WO2013139274A1 - 用于治疗循环血容量不足或失水伴失盐的丙酮酸钠(Pyruvate)口服补液盐组合物 - Google Patents
用于治疗循环血容量不足或失水伴失盐的丙酮酸钠(Pyruvate)口服补液盐组合物 Download PDFInfo
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- WO2013139274A1 WO2013139274A1 PCT/CN2013/072929 CN2013072929W WO2013139274A1 WO 2013139274 A1 WO2013139274 A1 WO 2013139274A1 CN 2013072929 W CN2013072929 W CN 2013072929W WO 2013139274 A1 WO2013139274 A1 WO 2013139274A1
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- 235000015816 nutrient absorption Nutrition 0.000 description 1
- 229940023486 oral product Drugs 0.000 description 1
- 239000013588 oral product Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 125000002467 phosphate group Chemical class [H]OP(=O)(O[H])O[*] 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 229920000157 polyfructose Polymers 0.000 description 1
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- 229940072925 sodium bicarbonate oral solution Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
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- 238000007910 systemic administration Methods 0.000 description 1
- LRBQNJMCXXYXIU-NRMVVENXSA-N tannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-NRMVVENXSA-N 0.000 description 1
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Definitions
- the present invention relates to a medicinal oral product, and more particularly to a pyruvate-enri ched Oral Rehydrating Salts (Pyuvate-enri ched Oral Rehydrating Salts, Pyr- for use in circulating blood loss or dehydration with loss of salt conditions such as shock and diarrhea. ORS) composition.
- a pyruvate-enri ched Oral Rehydrating Salts Pyr- for use in circulating blood loss or dehydration with loss of salt conditions such as shock and diarrhea. ORS
- Oral rehydration salt liquid can be absorbed into the blood through the gastrointestinal tract, which can stabilize the vital signs of the wounded and sick in a short period of time, gain time for subsequent treatment, or significantly reduce the amount of intravenous infusion, which will be on the scene of wars, accidents, natural disasters, etc. It plays a special role in the treatment of treatment and has application value (2) .
- OSRS Oral Resuscitation Salts
- the use of the same amount of sodium citrate to replace the original sodium bicarbonate is only to overcome the instability of aqueous sodium bicarbonate solution and easy to occur gastrointestinal gas, and can improve the mouthfeel of oral liquid, but also facilitate oral salt Long-term preservation for clinical application.
- the effects are similar, and there is no significant effect of enhancing the absorption of intestinal water and salt in diarrhea and improving the blood flow of intestinal mucosa.
- the latest improved hypotonic formula, 0RS III is a domestically replenished salt III (Boye), which is more suitable for non-cholera diarrhea, which can better reduce gastrointestinal side effects and diarrhea symptoms, increase intestinal water and
- the absorption of salt is beneficial to the early recovery of nutrient absorption in the intestine.
- oral rehydration salts The key factor affecting the resuscitation effect of oral rehydration salts is that in hypoxic shock and intestinal inflammatory diseases, intestinal ischemia and inflammation lead to gastrointestinal mucosal cell hypoxia, energy metabolism disorders and intestinal barrier function, resulting in gastrointestinal
- the drainage and absorption of water, salt and sugar are inhibited, which is manifested by the gastrointestinal tract is difficult to tolerate oral rehydration: oral 0RS may cause abdominal swelling, vomiting and diarrhea, and even lead to serious consequences; when hypoxia and inflammation damage the intestine
- the barrier function it can also cause intestinal bacteria and endotoxin to enter the blood circulation through the intestinal lymph or portal system, and even induce sepsis and multiple organ dysfunction.
- the present invention is directed to an orally replenishing salt composition containing pyruvate for circulating blood loss or loss of water with loss of salt such as shock and diarrhea.
- a sodium pyruvate oral rehydration salt composition for treating a circulating blood volume deficiency or dehydration with loss of salt comprising the following components:
- weight of the component (i) + ( ⁇ ) + (iii) + (iv) is 50-100% by weight based on the total weight of the composition.
- composition contains:
- the composition is an oral aqueous solution containing 1000 ml of the solution:
- the solution has an osmotic pressure of 300 to 1000 mOsm/L, and 1000 ml of the solution contains sodium chloride of 3.5 g or more, and contains 20.0 g or more of anhydrous glucose or other carbohydrate.
- the solution has an osmotic pressure of from 120 to 280 mOsm/L, and 1000 ml of the solution contains less than 3.5 g of sodium chloride and contains less than 20.0 g of anhydrous glucose or other carbohydrates.
- the composition further comprises a zinc salt, a magnesium salt, a selenium salt, a calcium salt, a phosphate salt, and an antioxidant.
- a zinc salt a magnesium salt, a selenium salt, a calcium salt, a phosphate salt, and an antioxidant.
- the antioxidant is selected from one or a combination of the following: vitamin C, vitamin E, N-acetylcysteine (N-Acetylcycte ine), pentoxifylline (Pentoxifyl l ine);
- the gastrointestinal motility and vasoactive ingredients are selected from one or more of the following combinations: Carbachol, Mosapri de, Ani sodamine, dobutol Dobutamine;
- the immunonutrient agent is selected from one or a combination of the following: L-isoleucine, L-histidine, arginine, glycine, glutamine, low Polyfructose, short chain fatty acids, probiotics.
- the symptoms of insufficient circulating blood volume or dehydration with loss of salt are shock and diarrhea.
- the sodium pyruvate oral rehydration salt composition provided by the above invention for the preparation of an oral medicament for treating a hypovolemic blood loss, a dehydration with a salt loss disorder, and/or for Supplementation of physiological body fluids.
- composition provided by the present invention can be used for perioperative fluid therapy, surgical bowel cleansing preparation and gastric lavage solution during poisoning; or for preparing sports drinks or under normal and special conditions Healthy drinks.
- the condition comprises burns, shock, cholera, diarrhea, or gastrointestinal inflammation.
- the burn is a burn. Accordingly, the present invention improves the composition of the WH0-0RS itself to directly protect and improve the metabolism and function of the intestinal tract caused by hypoxia and/or inflammation, thereby further improving the clinical effect.
- the inventors unexpectedly found that the administration of sodium pyruvate-containing sugar and saline solution via the gastrointestinal route can effectively improve the intestinal mucosal blood flow reduction in burned/scalded shock animals. It can damage the barrier function, inhibit the local inflammatory reaction of the intestine, enhance the absorption efficiency of water and salt in the intestinal tract, and more effectively exert the acidosis poisoning effect of sodium bicarbonate/sodium citrate in the original 0RS formula.
- oral administration of a simple sodium pyruvate solution did not achieve a similar resuscitation effect.
- the sodium pyruvate-containing 0RS solution (Pyr-ORS) is based on the advantage of retaining WH0-0RS (glucose and sodium) which is easily absorbed by intestinal mucosal cells, using pyruvate (sodium pyruvate, calcium pyruvate or A mixture of the two) replaces sodium bicarbonate / sodium citrate in 0-0RS, because pyruvate has acid, anti-inflammatory and anti-oxidant effects, It can effectively alleviate intestinal acidosis, inflammatory damage and peroxidative damage in intestinal tissue during intestinal ischemia and rehydration (reperfusion), improve the intestinal environment of absorption of glucose-electrolyte oral solution, and therefore, contain sodium pyruvate Compared with the currently used 0-0RS, the oral rehydration salt composition can further improve the resuscitation effect of oral rehydration
- oral sodium pyruvate syrup solution can significantly improve the absorption of water and salt in the intestinal tract under ischemia, improve intestinal ischemia and intestinal barrier function, promote systemic and visceral blood circulation, and correct intestinal parts. Acidosis, inflammatory damage and peroxidative damage significantly improve the recovery of shock animals.
- the oral composition containing sodium pyruvate provided by the present invention As used herein, "the oral composition containing sodium pyruvate provided by the present invention", “the oral rehydration salt containing sodium pyruvate provided by the present invention”, “the oral rehydration salt solution containing sodium pyruvate provided by the present invention” It is a composition which contains the following essential components: (i) 2. 0-6. 0 parts by weight of sodium pyruvate; (ii) 1. 5-17. 0 parts by weight of sodium chloride; (iii) 0 - 2. 0 parts by weight of potassium chloride or the corresponding equivalent of potassium citrate; and (iv) 10. 0-50. 0 parts by weight of anhydrous glucose or other corresponding amount of carbohydrates; but the composition is not in principle Contains sodium bicarbonate and / or sodium citrate.
- the content of sodium sulphate is preferably 0. 0-4. 0 ⁇ , ⁇ 5 ⁇ ; The content is 2. 5-3. 5 parts by weight;
- the preferred content of potassium chloride or the corresponding equivalent of potassium citrate is 1. 0-1. 8 parts by weight, the optimum content is 1. 5 parts by weight;
- the preferred content of anhydrous glucose is 13. 5-50. 0 parts by weight, more preferably 13. 5-20. 0 parts by weight, or other corresponding amount of carbohydrates.
- the oral composition containing sodium pyruvate provided by the present invention may be in a solid form such as, but not limited to, a powder; or may be in a liquid form, and in one embodiment, the liquid form is an aqueous solution per 1000 ml of the solution. Containing (a) 2. 0-6. 0 g of sodium pyruvate; (b) 1. 5-17. 0 g of sodium chloride; (c) 0-2. 0 g of potassium chloride or corresponding equivalent of tannic acid Potassium; and (d) 10. 0-50. 0 grams of anhydrous glucose or other corresponding amount of carbohydrates.
- the content of sodium chloride is preferably 0. 0. 0. 5 ⁇ ; The best content is 2. 5-3. 5 grams;
- the content of the four essential components may be preferably a preferred value, a better value or an optimum value, respectively.
- the oral rehydration salt solution containing sodium pyruvate provided by the present invention can be classified into a hypertonic oral solution, an isotonic oral solution, and a hypotonic oral solution according to its osmotic pressure.
- the osmotic water containing anhydrous sodium glucose is contained in the high-osmotic oral solution.
- the sodium chloride contained in the hypertonic oral solution is 3. 5-17. 0 g, containing anhydrous glucose. 0-50. 0 grams or other corresponding amount of carbohydrates.
- the osmotic pressure of the hypotonic rehydration oral solution is 120-280 m O sm / L, each 1000 ml isotonic (280-300 m 0 sm IL) or the hypotonic oral solution contains less than 3.5. ⁇ , containing anhydrous glucose is less than 20.0 grams or other corresponding amount of carbohydrates.
- the oral compositions containing sodium pyruvate provided by the present invention should be in liquid form for clinical use, and a preferred method is to dissolve the solid form of the composition in potable water in a practical application prior to use.
- concentrations, osmotic pressures and the like mentioned also refer to the conditions when dissolved.
- the pH of the solution is generally 4 to 4.9.
- other carbohydrates include aqueous glucose, starch, and cereals.
- the cereals include rice, millet, corn, sorghum, and wheat.
- the cereal used in the present invention may be a powdered food product such as, but not limited to, rice flour, corn flour, sorghum flour, and the like.
- the amount of rice flour that replaces or partially replaces 20 grams of anhydrous glucose is usually 50-80 grams. It is used clinically for diarrhea treatment, reducing the number of diarrhea and The effect of defecation may also be better than glucose.
- Oral Rehydrating Salts As used herein, "Oral Rehydrating Salts (ORS)" is in the form of a solid: a powder, a powder, a granule or a tablet. "Oral Rehydrating Salt Solution (ORS)” refers to an aqueous solution in which a powder or the like is dissolved.
- the hypertonic and isotonic oral rehydration salt solution provided by the present invention is suitable for the treatment of severe burns (including burns) with or without shock.
- the isotonic oral rehydration salt solution provided by the present invention is suitable for the treatment of various causes of circulating blood volume deficiency or dehydration with loss of salt, with or without shock.
- the various oral rehydration salt solutions provided by the present invention are suitable for the treatment of cholera diarrhea.
- hypotonic oral rehydration salt solution provided by the invention is more suitable for the treatment of non-cholera children and adult diarrhea, acute and chronic gastrointestinal inflammation, water loss and salt loss, with or without shock treatment.
- the hypertonic and isotonic oral rehydration salt solution provided by the present invention and the improved solution thereof are also suitable for perioperative liquid treatment, preparation for intestinal cleansing before surgery and gynecological surgery, and gastric lavage solution for food or chemical poisoning.
- the hypotonic oral rehydration salt solution provided by the invention can also be supplemented as a physiological body fluid, improved to a sports drink containing sugar and salt of sodium pyruvate and/or calcium pyruvate, or suitable for ordinary or special conditions such as: alpine
- the composition of beverages such as hypoxia, long-term deep sea working conditions.
- the sodium pyruvate-containing oral rehydration salt solution provided by the present invention is also suitable for the above-mentioned related clinical conditions of various animals.
- the above-mentioned features mentioned in the present invention, or the features mentioned in the embodiments, may be arbitrarily combined. All of the features disclosed in the present specification can be used in combination with any of the compositions, and the various features disclosed in the specification can be replaced by any alternative feature that provides the same, equal or similar purpose. Therefore, the features disclosed are only general examples of equal or similar features, unless otherwise stated.
- the main advantages of the invention are:
- the oral composition containing sodium pyruvate provided by the present invention enhances the absorption of oral rehydration salt solution (water, electrolyte and sugar), thereby increasing blood volume, and its effect is superior to conventional 0-0RS.
- the oral composition containing sodium pyruvate provided by the invention can exert its superior alkaline agent function for correcting acidosis, and is more suitable for acidosis of refractory shock and severe diarrhea, and is superior to carbonic acid in conventional oral salt.
- the oral composition containing sodium pyruvate provided by the invention has the anti-acid, anti-inflammatory and anti-oxidation effects not contained in the alkaline agent of WH0-0RS, can increase the intestinal blood flow, and enhance the tolerance of intestinal epithelial cells to hypoxia.
- Pyr-ORS containing sodium pyruvate can further improve the resuscitation effect of oral rehydration salts on hypovolemic shock, and to some extent, can replace intravenous rehydration or reduce intravenous infusion more effectively.
- the invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention.
- the experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or in accordance with the conditions recommended by the manufacturer. All percentages, ratios, ratios, or parts are by weight unless otherwise stated.
- the units in the weight percent by weight in the present invention are well known to those skilled in the art and, for example, refer to the weight of the solute in a 100 ml solution.
- Essential component content (g) / 1, 000 ml molecular weight (MW) osmotic pressure (mOsm / L) Sodium pyruvate 3. 5 110 64 Sodium chloride 2. 0 58. 5 68
- Example 1 hypothermic WH0-0RS
- Sodium pyruvate with sodium bicarbonate or sodium citrate is superior to three representative formulations of WH0-0RS.
- WH0-0RS World Health Organization standard oral rehydration salt
- WHO-ORS World Health Organization's standard oral rehydration salt
- the first 24 hours of fluid replacement after injury 4 ml ⁇ kg - 1 ⁇ (1% TBSA) - 1
- the provided Pyr-ORS l is superior to the standard prescription book 0-0RSl in promoting the absorption of water and salt in the intestinal tract of the burned rats, increasing the blood flow of the intestinal mucosa and correcting the acidosis of the intestinal mucosa.
- Table 6 Rats 35% of total surface area III degree scald after oral administration of oral rehydration salt solution
- the Pyr-ORS l provided by the present invention is also superior to the improved prescription WHO-ORS2 in promoting the absorption of water and salt in the intestinal tract of the burned animal and increasing the blood flow of the intestinal mucosa.
- experimental evidence indicates that Pyr-ORS l is also superior to WHO-ORS2 in improving intestinal barrier structure and function.
- Test indicator experiment group Burns, burns, fake hot, hot, burns, no rehydration
- Pyr-ORS compares the resuscitation effect of low blood volume shock caused by 50% total surface area III degree burn in dogs A model of oral rehydration salt resuscitation in low-volume shock caused by 50% overall surface area III degree burn in Beagle dogs (21).
- Health Organization oral rehydration solution a potential solution
- Hu Sen et al The effect of early oral rehydration on organ function and mortality in 50% body surface burn dogs during shock stage. Chinese Journal of Medicine 2008; 88(44): 3149-52.
- Hu Sen et al The effect of early oral rehydration on hemodynamics and tissue perfusion in 50% of total surface area burn shock. Chinese Journal of Surgery 2009; 47 (19): 1499-1502.
- Hassoun HT, et al Post-injury multiple organ failure: the role of the gut. Shock 2001; 15(1) :1-10.
- Hu S, et al Carbachol promotes gastrointestinal function during oral resuscitation of burn shock.
- Bao C, et al Effect of carbachol on intestinal mucosal blood flow, activity of Na + - K + - ATPase, expression of aquaporin-1, and intestinal Absorption rate during enteral resuscitation of burn shock in rats. J Burn Care Res 2010; 31(1) :200-6.
- Alam NH, et al L-isoleucine- supplemented oral rehydration solution in the treatment of acute diarrhoea in children: a randomized controlled trial. J Health Popul Nutr 2011; 29 (3) : 183- 90.
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Abstract
本发明公开了一种用于治疗循环血容量不足或失水伴失盐的丙酮酸钠口服补液盐组合物,所述的组合物含有以下组分:( i ) 2. 0 - 6. 0 重量份丙酮酸钠;(ii)1.5-17.0 重量份氯化钠;(iii)0-2.0 重量份氯化钾;和(iv)10.0-50.0 重量份无水葡萄糖或其它碳水化合物;并且组分(i)+(ii)+(iii)+(iv)的重量占组合物总重量的 50-100%。
Description
用于治疗循环血容量不足或失水伴失盐的丙酮酸钠 (Pyruvate)
口服补液盐组合物
技术领域
本发明涉及药用口服产品,尤其涉及一种用于循环血容量不足或失水伴失盐状 态如休克和腹泻的含有丙酮酸钠的口服补液盐(Pyruvate-enri ched Oral Rehydrat ion Salts, Pyr- ORS)组合物。 背景技术
在严重失血, 创伤、 脱水引起的低血容量休克、 尤其是大面积烧(烫)伤休克救 治过程中,早期快速补充血容量是抗休克的关键医疗措施。 但在战争、 严重自然 灾害、 疾病流行或突发事故(如森林火灾、 恐怖袭击)现场, 短时间内常出现批量 休克伤员, 由于环境和医疗条件受限等困难,常规静脉抗休克手段(如输血、输液) 难以实施或延迟实施, 从而导致阵亡率、 伤死率或并发症发生率增高 )。 动物实 验和临床试验已显示经口或胃肠道途径及时补充口服补液盐溶液(Oral Rehydrat ion Solut ions, ORS) 是一种有效的烧伤抗休克手段。 口服补液盐液通过 胃肠道吸收入血, 能在短期内稳定伤病员生命体征,为后继救治争取时间,或明显 减少静脉输液量,将会在战争、突发事故、 自然灾害等的现场救治处理中发挥特殊 的作用,具有应用价值 (2)。
目前, 急性腹泻仍然是全世界占第二位的儿童疾病死亡原因,每年全球约有
200万左右儿童死于腹泻,主要原因是脱水和失盐。 30多年来,世界卫生组织(WHO) 的口服补液盐的推广应用拯救了发展中国家数百万计腹泻患者的生命, 极大地降 低了全球儿童腹泻的死亡率。 半个世纪前发现的肠上皮钠盐 -葡萄糖联合转运体 (Sodium-Glucose Cotransporter)和在此基础上发展和推广的口服补液盐被权威 医学杂志 Lancet (柳叶刀)誉为 20世纪最重要的医学进展 ω。 最新的低渗配方进 一步提高了救治儿童腹泻的临床效果, 数年来已被多国包括我国列为国家基本药 物之一,将有力推进 WHO提出的旨在 2015年之前将全球儿童死亡率在 1990年基础 上减少三分之二的联合国千年发展目标 (4)。
数十年来, 在失血、 烧伤、 成人急性腹泻引起的低血容量休克的液体复苏中已 有多个实验研究和临床报道证明应用 WHO的标准或改良的口服补液盐溶液 (总渗 透压为 331毫渗量 /升或 270毫渗量 /升) 能有效的替代静脉补液, 在扩充血容量、
维持血压、 延长生命方面有显著的疗效 (5_9)。
口服补液盐(Oral Resusc itation Salts, 0RS)是上世纪 70 年代初起由 WHO 指导和开发,推荐为霍乱和儿童急性腹泻一线治疗药物的产品, 已全球推广应用, 近 30年来, WHO 的口服补液盐(WH0-0RS)配方不断改进, 主要有:
I . 早期的标准配方: 每升水含氯化钠 3. 5克, 氯化钾 1. 5克, 碳酸氢钠 2. 5 克和葡萄糖 20 克, 总渗透压为 331毫渗量 /升;
II . 90年代改进的配方: 每升水含枸橼酸钠 2. 9克来取代碳酸氢钠, 总渗 透压为 311毫渗量 /升;
III. 2006年由 WHO和联合国儿童基金会(UNICEF)共同发布的低渗配方: 每升 水含氯化钠 2. 5 克, 氯化钾 1. 5 克, 枸橼酸钠 2. 9 克和葡萄糖 13. 5 克,总渗 透压为 245毫渗量 /升。
其中,应用等量的枸橼酸钠取代原来的碳酸氢钠只是为克服碳酸氢钠水溶液的 不稳定性和容易发生胃肠涨气的缺陷, 并能改善口服液的口感, 也便于口服盐的 长期保存,方便临床应用。 但其效果类同, 并无显著增强腹泻病变肠道水盐吸收, 提高肠粘膜血流量的疗效作用。 最新改进的低渗配方,即 0RS III, 国产产品为口 服补液盐 III (博叶),更适用于非霍乱性腹泻, 能更好地减少胃肠道副作用和腹泻 症状,增加肠道对水和盐的吸收,有利早期恢复肠道对营养的吸收。
影响口服补液盐复苏效果的关键因素是在低血容量休克和肠道炎症性疾病时, 肠道缺血和炎症导致胃肠黏膜细胞缺氧、 能量代谢障碍及肠屏障功能受损, 致使 胃肠道对水、 盐和糖的排空和吸收受到抑制,表现为胃肠道对口服补液难以耐受: 口服 0RS可能引起腹涨,呕吐和腹泻、甚至导致严重后果; 当缺氧和炎症损害肠屏 障功能时, 还可导致肠道细菌和内毒素经肠淋巴或门静脉系统进入血循环, 甚至 诱发脓毒症和多器官功能障碍 。
现有的 WH0-0RS 虽然已经过不断改进, 但至今其组成成分本身对腹泻疾病肠 道功能并不直接起明显的保护和治疗作用, 而是为改进浓度和渗透压,减轻胃肠 道症状; 或者增加辅助成分、 改善口服补液盐溶液的排空, 增加水和盐的吸收比 率和增强其抗菌性能等(11— 14)。因此,本领域迫切需要进一步改进 WH0-0RS的组成成 分, 以达到直接保护和改善受缺氧和 /或炎症应激状态的肠道细胞的代谢和功能, 进一步提高口服补液的复苏效果。 发明内容
本发明旨在提供一种用于循环血容量不足或失水伴失盐,如休克和腹泻的含有 丙酮酸钠(Pyruvate)的口服补液盐组合物。 在本发明的第一方面, 提供了一种用于治疗循环血容量不足或失水伴失盐的丙 酮酸钠口服补液盐组合物, 所述组合物含有以下组分:
(i) 2.0-6.0 重量份丙酮酸钠;
(ii) 1.5-17.0 重量份氯化钠;
(iii) 0-2.0 重量份氯化钾或相应当量的枸橼酸钾; 和
(iv) 10.0-50.0 重量份无水葡萄糖或其它碳水化合物;
并且组分(i) + (ϋ) + (iii) + (iv)的重量占组合物总重量的 50-100%。
在另一优选例中, 所述组合物含有:
(i) 3.0-4.0 重量份丙酮酸钠;
(ii) 2.0-5.0 重量份氯化钠;
(iii) 1.0-1.8 重量份氯化钾或相应当量的枸橼酸钾; 和
(iv) 13.5-20.0 重量份无水葡萄糖或其它碳水化合物。
在另一优选例中, 所述的组合物为口服水溶液, 在 1000ml所述溶液中含有:
(a) 2.0-6.0 克丙酮酸钠;
(b) 1.5-17.0 克氯化钠;
(c) 0-2.0 克氯化钾或相应当量的枸橼酸钾; 和
(d) 10.0-50.0 克无水葡萄糖或其它碳水化合物。
在另一优选例中, 在 1000ml所述溶液中含有:
(a) 3.0-4.0 克丙酮酸钠;
(b) 2.0-5.0 克氯化钠;
(c) 1.0-1.8 克氯化钾或相应当量的枸橼酸钾; 和
(d) 13.5-20.0 克无水葡萄糖或其它碳水化合物。
在另一优选例中, 所述溶液的渗透压为 300-1000mOsm/L, 并且 1000ml所述溶液 中含有的氯化钠大于等于 3.5克, 含有大于等于 20.0克的无水葡萄糖或其它碳水化 合物。
在另一优选例中, 所述溶液的渗透压为 120-280mOsm/L, 并且 1000ml所述溶液 中含有的氯化钠小于 3.5克, 含有小于 20.0克的无水葡萄糖或其它碳水化合物。
在另一优选例中, 所述组合物中还含有锌盐、 鎂盐、 硒盐、 钙盐、 磷酸盐、 抗氧
化剂、 胃肠动力和血管活性成分、 免疫营养剂、 中药成分、 和 /或调味剂。 所述的抗氧化剂选自下述的一种或一种以上的组合: 维生素 C、 维生素 E、 N- 乙酰半胱氨酸(N-Acetylcycte ine)、 己酮可可碱(Pentoxifyl l ine); 所述的胃肠 动力和血管活性成分选自下述的一种或一种以上的组合: 卡巴胆碱(Carbachol)、 莫沙比利(Mosapri de)、 山莨菪碱(Ani sodamine) 、 多巴酚丁胺(Dobutamine); 所 述的免疫营养剂选自下述的一种或一种以上的组合: L-异亮氨酸、 L-组氨酸、 精 氨酸、 甘氨酸、 谷氨酰胺、 低聚果糖、 短链脂肪酸、 益生菌。
在另一优选例中, 所述循环血容量不足或失水伴失盐的症状为休克和腹泻。 在本发明的第二方面,提供了上述本发明提供的丙酮酸钠口服补液盐组合物的用 途, 用于制备治疗循环血容量不足、 失水伴失盐病症的口服药物、 和 /或用于生理性 体液的补充。
在另一优选例中,本发明提供的组合物可用于围手术期的液体治疗,外科手术的 肠道清洁准备和中毒时的洗胃溶液;或用于制备运动饮料或通常和特殊条件下的健康 饮料。
在另一优选例中, 所述病症包括烧伤、 休克、 霍乱、 腹泻、 或肠胃道炎症。 在另一优选例中, 所述烧伤是烫伤。 据此, 本发明改进了 WH0-0RS 自身的组成成分, 以达到直接保护和改善受缺氧 和 /或炎症损伤肠道的代谢和功能, 进一步提高了临床效果。 具体实施方式
发明人在研究丙酮酸钠水溶液给药途径的动物实验过程中,意外发现经胃肠道 途径给予含丙酮酸钠(Pyruvate)的糖和盐水溶液能有效改善烧 /烫伤休克动物肠 黏膜血流量减少和屏障功能损害, 抑制肠道局部炎症反应, 增强肠道对水和盐的 吸收效率, 并更有效发挥原有 0RS配方中碳酸氢钠 /枸橼酸钠所具有的纠正酸中毒 作用。但口服单纯的丙酮酸钠水溶液并不能达到相似的复苏效果。这个发现提示: 口服补液盐中所含丙酮酸钠能直接起到 WH0-0RS 成分中所不具备的肠道保护作 用。 含丙酮酸钠的 0RS液 (Pyr-ORS)在保留 WH0-0RS中(葡糖糖和钠)易于被肠黏 膜细胞吸收的优点的基础上, 用丙酮酸盐(丙酮酸钠、 丙酮酸钙或二者的混合)替 代冊 0-0RS中的碳酸氢钠 /枸橼酸钠,由于丙酮酸盐具有抗酸、抗炎和抗氧化作用,
能有效减轻肠缺血和补液(再灌注)时存在的肠组织局部酸中毒、 炎症损害和过氧 化损伤, 改善葡糖糖-电解质口服液的吸收的肠道环境, 因此, 含有丙酮酸钠的口 服补液盐的组合物与目前常用的冊 0-0RS相比, 能进一步提高口服补液对低血容 量休克的复苏效果, 并在一定程度上可以替代静脉补液。 新近的动物实验已证实 以上所叙的效果,在此基础上完成了本发明。
尽管以往对丙酮酸盐的细胞 /器官保护功能已广泛报道, 其改善缺氧条件下的 糖代谢,提高细胞的缺氧耐受性, 直接或间接的抗氧化 /硝基化应激反应和纠正酸 中毒等特性也已被阐明。但是,以上发现都是经静脉,腹腔或动脉途径给药的结果, 从未有经口服或经胃肠道途径给予单一丙酮酸盐或与糖盐溶液组合保护肠道细胞 和增强水和盐吸收的报道。在人体, 除了全身给药的方式有心和肝脏保护效果外, 口服钙盐的既使大剂量给药: 7-25 克 /次或 7 克 /日持续一周, 甚至 10克 /日、 持续 30 天也并未证实有全身糖代谢和器官功能改善以及提高运动技能或减肥的 作用。 因此, 口服丙酮酸钠从未被应用于临床, 也从未有口服它用来治疗任何疾 病的报道。 而发明人首次发现: 口服丙酮酸钠糖盐溶液能显著提高缺血状态下的 肠道对水和盐的吸收, 改善肠缺血和肠屏障功能、 促进全身和内脏血液循环, 纠 正肠道局部酸中毒、 炎症损害和过氧化损伤, 显著提高休克动物的复苏效果。 组合物
如本发明所用, "本发明提供的含有丙酮酸钠的口服组合物"、 "本发明提供 的含有丙酮酸钠的口服补液盐" 、 "本发明提供的含有丙酮酸钠的口服补液盐溶 液" 都是指其中含有下述必要组分的组合物: (i) 2. 0-6. 0 重量份丙酮酸钠; (i i) 1. 5-17. 0重量份氯化钠; (i i i) 0-2. 0重量份氯化钾或相应当量的枸橼酸钾; 和(iv) 10. 0-50. 0 重量份无水葡萄糖或其它相应量的碳水化合物; 但是该组合物 中原则上不含有碳酸氢钠和 /或枸橼酸钠。
其中丙酮酸钠的较佳含量为 3. 0-4. 0重量份, 最佳含量为 3. 5重量份; 氯化钠的较佳含量为 2. 0-5. 0重量份, 更佳含量为 2. 0-3. 5重量份, 最佳含量 为 2. 5-3. 5重量份;
氯化钾或相应当量的枸橼酸钾的较佳含量为 1. 0-1. 8重量份, 最佳含量为 1. 5 重量份;
无水葡萄糖的较佳含量为 13. 5-50. 0重量份, 更佳含量为 13. 5-20. 0重量份, 或其它相应量的碳水化合物。
本发明提供的含有丙酮酸钠的口服组合物可以是固体形式,例如但不限于粉末 状; 也可以是液体形式, 在一实施例中, 所述的液体形式是水溶液, 每 1000毫升 该溶液中含有(a) 2. 0-6. 0 克丙酮酸钠; (b) 1. 5-17. 0 克氯化钠; (c) 0-2. 0 克氯 化钾或相应当量的枸橼酸钾; 和(d) 10. 0-50. 0 克无水葡萄糖或其它相应量的碳 水化合物。
每 1000毫升该溶液中丙酮酸钠的较佳含量为 3. 0-4. 0克,最佳含量为 3. 5克; 氯化钠的较佳含量为 2. 0-17. 0克,更佳含量为 2. 0-5. 0克,最佳含量为 2. 5-3. 5 克;
氯化钾或相应当量的枸橼酸钾的较佳含量为 1. 0-1. 8克, 最佳含量为 1. 5克; 无水葡萄糖的较佳含量为 13. 5-50. 0克, 更佳含量为 13. 5-20. 0克, 或其它相 应量的碳水化合物
在本发明提供的含有丙酮酸钠的口服组合物中,四种必要组分的含量可以分别 或同时取其较佳值、 更佳值或最佳值。
本发明提供的含有丙酮酸钠的口服补液盐溶液按其渗透压可分为高渗口服溶 液、 等渗口服溶液、 和低渗口服溶液。 所述高渗口服补液盐溶液的渗透压为 300-1000m 0 s m / L, 每 1000毫升该高渗口服溶液中含有的氯化钠 3. 5-17. 0 克, 含有的无水葡萄糖 20. 0-50. 0克或其它相应量的碳水化合物。 所述低渗补液 盐口服溶液的渗透压为 120-280 m O s m / L, 每 1000毫升等渗(280-300 m 0 s m I L )或低渗口服溶液中含有的氯化钠小于 3. 5克,含有的无水葡萄糖小于 20. 0 克或其它相应量的碳水化合物。 本发明提供的含有丙酮酸钠的口服组合物在临床应用时应是液体形式,一个较 佳的方式是在实际应用中, 在临用前将固体形式的组合物溶解在可饮用水中。 所 提到的浓度,渗透压等也是指当溶解时的条件下。
如果本发明提供的含有丙酮酸钠的口服组合物要以液体形式保存,需考虑丙酮 酸钠的水溶液稳定性问题,一般溶液的 pH为 4-4. 9。 如本发明所用, "其它碳水化合物"包括含水葡萄糖、 淀粉和谷类。 所述谷类 包括大米、 小米、 玉米、 高粱和麦类等。 本发明所用的谷类可以是粉剂粮食制品, 例如但不限于, 米粉、 玉米粉、 高粱面粉等。 实际应用中替代或部分替代 20 克 无水葡萄糖的米粉等用量通常是 50-80克, 临床用于腹泻治疗, 减少腹泻次数和
排便量效果还可能优于葡萄糖。
如本发明所用, "口服补液盐(Oral Rehydrat ion Salts, ORS) " 是呈固体状: 粉剂,散剂, 颗粒剂或片剂。 "口服补液盐溶液(Oral Rehydrat ion Solut ions, ORS) " , 指将粉剂等溶解后的水溶液。 用途
本发明提供的高渗和等渗口服补液盐溶液适用于严重烧伤(含烫伤), 伴或不 伴有休克的治疗。
本发明提供的等渗口服补液盐溶液适用于多种病因的循环血容量不足或失水 伴失盐, 伴或不伴有休克的治疗。
本发明提供的各种口服补液盐溶液适用于霍乱腹泻的治疗。
本发明提供的低渗口服补液盐溶液更适用于非霍乱小儿和成人腹泻, 急性和 慢性胃肠道炎症失水伴失盐的病例, 伴或不伴有休克的治疗。
本发明提供的高渗和等渗口服补液盐溶液及其改良溶液也适用于围手术期的 液体治疗,外科和妇产科手术前的肠道清洁准备, 以及食物或化学品中毒的洗胃 溶液。 本发明提供的低渗口服补液盐溶液也可作为生理性体液的补充, 改进为含 有丙酮酸钠和 /或丙酮酸钙的糖和盐的运动饮料,或适用于普通或特殊条件下如: 高山缺氧, 长期深海工作条件等饮料的组成。
本发明提供的含丙酮酸钠的口服补液盐溶液也适用于各种动物的上述相关临 床病症。 本发明提到的上述特征, 或实施例提到的特征可以任意组合。 本案说明书所揭示 的所有特征可与任何组合物形式并用, 说明书中所揭示的各个特征, 可以被任何可提 供相同、 均等或相似目的的替代性特征取代。 因此除有特别说明, 所揭示的特征仅为 均等或相似特征的一般性例子。 本发明的主要优点在于:
1、本发明提供的含有丙酮酸钠的口服组合物能增强口服补液盐溶液 (水,电解 质和糖)的吸收, 进而提高血容量, 其作用优于常规的冊 0-0RS。
2、 本发明提供的含有丙酮酸钠的口服组合物能够发挥其优越的纠正酸中毒的 碱剂功能, 更适用于难治性休克和重症腹泻的酸中毒,优于常规口服盐中的碳酸
氢钠或枸橼酸钠的碱剂纠酸功能。
3、 本发明提供的含有丙酮酸钠的口服组合物具有 WH0-0RS中碱剂所没有的抗 酸、 抗炎和抗氧化作用, 能增加肠道血流量,增强肠上皮细胞对缺氧的耐受能力, 有效减轻肠缺血和补液(再灌注)时存在的肠组织局部酸中毒、 炎症损害和过氧化 损伤, 保护肠粘膜上皮屏障和吸收功能, 改善葡糖糖-电解质口服液吸收的肠道环 境, 并有助全身代谢紊乱的纠正。 因此, 含丙酮酸钠的 Pyr-ORS 比冊 0-0RS能进 一步提高口服补液盐对低血容量休克的复苏效果, 在一定程度上能更有效地替代 静脉补液或减少静脉输液量。 下面结合具体实施例, 进一步阐述本发明。 应理解, 这些实施例仅用于说明本 发明而不用于限制本发明的范围。 下列实施例中未注明具体条件的实验方法, 通 常按照常规条件或按照制造厂商所建议的条件。 除非另外说明, 否则所有的百分 数、 比率、 比例、 或份数按重量计。
本发明中的重量体积百分比中的单位是本领域技术人员所熟知的,例如是指在 100毫升的溶液中溶质的重量。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的 意义相同。 此外, 任何与所记载内容相似或均等的方法及材料皆可应用于本发明 方法中。 文中所述的较佳实施方法与材料仅作示范之用。 针对现有技术中的 0RS, 在下述实施例中, 用丙酮酸盐取代碳酸氢盐 /枸橼酸 盐获得了本发明提供的口服补液盐溶液, 并通过文献记载的方法进行了一系列实 验。 制备实施例 1
含有丙酮酸钠的口服补液盐溶液 1
将列于下表的物质按照配方混合后溶解在水中, 得到口服补液盐溶液 1 :
表 1 高渗丙酮酸钠口服补液盐溶液
必要组分 含量(克) / 1, 000 毫升 分子量(MW) 渗透压(mOsm/L) 丙酮酸钠 3. 5 110 64
氯化钠 3. 5 58. 5 120
氯化钾 1. 5 74. 5 40
葡萄糖(无水) 20. 0 (溶解后浓度 2%) 180. 0 111 总渗透压 335 制备实施例 2
含有丙酮酸钠的口服补液盐溶液 2
将列于下表的物质按照配方混合后溶解在水中, 得到口服补液盐溶液 2 :
含有丙酮酸钠的口服补液盐溶液 3
将列于下表的物质按照配方混合后溶解在水中, 得到口服补液盐溶液 3 :
含有丙酮酸钠的口服补液盐溶液 4
将列于下表的物质按照配方混合后溶解在水中, 得到口服补液盐溶液 4 :
表 4 低渗丙酮酸钠口服补液盐溶液
必要组分 含量(克) / 1, 000 毫升 分子量(MW) 渗透压(mOsm/L)
丙酮酸钠 3. 5 110 64 氯化钠 2. 0 58. 5 68
氯化钾 1. 5 74. 5 40
葡萄糖(无水) 13. 5 (溶解后浓度 1. 35%) 180. 0 75
总渗透压 247 实验实施例
北京解放军总医院第一附属医院烧伤研究所休克与多器官衰竭实验室完成了
Pyr-ORS 对烧 /烫伤休克动物 (狗和大鼠) 的体内实验。
以下证明本发明提供的含有丙酮酸钠的组合物优于常规的组合物的比较实验 都是以实施例 1得到的溶液(高渗 WH0-0RS)为例, 已能充分确定本发明因含有取 代了碳酸氢钠或枸橼酸钠的丙酮酸钠, 优于 WH0-0RS 的三个代表性的配方。
测定方法-
1.空肠 ¾0和 Na+ 吸收率测定方法:
实验按常规方法, 参见文献(15— 16);
2.肠粘膜血流量测定方法:
采用激光多普勒血流仪(PeriFlux Systm 5000.瑞典 RERIMED公司)进行测量, 参见文献(13' 17);
3.肠粘膜二氧化碳分压 (PC02)测定:
采用 PC02张力测定仪(芬兰, Tonocap型 Tonometry)进行测量, 实验按常规方 法改进, 参见文献 (18);
动物烧 /烫伤后胃肠血流量减少, 可导致胃肠粘膜处于缺血缺氧状态, 酸性代 谢产物积聚导致胃肠粘膜 PC02增高, pH值降低。 研究显示, 胃肠粘膜 pH值随休 克程度加重而进行性降低: PC02与 pH值呈负相关, 是反映黏膜局部酸中毒的敏感 指标。
实验过程:
材料: 制备实施例 1得到的含有丙酮酸钠的口服溶液 1 (Pyr-ORS 1,总渗透压 为 335 毫渗量 /升)。
按照世界卫生组织的标准口服补液盐 (WH0-0RS) 的配方 1 (每升含氯化钠 3. 5 克, 氯化钾 1. 5 克, 碳酸氢钠 2. 5克和葡萄糖 20 克, 总渗透压为 331毫渗量 / 升)得到作为对照的 WH0-0RS1。
按照世界卫生组织的标准口服补液盐 (WHO-ORS) 的配方 II (每升含氯化钠 3.5 克, 氯化钾 1.5 克, 枸橼酸钠 2.9 克和葡萄糖 20 克, 总渗透压为 311毫渗 量 /升) 得到作为对照的 WHO-ORS2。 方法: 经胃肠造口手术后, 在 35% 总体表 面积 (TBSA) 烫伤大鼠 (n = 10) 引起的低血容量休克模型经造痿口输入口服补 液盐的实验中比较了 Pyr-ORSl和 WH0-0RS 1的复苏疗效,伤后输入的口服溶液量 按烧伤临床常规补液公式: Parkland 公式计算:
伤后第 1个 24小时补液量 = 4 ml · kg—1 · (1% TBSA)—1
结果数据-
1. Pyr-ORS对烫伤后水和 Na+吸收速率、 肠粘膜血流量及肠粘膜 PC02的影响 表 5 大鼠 35%总体表面积 ΙΠ度烫伤输入口服补液盐溶液后 4小时对水和 Na+吸收速率、 肠粘 膜血流量及肠粘膜 PC02的影响
注: * 与假烫 + 相同处理组比较, P< 0. 05 ; # 与烫伤 + WH0-0RS组比, P< 0. 05 以上一组大鼠烫伤后和输入 WHO-ORS1 (含碳酸氢钠) 比较的实验结果(表 5) 表明, 烫伤后输入 Pyr-ORSl 组 4 小时后肠道对水的吸收速率比烫伤后输入 WH0-0RS1组增加 26. 1%, 对钠的吸收速率增加 18. 8%,肠粘膜血流量增加 6. 9%,肠 粘膜 PC02降低 18. 7%。 各指标之间差别均有统计学意义(p <0. 05)。 说明本发明
提供的 Pyr-ORS l在促进烫伤大鼠肠道对水和盐的吸收,增加肠粘膜血流量以及纠 正肠粘膜局部的酸中毒诸方面均明显优于标准处方冊 0-0RSl。 表 6 大鼠 35%总体表面积 III度烫伤输入口服补液盐溶液后
4 小时对水和 Na+吸收速率、 肠粘膜血流量的影响
注: # 与烫伤 + WHO-ORS2组比, Ρ< 0. 05 ; Δ 与假烫 + WHO-ORS2组比较, P< 0. 05. 以上另一组烫伤后和输入 WHO-ORS2 (含枸橼酸钠) 比较的实验结果 (表 6) 表明,烫伤后输入 Pyr-ORS l 组 4 小时后肠道对水和钠的吸收速率, 以及肠粘膜 血流量比烫伤后输入 WHO-ORS2 组也都有增加, 二组各指标之间差别均有统计 学意义 (p < 0.05)。
说明本发明提供的 Pyr-ORS l 在促进烫伤动物肠道对水和盐的吸收, 以及增 加肠粘膜血流量等方面也均明显优于改良处方 WHO-ORS2。此外, 实验证据还表 明在改善肠道屏障结构和机能上 Pyr-ORS l 也优于 WHO-ORS2。
2. Pyr-ORS对烫伤后肠粘膜屏障功能指标的影响
表 7 大鼠 35%总体表面积 ΙΠ度烫伤输入口服补液盐溶液后 4小时对
肠粘膜屏障功能指标的影响
检测指标 实验分组
烫伤 烫伤 假烫 假烫 烫伤不补液
+Pyr-0RS1 +WH0-0RS1 +Pyr-0RS1 +WH0-0RS1 (n = 10) (n = 10) (n = 10) (n = 10) (n = 10) 肠组织二胺 59. 71士 52. 70 + 62. 13 + 59. 05士 40. 82士 氧化酶 11. 89*+ 4. 65*s 7. 71* 4. 73* 2. 43
(U/mgprot)
肠组织脂肪 420. 27士 391. 4士 466. 27士 425. 32士 358. 42士 酸结合蛋白 40. 36*+ 14. 52*s 20. 95* 32. 95* 18. 99
(pg/ml)
注: * 与烫伤不补液比较, P < 0. 05 ; # 与假烫相同处理组比较, P < 0. 05 ; +与烫伤 + WHO- 0RS1组比较, P < 0. 05。
二胺氧化酶和脂肪酸结合蛋白测定方法见相关参考文献 9—2ΰ)。
肠二胺氧化酶 (DA0)活性和肠脂肪酸结合蛋白含量均是反映肠粘膜屏障功能完 整性的敏感指标。 实验结果显示: 烫伤 + Pyr-0RS 1组二胺氧化酶活性和脂肪酸结 合蛋白含量不仅显著高于烫伤不补液组, 而且均显著高于烫伤 +WH0-0RS 1 组。 Pyr-ORS l 对肠屏障的保护作用优于 WH0-0RS1 (p < 0. 05),并接近假烫组水平(p > 0. 05)。提示烫伤后肠内输入 Pyr-ORS能减轻烫伤引起的肠黏膜上皮屏障损害。
以上二方面:水盐的吸收和屏障功能结果有力说明 Pyr-ORS保护伤后肠道屏障 功能, 促进受损肠道对水和盐的吸收,能更有利发挥其休克复苏效果。
3. Pyr-ORS对烫伤后肠组织 Na+_K+-ATP酶活力和肠上皮水通道蛋白表达的影 响
维持肠道屏障完整性的重要条件之一是足够的能量代谢, 烫伤后肠粘膜 Na+-K+-ATP 酶活性显著下降; 但 Pyr-ORS 能使其活性维持较高水平,明显高于 WH0-0RS (p <0. 05)。 进一步的动物实验局部肠道免疫组化的病理检查: 肠上皮水 通道蛋白(Aquaporin-l, AQP1)免疫组化检测显示 Pyr-ORS 明显提高它在上皮的 表达,显著优于冊 0-0RS的作用。全身代谢的观察也表明改善体内糖代谢和酸中毒 的异常也显著优于冊 0-0RS的作用。
以上表明胃肠道途径给于 Pyr-ORS 不仅有显著的保护肠道局部功能, 增强对 水和盐的吸收, 还有改善全身代谢的保护作用。
4. Pyr-ORS对比格犬 50%总体表面积 III度烧伤引起的低血容量休克的复苏效果
制作比格犬 50%总体表面积 III度烧伤引起低血容量休克的口服补液盐复苏的模 型(21)。 实验分为 3组: 不补液组(n=8),丙酮酸钠口服液 (Pyr-ORSl)组(n=10)和碳酸 氢钠口服液(WH0-0RS1)组(n=10),伤后立即按首个 24小时内烧伤临床常规补液公 式(parkland 公式, 4 ml · kg—1 · %TBSA— 计算量分别经胃内输入 Pyr- 0RS1 和 WH0-0RS1,与不(胃内)补液组比较, Pyr-ORSl组平均动脉血压和血容量显著增加, 24小时存活率为 60 %, 显著高于不补液组(0 %),也高于 WH0-0RS1组的 40%。 并 且, Pyr-ORSl组伤后 6和 24小时的心、 肝及肠道功能指标均优于冊 0-0RS1组。 采用荧光葡聚糖标记法证明, 前者脏器烧伤后 6小时脏器微血管通透性显著低于 不补液组和 WH0-0RS1组。
以上烧 /烫伤后动物经胃肠道输入 Pyr-ORS 的体内实验结果充分证明本发明以 丙酮酸钠取代 WH0-0RS 口服盐组合物中的碳酸氢钠 /枸橼酸钠,有助于促进缺血肠 道对水和盐的吸收, 纠正有效血容量不足、 改善局部和全身器官代谢和功能以及 提高动物生存率的有效性和优越性。 在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单 独引用作为参考那样。 此外应理解, 在阅读了本发明的上述讲授内容之后, 本领 域技术人员可以对本发明作各种改动或修改, 这些等价形式同样落于本申请所附 权利要求书所限定的范围。
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absorption rate during enteral resuscitation of burn shock in rats. J Burn Care Res 2010; 31(1) :200-6.
14. Alam NH, et al: L-isoleucine- supplemented oral rehydration solution in the treatment of acute diarrhoea in children: a randomized controlled trial. J Health Popul Nutr 2011; 29 (3) : 183- 90.
15. Cooper H, et al: A method for studying absorption of water and solute from the human small intestine. Gastroenterology 1966; 50(1) :1-7.
16.胡森等: 35% TBSA III 燙伤大鼠肠内补液时葡萄糖电解质溶液吸收率的研 .
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17.耿世佳等:卡巴胆碱对烫伤大鼠肠内补液时肠粘膜血流量, Na+ -K+ -ATP酶 活性和水通道蛋白 -1表达的影响.解放军医学杂志 2008; 33(6) :649-51.
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Claims
1.一种用于治疗循环血容量不足或失水伴失盐的丙酮酸钠(Pyruvate)口服补液 盐组合物, 其特征在于, 它含有以下组分:
(i) 2.0-6.0 重量份丙酮酸钠;
(ii) 1.5-17.0 重量份氯化钠;
(iii) 0-2.0 重量份氯化钾或相应当量的枸橼酸钾; 和
(iv) 10.0-50.0 重量份无水葡萄糖或其它碳水化合物;
并且组分(i) + (ϋ) + (iii) + (iv)的重量占组合物总重量的 50-100%。
2. 如权利要求 1所述的组合物, 其特征在于, 所述组合物含有:
(i) 3.0-4.0 重量份丙酮酸钠;
(ii) 2.0-5.0 重量份氯化钠;
(iii) 1.0-1.8 重量份氯化钾或相应当量的枸橼酸钾; 和
(iv) 13.5-20.0 重量份无水葡萄糖或其它碳水化合物。
3. 如权利要求 1所述的组合物, 其特征在于, 所述的组合物为口服水溶液, 在 1000ml所述溶液中含有:
(a) 2.0-6.0 克丙酮酸钠;
(b) 1.5-17.0 克氯化钠;
(c) 0-2.0 克氯化钾或相应当量的枸橼酸钾; 和
(d) 10.0-50.0 克无水葡萄糖或其它碳水化合物。
4. 如权利要求 3所述的组合物, 其特征在于, 在 1000ml所述溶液中含有: (a) 3.0-4.0 克丙酮酸钠;
(b) 2.0-5.0 克氯化钠;
(c) 1.0-1.8 克氯化钾或相应当量的枸橼酸钾; 和
(d) 13.5-20.0 克无水葡萄糖或其它碳水化合物。
5. 如权利要求 4 所述的组合物, 其特征在于, 所述溶液的渗透压为
300-1000mOsm/L, 并且 1000ml所述溶液中含有的氯化钠大于等于 3.5克, 含有大于 等于 20.0克的无水葡萄糖或其它碳水化合物。
6. 如权利要求 4 所述的组合物, 其特征在于, 所述溶液的渗透压为 120-280mOsm/L, 并且 1000ml所述溶液中含有的氯化钠小于 3. 5克, 含有小于 20. 0 克的无水葡萄糖或其它碳水化合物。
7. 如权利要求 1-6任一项所述的组合物, 其特征在于, 所述组合物中还含有锌 盐、 鎂盐、 硒盐、 钙盐、 磷酸盐、 抗氧化剂、 胃肠动力和血管活性成分、 免疫营养剂、 中药成分、 和 /或调味剂。
8. 如权利要求 7 所述的组合物, 其特征在于, 所述的抗氧化剂选自下述的 一种或一种以上的组合: 维生素 C、 维生素 E、 N-乙酰半胱氨酸 (N-Acetylcycteine)、 己酮可可碱(Pentoxifyl l ine); 所述的胃肠动力和血管活 性成分选自下述的一种或一种以上的组合: 卡巴胆碱(CarbaCh0l)、 莫沙比利 (Mosapride)、 山莨菪碱(Ani sodamine) 、 多巴酚丁胺(Dobutamine); 所述的免疫 营养剂选自下述的一种或一种以上的组合: L-异亮氨酸、 L-组氨酸、 精氨酸、 甘 氨酸、 谷氨酰胺、 低聚果糖、 短链脂肪酸、 益生菌。
9. 一种如权利要求 1-8任一项所述的组合物的用途, 其特征在于, 用于制备治 疗循环血容量不足、 失水伴失盐病症的口服药物、 和 /或用于生理性体液的补充。
10. 如权利要求 9所述的用途, 其特征在于, 所述病症包括烧伤、 休克、 霍乱、 腹泻、 或肠胃道炎症。
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CN201210074342.9A CN103316038B (zh) | 2012-03-20 | 2012-03-20 | 用于治疗循环血容量不足或失水伴失盐的丙酮酸钠(Pyruvate)口服补液盐组合物 |
CN201210074342.9 | 2012-03-20 |
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CN109528640A (zh) * | 2018-12-24 | 2019-03-29 | 江西润泽药业有限公司 | 一种品质稳定的盐酸消旋山莨菪碱注射液及其制备方法 |
CN110859307A (zh) * | 2019-12-10 | 2020-03-06 | 周方强 | 含有丙酮酸钠的组合物及其用途 |
CN113425696B (zh) * | 2021-07-02 | 2022-09-02 | 上海耀大生物科技有限公司 | 一种复方口服补液盐的泡腾制剂及其制备工艺和应用 |
CN116870026A (zh) * | 2023-09-07 | 2023-10-13 | 中国人民解放军总医院第四医学中心 | 一种口服补液盐药物组合物及其制备方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1276717A (zh) * | 1997-08-22 | 2000-12-13 | 清水制药株式会社 | 含有葡萄糖的制剂 |
US20030124503A1 (en) * | 2001-12-28 | 2003-07-03 | Olivencia-Yurvati Albert H. | Pyruvate cardioplegia solutions for administration to the heart during cardiopulmonary surgery and methods of use thereof |
CN1559434A (zh) * | 2004-03-12 | 2005-01-05 | 杨理林 | 一种口服补液盐分散片剂及其制备方法 |
CN101164530A (zh) * | 2006-10-18 | 2008-04-23 | 周方强 | 含稳定的丙酮酸钠的水溶液及其制法和用途 |
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US20040071664A1 (en) * | 1999-07-23 | 2004-04-15 | Gendel Limited | Delivery of an agent |
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2013
- 2013-03-20 WO PCT/CN2013/072929 patent/WO2013139274A1/zh active Application Filing
- 2013-03-20 US US14/385,673 patent/US20150105463A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1276717A (zh) * | 1997-08-22 | 2000-12-13 | 清水制药株式会社 | 含有葡萄糖的制剂 |
US20030124503A1 (en) * | 2001-12-28 | 2003-07-03 | Olivencia-Yurvati Albert H. | Pyruvate cardioplegia solutions for administration to the heart during cardiopulmonary surgery and methods of use thereof |
CN1559434A (zh) * | 2004-03-12 | 2005-01-05 | 杨理林 | 一种口服补液盐分散片剂及其制备方法 |
CN101164530A (zh) * | 2006-10-18 | 2008-04-23 | 周方强 | 含稳定的丙酮酸钠的水溶液及其制法和用途 |
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CN103316038A (zh) | 2013-09-25 |
US20150105463A1 (en) | 2015-04-16 |
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