Polyethylene glycol powder containing acidulant and preparation method of polyethylene glycol powder

Abstract

The invention discloses acidulant-containing polyethylene glycol powder. The acidulant-containing polyethylene glycol powder comprises polyethylene glycol 3350, an anti-sticking agent, citric acid, sodium citrate, a sweetening agent and essence. According to the invention, one or more of polyethylene glycol, povidone and hydroxyethyl cellulose with the molecular weight of 3000-4000 Da are used as anti-sticking agents, and meanwhile, a partial one-step granulation method is used for solving the problem that the polyethylene glycol powder is easy to cake in the preparation and storage process of the product caused by the acidulant, so that the process feasibility and the product quality of the polyethylene glycol 3350 powder containing the acidulant are improved.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a polyethylene glycol powder containing an acidulant and a preparation method thereof. Background Art

[0002] Polyethylene glycol (PEG) is a high molecular weight polymer with the chemical formula H-(O-CH2-CH2)n-OH. Depending on the value of n, PEG products with different average molecular weights can be obtained. Among them, polyethylene glycol 3350 refers to a specific type of this substance, with an average relative molecular mass of approximately 3350 Daltons. Polyethylene glycol with a relative molecular mass exceeding 3000 cannot be absorbed in the intestine, as the intestine lacks enzymes that can degrade polyethylene glycol (PEG) 3350. It is not broken down by intestinal bacteria. After oral administration, it can fix water molecules through the action of hydrogen bonds in the molecules, increase the osmotic pressure in the intestine to attract water, increase the amount of fecal fluid in the intestine of constipated patients, soften the stool, and facilitate excretion, but there is no significant increase in stool volume. It is an osmotic laxative.

[0003] Chronic constipation is a common digestive symptom. The primary pathophysiological change in functional constipation is prolonged colonic transit time, and its incidence increases with age. Recent data show that constipation is becoming increasingly prevalent worldwide. Over the past five years, the number of people suffering from constipation has increased by approximately 5% annually. Constipation also exhibits distinct characteristics in different regions. For example, the incidence of constipation is higher in Asia, particularly among middle-aged and elderly people. Epidemiological surveys show that the prevalence of constipation in my country ranges from 3% to 17.6%, with the prevalence of chronic constipation in adults at 4% to 6%, increasing with age. The prevalence is as high as 22% in people over 60 years old, and one in four people over 70 years old suffers from constipation. Among elderly people requiring ongoing care, the prevalence is as high as 80%. These data indicate that constipation has become a widespread health problem, particularly severe among the elderly. Furthermore, the prevalence of constipation continues to rise annually. This may be due to factors such as modern lifestyles, dietary patterns, and work pressure. For example, insufficient dietary fiber intake, insufficient water intake, lack of exercise, poor bowel habits and irregular lifestyle may all lead to constipation.

[0004] Medications for constipation treatment primarily include laxatives, prokinetic drugs, traditional Chinese medicines, Western medicines, and drugs that regulate intestinal flora. Laxatives are commonly used to treat constipation, and they promote stool excretion through different mechanisms. They can be categorized as stimulant laxatives, bulking laxatives, osmotic laxatives, and lubricating laxatives. Stimulant laxatives, such as phenolphthalein, work by stimulating intestinal muscles and nerves, resulting in a strong and rapid effect. However, long-term use can damage the nerves of the intestinal wall and lead to melanosis coli. Bulking laxatives work by increasing stool volume and softening it, often causing unbearable abdominal distension. Lubricating laxatives, such as paraffin oil and glycerin, have an unpleasant taste and weak effect. Long-term use can lead to malabsorption of fat-soluble vitamins. Therefore, osmotic laxatives are gaining increasing attention in the treatment of functional constipation. Examples of osmotic laxatives include polyethylene glycol powder, lactulose oral solution, and magnesium sulfate.

[0005] The polyethylene glycol 3350 powders currently on the market are mainly single-ingredient polyethylene glycol powders and compound polyethylene glycol powders containing electrolytes. By comparing the prescriptions of marketed products, different products have different flavoring agents, but no polyethylene glycol powder containing acidulants was found.

[0006] In some cultures and family settings, and for those who are trying to manage their weight or lose weight, foods high in sugar are seen as unhealthy. This perception can lead to feelings of guilt after consuming sweet foods. Adding sourness to products while keeping the sweetness low can improve patient compliance by creating a sweet and sour taste.

[0007] CN202310508357 discloses a method for preparing polyethylene glycol 4000 powder. The method comprises crushing different flavoring agents into fine powders and then mixing them with polyethylene glycol 4000. This method improves the dissolution rate of the product. However, due to the small proportion of flavoring agents and the large difference in particle size between raw materials and auxiliary materials, there is a greater risk of uneven mixing of flavoring agents.

[0008] CN201911163653.0 discloses a method for spraying polyethylene glycol 4000 and flavoring agents to achieve good mixing uniformity between the raw materials and the flavoring agents, and solves the problem of raw material dissolution during the addition process through parameter optimization. However, the powder only uses flavoring essence to improve the taste, and the taste is simple. Summary of the Invention

[0009] The invention uses the sour agent as a flavoring agent to provide a polyethylene glycol powder with a sour taste, enriches the taste of the polyethylene glycol powder, and provides a new choice for the market.

[0010] The present invention uses citric acid and sodium citrate as acidulants and uses spray drying to evenly distribute the acidulants on the surface of polyethylene glycol, ensuring a uniform taste, pH, and osmotic pressure. However, citric acid readily absorbs moisture and forms crystals on the polyethylene glycol surface, causing the polyethylene glycol to clump. Through research, the present invention unexpectedly discovered that granulating citric acid, sodium citrate, and an anti-sticking agent with a portion of polyethylene glycol 3350 and then mixing them with the remaining polyethylene glycol raw material can solve the polyethylene glycol de-caking problem.

[0011] The specific technical solutions of the present invention are as follows:

[0012] A polyethylene glycol powder containing an acidulant, comprising polyethylene glycol 3350 as an active ingredient, citric acid and sodium citrate as acidulants, and one or more of polyethylene glycol with a molecular weight of 3000 to 4000 Da, povidone, and hydroxyethyl cellulose as anti-adhesive agents, is prepared by the following method:

[0013] (1) Granulation: Add 5% to 100% of the total amount of the API to the fluidized bed, dissolve the anti-adherent, sweetener, and acidulant in purified water to prepare a solution, and spray the solution into the fluidized polyethylene glycol 3350. During the granulation process, control the air intake to 800m 3 / h~1800m 3 / h, spray speed 10rpm~25rpm, atomizing pressure 1bar~3bar, material temperature 25℃~35℃, drying to material temperature 35℃~45℃, moisture control not higher than 1% granulation is completed, use 0.6mm sieve, rotation speed 500rpm to dry granulate to obtain dry granules;

[0014] (2) Mixing: The remaining amount of the raw material polyethylene glycol 3350 is mixed with the dry granules obtained by granulation using a mixer for a mixing time of not less than 10 minutes.

[0015] The total mixture can be further divided into aliquots.

[0016] The polyethylene glycol powder of the present invention comprises the following components in parts by weight:

[0017] 170 parts of polyethylene glycol 3350 powder, 0.1-0.5 parts of anti-adherent agent, 1-4 parts of citric acid, 3-6 parts of sodium citrate, and 0.05-0.3 parts of sweetener.

[0018] Preferably, the anti-adhesive agent is polyethylene glycol 3350.

[0019] Preferably, the sweetener is selected from one or more of sucralose, saccharin sodium, aspartame, acesulfame potassium, neotame, and stevioside. In a specific example of the present invention, the sweetener is selected from sucralose.

[0020] The polyethylene glycol powder of the present invention further comprises flavor, preferably 0.01 to 0.1 parts by weight of the flavor in each of the above components.

[0021] A specific example of the present invention:

[0022] 170 parts of polyethylene glycol 3350 powder, 0.2 parts of anti-adherent agent, 2.55 parts of citric acid, 4.25 parts of sodium citrate, 0.17 parts of sweetener, and 0.05 parts of flavor.

[0023] The advantages and positive effects of the present invention are:

[0024] During the development of the present invention, in order to improve the mixing uniformity of the flavoring agents citric acid and sodium citrate in the product, a one-step granulation process was used to dissolve the flavoring agents in water and then spray them onto the polyethylene glycol 3350 raw material. However, citric acid may cause the polyethylene glycol to easily agglomerate due to moisture absorption or static electricity. After drying, the prepared granules are prone to agglomeration if left for a short period of time, resulting in poor fluidity and difficulty in packaging.

[0025] The present invention addresses this issue through extensive research and unexpectedly discovered that using polyethylene glycol and / or povidone with a molecular weight of 3000-4000 Da as an anti-sticking agent can solve the product's caking problem. This solves the problem of polyethylene glycol powder easily agglomerating during product preparation and storage, improves the process feasibility of sour polyethylene glycol 3350 powder, and enhances product quality. DETAILED DESCRIPTION

[0026] In order to make the purpose, technical solutions 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 intended to limit the present invention.

[0027] Examples 1 to 10 One-step granulation process study

[0028] Considering that (1) the polyethylene glycol 3350 raw material has good water solubility and a low melting point, polyethylene glycol may have dissolution and re-crystallization problems during the preparation process, as well as field problems caused by untimely drying at low temperatures. (2) The process parameters of the one-step granulation may affect the particle size of the particles, resulting in uneven mixing. (3) Due to the large difference in particle size between the flavoring agent and the raw material, using a direct mixing process will result in uneven mixing. To address the above problems, the present invention studies the one-step granulation process to ensure that the prepared product has good mixing uniformity.

[0029] 1. Prescription (10,000 bags per kg)

[0030]

[0031] 2. Process

[0032] The raw material polyethylene glycol 3350 was passed through an 80-mesh sieve (80-mesh sieve oversize was 84.88%, 80-mesh sieve undersize was 14.61%). The percentage of 80-mesh sieve oversize and 80-mesh undersize of the raw material and the products of different processes (Examples 1-9) were compared. The process with the product with a particle size close to that of the raw material was preferred. Example 10 Direct Mixing Process The auxiliary materials were sieved to a particle size close to that of the raw material.

[0033] Process 1

[0034] One-step granulation: A specific proportion of polyethylene glycol 3350 is added to a fluidized bed. Sucralose, citric acid, and sodium citrate are dissolved in purified water as a flavoring solution. The inlet air temperature is set. Granulation is performed by adjusting the spray rate and atomization pressure. The flavoring solution is sprayed into the fluidized polyethylene glycol 3350. During granulation, the material is controlled and dried until the temperature is suitable for granulation. Dry granules are obtained by sieving using a 0.6 mm mesh at a speed of 500 rpm.

[0035] Final Blending: Combine the dry granules from the one-step granulation process with the remaining amount of polyethylene glycol 3350 and sweet orange microencapsulated powdered flavor at 15 rpm for 10 minutes. Check for uniformity.

[0036] Packaging: Use a granular strip packaging machine to pack the total mixture.

[0037] Process 2

[0038] Direct mixing process: The weighed excipients were sieved through a 0.6 mm sieve to a particle size close to that of the raw materials, and then added to the wet granulator. The stirring speed was set to 500 rpm and the cutter speed to 2000 rpm, and premixed for 10 minutes.

[0039] Mixing: Combine the premixed materials and the sweet orange microcapsule powdered flavor at a mixer speed of 15 rpm for 10 minutes. Check for uniformity.

[0040] Packaging: Use a granular strip packaging machine to pack the total mixture.

[0041] The mixing uniformity test method is as follows:

[0042] After mixing, sample the total blend at ten locations in the blender. Sample three aliquots of approximately 17 g each at each location. Calculate the relative standard deviations (RSDs) of sucralose and citric acid-sodium citrate for all samples. All individual values ​​should be within ±10.0% (absolute) of the mean, and the RSD should be ≤5.0%.

[0043] 3. Results

[0044]

[0045]

[0046] The results show that under the prior art direct mixing process, the mixing uniformity of the flavoring agent in the product is poor (Example 10) and it is also difficult to mix the flavoring agent evenly.

[0047] In the one-step granulation process, if the spraying speed is too fast, the material temperature will be low, thereby causing bed collapse (Example 1).

[0048] When the dosage of polyethylene glycol in granulation is between 5% and 100%, the air inlet volume is 800m 3 / h~1800m 3 / h, a spray rate of 10-25 rpm, an atomization pressure of 1-3 bar, and a material temperature of 25-35°C during granulation, dried to a temperature of 35-45°C, with moisture content below 1%. This effectively produces polyethylene glycol 3350 granules with a particle size similar to that of the raw material, good process feasibility, and good subsequent mixing uniformity. However, due to the physical properties of citric acid and sodium citrate, the prepared mixture easily absorbs moisture and forms lumps during storage, resulting in significant variations in the amount of material loaded during packaging.

[0049] Examples 11-17 Anti-adhesive Study

[0050] Since the granules prepared in Examples 1 to 10 are easy to stand for a short period of time after drying, resulting in poor fluidity and difficulty in packaging, this example adds anti-adherents (polyethylene glycol 3350, polyethylene glycol 4000, polyethylene glycol 6000, hypromellose E5, hypromellose K100M, povidone, and hydroxyethyl cellulose) to the formulation to solve the problem of product agglomeration.

[0051] 1. Prescription (10,000 bags per kg)

[0052]

[0053] 2. Process

[0054] One-step granulation: 20% polyethylene glycol is added to the fluidized bed, anti-sticking agent, sweetener, citric acid and sodium citrate are dissolved in purified water as the flavoring solution, and the air inlet volume is 1500m 3 / h, spray speed 20rpm, atomization pressure 2bar, control the material temperature at 30℃ during granulation, and dry to 40℃ before granulation is completed. Moisture content is controlled to less than 1%. Use a 0.6mm sieve and rotate at 500rpm to obtain dry granules.

[0055] Total mixing: The dry granules after one-step granulation were mixed with the remaining amount of polyethylene glycol 3350 and sweet orange microcapsule powder flavor at a mixer speed of 15 rpm and a mixing time of 10 minutes.

[0056] Packaging: Use a granular strip packaging machine to pack the total mixture.

[0057] 3. Results

[0058]

[0059] The results showed that different anti-adhesive agents had varying anti-caking effects. Povidone, hydroxyethyl cellulose, polyethylene glycol 3350, and polyethylene glycol 4000 were effective anti-adhesive agents. The resulting granules exhibited good mixing uniformity and a particle size close to that of the raw materials. Other polymer materials were not immune to the agglomeration problem.

[0060] Examples 18-22 Study on the dosage of anti-adhesive agent

[0061] 1. Prescription (10,000 bags per kg)

[0062]

[0063]

[0064] 2. Process

[0065] One-step granulation: polyethylene glycol 3350 was added to the fluidized bed, anti-sticking agent (investigation amount), sweetener, citric acid and sodium citrate were dissolved in purified water as the flavoring solution, and the air inlet volume was 1500m 3 / h, spray speed 20rpm, atomization pressure 2bar, control the material temperature at 30℃ during granulation, and dry to 40℃ before granulation is completed. Moisture content is controlled to less than 1%. Use a 0.6mm sieve and rotate at 500rpm to obtain dry granules.

[0066] Total mixing: The dry granules after one-step granulation were mixed with the remaining amount of polyethylene glycol 3350 and sweet orange microcapsule powder flavor at a mixer speed of 15 rpm and a mixing time of 10 minutes.

[0067] Packaging: Use a granular strip packaging machine to pack the total mixture.

[0068] 3. Results

[0069]

[0070] The particle size of the raw material accounts for 84.88% of the material on the 80-mesh sieve and 14.61% of the material under the 80-mesh sieve. The results show that when the anti-adherent agent dosage is 0.05kg, caking occurs, resulting in a large difference in the amount of loading. Increasing the amount of anti-adherent to 0.7kg will cause the particles to become larger and the difference in raw material particle size will become larger, the mixing uniformity RSD will become larger, and the loading difference will change greatly, resulting in unqualified mixing uniformity. Therefore, it is necessary to use an appropriate amount of anti-adherent to ensure that each indicator is qualified. According to the results in Examples 19 to 21, qualified particles can be obtained when the anti-adherent ratio is within the range of 0.1 to 0.5 parts.

[0071] Examples 23-25 ​​Study on Different Acidulants

[0072] 1. Prescription (10,000 bags per kg)

[0073]

[0074]

[0075] 2. Process

[0076] One-step granulation: 20% polyethylene glycol 3350 is added to the fluidized bed, anti-sticking agent, sweetener, citric acid and sodium citrate are dissolved in purified water as the flavoring solution, and the air inlet volume is 1500m 3 / h, spray speed 20rpm, atomization pressure 2bar, control the material temperature at 30℃ during granulation, and dry to 40℃ before granulation is completed. Moisture content is controlled to less than 1%. Use a 0.6mm sieve and rotate at 500rpm to obtain dry granules.

[0077] Total mixing: The dry granules after one-step granulation were mixed with the remaining amount of polyethylene glycol 3350 and sweet orange microcapsule powder flavor at a mixer speed of 15 rpm and a mixing time of 10 minutes.

[0078] Packaging: Use a granular strip packaging machine to pack the total mixture.

[0079] 3. Results

[0080]

[0081] The results showed that malic acid and tartaric acid still agglomerated when polyethylene glycol was used as an anti-adhesive agent, indicating that the anti-adhesive effects of anti-adhesive agents on different acidulants were different.

Claims

1. A polyethylene glycol powder containing an acidulant, characterized in that The active ingredient is polyethylene glycol 3350, the acidulants are citric acid and sodium citrate, and one or more of polyethylene glycol with a molecular weight of 3000 to 4000 Da, povidone, and hydroxyethyl cellulose are used as anti-adhesive agents. The preparation method is as follows: (1) Granulation: Add 5% to 100% of the total amount of the API to the fluidized bed, dissolve the anti-adherent, sweetener, and acidulant in purified water to prepare a solution, and spray the solution into the fluidized polyethylene glycol 3350. During the granulation process, control the air intake to 800m 3 / h~1800m 3 / h, spray speed 10rpm~25rpm, atomizing pressure 1bar~3bar, material temperature 25℃~35℃, drying to material temperature 35℃~45℃, moisture control not higher than 1% granulation is completed, use 0.6mm sieve, rotation speed 500rpm to dry granulate to obtain dry granules; (2) Mixing: The remaining amount of the raw material polyethylene glycol 3350 is mixed with the dry granules obtained by granulation using a mixer for a mixing time of not less than 10 minutes.

2. The polyethylene glycol powder according to claim 1, wherein The weight parts of each component in the powder are as follows: 170 parts of polyethylene glycol 3350 powder, 0.1-0.5 parts of anti-adherent agent, 1-4 parts of citric acid, 3-6 parts of sodium citrate, and 0.05-0.3 parts of sweetener.

3. The polyethylene glycol powder according to claim 1, wherein The weight proportions of the components in the powder are as follows: 170 parts of polyethylene glycol 3350 powder, 0.2 parts of anti-adherent agent, 2.55 parts of citric acid, 4.25 parts of sodium citrate, and 0.17 parts of sweetener.

4. The polyethylene glycol powder according to claim 1, wherein The anti-adhesive agent is polyethylene glycol 3350.

5. The polyethylene glycol powder according to claim 1, characterized in that The sweetener is selected from one or more of sucralose, saccharin sodium, aspartame, acesulfame potassium, neotame, and stevioside.

6. The polyethylene glycol powder according to any one of claims 1 to 5, characterized in that The powder also contains flavoring.

7. The polyethylene glycol powder according to claim 6, characterized in that The powder further comprises 0.01 to 0.1 parts of flavor.

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