225 A1 WO2016110225 A1 WO 2016110225A1 CN 2016070015 W CN2016070015 W CN 2016070015W WO 2016110225 A1 WO2016110225 A1 WO 2016110225A1
Authority
WO
WIPO (PCT)
Prior art keywords
solution
pharmaceutical composition
composition according
container
mixed
Prior art date
Application number
PCT/CN2016/070015
Other languages
English (en)
French (fr)
Inventor
吴宜庄
姚小青
孙长海
田莉
赵欣颖
韩志东
林创裕
Original Assignee
天津红日健达康医药科技有限公司
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority to CA2972834A priority Critical patent/CA2972834C/en
Priority to US15/541,776 priority patent/US20170354621A1/en
Priority to CN201680005040.2A priority patent/CN107205974A/zh
Priority to SG11201705543VA priority patent/SG11201705543VA/en
Priority to EP16734885.3A priority patent/EP3243510B1/en
Priority to RU2017126976A priority patent/RU2715700C2/ru
Application filed by 天津红日健达康医药科技有限公司 filed Critical 天津红日健达康医药科技有限公司
Priority to MX2017008983A priority patent/MX2017008983A/es
Priority to AU2016206154A priority patent/AU2016206154B2/en
Priority to JP2017536587A priority patent/JP6502507B2/ja
Priority to KR1020177018819A priority patent/KR101949810B1/ko
Publication of WO2016110225A1 publication Critical patent/WO2016110225A1/zh
Priority to US16/377,428 priority patent/US11040020B2/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the field of medical technology. Specifically, it relates to a sulfonamide pharmaceutical composition, a preparation method thereof and use thereof.
  • Cancer as the most common disease in the world today, is mostly found late and the cure rate is relatively low.
  • the current anticancer drugs generally have the characteristics of large toxic and side effects, such as: hair loss, vomiting, leukopenia, bone marrow suppression, decreased immune function, etc., mainly because anticancer drugs act on a certain part of cell metabolism, on normal cells.
  • the selectivity to tumor cells is poor, and the killing effect on tumor cells is also destructive to normal cells, especially normal cells with fast metabolism.
  • Sulfonamides have been used clinically as antibacterial agents for decades. They have a broad spectrum of antibacterial properties, stable properties, easy to use, and low in price. They are still the most commonly used antibacterial drugs after antibiotics. With the deepening of research on sulfonamides, it has been found to have a wider range of biological activities, such as diuretic, anti-thyroid, anti-diabetes, anti-hypoglycemia, treatment of cataracts. In recent years, a large number of sulfonamide compounds having antitumor activity have been reported, some of which have entered the clinical trial stage. These compounds act on different molecular targets and show significant biological activity, while others exhibit high selectivity and specificity for different targets.
  • Sulfonamides their mechanisms of action show diversity, such as interference with tubulin polymerization, blockade of normal cell cycle, inhibition of carbonic anhydrase, folate-dependent enzymes, methionyl aminopeptidase and histones Acetylase, inhibition of vascular endothelial growth factor, and the like.
  • Chinese Patent No. ZL97108988.4 discloses a preparation and a process for preparing an injection of a sulfonamide compound, and the compounds thereof include:
  • R H, C 2 H 5 or
  • the sulfonamide compound is selected from the group consisting of:
  • the invention relates to the study of p-toluenesulfonamide injection, which is prepared by using the above formula. It is unexpectedly found that the p-toluenesulfonamide injection prepared by the above formula has poor stability, is easy to be devitrified for a long time, and the injection site is highly irritating.
  • the present invention has studied the formulation and the preparation method, and found that the above defects are derived from suberic acid and p-toluenesulfonic acid. For this reason, the present invention changes the suberic acid to azelaic acid, and the p-toluenesulfonic acid is changed.
  • the above problem is effectively solved by 2-ethyl-1,3-hexanediol.
  • the present invention solves the problem that the original injection has poor solubility and easy crystallization, and the toxicological comparison test shows that the product has less toxicity.
  • the clinical application is safer.
  • Polyethylene glycol-400 (PEG-400), 1,2-propanediol, sebacic acid, 2-ethyl-1,3-hexanediol, dimethyl sulfoxide and ethanol, of which dimethyl sulfoxide, Ethanol may or may not be added, and other substances must be added.
  • sulfonamide compound is selected from the group consisting of one or two or more compounds in any ratio:
  • R H, C 2 H 5 or
  • the sulfonamide compound is selected from the group consisting of:
  • the injection according to the present invention is processed from the following raw materials:
  • the injection of the present invention is produced by processing the following raw materials:
  • the invention is improved on the basis of the existing injection, the p-toluenesulfonic acid is removed, and the solubilizer 2-ethyl-1,3-hexanediol is added, and the prescription is polyethylene glycol-400, 2-B.
  • the combination of 1,3-hexanediol and 1,2-propanediol can reduce the amount of 1,2-propanediol in the injection solution and reduce the irritation to the injection site.
  • Another object of the present invention is to provide a process for the preparation of the injection.
  • the preparation method of the injection according to the present invention comprises the following steps:
  • the present invention is an improvement based on the prior art (CN1073415C). As shown in the above table, the prescription of the present invention is improved as compared with the prescription disclosed in Example 2 of the Chinese patent CN1073415C:
  • the present inventors have studied the formulation after discovering the above problems, and we have found that the cause of deterioration of the drug stability may be the suberic acid and p-toluenesulfonic acid in the prescription, for the following reasons:
  • polyethylene glycol-400 in the formulation is as follows: a water soluble solvent to increase the compatibility of the formulation with the tissues in the body.
  • 1,2-propanediol in the formulation is as follows: a water-soluble solvent to increase the compatibility of the formulation with the tissues in the body and inhibit crystallization.
  • suberic acid in the formulation is as follows: a dibasic fatty acid, a fat-soluble solvent, used to increase the solubility of the mixed solvent to the toluenesulfonamide of the drug substance, and to inhibit crystallization.
  • the effect of p-toluenesulfonic acid in the formulation is as follows: an aromatic sulfonic acid compound for increasing the solubility of the mixed solvent to the toluenesulfonamide of the drug substance and inhibiting crystallization.
  • dimethyl sulfoxide in the formulation is as follows: an amphiphilic solvent to increase the solubility of the mixed solvent to the toluenesulfonamide of the drug substance and inhibit crystallization.
  • ethanol in the formulation is as follows: an amphiphilic solvent to increase the solubility of the mixed solvent to the toluenesulfonamide of the drug substance, and also to adjust the overall volume of the formulation due to its good fluidity.
  • the present invention is further compared with existing drugs.
  • Example 1 Example 5, Example 6 and Example 7 (ie, prescription III-VI) of the present invention (numbered AD, respectively) and the sample of Example 2 of CN1073415C (No. E) prepared by themselves.
  • the cells were stored at 4 ° C ⁇ 2 ° C for 10 days, and the samples were observed for crystal precipitation on 0 days, 5 days, and 10 days, respectively.
  • the experimental results are shown in Table 2.
  • the stability of the prescription III-VI of the present invention was significantly increased when it was refrigerated at 4 ° C compared with the self-prepared CN 1073415 C Example 2. Specifically, the solution remained clear and transparent for 10 days, and no crystals were precipitated.
  • Example 1 Taking the sample of Example 1, Example 5, Example 6 and Example 7 (ie, prescription III-VI) of the present invention (numbered AD, respectively) and the self-prepared CN1073415C sample of Example 2 (No. E), the appropriate amounts were respectively set.
  • the prescription III-IV of the present invention is stable in the prescription III-IV of the present invention after being stored at 40 ° C ⁇ 2 ° C, 75% ⁇ 5% RH for 6 months as compared with the sample of the invention III-IV and CN 1073415C. It is obviously stronger than the sample of CN1073415C in Example 2, which shows that the growth rate of the largest single impurity and total impurities is slow, the growth is less, the degradation rate of the drug substance content is slower, and the degradation is less.
  • the purpose of adding anhydrous ethanol is to control the total volume of the solution and further control the content of the drug substance. Therefore, the amount of the small amount of anhydrous ethanol described in the step 4 is slightly less than the amount of the prescription.
  • Example 1 Sample animal mortality decreased.
  • Example 2 sample group LD50 is 11.30 mg / kg, (95% confidence limit is 9.47 ⁇ 13.13 mg / kg)
  • Example 1 sample LD50 is 18.10 mg / kg (95% confidence limit of 15.2 ⁇ 21.0mg /kg).
  • the LD50 of the drug was increased by 60% (P ⁇ 0.01) after replacing the p-toluenesulfonic acid in the original patent preparation excipient with 2-ethyl-1,3-hexanediol. Significantly reduced drug toxicity.
  • Example 1 of the present invention was subjected to an animal experiment, and Table 2 shows the effect of intramuscular injection Example 1 on the growth of mouse lung cancer.
  • Example 1 The injection of Example 1 at a dose of 0.5 ml, 1.0 mI and 2.0 ml and 2.0 ml/kg/d x 10 d has different degrees of anti-tumor effect on mouse transplanted lung cancer mice. The anti-tumor effect is enhanced with increasing dose.
  • Example 3 illustrates that Example 1 has a significant anti-tumor effect on mouse lung cancer at the dose selected for this experiment.
  • Example 1 has a higher therapeutic index for cancer in mice.
  • the age ranged from 23 to 79, including 59 males and 13 females.
  • lung cancer staging 46 cases in stage IV, 22 cases in stage IIIb, and 4 cases in stage IIIa; according to tumor location: 6 cases in the airway, 28 cases in the left main bronchus, 30 cases in the right main bronchus, right middle bronchus There are 8 cases.
  • Main efficacy indicators objective response rate of target lesions in the lumen - RECIST criteria assessment: CT assessment, the objective response rate of intraluminal target lesions within 7 days after the last administration and 30 days after the withdrawal period were 68.06% and 48.61%, respectively. .
  • Main efficacy indicators objective response rate of target lesions in the lumen - according to WHO criteria: using CT assessment, 77.78% and 54.17%, respectively, within 7 days after the last administration and 30 days after the withdrawal period.
  • the main efficacy index the improvement rate of tumor obstruction in the lumen, using CT evaluation, within 7 days after the last medication and withdrawal The 30 days after the period were 70.45% and 70.47% respectively.
  • Clinical benefit index Compared with baseline, the pulmonary function index FEV1 showed a statistically significant improvement within 7 days after the last administration, the improvement rate was 34.72%, and 18.06% after 30 days after the withdrawal period; patients with atelectasis of different leaf segments The total re-expansion rate was 44.44% (20/45), and the re-expansion rate by site was from high to low, 50.00% in the right middle lobe, 43.75% in the left lung, and 42.11% in the left lower lobe. The leaves were 38.46%, the left lung tongue was 35.00%, and the right lung was 25.00%.
  • target lesions were significantly reduced after intratumoral injection of PTS, objective response rate and intraluminal tumor blockage improvement rate were close to 70%, clinical benefit index FEV1 improved more than 30%, lung recruitment rate exceeded 40%, the above indicators It is directly shown that the target lesions are reduced after the PTS treatment, and the airway obstruction is improved, indicating that the respiratory function is significantly and measurably improved after PTS treatment, and the quality of life is improved.
  • the preparation method was the same as in Example 1.
  • the preparation method was the same as in Example 1.
  • the preparation method was the same as in Example 1.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

一种磺酰胺类药物组合物。本发明涉及一种磺酰胺类化合物注射制剂。其包含磺酰胺类化合物或其衍生物；它是以磺酰胺类化合物与药学上可接受的辅料通过一定的制剂技术而制成的注射制剂。本发明中涉及的磺酰胺类化合物注射制剂质量稳定、可控，有效。

Description

一种磺酰胺类药物组合物 技术领域
本发明属于医药技术领域。具体涉及一种磺酰胺类药物组合物及其制备方法和用途。
背景技术
癌症，作为当今世界的多发病，大部分发现较晚，治愈率相对较低。目前的抗癌药物，普遍存在毒副作用大的特点，例如：脱发、呕吐、白血球减少、骨髓抑制、免疫功能下降等，主要原因是因为抗癌药物作用于细胞新陈代谢的某一个环节，对正常细胞和肿瘤细胞的选择性性较差，在对肿瘤细胞起杀灭作用的同时，对正常细胞尤其是新陈代谢快的正常细胞破坏性也较大。
磺酰胺类化合物在临床上作为抗菌药应用已有几十年的历史,其抗菌谱广、性质稳定、使用简便、价格便宜,目前仍是仅次于抗生素的常用抗菌药物。随着对磺酰胺类化合物研究的深入,人们发现其有着更广泛的生物活性,例如利尿、抗甲状腺、抗糖尿病、抗低血糖、治疗白内障等。近年来,大量具有抗肿瘤活性的磺酰胺类化合物被报道,其中一些化合物已进入临床试验阶段。这些化合物作用于不同的分子靶点,显示出显著的生物活性,同时有的化合物还对不同的作用靶点表现出高度选择性和特异性。
磺酰胺类药物，它们的作用机制却表现出多样性,如干扰微管蛋白聚合、阻滞细胞周期正常进行、抑制碳酸酐酶、叶酸依赖性酶、甲硫氨酰氨肽酶和组蛋白去乙酰酶、抑制血管内皮细胞生长因子等。
中国专利ZL97108988.4中公开了磺酰胺类化合物的注射剂的制备处方及工艺，其中的化合物包括：
Figure PCTCN2016070015-appb-000001
其中，R＝H，C2H5或
Figure PCTCN2016070015-appb-000002
优选的，磺酰胺类化合物选自：
Figure PCTCN2016070015-appb-000003
其配方组成如下：
Figure PCTCN2016070015-appb-000004
本发明为研究对甲苯磺酰胺注射液，采用上述配方进行配制，意外的发现，用上述配方制备的对甲苯磺酰胺注射液稳定性差，长时间放置容易析晶，同时注射部位刺激性严重。
为此，本发明对配方和制备方法进行了研究，发现，上述缺陷来源于辛二酸和对甲苯磺酸，为此，本发明将辛二酸更改为癸二酸，将对甲苯磺酸更改为2-乙基-1,3-己二醇有效的解决了上述问题。
发明内容
本申请通过对磺酰胺类化合物注射制剂处方及制备工艺的改进，更好的解决了原注射剂溶解性差，易析晶的问题，且通过毒理对比试验，临床试验得出本品的毒性更小，临床应用更安全。
本发明的目的在于提供一种含有磺酰胺类化合物的注射制剂，由以下原料加工制成：
Figure PCTCN2016070015-appb-000005
Figure PCTCN2016070015-appb-000006
聚乙二醇-400(PEG-400)、1,2-丙二醇、癸二酸、2-乙基-1,3-己二醇、二甲基亚砜和乙醇，其中二甲基亚砜、乙醇可以添加也可以不添加，其它物质一定要添加。
其中，所述磺酰胺类化合物选自以下一种或任意比例的两种或两种以上化合物的组成：
Figure PCTCN2016070015-appb-000007
其中，R＝H，C2H5或
Figure PCTCN2016070015-appb-000008
优选的，磺酰胺类化合物选自：
Figure PCTCN2016070015-appb-000009
优选的，本发明所述的注射剂，由以下原料加工制成：
Figure PCTCN2016070015-appb-000010
进一步优选的，本发明的注射剂，由以下原料加工制成：
Figure PCTCN2016070015-appb-000011
Figure PCTCN2016070015-appb-000012
本发明是在现有注射剂的基础上进行了改进，去掉了对甲苯磺酸，加入了增溶剂2-乙基-1,3-己二醇，处方中聚乙二醇-400、2-乙基-1,3-已二醇、1,2-丙二醇配伍可降低1,2-丙二醇在注射液中的用量，减轻对注射部位的刺激性。
本发明的另一个目的在于提供该注射剂的制备方法。
本发明所述注射剂的制备方法，包括以下步骤：
1)取处方量的磺酰胺类化合物、聚乙二醇-400及2-乙基-1,3-己二醇，置容器中，
在85℃-95℃缓慢搅拌，混溶，得溶液A，备用；
2)取处方量癸二酸及1,2-丙二醇于另一容器中，同样于85℃-95℃缓慢搅拌，混溶，得溶液B，备用；
3)将上述所得溶液A和溶液B保持在85℃-95℃温度中混合，搅拌均匀，备用；
4)取处方量二甲基亚砜和少量无水乙醇置容器中，搅拌混合均匀，得溶液C，备用；
5)将溶液A和溶液B混合溶液冷却至60℃，注入溶液C，充分搅拌混合均匀，冷却至室温后，补充无水乙醇至全量，搅拌均匀；
6)以0.45um微孔滤膜过滤，并灌装于5ml安瓿瓶中，封口；
7)121℃,30分钟灭菌。
通过以下实验，进一步说明本发明的有益效果。
表1、本发明处方和CN1073415C所公开处方对比
Figure PCTCN2016070015-appb-000013
本发明是在现有技术(CN1073415C)的基础上进行的改进，如上表所示，本发明所述处方与中国专利CN1073415C实施例2公开处方相比，作了如下改进：
1.使用癸二酸替代辛二酸
2.使用2-乙基-1,3-己二醇替代对甲苯磺酸
经过上述改进，有效解决了原有处方所存在稳定性差等一系列问题。
通过以下数据进一步说明本发明的有益效果。
实验一、对中国专利CN1073415C进行研究
按照该专利中的实施例配制相应的药品，并进行比较研究。
Figure PCTCN2016070015-appb-000014
结果显示，该药物在冷藏条件下放置一段时间后就会有结晶析出，严重影响药物的稳定性。本发明人在发现了上述问题存在后，对配方进行了研究，我们发现导致药物稳定性变差的原因可能是处方中的辛二酸和对甲苯磺酸，理由如下：
聚乙二醇-400在配方中的作用如下：水溶性溶剂，用以增加制剂与体内组织的相容性。
1,2-丙二醇在配方中的作用如下：水溶性溶剂，用以增加制剂与体内组织的相容性，抑制结晶。
辛二酸在配方中的作用如下：为二元脂肪酸，为脂溶性溶剂，用以增加混合溶剂对原料药对甲苯磺酰胺的溶解性，抑制结晶。
对甲苯磺酸在配方中的作用如下：为芳香族磺酸化合物，用以增加混合溶剂对原料药对甲苯磺酰胺的溶解性，抑制结晶。
二甲基亚砜在配方中的作用如下：为两亲性溶剂，用以增加混合溶剂对原料药对甲苯磺酰胺的溶解性，抑制结晶。
乙醇在配方中的作用如下：为两亲性溶剂，用以增加混合溶剂对原料药对甲苯磺酰胺的溶解性，同时由于其良好的流动性，亦用于调整制剂整体体积。
为了进一步验证上述结论，发明人进行了以下实验：
在辛二酸和对甲苯磺酸的用量不变的情况下，调整其他试剂，上述问题依然存在。
Figure PCTCN2016070015-appb-000015
实验结果显示，上述配方在经过调整后，在辛二酸和对甲苯磺酸的用量不变的情况下问题依然存在，为此，我们更进一步确定，辛二酸和对甲苯磺酸是问题出现的所在。
我们随后对辛二酸和对甲苯磺酸进行了替换。
实验二、配方筛选实验
在其他条件不变的情况下对辛二酸和对甲苯磺酸进行替换，进行了多种物质的遴选：筛选过程如下：
处方筛选试验
Figure PCTCN2016070015-appb-000016
Figure PCTCN2016070015-appb-000017
实验结果显示，使用癸二酸替代辛二酸，或使用2-乙基-1,3-己二醇替代对甲苯磺酸可以解决现有技术中存在的问题，但由于现有技术中配方的用量不科学，导致配制过程溶解时间过长，因此对两种配方组分进行了结合并对配方中各组分的用量进行了筛选。
实验三、配方中辅料用量筛选实验：
处方中辅料用量筛选试验
原辅料 处方I 处方II 处方III 处方IV 处方V 处方VI
对甲苯磺酰胺 30％ 40％ 30％ 25％ 30％ 40％
聚乙二醇-400 33.5％ 40％ 40％ 35％ 30％ 30％
1,2-丙二醇 16.4％ 10％ 5％ 7％ 8％ 10％
癸二酸 2％ 2％ 5％ 4％ 4％ 2％
2-乙基-1,3-己二醇 8％ 3％ 10％ 15％ 15％ 18％
二甲基亚砜 6.7％ 3％ 5％ 7％ 5％ 0
无水乙醇 1.5％ 2％ 5％ 7％ 8％ 0
溶解时间 8min 10min 4min 3min 5min 3.8min
试验结果显示，处方I和处方II，虽然最终能使原料药全部溶解，但所耗费时间较长，处方III-VI溶解变得容易，所得溶液澄清透明。
另外，本发明和现有药品作了进一步比较。
取本发明所述实施例1，实施例5，实施例6和实施例7(即处方III-VI)样品(分别编号A-D)与自行制备的CN1073415C实施例2样品(编号E)各3支，置于4℃±2℃冷藏10天，分别于0天，5天，10天，观察样品是否有晶体析出。实验结果如表2所示。
本发明处方III-VI与CN1073415C实施例2样品低温析晶试验观察结果
样品 0天 5天 10天
A1 澄清透明溶液 澄清透明溶液 澄清透明溶液
A2 澄清透明溶液 澄清透明溶液 澄清透明溶液
A3 澄清透明溶液 澄清透明溶液 澄清透明溶液
B1 澄清透明溶液 澄清透明溶液 澄清透明溶液
B2 澄清透明溶液 澄清透明溶液 澄清透明溶液
B3 澄清透明溶液 澄清透明溶液 澄清透明溶液
C1 澄清透明溶液 澄清透明溶液 澄清透明溶液
C2 澄清透明溶液 澄清透明溶液 澄清透明溶液
C3 澄清透明溶液 澄清透明溶液 澄清透明溶液
D1 澄清透明溶液 澄清透明溶液 澄清透明溶液
D2 澄清透明溶液 澄清透明溶液 澄清透明溶液
D3 澄清透明溶液 澄清透明溶液 澄清透明溶液
E1 澄清透明溶液 析出细小结晶 析出结晶
E2 澄清透明溶液 析出细小结晶 析出结晶
E3 澄清透明溶液 澄清透明溶液 析出细小结晶
如上表所示比较结果，本发明处方III-VI与自行制备的CN1073415C实施例2相比，在4℃冷藏时，稳定性明显增加，具体表现为存储10天溶液仍然澄清透明，没有结晶析出。
加速稳定性实验：
取本发明所述实施例1，实施例5，实施例6和实施例7(即处方III-VI)样品(分别编号A-D)与自行制备的CN1073415C实施例2样品(编号E)样品适量分别置40℃±2℃，75％±5％RH存储，测定相关性质，得到相关数据，如下表所示：
Figure PCTCN2016070015-appb-000018
Figure PCTCN2016070015-appb-000019
如上表所示，本发明所述处方III-IV和CN1073415C实施例2样品相比，在40℃±2℃，75％±5％RH存储6个月后，本发明所述处方III-IV稳定性明显强于CN1073415C实施例2样品，具体表现为最大单一杂质及总杂质增长速度慢，增长较少，原料药含量降解速度较慢，降解较少。
具体实施方式：
通过以下具体实施例对本发明作进一步的解释，但不作为本发明的限制。
实施例1、注射剂
Figure PCTCN2016070015-appb-000020
制备方法：
1)取处方量的对甲苯磺酰胺、聚乙二醇-400及2-乙基-1,3-己二醇，置适当容器中，在85-95℃缓慢搅拌，混溶，得溶液A，备用；
2)取处方量癸二酸及1,2-丙二醇于另一容器中，同样于85℃-95℃缓慢搅拌，混溶，得溶液B，备用；
3)将上述所得溶液A和溶液B保持在85℃-95℃温度中混合，搅拌均匀，备用。
4)取处方量二甲基亚砜和少量无水乙醇置适当容器中，搅拌混合均匀，得溶液C，备用；
5)将溶液A和溶液B混合溶液冷却至60℃，注入溶液C，充分搅拌混合均匀，冷却至室温后，补充无水乙醇至全量，搅拌均匀。
6)以0.45um微孔滤膜过滤，并灌装于5ml安瓿瓶中，封口。
7)121℃,30分钟灭菌。
本处方中，加入无水乙醇的目的，在于控制溶液总体积，并进一步控制原料药含量。故步骤4中所述的少量无水乙醇的用量比处方量略少，即可。
实施例2、安全性比较实验
按照CN 1073415C实施例2所提及磺酰胺类化合物的注射剂的制备处方及工艺制备对甲苯磺酰胺注射液和实施例1样品做对照，以小鼠为实验动物，尾静脉一次给药，做毒性对比实验。结果如下：
实施例1样品动物死亡率下降。CN 1073415C实施例2样品组LD50为11.30mg/kg,(95％可信限为9.47～13.13mg/kg),实施例1样品LD50为18.10mg/kg(95％可信限为15.2～21.0mg/kg)。经过如本专利的工艺改良后，即将原专利制剂辅料中对甲苯磺酸替换为2-乙基-1,3-己二醇后，药物LD50提高60％(P<0.01)。显著降低了药物毒性。
实施例3、疗效实验
本发明的实施例1经动物实验，表2给出肌注实施例1对小鼠肺癌生长情况的影响。
表2 肌注实施例1对小鼠肺癌生长的影响
Figure PCTCN2016070015-appb-000021
Figure PCTCN2016070015-appb-000022
实验结果显示：
1.实施例1注射液在0.5ml、1.0mI和2.0ml和2.0ml/kg/d×l0d剂量，对小鼠移植性肿瘤鼠肺癌有不同程度的抗瘤作用。抗瘤作用随剂量增加而加强。
2溶剂在2.0ml/kg/d x l0d剂量下，对小鼠肝癌和小鼠肉瘤S-180无抗瘤作用。
3说明本实验所选用的剂量下实施例1对小鼠肺癌有显著的抗瘤作用。
4.实施例1注射液对小鼠癌症治疗指数较高。
实施例4、临床试验研究
实施例1注射液(PTS注射液)局部肿瘤内注射治疗中央型肺癌严重气道阻塞患者的单臂临床试验研究
经广州呼吸疾病研究所及其他21个卫生部批准的临床研究机构对PTS注射液进行临床研究得出如下结论：
进入PTS临床试验可分析病人89例。其中有10例脱落，7例剔除(受试者不符合入选条件或研究者违规临床方案)仅作安全性评估，共计72例进入疗效分析。
72例受试者中，入组年龄范围在23－79之间，其中男性59例，女性13例。按肺癌分期：IV期有46例，IIIb期有22例，IIIa期有4例；按肿瘤位置分：大气道有6例，左主支气管有28例，右主支气管有30例，右中间支气管有8例。
有效性结果：
72例中央型肺癌受试者经2－4周的PTS局部目标肿瘤内注射治疗后：
主要疗效指标：管腔内目标病灶的客观缓解率——RECIST标准评估：采用CT评估，末次用药后7天内和退出期后30天管腔内目标病灶的客观缓解率分别为68.06％和48.61％。
主要疗效指标：管腔内目标病灶的客观缓解率——依据WHO标准：采用CT评估，末次用药后7天内和退出期后30天分别为77.78％和54.17％。
主要疗效指标：管腔内肿瘤阻塞改善率，采用CT评估，末次用药后7天内和退出 期后30天分别为70.45％和70.47％。
临床获益指标：与基线相比，肺功能指标FEV1末次用药后7天内出现具有统计学意义改善，改善率为34.72％，退出期后30天为18.06％；对不同叶段的肺不张患者总的复张率为44.44％(20/45)，其中按部位统计的复张率由高到低依次为右肺中叶50.00％，左肺固有43.75％，左肺下叶42.11％，右肺下叶38.46％，左肺舌叶35.00％，右肺上叶25.00％。
整体疗效分析，肿瘤内注射PTS后目标病灶明显缩小，客观缓解率和管腔内肿瘤阻塞改善率均接近70％，临床获益指标FEV1改善超过30％，肺复张率超过40％，以上指标直接显示患者在经过PTS治疗后目标病灶缩小，气道阻塞情况得到改善，说明经PTS治疗后呼吸功能得到显著和可测量的改善,生活质量提高。
安全性结果：
在本研究89例受试者治疗全程中，未见全身化疗药物常见的骨髓抑制，消化道反应等不良反应。
整个试验过程中对患者生命体征、体检情况、血液学检查、血生化检查、免疫学检查及心电图等多方面进行监测，均未见有统计学意义的变化。
表明瘤内局部注射PTS对患者的全身影响甚微。
实施例5、注射剂
Figure PCTCN2016070015-appb-000023
制备方法同实施例1。
实施例6、注射剂
Figure PCTCN2016070015-appb-000024
Figure PCTCN2016070015-appb-000025
制备方法同实施例1。
实施例7、注射剂
Figure PCTCN2016070015-appb-000026
制备方法同实施例1。

Claims (10)

  1. 一种磺酰胺类药物组合物，其特征在于，由以下原料加工制成：
    Figure PCTCN2016070015-appb-100001
  2. 根据权利要求1所述的药物组合物，其特征在于，所述磺酰胺类化合物选自以下一种或任意比例的两种或两种以上化合物的组成：
    Figure PCTCN2016070015-appb-100002
    其中，R＝H，C2H5或
    Figure PCTCN2016070015-appb-100003
  3. 根据权利要求1所述的药物组合物，其特征在于，所述磺酰胺类化合物选自：
    Figure PCTCN2016070015-appb-100004
  4. 根据权利要求1所述的药物组合物，其特征在于，由以下原料加工制成：
    Figure PCTCN2016070015-appb-100005
    Figure PCTCN2016070015-appb-100006
  5. 根据权利要求1所述的药物组合物，其特征在于，由以下原料加工制成：
    Figure PCTCN2016070015-appb-100007
  6. 根据权利要求1-5任一所述的药物组合物，其特征在于，该药物组合物为注射用制剂。
  7. 权利要求1所述的药物组合物的制备方法，其特征在于，包括以下步骤：
    1)取处方量的磺酰胺类化合物、聚乙二醇-400及2-乙基-1,3-己二醇，置容器中，在85℃-95℃缓慢搅拌，混合物，得溶液A，备用；
    2)取处方量癸二酸及1,2-丙二醇于另一容器中，同样于85℃-95℃缓慢搅拌，混溶，得溶液B，备用；
    3)将上述所得溶液A和溶液B保持在85℃-95℃温度中混合，搅拌均匀，备用；
    4)取处方量二甲基亚砜和少量无水乙醇置容器中，搅拌混合均匀，得溶液C，备用；
    5)将溶液A和溶液B混合溶液冷却至60℃，注入溶液C，充分搅拌混合均匀，冷却至室温后，补充无水乙醇至全量，搅拌均匀；
    6)以0.45um微孔滤膜过滤，并灌装于5ml安瓿瓶中，封口；
    7)121℃,30分钟灭菌。
  8. 权利要求1所述的药物组合物的制备方法，其特征在于，包括以下步骤：
    Figure PCTCN2016070015-appb-100008
    Figure PCTCN2016070015-appb-100009
    1)取处方量的磺酰胺类化合物、聚乙二醇-400及2-乙基-1,3-己二醇，置容器中，在85℃-95℃缓慢搅拌，混溶，得溶液A，备用；
    2)取处方量癸二酸及1,2-丙二醇于另一容器中，同样于85℃-95℃缓慢搅拌，混溶，得溶液B，备用；
    3)将上述所得溶液A和溶液B保持在85℃-95℃温度中混合，搅拌均匀，备用；
    4)取处方量二甲基亚砜和少量无水乙醇置容器中，搅拌混合均匀，得溶液C，备用；
    5)将溶液A和溶液B混合溶液冷却至60℃，注入溶液C，充分搅拌混合均匀，冷却至室温后，补充无水乙醇至全量，搅拌均匀；
    6)以0.45um微孔滤膜过滤，并灌装于5ml安瓿瓶中，封口；
    7)121℃,30分钟灭菌。
  9. 权利要求1-5任一所述的药物组合物在制备治疗肿瘤的药物中的应用。
  10. 权利要求1-5任一所述的药物组合物在制备治疗中央型肺癌的药物中的应用。
PCT/CN2016/070015 2015-01-06 2016-01-04 一种磺酰胺类药物组合物 WO2016110225A1 (zh)

Priority Applications (11)

Application Number Priority Date Filing Date Title
US15/541,776 US20170354621A1 (en) 2015-01-06 2016-01-04 Sulfonamide pharmaceutical composition
CN201680005040.2A CN107205974A (zh) 2015-01-06 2016-01-04 一种磺酰胺类药物组合物
SG11201705543VA SG11201705543VA (en) 2015-01-06 2016-01-04 Sulfonamide pharmaceutical composition
EP16734885.3A EP3243510B1 (en) 2015-01-06 2016-01-04 Sulfonamide pharmaceutical composition
RU2017126976A RU2715700C2 (ru) 2015-01-06 2016-01-04 Сульфонамидная фармацевтическая композиция
CA2972834A CA2972834C (en) 2015-01-06 2016-01-04 Sulfonamide pharmaceutical composition
MX2017008983A MX2017008983A (es) 2015-01-06 2016-01-04 Composición farmaceútica de sulfonamida.
AU2016206154A AU2016206154B2 (en) 2015-01-06 2016-01-04 Sulfonamide pharmaceutical composition
JP2017536587A JP6502507B2 (ja) 2015-01-06 2016-01-04 スルホンアミド系医薬組成物の調製方法
KR1020177018819A KR101949810B1 (ko) 2015-01-06 2016-01-04 설폰아마이드류 약학 조성물
US16/377,428 US11040020B2 (en) 2015-01-06 2019-04-08 Sulfonamide pharmaceutical composition

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2015100059955 2015-01-06
CN201510005995.5A CN104473914B (zh) 2015-01-06 2015-01-06 一种磺酰胺类药物组合物

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US15/541,776 A-371-Of-International US20170354621A1 (en) 2015-01-06 2016-01-04 Sulfonamide pharmaceutical composition
US16/377,428 Continuation US11040020B2 (en) 2015-01-06 2019-04-08 Sulfonamide pharmaceutical composition

Publications (1)

Publication Number Publication Date
WO2016110225A1 true WO2016110225A1 (zh) 2016-07-14

Family

ID=52748619

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/070015 WO2016110225A1 (zh) 2015-01-06 2016-01-04 一种磺酰胺类药物组合物

Country Status (11)

Country Link
US (2) US20170354621A1 (zh)
EP (1) EP3243510B1 (zh)
JP (1) JP6502507B2 (zh)
KR (1) KR101949810B1 (zh)
CN (2) CN104473914B (zh)
AU (1) AU2016206154B2 (zh)
CA (1) CA2972834C (zh)
MX (1) MX2017008983A (zh)
RU (1) RU2715700C2 (zh)
SG (1) SG11201705543VA (zh)
WO (1) WO2016110225A1 (zh)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104473914B (zh) * 2015-01-06 2017-01-11 天津红日药业股份有限公司 一种磺酰胺类药物组合物
CN113368251A (zh) * 2020-02-25 2021-09-10 上海和绎实业有限公司 一种组合溶剂及其制备方法和应用
US11752160B2 (en) * 2020-09-24 2023-09-12 Gongwin Biopharm Co., Ltd Method for reducing fat by administering benzenesulfonamide compositions
US12109210B2 (en) * 2021-09-29 2024-10-08 Gongwin Biopharm Co., Ltd Methods for treating mast cell tumors

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5891454A (en) * 1997-03-28 1999-04-06 Alexander Wu Anti-cancer drug and special tumor necrotizing agent
CN1511032A (zh) * 2001-04-16 2004-07-07 Pts���ʹ�˾ 含有抗肿瘤成分的甲苯磺胺及其用法
CN102389410A (zh) * 2011-11-03 2012-03-28 黄漫翔 对-甲苯磺酰胺在制备癌症治疗药物中的应用
CN104473914A (zh) * 2015-01-06 2015-04-01 天津红日健达康医药科技有限公司 一种磺酰胺类药物组合物

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5783705A (en) * 1997-04-28 1998-07-21 Texas Biotechnology Corporation Process of preparing alkali metal salys of hydrophobic sulfonamides
CN1073415C (zh) * 1997-07-03 2001-10-24 吴宜庄 磺酰胺类化合物在制备抗癌药物中的应用
AU2845599A (en) * 1998-03-05 1999-09-20 Phares Pharmaceutical Research N.V. Pharmaceutical compositions and their use

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5891454A (en) * 1997-03-28 1999-04-06 Alexander Wu Anti-cancer drug and special tumor necrotizing agent
CN1511032A (zh) * 2001-04-16 2004-07-07 Pts���ʹ�˾ 含有抗肿瘤成分的甲苯磺胺及其用法
CN102389410A (zh) * 2011-11-03 2012-03-28 黄漫翔 对-甲苯磺酰胺在制备癌症治疗药物中的应用
CN104473914A (zh) * 2015-01-06 2015-04-01 天津红日健达康医药科技有限公司 一种磺酰胺类药物组合物

Also Published As

Publication number Publication date
EP3243510B1 (en) 2022-08-31
KR20170095926A (ko) 2017-08-23
RU2017126976A3 (zh) 2019-08-22
EP3243510A4 (en) 2018-08-08
AU2016206154B2 (en) 2018-11-01
JP2018501291A (ja) 2018-01-18
US11040020B2 (en) 2021-06-22
CN104473914B (zh) 2017-01-11
RU2715700C2 (ru) 2020-03-03
US20170354621A1 (en) 2017-12-14
US20190231721A1 (en) 2019-08-01
CN107205974A (zh) 2017-09-26
JP6502507B2 (ja) 2019-04-17
EP3243510A1 (en) 2017-11-15
CA2972834A1 (en) 2016-07-14
CA2972834C (en) 2020-07-14
RU2017126976A (ru) 2019-02-08
AU2016206154A1 (en) 2017-07-27
MX2017008983A (es) 2018-03-23
SG11201705543VA (en) 2017-08-30
KR101949810B1 (ko) 2019-02-19
CN104473914A (zh) 2015-04-01

Similar Documents

Publication Publication Date Title
US11040020B2 (en) Sulfonamide pharmaceutical composition
JP5357049B2 (ja) 癌の治療のためのフォスフォルアミデートアルキル化剤プロドラッグ
KR100359556B1 (ko) 티릴라자드의조용매비경구제
JP5406197B2 (ja) ダントロレン治療剤の送達を改善するための、共溶媒組成物および方法
MX2010011165A (es) Composiciones de derivados de taxano hidrofobos y sus usos.
KR20090052920A (ko) 우수한 안정성을 갖는 택산 유도체 함유 주사제용동결건조 조성물 및 이의 제조방법
AU2006208109A1 (en) Formulations for injection of catecholic butanes, including NDGA compounds, into animals
KR20230009425A (ko) 신경보호에서의 글루타티온 트리술피드 (gsssg)
CN104800172A (zh) 注射用卡络磺钠粉针剂和制法
RU2538658C2 (ru) Растворимые лекарственные формы n,n&#39;-диаминодифенилсульфона для оптимального применения в лечении различных заболеваний
EP3340985B1 (en) Pharmaceutical compositions and methods for the treatment of hypoxia-related diseases
CN104814933A (zh) 栀子提取物冻干粉针剂及其制备方法
CN111643498B (zh) 一种治疗肾结石的药物组合物及其用途
US20230302042A1 (en) Methods for the prevention of cholesterol crystal embolization with cyclodextrins
CN110652511B (zh) 中乌宁在制备防治肾功能衰竭药物中的应用
US20230330133A1 (en) Methods for the treatment of cholesterol crystal embolization with cyclodextrins
WO2005110401A1 (en) Pharmaceutical nitrones
WO2020077564A1 (zh) 一种稀释稳定性好的替尼泊苷注射用溶液及其制备方法
CN104771371B (zh) 4-(3,5-二甲氧苯基)-5-(3-羟基-4-甲氧基苯基)咪唑制剂
CN113491668A (zh) 注射用药物组合制剂及其制备方法与应用
CN101366701A (zh) N，n-二甲基甘氨酸-2，6-二异丙基苯酯盐类注射剂

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16734885

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2972834

Country of ref document: CA

REEP Request for entry into the european phase

Ref document number: 2016734885

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2017536587

Country of ref document: JP

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20177018819

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 15541776

Country of ref document: US

Ref document number: MX/A/2017/008983

Country of ref document: MX

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 11201705543V

Country of ref document: SG

ENP Entry into the national phase

Ref document number: 2016206154

Country of ref document: AU

Date of ref document: 20160104

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2017126976

Country of ref document: RU

Kind code of ref document: A