Peritoneal dialysis solution and preparation method thereof

Abstract

The invention relates to the technical field of biological medicines, and discloses a peritoneal dialysis solution and a preparation method thereof. The peritoneal dialysis solution provided by the invention comprises polygelatin peptide as well as a micromolecular penetrant, an electrolyte, a buffer salt and a pH regulator which are acceptable in peritoneal dialysis. According to the peritoneal dialysis solution provided by the invention, a proper amount of polygelatin peptide is used as a colloid penetrant and is matched with a small molecule penetrant, so that effective dehydration at the initial stage of dialysis can be ensured, a long-time dehydration effect can be maintained, and the removal efficiency and stability of peritoneal dialysis on moisture and metabolites are improved; besides, the level of a harmful glucose product 5-hydroxymethylfurfural in the peritoneal dialysis solution is reduced, and the pH value is neutral, so that the stimulation to peritoneal mesothelial cells can be further reduced, and the patient compliance is improved.

Description

Technical Field

[0001] The invention relates to the technical field of biomedicine, and specifically discloses a peritoneal dialysis fluid and a preparation method thereof. Background Art

[0002] As an important form of renal replacement therapy, peritoneal dialysis plays a key role in the treatment of patients with end-stage renal disease. It uses the peritoneum as a semipermeable membrane to inject dialysate into the abdominal cavity, and uses the solute concentration gradient and osmotic gradient in the capillary plasma on both sides of the peritoneum and the dialysate in the peritoneal cavity to remove the body's metabolic waste and retained water through the principles of diffusion and osmosis. Compared with hemodialysis, the advantages of peritoneal dialysis are relatively low treatment costs, simple operation, no reliance on large dialysis equipment, and can be achieved at home, with fewer restrictions on the patient's freedom of life.

[0003] Peritoneal dialysis fluid is an indispensable part of peritoneal dialysis treatment, mainly composed of osmotic agents, buffers and electrolytes. Glucose peritoneal dialysis fluid is the most widely used peritoneal dialysis fluid at present, and its prescription is: glucose, sodium chloride, sodium lactate, calcium chloride and magnesium chloride. The pH value of glucose peritoneal dialysis fluid must be maintained at a low pH level (about 5.0). However, long-term exposure of the peritoneal cavity of uremic patients to acidic, high-concentration glucose and glucose degradation products in peritoneal dialysis fluid can lead to intracellular acidosis of peritoneal mesangial cells, mesothelial cells, macrophages, etc., cell dysfunction, accelerated cell apoptosis and death, reduced ultrafiltration function of the peritoneum, and may even induce a series of inflammatory reactions. Furthermore, the biocompatibility of glucose peritoneal dialysis fluid is poor, and its components will affect the microenvironment in the peritoneal cavity, which is not conducive to the long-term treatment and rehabilitation of patients. Therefore, it is of great significance to develop a neutral pH peritoneal dialysis fluid with good biocompatibility. Summary of the invention

[0004] In view of the shortcomings of glucose peritoneal dialysis fluid in the prior art, the present invention creatively discovered that the use of polygelatin as an osmotic agent for peritoneal dialysis can not only regulate the osmotic pressure of peritoneal dialysis fluid and help maintain a more stable ultrafiltration effect, but also has the function of protecting the peritoneum, reducing peritoneal damage caused by traditional dialysis fluid components, thereby extending the effective use time of the peritoneum and improving the long-term dialysis quality of patients.

[0005] In order to achieve the above-mentioned object of the invention, the present invention adopts the following technical solutions: In a first aspect, the present invention provides a peritoneal dialysis fluid, wherein each 1000 mL of peritoneal dialysis fluid contains 5.2 g to 6.2 g (in terms of nitrogen content) of polygeline, as well as small molecule osmotic agents, electrolytes, buffer salts and pH regulators acceptable in peritoneal dialysis.

[0006] The peritoneal dialysis fluid provided by the present invention has an excellent ultrafiltration effect, and it uses an appropriate amount of polygeline as a colloidal osmotic agent and is used in combination with a small molecule osmotic agent. Polygeline has a large molecular weight and is not easily absorbed by the peritoneum. It can maintain a high concentration in the dialysis fluid and maintain a stable colloidal osmotic pressure. At the same time, it is a substance with good biocompatibility, which is less irritating to peritoneal tissue, reduces the risk of adverse reactions such as peritoneal inflammation caused by the components of the dialysis fluid, and is suitable for long-term use in peritoneal dialysis fluid. The small molecule osmotic agent can quickly increase the osmotic pressure of the dialysis fluid in the early stage, prompting water to move from the peritoneal capillaries to the dialysis fluid, thereby achieving the purpose of removing excess water from the body.

[0007] When small molecule osmotic agents are used in combination with polygeline, the small molecule osmotic agents can quickly take effect and quickly establish an osmotic pressure gradient in the early stage of dialysis, while polygeline maintains the stability of osmotic pressure in the subsequent period. The combination of the two can not only ensure effective dehydration in the early stage of dialysis, but also maintain the dehydration effect for a longer period of time, thereby improving the efficiency and stability of peritoneal dialysis in removing water and metabolites.

[0008] Preferably, the electrolyte includes at least one of calcium chloride, magnesium chloride, sodium chloride or potassium chloride; the small molecule osmotic agent includes glucose; the buffer salt includes at least one of bicarbonate, lactate, pyruvate or acetate; and the pH adjuster includes at least one of hydrochloric acid, acetic acid or sodium hydroxide.

[0009] Polygeline is a macromolecular colloidal substance that can produce colloidal osmotic pressure in peritoneal dialysis fluid. Colloidal osmotic pressure plays an important role in maintaining water balance inside and outside blood vessels and inside and outside cells. During peritoneal dialysis, it can adjust the osmotic pressure gradient between the dialysate and the interstitial fluid, which is beneficial to the removal of water and the exchange of solutes. Compared with glucose, the colloidal osmotic pressure produced by polygeline is relatively stable, and it will not pass through the peritoneum as easily and quickly as glucose, so it can maintain effective osmotic pressure for a long time, ensuring that water continues to transfer from the body to the dialysate during dialysis, which can make up for the problem of osmotic pressure drop caused by rapid absorption of glucose and prolong ultrafiltration time. Glucose can quickly establish an osmotic gradient and achieve initial efficient dehydration. However, long-term high-concentration glucose may cause peritoneal fibrosis, glucose metabolism disorders and other problems.

[0010] In the present invention, the combination of polygelatin and glucose can not only reduce the amount of glucose used, reduce the risk of peritoneal fibrosis and metabolic disorders, but also improve biocompatibility and enhance the safety of the product; in addition, the compounding of colloid and crystal osmotic agent can not only ensure effective dehydration in the early stage of dialysis, but also maintain long-term ultrafiltration.

[0011] Preferably, each 1000 mL of peritoneal dialysis fluid contains 0.24 g to 0.27 g of calcium chloride, 0.048 g to 0.053 g of magnesium chloride, and 5.20 g to 5.49 g of sodium chloride.

[0012] Reasonable electrolyte concentration can ensure the electrolyte balance in the patient's body during dialysis, avoid electrolyte imbalance caused by dialysis, and also help maintain the physiological function of the peritoneum and promote solute exchange and water removal.

[0013] Preferably, each 1000 mL of peritoneal dialysis fluid contains 4 g to 7 g of glucose.

[0014] Preferably, each 1000 mL of peritoneal dialysis fluid contains 2 g to 3 g of sodium lactate, illustratively 2.13 g, 2.24 g or 2.36 g.

[0015] Preferably, the peritoneal dialysis fluid also contains glutathione and mannitol.

[0016] As an antioxidant, glutathione can prevent the oxidation and deterioration of other ingredients (such as polygelatin, glucose, etc.). During the storage and use of dialysate, it may be affected by factors such as oxygen and light, which may cause oxidation reactions of the ingredients and affect the quality and effect of the dialysate. Glutathione can react with oxidants preferentially to protect other ingredients. In addition, glutathione also has a certain anti-inflammatory effect, which helps to reduce the peritoneal inflammatory response that may be caused during peritoneal dialysis and further protect the peritoneal function; in addition, glutathione is an essential nutrient for the human body. Even if a small amount is absorbed during the dialysis process, it will not have adverse effects on the human body. On the contrary, it may have a certain supplementary effect on the patient's nutrition.

[0017] Mannitol plays a major role in stabilizing osmotic pressure and preventing crystallization in peritoneal dialysis fluid. It can adjust the osmotic pressure of the dialysate to make it more stable and avoid damage to the peritoneum due to excessive fluctuations in osmotic pressure. At the same time, mannitol has a certain solubility and stability, which can prevent other components from crystallizing during low temperature or long-term storage, and ensure the uniformity and fluidity of the dialysate. These properties of mannitol help maintain the physical stability of the dialysate and ensure the quality and safety of the dialysate during use. In addition, mannitol also has a certain osmotic dehydration effect during peritoneal dialysis, and synergizes with glucose and polygeline to further enhance the dialysate's ability to remove water.

[0018] Every 1000mL of peritoneal dialysis fluid may contain 0.46g~0.92g of glutathione and 6g~10g of mannitol.

[0019] Preferably, the pH of the peritoneal dialysis fluid is 7.2-7.4.

[0020] Compared with the traditional acidic (pH 5.2) glucose peritoneal dialysis fluid, the pH of the peritoneal dialysis fluid provided by the present invention is 7.2-7.4. The neutral pH can reduce the stimulation to the peritoneal mesothelial cells, alleviate the discomfort of the patients during use, and improve the compliance.

[0021] Preferably, each 1000 mL of peritoneal dialysis fluid contains 5.8 g of polygeline (in terms of nitrogen content), 0.257 g of calcium chloride, 0.051 g of magnesium chloride, 5.38 g of sodium chloride, 2.24 g of sodium lactate, 6 g of glucose, 0.61 g of glutathione and 6 g of mannitol, and an appropriate amount of pH regulator; the pH of the peritoneal dialysis fluid is 7.35.

[0022] The formula of the present invention provides a peritoneal dialysis fluid with a physiological pH value and significantly reduced glucose degradation products through the compounding of colloid-crystal osmotic agents, the combination of antioxidant stabilizers and physiological electrolyte regulation. The peritoneal dialysis fluid can balance ultrafiltration efficiency and safety, improve biocompatibility and patient compliance during use, and has an excellent ultrafiltration effect.

[0023] In a second aspect, the present invention further provides a method for preparing the above peritoneal dialysis fluid, the preparation method comprising the following steps: S1. Weigh each component according to the formula of peritoneal dialysis fluid; S2. Add the salt components of each component to the water for injection, sterilize at high temperature, and obtain a sterile salt solution; S3. Dissolve the polygeline and small molecule osmotic agent in the sterile salt solution, adjust the pH, filter and sterilize to obtain peritoneal dialysis fluid.

[0024] The preparation method of the peritoneal dialysis fluid provided by the present invention is relatively simple, does not need to be stored and filled separately according to pH value or to prevent reaction between components, does not need to be mixed according to ratio when used, is easy to operate, and can significantly reduce the content of 5-hydroxymethylfurfural. DETAILED DESCRIPTION

[0025] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0026] The raw materials and reagents used in the present invention, unless otherwise specified, are conventional commercially available products; the methods used in the present invention, unless otherwise specified, are conventional methods in the art.

[0027] Example 1 This embodiment provides a peritoneal dialysis solution, wherein each 1000 mL of the peritoneal dialysis solution comprises the following components: each 1000 mL of the peritoneal dialysis solution contains 5.8 g of polygeline (in terms of nitrogen content), 0.257 g of calcium chloride, 0.051 g of magnesium chloride, 5.38 g of sodium chloride, 2.24 g of sodium lactate, 6 g of glucose, 0.61 g of glutathione and 6 g of mannitol, an appropriate amount of sodium hydroxide, and the remainder is water for injection; This embodiment also provides a method for preparing the above peritoneal dialysis fluid, which is as follows: S1. According to the formula of peritoneal dialysis solution, weigh 58 g of polygeline, 2.57 g of calcium chloride, 0.51 g of magnesium chloride, 53.8 g of sodium chloride, 22.4 g of sodium lactate, 60 g of glucose, 6.1 g of glutathione and 60 g of mannitol; S2. Add calcium chloride, magnesium chloride, sodium chloride and sodium lactate to 900 mL of water for injection and sterilize at 121°C for 15 min to obtain a sterile salt solution; S3. In an ultra-clean workbench, dissolve the weighed polygeline, glucose, glutathione and mannitol in a sterile salt solution cooled to 50°C, mix well, add sterile water for injection to 10L, adjust the pH to 7.35, and filter through filter membranes with pore sizes of 0.45μm and 0.22μm in turn to obtain the filtrate. Fill it into a medical dialysis bag, and then put it into an outer coat bag with light-proof and high barrier properties. Evacuate, fill with nitrogen, and package to obtain peritoneal dialysis fluid, recorded as peritoneal dialysis fluid I.

[0028] Example 2 This embodiment provides a peritoneal dialysis solution, wherein each 1000 mL of the peritoneal dialysis solution comprises the following components: each 1000 mL of the peritoneal dialysis solution contains 5.2 g of polygeline (in terms of nitrogen content), 0.257 g of calcium chloride, 0.051 g of magnesium chloride, 5.38 g of sodium chloride, 2.24 g of sodium lactate, 7 g of glucose, 0.92 g of glutathione, and 4 g of mannitol, an appropriate amount of sodium hydroxide, and the remainder is water for injection; This embodiment also provides a method for preparing the above peritoneal dialysis fluid, which is as follows: S1. According to the formula of peritoneal dialysis solution, weigh 52 g of polygeline, 2.57 g of calcium chloride, 0.51 g of magnesium chloride, 53.8 g of sodium chloride, 22.4 g of sodium lactate, 70 g of glucose, 9.2 g of glutathione and 40 g of mannitol; S2. Add calcium chloride, magnesium chloride, sodium chloride and sodium lactate to 900 mL of water for injection and sterilize at 121°C for 18 min to obtain a sterile salt solution; S3. In an ultra-clean workbench, dissolve the weighed polygeline, glucose, glutathione and mannitol in a sterile salt solution cooled to 50°C, mix well, add sterile water for injection to 10L, adjust the pH to 7.2, and filter through filter membranes with pore sizes of 0.45μm and 0.22μm in turn to obtain the filtrate, fill it into a medical dialysis bag and then put it into an outer coat bag with light-proof and high barrier properties, evacuate, fill with nitrogen, and package to obtain peritoneal dialysis fluid, recorded as peritoneal dialysis fluid II.

[0029] Example 3 This embodiment provides a peritoneal dialysis solution, wherein each 1000 mL of the peritoneal dialysis solution comprises the following components: each 1000 mL of the peritoneal dialysis solution contains 6.2 g of polygeline (in terms of nitrogen content), 0.257 g of calcium chloride, 0.051 g of magnesium chloride, 5.38 g of sodium chloride, 2.36 g of sodium lactate, 4 g of glucose, 0.46 g of glutathione, and 8 g of mannitol, an appropriate amount of sodium hydroxide, and the remainder is water for injection; This embodiment also provides a method for preparing the above peritoneal dialysis fluid, which is as follows: S1. According to the formula of peritoneal dialysis solution, weigh 62 g of polygeline, 2.57 g of calcium chloride, 0.51 g of magnesium chloride, 53.8 g of sodium chloride, 23.6 g of sodium lactate, 40 g of glucose, 4.6 g of glutathione and 80 g of mannitol; S2. Add calcium chloride, magnesium chloride, sodium chloride and sodium lactate to 900 mL of water for injection and sterilize at 121°C for 15 min to obtain a sterile salt solution; S3. In an ultra-clean workbench, dissolve the weighed polygeline, glucose, glutathione and mannitol in a sterile salt solution cooled to 50°C, mix well, add sterile water for injection to 10L, adjust the pH to 7.4, and filter through filter membranes with pore sizes of 0.45μm and 0.22μm in turn to obtain the filtrate, fill it into a medical dialysis bag and then put it into an outer coat bag with light-proof and high barrier properties, evacuate, fill with nitrogen, and package to obtain peritoneal dialysis fluid, recorded as peritoneal dialysis fluid III.

[0030] Effect Example 1 The present invention uses an ice point osmometer to test the osmotic pressure of the peritoneal dialysis fluid prepared in Examples 1-3, and uses the company's commercially available products 1.5% G peritoneal dialysis fluid (lactate) and 2.5% G peritoneal dialysis fluid (lactate) as control samples. The osmotic pressures of different peritoneal dialysis fluids are shown in Table 1.

[0031] Table 1

[0032] It can be seen from the data in Table 1 that within the scope of this experiment, the osmotic pressure of the peritoneal dialysis fluid prepared by the present invention is 350mOsmol / L~368mOsmol / L, and the osmotic pressure is basically stable, which is between the 1.5% G peritoneal dialysis fluid (lactate) and 2.5% G peritoneal dialysis fluid (lactate) commonly used in clinical practice.

[0033] Effect Example 2 The present invention measures the ultrafiltration volume of different peritoneal dialysis fluids, and also measures the creatinine and urea contents, and the specific contents are as follows: Male SD rats weighing 200 g ± 10 g were fed with 0.5% adenine feed for 4 weeks to establish a rat chronic kidney disease model. After successful modeling, 60 rats with chronic kidney disease were randomly divided into 6 groups, namely, normal saline group, peritoneal dialysis fluid group I, peritoneal dialysis fluid group II, peritoneal dialysis fluid group III, 1.5% G peritoneal dialysis fluid group, and 2.5% G peritoneal dialysis fluid group. During the study, each group of rats was injected with the corresponding peritoneal dialysis fluid (100 mL / kg BW) once a day for 6 consecutive weeks, and then dialysis was terminated.

[0034] Among them, the peritoneal dialysis fluid injected into different groups is shown in Table 2.

[0035] Table 2

[0036] (1) Determination of ultrafiltration volume 24 hours after the end of dialysis, the rats in different groups were anesthetized and injected with 0.9% saline (100 mL / kg BW) intraperitoneally. 4 hours later, the abdominal wall was cut open along the white line of the abdomen, the peritoneal fluid was measured, and the volume of the total dialysis effluent (mL) was measured to calculate the ultrafiltration volume. The ultrafiltration volume of different groups is shown in Table 3.

[0037] The ultrafiltration volume was calculated according to the following formula: ultrafiltration volume = final water output - 25 mL.

[0038] Table 3

[0039] As shown in Table 3, the ultrafiltration volume of peritoneal dialysis fluid I to peritoneal dialysis fluid III provided by the present invention is significantly higher than that of the normal saline group and the conventional commercially available glucose peritoneal dialysis fluid.

[0040] (2) Determination of creatinine and urea content 1 mL of the above dialysis solution was taken, allowed to stand for 1 hour, and then centrifuged at 4000 rpm for 10 minutes to separate the supernatant for use; the contents of creatinine and urea were measured by an automatic biochemical analyzer. The contents of creatinine and urea in the dialysis solution after 16 hours of abdominal retention are shown in Table 4.

[0041] Table 4

[0042] It can be seen from Table 4 that, compared with normal saline and conventional commercially available glucose peritoneal dialysis fluid, the peritoneal dialysis fluid I to peritoneal dialysis fluid III provided by the present invention have significantly improved creatinine and urea clearance capabilities.

[0043] In summary, the peritoneal dialysis fluid provided by the present invention has an excellent ultrafiltration effect, and its ability to remove creatinine and urea is significantly better than that of traditional glucose peritoneal dialysis fluid. The reasons may be that: the colloidal osmotic pressure generated by polygeline substitution is relatively stable, and can maintain an effective osmotic pressure for a long time, ensuring that water continues to transfer from the body to the dialysis fluid during dialysis, thereby extending the ultrafiltration time; (2) mannitol also has a certain osmotic dehydration effect during peritoneal dialysis, and synergistically acts with glucose and polygeline to further enhance the dialysis fluid's ability to remove metabolic waste and retained water. In addition, in view of the analysis of the components and preparation process in the peritoneal dialysis fluid formula, the peritoneal dialysis fluid provided by the present invention has a lower level of glucose metabolites and better biocompatibility.

[0044] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A peritoneal dialysis fluid, characterized in that: Each 1000 mL of peritoneal dialysis fluid contains 5.2 g to 6.2 g of polygeline (in terms of nitrogen content), as well as small molecule osmotic agents, electrolytes, buffer salts and pH regulators acceptable in peritoneal dialysis.

2. The peritoneal dialysis fluid according to claim 1, characterized in that The electrolyte comprises at least one of calcium chloride, magnesium chloride, sodium chloride or potassium chloride; and / or The small molecule osmotic agent includes glucose; and / or The buffer salt comprises at least one of bicarbonate, lactate, pyruvate or acetate; and / or The pH adjuster includes at least one of hydrochloric acid, acetic acid or sodium hydroxide.

3. The peritoneal dialysis fluid according to claim 2, characterized in that Every 1000mL of peritoneal dialysis fluid contains 0.24g~0.27g of calcium chloride, 0.048g~0.053g of magnesium chloride, and 5.20g~5.49g of sodium chloride.

4. The peritoneal dialysis fluid according to claim 2, characterized in that Every 1000mL of peritoneal dialysis fluid contains 4g~7g of glucose.

5. The peritoneal dialysis fluid according to claim 2, characterized in that Every 1000mL of peritoneal dialysis fluid contains 2g~3g of sodium lactate.

6. The peritoneal dialysis fluid according to claim 1, characterized in that The peritoneal dialysis fluid also contains glutathione and mannitol.

7. The peritoneal dialysis fluid according to claim 1, characterized in that Every 1000mL of peritoneal dialysis fluid contains 0.3g~1.0g of glutathione and 4g~8g of mannitol.

8. The peritoneal dialysis fluid according to claim 1, characterized in that The pH of the peritoneal dialysis fluid is 7.2-7.

4.

9. The peritoneal dialysis fluid according to claim 1, characterized in that Each 1000 mL of peritoneal dialysis fluid contains 5.8 g of polygeline (in terms of nitrogen content), 0.257 g of calcium chloride, 0.051 g of magnesium chloride, 5.38 g of sodium chloride, 2.24 g of sodium lactate, 6 g of glucose, 0.61 g of glutathione and 8 g of mannitol; the pH of the peritoneal dialysis fluid is 7.

35.

10. The method for preparing a peritoneal dialysis fluid according to any one of claims 1 to 9, characterized in that: The preparation method comprises the following steps: S1. Weigh each component according to the formula of peritoneal dialysis fluid; S2. Add the salt components of each component to the water for injection, sterilize at high temperature, and obtain a sterile salt solution; S3. Dissolve the polygeline and small molecule osmotic agent in the sterile salt solution, adjust the pH, filter and sterilize to obtain peritoneal dialysis fluid.

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