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CN-121987564-A - Preparation method of Du Mishan g imitation oral solution for lactulose

CN121987564ACN 121987564 ACN121987564 ACN 121987564ACN-121987564-A

Abstract

The invention discloses a preparation method of a imitated oral solution for Du Mishan g of lactulose, which comprises the following steps of pretreatment of raw materials; the preparation method comprises the steps of preparing a buffer system, dissolving and mixing core components, regulating flavor and optimizing taste, regulating osmotic pressure, carrying out aseptic treatment, regulating constant-temperature curing and stability, detecting and packaging quality, clathrating lactulose by adopting beta-cyclodextrin, effectively protecting the molecular structure of the lactulose from hydrolytic degradation in the preparation and storage processes, and simultaneously, combining citric acid-sodium citrate composite buffer pair with EDTA disodium to stabilize the pH value of the system and chelate metal ions, further inhibit the degradation of the lactulose and prolong the effective period of the preparation. The sweetness is regulated by the compound sweetener of the sucralose and the maltitol, so that the sweet greasy feeling of a single sweetener is avoided.

Inventors

  • ZHANG TIANYU
  • QIAN ZHIXIN

Assignees

  • 江苏晨牌邦德药业有限公司

Dates

Publication Date
20260508
Application Date
20251229

Claims (10)

  1. 1. A preparation method of a simulated oral solution for Du Mishan g of lactulose is characterized by comprising the following steps: Step one, raw material pretreatment, namely performing beta-cyclodextrin inclusion treatment on lactulose, and performing pretreatment on compound sweetener, EDTA disodium and malic acid; Preparing a buffer system, namely adding EDTA disodium solution into a citric acid-sodium citrate composite buffer pair, and adjusting the pH to 4.8-5.2 to prepare the composite buffer system; Dissolving and mixing the core components, namely dissolving and mixing the sweetener, the preservative, the composite buffer system and the lactulose inclusion compound in two stages to form a core mixed system; Step four, flavor adjustment and taste optimization, namely adding malic acid, orange peel extract and vanillin solution to adjust the flavor to form a flavor optimization system; Regulating the osmotic pressure, namely controlling the osmotic pressure of the system to be 280-320 mOsm/kg through compound regulation of sodium chloride and glycerol to obtain an osmotic pressure adaptive system; step six, microfiltration clarification treatment, namely performing microfiltration on the osmotic pressure adaptive system by adopting a ceramic microfiltration membrane to obtain a clarification system; step seven, aseptic treatment, namely sterilizing the clarified system by adopting high-temperature instantaneous sterilization to obtain an aseptic system; step eight, constant temperature curing and stability regulation, namely performing constant temperature curing on the sterile system to obtain a stable oral solution matrix; And step nine, quality detection and encapsulation, namely detecting the quality of the oral solution matrix, and aseptically encapsulating and storing according to the specified conditions after the quality is qualified.
  2. 2. The method for preparing the simulated oral solution of Du Mishan g of lactulose according to claim 1, wherein the first step is as follows: The lactulose inclusion treatment comprises the steps of selecting lactulose raw materials with purity of more than or equal to 98%, adding beta-cyclodextrin as an inclusion material, wherein the mass ratio of the lactulose to the beta-cyclodextrin is 1:0.6-1:1.0, adding the beta-cyclodextrin into purified water, heating to 60-65 ℃, stirring and dissolving at 200-300 rpm to prepare beta-cyclodextrin solution with mass fraction of 10% -15%, regulating pH of the solution to 4.5-5.0, slowly adding lactulose powder, stirring at 250-300 rpm for 40-60 minutes while maintaining 50-55 ℃ to form a lactulose-beta-cyclodextrin inclusion system, then cooling to 10-15 ℃ at a speed of 1-2 ℃ per minute, preserving heat for 20-30 minutes, promoting the complete precipitation of the inclusion, centrifugally separating and collecting sediment, drying in a freeze dryer for 24-36 hours to obtain the lactulose inclusion, and sealing for later use; the auxiliary material pretreatment comprises the steps of selecting sucralose and maltitol as compound sweeteners, mixing the sucralose and the maltitol at a mass ratio of 1:80-1:100, adding purified water, heating to 40-45 ℃, stirring and dissolving to prepare sweetener solution with a mass fraction of 5% -8% for standby, selecting disodium EDTA as a metal ion chelating agent, adding a small amount of purified water, heating to 50-55 ℃ and stirring and dissolving to prepare EDTA disodium solution with a mass fraction of 2% -3% for standby, selecting malic acid as a flavor regulator, crushing, sieving with a 80-100-mesh sieve, and removing coarse particle impurities for standby.
  3. 3. The method for preparing the simulated oral solution for the lactulose Du Mishan g as claimed in claim 1, wherein the second step is as follows: preparing a basic buffer solution, namely selecting citric acid and sodium citrate as a composite buffer pair, wherein the mass ratio of the citric acid to the sodium citrate is 1:1.2-1:1.5, adding purified water, heating to 35-40 ℃, and stirring at 150-200 rpm for 15-20 minutes until the citric acid and the sodium citrate are completely dissolved to prepare the basic buffer solution with the mass fraction of 3% -5%; And (3) optimizing a buffer system, namely adding the EDTA disodium solution prepared in the step (A) into a basic buffer solution, continuously stirring for 10-15 minutes, uniformly mixing, adjusting the pH value of the system to 4.8-5.2, and obtaining a stable composite buffer system, wherein the volume ratio of the EDTA disodium solution to the basic buffer solution is 1:50-1:60, and preserving the heat at 35-40 ℃ for later use.
  4. 4. The method for preparing the simulated oral solution for the lactulose Du Mishan g as claimed in claim 1, wherein the third step is as follows: The first stage of dissolution, namely adding the prescribed amount of purified water into a material mixing tank, heating to 50-55 ℃, stirring at 200-250 rpm, adding the compound sweetener solution pretreated in the first step, stirring for 15-20 minutes to completely disperse, and then adding the prescribed amount of ethylparaben, continuously stirring for 10-15 minutes until the ethylparaben is completely dissolved to form a premix system; And the second stage of mixing, namely slowly injecting the composite buffer system prepared in the second step into a premix system at the injection speed of 3-5 mL/min, stirring while injecting, maintaining the temperature of 50-55 ℃ and stirring at 250-300 rpm for 20-30 minutes, and then adding the lactulose inclusion compound prepared in the first step, and continuing stirring for 30-40 minutes to ensure that the lactulose inclusion compound is uniformly dispersed and has no local aggregation phenomenon, so as to form a core mixed system.
  5. 5. The method for preparing the simulated oral solution for the lactulose Du Mishan g as claimed in claim 1, wherein the fourth step is as follows: Adding the malic acid powder pretreated in the step one into a core mixed system, wherein the addition amount of the malic acid is 0.03% -0.05% of the total mass of the core mixed system, and stirring at 50-55 ℃ and 250-300 rpm for 15-20 minutes until the malic acid is completely dissolved; The preparation method comprises the steps of adding a prescription amount of orange peel extract, stirring for 10-15 minutes, adding a small amount of vanillin solution diluted by purified water, wherein the mass ratio of the orange peel extract to a core mixed system is 1:1000-1:1200, and continuously stirring for 15-20 minutes, so as to form a flavor optimization system, and cooling to 40-45 ℃ for standby.
  6. 6. The method for preparing the simulated oral solution of Du Mishan g of lactulose according to claim 1, wherein the fifth step is as follows: pre-adjusting, namely adding a prescription amount of sodium chloride into the flavor optimization system, wherein the addition amount of the sodium chloride is 0.1% -0.15% of the total mass of the system, and stirring at 250-300 rpm for 10-15 minutes until the sodium chloride is completely dissolved; And (3) accurately adjusting, namely adding the glycerol with the prescription dosage, wherein the volume ratio of the glycerol to the system is 1:50-1:60, maintaining the temperature of 40-45 ℃ and stirring at 200-250 rpm for 20-30 minutes, and monitoring the osmotic pressure of the system in real time by adopting an osmotic pressure instrument during stirring to ensure that the osmotic pressure is controlled to be 280-320 mOsm/kg, so as to obtain the osmotic pressure adaptation system.
  7. 7. The method for preparing the simulated oral solution of Du Mishan g of lactulose according to claim 1, wherein the step six is as follows: Selecting a ceramic micro-filtration membrane with the pore diameter of 0.22 mu m, firstly flushing the surface of the membrane with a sodium hydroxide solution with the mass fraction of 1% for 10-15 minutes, then flushing with purified water until the pH value of flushing fluid is neutral, and finally flushing with a hydrochloric acid solution with the mass fraction of 0.5% for 5-10 minutes, and flushing with purified water again until the pH value is neutral, thereby finishing the membrane pretreatment; The micro-filtration operation comprises the steps of cooling an osmotic pressure adaptation system to 30-35 ℃, introducing the osmotic pressure adaptation system into pretreated ceramic micro-filtration membrane equipment, controlling the operation pressure to be 0.2-0.4 MPa, controlling the cross flow speed to be 1-2 m/s, carrying out micro-filtration treatment, sampling and observing the clarity every 20 minutes in the micro-filtration process, ensuring that filtrate is free of turbidity and particles visible to naked eyes, flushing a membrane surface residual system with purified water after the micro-filtration is completed, and merging the filtrate to obtain a clarification system.
  8. 8. The method for preparing the simulated oral solution of Du Mishan g of lactulose according to claim 1, wherein the step seven is specifically as follows: Preheating equipment, namely preheating a high-temperature instantaneous sterilizer to 121-123 ℃, maintaining the internal temperature of the equipment stable, and sterilizing a conveying pipeline by using steam for 15-20 minutes; The sterilization operation comprises the steps of introducing the clarified system into a high-temperature instantaneous sterilizer through a sterile conveying pipeline, controlling the sterilization temperature to be 121 ℃ and the sterilization time to be 8-10 seconds, keeping the flow rate of the system stable in the sterilization process, and rapidly cooling the system to be 25-30 ℃ after sterilization to obtain the sterile system.
  9. 9. The method for preparing the simulated oral solution of Du Mishan g of lactulose according to claim 1, wherein the step eight is specifically as follows: Curing treatment, namely transferring the sterile system into a sterile curing tank, maintaining the temperature at 25-30 ℃, slowly stirring at 100-150 rpm, and curing for 60-90 minutes to promote the components of the system to be fully fused to achieve a thermodynamically stable state; and (3) stability enhancement, namely sampling and detecting the pH value and the clarity of the system every 30 minutes in the curing process, ensuring that the pH value is maintained at 4.8-5.2 and the clarity is unchanged, and continuing stirring for 30-40 minutes after curing is finished, so as to obtain the stable oral solution matrix.
  10. 10. The method for preparing the simulated oral solution of Du Mishan g of lactulose according to claim 1, wherein the step nine is specifically: Quality detection, namely performing multiple index detection on an oral solution matrix, wherein the multiple index detection comprises lactulose content, impurity content, pH value, osmotic pressure, clarity, microorganism limit and taste grading; And (3) sterile packaging, namely after all detection indexes are qualified, filling an oral solution matrix into sterile oral solution bottles through sterile filling equipment, wherein the filling quantity of each bottle is controlled according to the specification requirement, the filling speed is controlled to be 10-15 mL/s in the filling process, air bubbles are avoided, immediately performing tamponade and cap screwing sealing after filling, cleaning and drying a bottle body after sealing, attaching a label, and storing at a shade and dry place below 25 ℃.

Description

Preparation method of Du Mishan g imitation oral solution for lactulose Technical Field The invention relates to the technical field of preparation of a simulated oral solution of Du Mishan g of lactulose, in particular to a preparation method of a simulated oral solution of Du Mishan g of lactulose. Background The oral solution of the lactulose Du Mishan g is a common clinical osmotic cathartic, the main component is the lactulose, and a small amount of auxiliary materials are contained to adjust the taste and the stability, so that the lactulose can be widely applied to the treatment of chronic functional constipation and also can be used for the auxiliary treatment of hepatic encephalopathy, and plays roles in adjusting the balance of intestinal flora, improving the osmotic pressure of intestinal tracts and promoting the peristalsis of the intestinal tracts. However, the chemical nature of lactulose itself has led to a number of technical challenges in its formulation. The lactulose is a condensate of galactose and fructose, the molecular structure of the lactulose contains a plurality of hydroxyl groups, hydrolysis reaction is easy to occur under the conditions of high temperature, acid-base unbalance or long-time storage, impurities such as fructose, glucose and the like are generated, so that the drug effect is reduced, meanwhile, the lactulose is high in sweetness and bitter and astringent in taste, smooth taste of an original ground product is difficult to achieve due to adjustment of single auxiliary material, patient compliance is poor, in addition, the existing preparation method mainly adopts a process of directly sterilizing and packaging after simple mixing and dissolving, the lactulose is unevenly dispersed in a system, local concentration is easy to be excessively high, crystallization precipitation can occur in the storage process, the appearance and the using effect of the preparation are influenced, moreover, osmotic pressure of a conventional preparation is often not matched with physiological osmotic pressure of human intestinal tracts, intestinal irritation reactions such as abdominal distension and abdominal pain can occur after a part of patients take the lactulose, and finally trace impurities possibly remain in the lactulose raw material, the conventional preparation process lacks specific purification and clarification steps, so that the impurity content of the preparation is excessively high, and the safety risk can be increased after long-term taking. In the prior art, aiming at the preparation of lactulose oral solution, the preparation is focused on the solution of a single problem, such as the inhibition of degradation by adding a single stabilizer or the improvement of taste by adding a sweetener, and a preparation system with multi-dimensional synergistic regulation is not formed. Part of the methods adopt high-temperature long-time sterilization, although the sterilization requirement can be ensured, the degradation of lactulose can be accelerated, part of the methods do not carry out accurate osmotic pressure regulation, so that the intestinal tract irritation is stronger, and other methods lack effective clarification and purification steps, so that the preparation has insufficient clarity and purity. Therefore, there is a need to develop a method for preparing a Du Mishan g simulated oral solution for lactulose to solve the above-mentioned problems. Disclosure of Invention The invention aims to provide a preparation method of a imitated oral solution for Du Mishan g of lactulose, which aims to solve the problems in the prior art. In order to achieve the aim, the invention provides the following technical scheme that the preparation method of the imitated oral solution for Du Mishan g of lactulose comprises the following steps: Step one, raw material pretreatment, namely performing beta-cyclodextrin inclusion treatment on lactulose, and performing pretreatment on compound sweetener, EDTA disodium and malic acid; Preparing a buffer system, namely adding EDTA disodium solution into a citric acid-sodium citrate composite buffer pair, and adjusting the pH to 4.8-5.2 to prepare the composite buffer system; Dissolving and mixing the core components, namely dissolving and mixing the sweetener, the preservative, the composite buffer system and the lactulose inclusion compound in two stages to form a core mixed system; Step four, flavor adjustment and taste optimization, namely adding malic acid, orange peel extract and vanillin solution to adjust the flavor to form a flavor optimization system; Regulating the osmotic pressure, namely controlling the osmotic pressure of the system to be 280-320 mOsm/kg through compound regulation of sodium chloride and glycerol to obtain an osmotic pressure adaptive system; step six, microfiltration clarification treatment, namely performing microfiltration on the osmotic pressure adaptive system by adopting a ceramic microfiltration membrane to