WO2011107007A1 - Polyethylene glycol electrolyte granues and its preparing process - Google Patents

Polyethylene glycol electrolyte granues and its preparing process Download PDF

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Publication number
WO2011107007A1
WO2011107007A1 PCT/CN2011/071115 CN2011071115W WO2011107007A1 WO 2011107007 A1 WO2011107007 A1 WO 2011107007A1 CN 2011071115 W CN2011071115 W CN 2011071115W WO 2011107007 A1 WO2011107007 A1 WO 2011107007A1
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Prior art keywords
polyethylene glycol
electrolyte
weight
granule preparation
glycol electrolyte
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PCT/CN2011/071115
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French (fr)
Chinese (zh)
Inventor
谭剑平
张洪山
蒋立新
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舒泰神（北京）生物制药股份有限公司
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Publication of WO2011107007A1 publication Critical patent/WO2011107007A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers

Definitions

  • the present invention relates to a polyethylene glycol electrolyte soluble granule formulation and a method of producing the same.
  • the compound preparation of polyethylene glycol and electrolyte dissolves in water to form an isotonic solution, and the combination of polyethylene glycol and water molecules forms a relatively stable hydrogen bond, and after entering the intestinal tract, the moisture of the intestinal contents is not excessively absorbed by the colon. Thereby, it can lubricate the intestinal tract, soften the feces, increase the volume of the intestinal contents, and promote the colon to resume normal physiological movement. Large doses (2-3 liters) of polyethylene glycol electrolyte compound preparation can wash and lavage the intestinal tract. Further, when used, the net exchange of water and electrolyte between the preparation and the gastrointestinal mucosa is substantially zero, so that the water and electrolyte balance of the body before and after defecation or intestinal cleansing can be maintained.
  • the pharmacological action characteristics of the polyethylene glycol electrolyte compound preparation must ensure that the composition and concentration of the drug are within the specified range, so as to ensure that the osmotic pressure in the intestinal tract is in the range of 280 to 330 mOsmol/kg, so that the intestinal tract is completely completed. Isotonic, electrolyte balance, maintaining water, increasing the moisture content of the feces and softening the feces to promote bowel movements and excretion, so that it only acts as a laxative and bowel.
  • the compound preparation of polyethylene glycol and electrolyte has a commercially available compound polyethylene glycol electrolyte powder (Hengkang Zhengqing, trade name, Jiangxi Hengkang Pharmaceutical Co., Ltd.; Heshuang, trade name, Shenzhen Wanhe Pharmaceutical Co., Ltd. ), compound polyethylene glycol 4000 oral solution powder (Fu Jingqing, trade name, produced by Beaufour Ipsen Industrie, France), polyethylene glycol electrolyte powder (trade name Shu Taiqing, Shu Tai Shen (Beijing) Pharmaceutical Co., Ltd.; ).
  • polyethylene glycol and electrolyte have different densities, particle diameters, particle morphology, specific surface area, void ratio, fluidity, etc., the ratios of the components vary widely, and the particle size and density of each component are different or their forms are not Suitably, it may be difficult to mix or stratify the mixed particles due to vibrations in the operation of the equipment. Moreover, since the materials are mixed, they are often accompanied by segregation. Therefore, it has been difficult to prepare a solid preparation in which polyethylene glycol and an electrolyte are uniformly mixed.
  • the conventional preparation of polyethylene glycol and electrolyte is a powder which is separately packaged with powders having different densities, particle diameters, and morphology, and mixed with a plurality of packaged powders at the time of use.
  • the compound polyethylene glycol electrolyte powder "Hengkang Zhengqing" divides the powder in the complete dose package into 3 small packages A, B, C, each complete dose consists of 1 packet of A, B, C, and A contains 0.74 potassium chloride.
  • B contains 1.46 g of sodium chloride, 5.68 g of sodium sulfate
  • C contains 60 g of polyethylene glycol 4000.
  • the problems existing in the current polyethylene glycol electrolyte compound preparation are as follows: 1. Since it is divided into a plurality of small packages, the production and packaging process is cumbersome; 2. It is easy to agglomerate during production, the volume is uneven, and the yield is low; 3 Easy to produce dust when taking, the powder has a poor fluidity of 4 ,, easy to adsorb on the composite membrane; 4. Poor mouthfeel; 5. Due to the poor fluidity of polyethylene glycol and electrolyte powder, users sometimes cannot take all polyethylene Alcohol and electrolytes are poured out, or the user sometimes forgets to take some of the drugs because of too much packaging of the medicine.
  • the problem to be solved by the present invention is that the quality of the polyethylene glycol electrolyte compound preparation is uncontrollable, the administration is cumbersome, and the treatment effect is poor.
  • the present invention provides the following technical solutions.
  • a polyethylene glycol electrolyte granule preparation comprising: polyethylene glycol electrolyte particles, the polyethylene glycol electrolyte particles comprising polyethylene glycol having an average molecular weight of 3000 to 4000 and an electrolyte, the polyethylene glycol
  • the particle size of the electrolyte particles is 180 to 850 ⁇ m.
  • polyethylene glycol electrolyte particle preparation according to claim 1, wherein the polyethylene glycol The alcohol has an average molecular weight of 4000, and the electrolyte is a mixture of two or more electrolytes selected from the group consisting of sodium hydrogencarbonate, sodium chloride, potassium chloride, and sodium sulfate.
  • polyethylene glycol electrolyte granule preparation according to claim 1 or 2, wherein the polyethylene glycol is 80 to 98 parts by weight, based on 100 parts by weight of the polyethylene glycol electrolyte particle preparation, the electrolyte It is 2 to 20 parts by weight.
  • the polyethylene glycol electrolyte granule preparation according to any one of claims 1 to 3, wherein the electrolyte is a mixture of sodium hydrogencarbonate, sodium chloride and potassium chloride, relative to the polyethylene glycol electrolyte
  • the granule preparation is 100 parts by weight, sodium hydrogencarbonate is 1 to 2 parts by weight, sodium chloride is 1.5 to 3 parts by weight, and potassium chloride is 0.2 to 1.2 parts by weight.
  • polyethylene glycol electrolyte granule preparation according to any one of claims 1 to 4, further comprising a sweetener and/or a flavoring agent, with respect to 100 parts by weight of the polyethylene glycol electrolyte particle preparation
  • the sweetener is 0.05 to 1.5 parts by weight
  • the flavoring agent is 0.2 to 1 part by weight.
  • polyethylene glycol electrolyte granule preparation according to any one of claims 1 to 5, wherein the polyethylene glycol electrolyte granule preparation is 13.08 g to 14.45 g with water at 40 ° C to 50 ° C.
  • the osmotic pressure is in the range of 280 to 330 mOsmol/kg.
  • a method for producing a polyethylene glycol electrolyte granule preparation comprising the steps of: pulverizing polyethylene glycol having an average molecular weight of 3,000 to 4,000 into fine particles, mixing the fine particles, and adding a wetting agent to make a soft The material is then granulated and dried to form polyethylene glycol electrolyte particles having a particle size of 180 ⁇ m to 850 ⁇ m.
  • polyethylene glycol electrolyte granule preparation produced by the production method according to any one of claims 7 to 13.
  • the polyethylene glycol electrolyte granule preparation of the invention has the controllable quality, good mouthfeel, and the use of the tube, the curative effect is safer and more reliable, and the completely isotonic solution can be ensured, the moisture in the colon is not absorbed, and the polyethylation is lowered.
  • the disadvantages of the use of diol electrolyte powder in the use and the incidence of side effects provide a better laxative and intestinal drug and its manufacturing method. In addition, there is no need to pack into a variety of small packages, so the production process can be completed.
  • the present invention provides a polyethylene glycol electrolyte particle preparation, comprising: polyethylene glycol electrolyte particles, the polyethylene glycol electrolyte particles comprising polyethylene glycol having an average molecular weight of 3000 to 4000 and an electrolyte, the polymerization
  • the particle diameter of the ethylene glycol electrolyte particles is from 180 to 850 ⁇ m, more preferably from 250 to 550 ⁇ m.
  • the particle size of the polyethylene glycol electrolyte particles has an influence on the fluidity, the loading accuracy, the dissolution rate, the osmotic pressure, etc. of the polyethylene glycol electrolyte particle preparation. If the particles are too large, the drying time is long, which causes carbonation. The content of hydrogen ion ions changes, and the dissolution time is longer when taken; when the particles are too small, the fluidity is poor, the difference in the loading is large, and the osmotic pressure is low when the dosage is taken.
  • the polyethylene glycol electrolyte particle preparation can have excellent fluidity, charge accuracy, dissolution rate, and osmotic pressure.
  • the polyethylene glycol is preferably polyethylene glycol 4000, and the polyethylene glycol content is 80 to 98 weights relative to 100 parts by weight of the polyethylene glycol electrolyte granule preparation.
  • the mixture is 92 to 98 parts by weight
  • the electrolyte is a mixture of two or more electrolytes selected from the group consisting of sodium hydrogencarbonate, sodium chloride, potassium chloride, and sodium sulfate, and the content of the electrolyte is 2 to 20 parts by weight, preferably 2 to 6 parts by weight.
  • the electrolyte is preferably a mixture of sodium hydrogencarbonate, sodium chloride and potassium chloride, and the sodium hydrogencarbonate is preferably 1 to 1.5 weights relative to 100 parts by weight of the polyethylene glycol electrolyte particle preparation.
  • the amount of sodium chloride is preferably 2 to 3 parts by weight, and the potassium chloride is preferably 0.2 to 0.5 parts by weight.
  • the polyethylene glycol electrolyte granule of the present invention may contain a sweetener, and the type of the sweetener is not limited, and a pharmaceutically acceptable sweetener may be used, and for example, acesulfame, sodium saccharin, or arsenic may be used. Spartan, sucralose.
  • the polyethylene glycol electrolyte granule preparation of the present invention may further contain a flavoring agent, and the type of the flavoring agent is not limited, and a pharmaceutically acceptable flavoring agent may be used, and for example, it may be a cherry flavored flavor or a pineapple. Flavor, lemon flavor, orange flavor.
  • the content of the sweetener and the flavoring agent may be 0.05 to 1.5 parts by weight, preferably 0.05 to 0.15 parts by weight, based on 100 parts by weight of the polyethylene glycol electrolyte particle preparation of the present invention.
  • the agent may be 0.2 to 1 part by weight, preferably 0.5 to 1 part by weight.
  • the mouthfeel of the preparation can be improved, making the patient more acceptable. Especially for young children, it is very practical in clinical practice. Further, the content of each of the sweetener and the flavoring agent is within the above range, and the texture is better.
  • the polyethylene glycol electrolyte granule preparation of the invention 13.08g ⁇ 14.45g is immersed in a range of 280-330 mOsmol/kg when formulated into a 125 ml solution with water at 40 ° C to 50 ° C.
  • the content of sodium ion, potassium ion, chloride ion and hydrogencarbonate ion contained in the polyethylene glycol electrolyte particles of the polyethylene glycol electrolyte particle preparation of the present invention is ⁇ 15%.
  • the sodium ion, potassium ion, chloride ion, and hydrogencarbonate ion contained in the polyethylene glycol electrolyte particle of the polyethylene glycol electrolyte particle preparation of the present invention are 95-105% of the labeled amount.
  • the polyethylene glycol electrolyte granule preparation of the present invention is suitable for use as a laxative and enteric medicine, which can be administered orally in a solution with water before use.
  • a laxative and enteric medicine which can be administered orally in a solution with water before use.
  • those skilled in the art can determine the specific conditions, for example, 13.8 g of the polyethylene glycol electrolyte granule preparation of the present invention can be dissolved in 125 ml of warm water to form a solution, and the adult takes 125 ml of the solution each time.
  • the method for producing a polyethylene glycol electrolyte granule preparation of the present invention is characterized in that polyethylene glycol and an electrolyte are separately pulverized into fine granules, and the fine granules are mixed, and a softener is added to a soft material, followed by granulation and drying. , forming polyethylene glycol electrolyte particles having a particle diameter of 180 ⁇ m to 850 ⁇ m. Further, a sweetener may be mixed in the electrolyte to pulverize the electrolyte together with the sweetener. In addition, it can also To granulate after drying.
  • the polyethylene glycol and the electrolyte vary according to the respective particle sizes, and the fluidity and morphology also change, directly affecting the mixing uniformity and the dose accuracy of the polyethylene glycol and the electrolyte, thereby controlling the particles of the polyethylene glycol and the electrolyte.
  • the diameter is the key to ensuring the mixing effect.
  • the particle diameter thereof is more preferably 180 ⁇ m to 250 ⁇ m; preferably, the electrolyte is pulverized into fine particles having a particle diameter of 125 ⁇ m to 250 ⁇ m.
  • the diameter is more preferably 150 ⁇ to 250 ⁇ , further preferably 180 ⁇ to 250 ⁇ .
  • the particle diameter referred to in the present invention means the particle diameter (D90), which means the particle diameter corresponding to the cumulative particle size distribution of 90%. Its physical meaning is that particles smaller than this particle size account for 90% of the total particles.
  • the particle size is determined by a sieving method.
  • the sieve used in the present invention is a chemical sieve of GB/T 15602-2008 industrial sieve standard.
  • the fluidity of the granule when preparing a polyethylene glycol electrolyte granule preparation, by selecting a suitable wetting agent, the fluidity of the granule can be better improved, the density of the material can be increased, and delamination of polyethylene glycol and electrolyte and fine powder can be avoided.
  • a suitable wetting agent when preparing a polyethylene glycol electrolyte granule preparation, by selecting a suitable wetting agent, the fluidity of the granule can be better improved, the density of the material can be increased, and delamination of polyethylene glycol and electrolyte and fine powder can be avoided.
  • the wetting agent is selected from the group consisting of 80% by volume or more of an aqueous ethanol solution, preferably 90 to 95% by volume of an aqueous ethanol solution, and may be, for example, 91, 92, 93, 94, 95, 96, 97, 98. 99, 100% by volume; the amount thereof is 5 to 20% by weight, preferably 8 to 16% by weight, based on the total amount of the polyethylene glycol fine particles and the electrolyte fine particles, and may be, for example, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20% by weight.
  • the fluidity of polyethylene glycol and electrolyte fine particles can be better improved, and the polyethylene glycol and electrolyte layering and fine powder flying can be avoided, and polyethylene glycol and electrolyte fine particles can be mixed.
  • the content is uniform and accurate, and the final formulation can have excellent properties such as good content uniformity.
  • the polyethylene glycol used in the present invention is preferably polyethylene glycol having an average molecular weight of 3,000 to 4,000, and electricity.
  • the detoxification is preferably a mixture of two or more electrolytes selected from the group consisting of sodium hydrogencarbonate, sodium chloride, potassium chloride, and sodium sulfate, more preferably a mixture of sodium hydrogencarbonate, sodium chloride, and potassium chloride.
  • the mixing ratio thereof is adjusted so that the weight ratio of the polyethylene glycol to the electrolyte is 80 to 98: 20 to 2.
  • the drying can be carried out at a temperature of from 10 ° C to 60 ° C.
  • the method for producing a polyethylene glycol electrolyte granule formulation may comprise the following steps:
  • Step 2) in the above method may also be the following steps: 2) mixing the electrolyte and the sweetener in a weight ratio of 20 to 2: 0.05-1.5, pulverizing, sieving, and preparing the particle size to 125 ⁇ ⁇ 250 ⁇ fine particles.
  • the method and apparatus for mixing are not limited, and methods and equipment which are commonly used in pharmacy may be employed.
  • the polyethylene glycol fine particles are mixed with the electrolyte fine particles, it is preferred to carry out mixing by an equal amount of addition.
  • the "equal amount addition method" as used in the present invention means that a part of the polyethylene glycol 4000 is taken out and mixed with the electrolyte in an equal amount, and a part of the polyethylene glycol 4000 is uniformly mixed with the above mixture, and the amount is increased. Polyethylene glycol 4000 until all is mixed.
  • the method and equipment for granulating and drying are not limited, and methods and equipment which are commonly used in pharmacy may be employed.
  • drying it is preferred to use a fluidized bed for drying, and granulation is preferably carried out by granulation, for example, it may be employed.
  • a granulation device such as a swing granulator, but is not limited thereto.
  • the obtained polyethylene glycol electrolyte particles may be directly used as a polyethylene glycol electrolyte particle preparation, or may be further mixed with a flavoring agent as a polyethylene glycol electrolyte particle preparation.
  • the method for producing a polyethylene glycol electrolyte granule formulation may comprise the following steps:
  • polyethylene glycol with an average molecular weight of 3000 ⁇ 4000 is pulverized and sieved to a particle size of 125 ⁇ m. ⁇ 250 ⁇ polyethylene glycol fine particles;
  • the flavoring agent is added in an amount of 0.2 to 1 part by weight based on 100 parts by weight of the polyethylene glycol electrolyte granule preparation.
  • the polyethylene glycol 4000 fine particles obtained above and the electrolyte fine particles were uniformly mixed by an equal amount, and then about 1371 g of a 95% by volume aqueous solution of ethanol was used to prepare a soft material, and then granulated with a 40 mesh sieve, and the fluidized bed was 10 ° C.
  • the mixture was boiled and dried at ⁇ 60 ° C for 20 minutes, and granulated with a 40 mesh sieve to prepare polyethylene glycol electrolyte particles having a particle diameter (D90) of 380 ⁇ m.
  • the granules obtained above were uniformly mixed with 100 g of orange flavor to obtain a polyethylene glycol electrolyte granule preparation of the present invention.
  • the evaluation method of fluidity (rest angle) is as follows.
  • Polyethylene glycol electrolyte particles were prepared in the same manner as in Preparation Example 1, except that the pellets were sieved with 14, 16, 18, 20, 30, 40, 60, 80, and 100 mesh, respectively.
  • the prepared granules were dispensed at 13.8 g per bag, and the indexes of the fluidity, the difference in the amount of the granules, the dissolution time, the osmotic pressure and the mouthfeel were examined. The results are shown in Table 2.
  • the method for determining the content uniformity is as follows.
  • the polyethylene glycol fine particles and the electrolyte fine particles before mixing the soft materials were packed at 13.8 g per bag to prepare a sample. Take 10 bags of samples and measure the content of potassium ions in each bag. The measured values of potassium ions in 10 bags are compared with the average value.
  • Preparation of the reference solution Take about 25mg of potassium chloride reference substance, accurately weighed, placed in a 200ml volumetric flask, add deionized water to the amount, shake to dissolve, otherwise called polyethylene glycol about 5.63g, sodium chloride About 0.15g, sodium bicarbonate about 76mg, acesulfame about 5.6mg, flavor about 21.4mg, accurately weighed, placed in the above measuring flask, shake to dissolve, add deionized water to dilute to the mark, shake.
  • Preparation of sample solution Take a bag of sample, place it in a 200ml volumetric flask, add deionized water to the appropriate amount, shake to dissolve, add deionized water to dilute to the mark, and shake well. Precisely measure 2ml into a 100ml volumetric flask, dilute with deionized water to the mark, and shake the hook as a sample solution.
  • Determination method Take the reference solution and the sample solution, and determine the content of potassium ions by the flame curve method (Chinese Pharmacopoeia 2005 edition two appendix IV F).
  • the polyethylene glycol fine particles and the electrolyte fine particles before mixing the soft materials were packed at 13.8 g per bag to prepare a sample. Take 10 bags of samples and measure the content of bicarbonate ions in each bag. The measured values of bicarbonate ions in 10 bags are compared with the average.
  • the results in Table 3 indicate that: Group 1 to Group 6, ie, the particle size of polyethylene glycol is 150 ⁇ to 250 ⁇ (60 mesh to 100 mesh) and the particle size of the electrolyte is 125 ⁇ to 250 ⁇ (60 mesh to 120 mesh).
  • the content of potassium ions and hydrogencarbonate ions before mixing the soft materials is less than ⁇ 10%, that is, The content of polyethylene glycol and electrolyte is uniform; especially the first group to the third group, that is, the diameter of polyethylene glycol is 60 mesh to 80 mesh (180 ⁇ 250 ⁇ ) and the particle size of the electrolyte is 150 ⁇ 180 ⁇ (80 mesh).
  • polyethylene glycol was pulverized and sieved (60 mesh) to prepare fine particles having a particle diameter (D90) of 250 ⁇ m, and the electrolyte was pulverized (80 mesh) to have a particle diameter (D90) of 180 ⁇ m.
  • D90 particle diameter of 250 ⁇ m
  • D90 particle diameter of 180 ⁇ m
  • Polyethylene glycol electrolyte particles were prepared in the same composition, ratio, and operation as in Preparation Example 1, except that ethanol was used as a wetting agent in various concentrations and amounts.
  • the prepared polyethylene glycol electrolyte particles were dispensed at 13.8 g per bag to prepare a sample.
  • the angle of repose is 40° to 50°.
  • the above test results show that 80% by volume to 100% by volume of aqueous ethanol solution has a good effect as a wetting agent in particle shape, fine powder state, particle fluidity and content.
  • the effect of 90% by volume to 95% by volume of the aqueous ethanol solution is more excellent.
  • the amount of the aqueous ethanol solution is 5 to 20% by weight based on the total amount of the polyethylene glycol and the electrolyte, and has a good effect on the particle properties, the fine powder state of the particles, the fluidity of the particles, and the uniformity of the content, especially The effect is more excellent when the amount is from 8 to 16% by weight.
  • polyethylene glycol electrolyte preparations Before the use of polyethylene glycol electrolyte preparations, 57% of patients required hospitalization and 26% needed special home care. Taking a good taste polyethylene glycol electrolyte preparation can reduce the time and difficulty of nursing work, and also improve the medical relationship.
  • the polyethylene glycol electrolyte powder has been badly tasted, the salt of the solution is heavy, and the patient is not easy to accept.
  • the ethylene glycol electrolyte particle preparation of the invention A variety of flavors of sweeteners and flavorings have been added.
  • Test method Weigh the prescription polyethylene glycol 4000 separately, pass 60 mesh sieve for use, sodium bicarbonate, sodium chloride, potassium chloride, sweetener mixture and crushed through 80 mesh sieve for use; then the prescription amount of polyethylene
  • the diol 4000 and the electrolyte are uniformly mixed by the equal amount, and the soft material is prepared by using the prepared ethanol aqueous solution, and the granules are sieved by a 40 mesh sieve, and the fluidized bed is boiled and dried, and the whole granules are added to the various flavors.
  • the scented agent was evenly mixed. After the test was passed, 13.8 g of each bag was dispensed and packed, and the taste was evaluated separately. The results are shown in Table 5.
  • the amount used is the amount relative to 100 parts by weight of the polyethylene glycol electrolyte particles.
  • test results in Table 5 show that the polyethylene glycol electrolyte preparations to which the sweetener and the flavoring agent are added have a better taste than before, and the patient is easier to compare with the polyethylene glycol electrolyte preparation without the sweetener and the flavoring agent. It is taste and taste, and the clinical effect is ideal.
  • the polyethylene glycol electrolyte granule preparation of Preparation Example 1 was packaged in a composite film and placed in a constant temperature and humidity chamber at 25 ° C and a relative humidity of 60%, and left for 24 months, and sampled in the 12th and 24th months, respectively. Determination of appearance properties before and after the test, polyethylene glycol 4000, sodium ion, potassium ion, chloride ion, carbon The acid hydrogen radical content and dissolution time are shown in Table 6.
  • control test was carried out using the polyethylene glycol electrolyte granule preparation of Preparation Example 1 of the present invention and the polyethylene glycol electrolyte powder (trade name: Shu Taiqing, Shu Tai Shen (Beijing) Pharmaceutical Co., Ltd.) as a control, respectively.
  • polyethylene glycol electrolyte granule preparation can effectively improve the frequency of defecation and stool characteristics in patients with functional constipation, and its effect is superior to that of polyethylene glycol electrolyte powder.
  • Controlled clinical study of intestinal cleansing patients 82 patients requiring intestinal cleansing were divided into 2 groups, polyethylene glycol electrolyte particle preparation group (41 persons) and polyethylene glycol electrolyte powder group (41 persons), respectively, oral polyethylene glycol electrolyte particle preparation and polyethylene glycol Alcohol electrolyte powder. Take the method, 27.6g / time, dissolve in 250ml warm water into a solution, take it every 10 ⁇ 15 minutes, until the water sample is clear.
  • the total effective rate was 97.56%, of which 63.42% and 34.15% were good and good, and 2.5% (1) were obvious adverse reactions.
  • the test showed that the effect of clearing the intestine of the polyethylene glycol electrolyte granule preparation group was better than that of the polyethylene glycol electrolyte powder control group, and the adverse reaction was lower than that of the control group.
  • the invention has the advantages of: solving the problem of uneven mixing of polyethylene glycol and electrolyte production, uncontrollable weight, cumbersome use, uneven particle size, poor fluidity and poor stability, and providing a polyethylene glycol and electrolyte
  • the uniformly mixed granule preparation has controllable quality, good mouthfeel, convenient use, safe and reliable use, and an isotonic solution formed thereof, which can keep the moisture in the colon from being absorbed.
  • the preparation method reduces the above disadvantages of the polyethylene glycol electrolyte powder and the occurrence of side effects of the polyethylene glycol electrolyte powder, and provides a better laxative and intestinal medicine, wherein the technical progress is Undoubtedly.

Abstract

A polyethylene glycol electrolyte granular preparation and its preparing process are provided. The polyethylene glycol electrolyte granular preparation comprises polyethylene glycol with the average molecular weight of 3000 to 4000 and electrolyte. The granule diameter of the polyethylene glycol electrolyte granule is 180 to 850μm.

Description

聚乙二醇电解质颗粒制剂及其制造方法 本申请要求于 2010 年 3 月 2 日提交中国知识产权局、 申请号为 201010116942.8、 发明名称为 "聚乙二醇电解质颗粒制剂及其制造方法" 的 中国专利申请的优先权， 其全部内容通过引用结合在本申请中。 技术领域  Polyethylene glycol electrolyte particle preparation and manufacturing method thereof The present application claims to be submitted to the China Intellectual Property Office on March 2, 2010, the application number is 201010116942.8, and the invention name is "polyethylene glycol electrolyte particle preparation and its manufacturing method" Priority of the patent application, the entire contents of which is incorporated herein by reference. Technical field
本发明涉及聚乙二醇电解质可溶性颗粒制剂及其制造方法。  The present invention relates to a polyethylene glycol electrolyte soluble granule formulation and a method of producing the same.
背景技术 Background technique
聚乙二醇与电解质的复方制剂溶于水后形成等渗溶液， 聚乙二醇和水分 子结合形成较稳定的氢键， 进入肠道后， 使肠道内容物的水分不被结肠过分 吸收， 从而起到润滑肠道、 软化粪便， 使肠道内容物体积增加， 促进结肠恢 复正常生理运动的作用。 大剂量（2-3升）服用聚乙二醇电解质复方制剂， 可 以起到沖刷、 灌洗肠道的作用。 并且， 使用时该制剂与胃肠道粘膜之间水、 电解质的净交换基本为零， 因而可以保持排便或肠道清洁前后机体的水、 电 解质平衡。  The compound preparation of polyethylene glycol and electrolyte dissolves in water to form an isotonic solution, and the combination of polyethylene glycol and water molecules forms a relatively stable hydrogen bond, and after entering the intestinal tract, the moisture of the intestinal contents is not excessively absorbed by the colon. Thereby, it can lubricate the intestinal tract, soften the feces, increase the volume of the intestinal contents, and promote the colon to resume normal physiological movement. Large doses (2-3 liters) of polyethylene glycol electrolyte compound preparation can wash and lavage the intestinal tract. Further, when used, the net exchange of water and electrolyte between the preparation and the gastrointestinal mucosa is substantially zero, so that the water and electrolyte balance of the body before and after defecation or intestinal cleansing can be maintained.
聚乙二醇电解质复方制剂的药理作用特点要求必须保证药物的组成及浓 度在规定的范围内， 这样才能保证其具有在肠道内的渗透压在 280 到 330mOsmol/kg的范围内， 使肠道内完全等渗、 电解质平衡、 保持水， 增加粪 便含水量及软化粪便促进肠蠕动和排泄， 使其只起通便及清肠作用。  The pharmacological action characteristics of the polyethylene glycol electrolyte compound preparation must ensure that the composition and concentration of the drug are within the specified range, so as to ensure that the osmotic pressure in the intestinal tract is in the range of 280 to 330 mOsmol/kg, so that the intestinal tract is completely completed. Isotonic, electrolyte balance, maintaining water, increasing the moisture content of the feces and softening the feces to promote bowel movements and excretion, so that it only acts as a laxative and bowel.
目前，聚乙二醇与电解质的复方制剂有市售的复方聚乙二醇电解质散（恒 康正清， 商品名， 江西恒康药业有限公司生产;和爽， 商品名， 深圳万和制药 有限公司生产）、 复方聚乙二醇 4000 口服溶液用粉（福静清， 商品名， 法国 Beaufour Ipsen Industrie生产 )、 聚乙二醇电解质散剂（商品名舒泰清，舒泰神 (北京） 药业有限公司生产；)。  At present, the compound preparation of polyethylene glycol and electrolyte has a commercially available compound polyethylene glycol electrolyte powder (Hengkang Zhengqing, trade name, Jiangxi Hengkang Pharmaceutical Co., Ltd.; Heshuang, trade name, Shenzhen Wanhe Pharmaceutical Co., Ltd. ), compound polyethylene glycol 4000 oral solution powder (Fu Jingqing, trade name, produced by Beaufour Ipsen Industrie, France), polyethylene glycol electrolyte powder (trade name Shu Taiqing, Shu Tai Shen (Beijing) Pharmaceutical Co., Ltd.; ).
但是， 因聚乙二醇和电解质的密度、 粒径、 粒子形态、 比表面积、 空隙 率、 流动性等各不相同， 各成分的比例相差悬殊， 且各成分的粒子大小及密 度不同或其形态不适宜， 因此可能使混合发生困难或使已混匀的粉粒因设备 运行中的振动而分层。 并且， 由于物料混合的同时本来就常伴随有离析现象， 因此， 一直以来 ^艮难制成聚乙二醇和电解质混合均匀的固体制剂。 由于上述 原因， 目前的聚乙二醇与电解质的复方制剂是把密度、 粒径、 形态等不同的 药粉分别包装， 在使用时将多个包装的药粉混合在一起来服用的散剂。 例如， 复方聚乙二醇电解质散 "恒康正清" 将完整剂量包装的散剂分成 3个小包装 A、 B、 C, 每完整剂量由 A、 B、 C各 1小包组成， A包含氯化钾 0.74g,碳酸 氢钠 1.68g; B包含氯化钠 1.46g, 硫酸钠 5.68g; C包含 60g聚乙二醇 4000。 聚乙二醇电解质散剂 "舒泰清"， 用于治疗功能性便秘及清洁肠道， 由 A、 B 两剂组成， A剂含聚乙二醇 4000; B剂含碳酸氢钠， 氯化钠， 氯化钾。 However, since polyethylene glycol and electrolyte have different densities, particle diameters, particle morphology, specific surface area, void ratio, fluidity, etc., the ratios of the components vary widely, and the particle size and density of each component are different or their forms are not Suitably, it may be difficult to mix or stratify the mixed particles due to vibrations in the operation of the equipment. Moreover, since the materials are mixed, they are often accompanied by segregation. Therefore, it has been difficult to prepare a solid preparation in which polyethylene glycol and an electrolyte are uniformly mixed. For the above reasons, the conventional preparation of polyethylene glycol and electrolyte is a powder which is separately packaged with powders having different densities, particle diameters, and morphology, and mixed with a plurality of packaged powders at the time of use. For example, the compound polyethylene glycol electrolyte powder "Hengkang Zhengqing" divides the powder in the complete dose package into 3 small packages A, B, C, each complete dose consists of 1 packet of A, B, C, and A contains 0.74 potassium chloride. g, sodium hydrogencarbonate 1.68 g; B contains 1.46 g of sodium chloride, 5.68 g of sodium sulfate; and C contains 60 g of polyethylene glycol 4000. Polyethylene glycol electrolyte powder "Shu Taiqing", used to treat functional constipation and clean the intestine, consisting of two agents A and B, A containing polyethylene glycol 4000; B containing sodium bicarbonate, sodium chloride, chlorine Potassium.
目前的聚乙二醇电解质复方制剂存在的问题是： 1.由于分为多种小包装， 因此生产包装工序繁瑣； 2.生产时易结块， 装量不均， 成品率 ^艮低； 3. 服用 时易产尘， 药粉流动性 4艮差， 容易吸附在复合膜上； 4.口感差； 5. 由于聚乙 二醇和电解质药粉的流动性不好， 使用者有时不能把全部聚乙二醇和电解质 倒出来， 或者由于药品包装太多而导致使用者有时忘记服用部分药物， 因此， 不仅服用麻烦， 而且容易造成不能严格按说明书配制溶液， 药物组分损失， 各组分配比不均勾， 最终导致药品配成溶液时的浓度存在偏差， 不能保证溶 液的渗透压在 280到 330mOsmol/kg的范围内， 也不能保证肠道内外等渗性 的问题， 这样不但影响治疗效果， 而且有可能引起严重的不良反应。  The problems existing in the current polyethylene glycol electrolyte compound preparation are as follows: 1. Since it is divided into a plurality of small packages, the production and packaging process is cumbersome; 2. It is easy to agglomerate during production, the volume is uneven, and the yield is low; 3 Easy to produce dust when taking, the powder has a poor fluidity of 4 ,, easy to adsorb on the composite membrane; 4. Poor mouthfeel; 5. Due to the poor fluidity of polyethylene glycol and electrolyte powder, users sometimes cannot take all polyethylene Alcohol and electrolytes are poured out, or the user sometimes forgets to take some of the drugs because of too much packaging of the medicine. Therefore, not only is it troublesome to take, but it is also easy to cause the solution to be prepared in strict accordance with the instructions, the loss of the drug components, and the distribution ratio of each group is not uniform. In the end, there is a deviation in the concentration of the drug when it is formulated into a solution. The osmotic pressure of the solution cannot be guaranteed to be in the range of 280 to 330 mOsmol/kg, and the problem of isotonicity inside and outside the intestine cannot be ensured, which not only affects the therapeutic effect, but also may cause Serious adverse reactions.
所以， 有必要对目前的聚乙二醇电解质复方制剂进行进一步的改进， 以 使其具有更好的治疗效果。  Therefore, it is necessary to further improve the current polyethylene glycol electrolyte compound preparation to have a better therapeutic effect.
发明内容 Summary of the invention
发明要解决的问题  Problems to be solved by the invention
鉴于以上情况， 本发明要解决的问题是聚乙二醇电解质复方制剂的质量 不可控， 服用繁瑣， 从而造成的治疗效果差等问题。  In view of the above circumstances, the problem to be solved by the present invention is that the quality of the polyethylene glycol electrolyte compound preparation is uncontrollable, the administration is cumbersome, and the treatment effect is poor.
解决问题的手段  Means of solving problems
为了解决上述技术问题， 本发明提供以下技术方案。  In order to solve the above technical problems, the present invention provides the following technical solutions.
1. 聚乙二醇电解质颗粒制剂， 其特征在于， 包括聚乙二醇电解质颗粒， 所述聚乙二醇电解质颗粒含有平均分子量为 3000~4000 的聚乙二醇和电解 质， 所述聚乙二醇电解质颗粒的粒径是 180~850μηι。  A polyethylene glycol electrolyte granule preparation, comprising: polyethylene glycol electrolyte particles, the polyethylene glycol electrolyte particles comprising polyethylene glycol having an average molecular weight of 3000 to 4000 and an electrolyte, the polyethylene glycol The particle size of the electrolyte particles is 180 to 850 μm.
2. 根据技术方案 1所述的聚乙二醇电解质颗粒制剂， 其中， 所述聚乙二 醇平均分子量为 4000, 所述电解质为选自碳酸氢钠、 氯化钠、 氯化钾、 硫酸 钠中的两种以上电解质的混合物。 2. The polyethylene glycol electrolyte particle preparation according to claim 1, wherein the polyethylene glycol The alcohol has an average molecular weight of 4000, and the electrolyte is a mixture of two or more electrolytes selected from the group consisting of sodium hydrogencarbonate, sodium chloride, potassium chloride, and sodium sulfate.
3. 根据技术方案 1或 2所述的聚乙二醇电解质颗粒制剂， 其中， 相对于 聚乙二醇电解质颗粒制剂 100重量份， 所述聚乙二醇为 80~98重量份， 所述 电解质为 2~20重量份。  3. The polyethylene glycol electrolyte granule preparation according to claim 1 or 2, wherein the polyethylene glycol is 80 to 98 parts by weight, based on 100 parts by weight of the polyethylene glycol electrolyte particle preparation, the electrolyte It is 2 to 20 parts by weight.
4. 根据技术方案 1~3的任一项所述的聚乙二醇电解质颗粒制剂， 所述电 解质为碳酸氢钠、 氯化钠和氯化钾的混合物， 相对于所述聚乙二醇电解质颗 粒制剂 100重量份， 碳酸氢钠为 1~2重量份， 氯化钠为 1.5~3重量份， 氯化 钾为 0.2~1.2重量份。  4. The polyethylene glycol electrolyte granule preparation according to any one of claims 1 to 3, wherein the electrolyte is a mixture of sodium hydrogencarbonate, sodium chloride and potassium chloride, relative to the polyethylene glycol electrolyte The granule preparation is 100 parts by weight, sodium hydrogencarbonate is 1 to 2 parts by weight, sodium chloride is 1.5 to 3 parts by weight, and potassium chloride is 0.2 to 1.2 parts by weight.
5. 根据技术方案 1~4的任一项所述的聚乙二醇电解质颗粒制剂， 其中， 还含有甜味剂和 /或矫味剂，相对于所述聚乙二醇电解质颗粒制剂 100重量份， 所述甜味剂为 0.05~1.5重量份， 所述矫味剂为 0.2~1重量份。  5. The polyethylene glycol electrolyte granule preparation according to any one of claims 1 to 4, further comprising a sweetener and/or a flavoring agent, with respect to 100 parts by weight of the polyethylene glycol electrolyte particle preparation The sweetener is 0.05 to 1.5 parts by weight, and the flavoring agent is 0.2 to 1 part by weight.
6. 根据技术方案 1~5的任一项所述的聚乙二醇电解质颗粒制剂， 其中， 所述聚乙二醇电解质颗粒制剂 13.08g~14.45g用 40°C~50°C的水配成 125ml溶 液时， 渗透压在 280~330mOsmol/kg的范围内。  The polyethylene glycol electrolyte granule preparation according to any one of claims 1 to 5, wherein the polyethylene glycol electrolyte granule preparation is 13.08 g to 14.45 g with water at 40 ° C to 50 ° C. When the solution is 125 ml, the osmotic pressure is in the range of 280 to 330 mOsmol/kg.
7. 聚乙二醇电解质颗粒制剂的制造方法， 其包括以下步骤： 将平均分子 量为 3000~4000的聚乙二醇和电解质分别粉碎成细粒， 将这些细粒混合后， 加入润湿剂制软材， 然后进行制粒， 干燥， 形成粒径 180μηι ~850μηι的聚乙 二醇电解质颗粒。  A method for producing a polyethylene glycol electrolyte granule preparation, comprising the steps of: pulverizing polyethylene glycol having an average molecular weight of 3,000 to 4,000 into fine particles, mixing the fine particles, and adding a wetting agent to make a soft The material is then granulated and dried to form polyethylene glycol electrolyte particles having a particle size of 180 μm to 850 μm.
8. 根据技术方案 7所述的聚乙二醇电解质颗粒制剂的制造方法， 其中， 在所述电解质中混入甜味剂后进行粉碎。  8. The method for producing a polyethylene glycol electrolyte granule preparation according to claim 7, wherein the electrolyte is mixed with a sweetener and then pulverized.
9. 根据技术方案 7或 8所述的聚乙二醇电解质颗粒制剂的制造方法， 其 中， 在粉碎时， 将聚乙二醇粉碎成粒径为 150μηι ~250μηι的细粒， 将电解质 粉碎成粒径为 125μηι ~250μηι的细粒。  9. The method for producing a polyethylene glycol electrolyte granule preparation according to claim 7 or 8, wherein, in the pulverization, the polyethylene glycol is pulverized into fine particles having a particle diameter of 150 μm to 250 μm, and the electrolyte is pulverized into granules. Fine particles having a diameter of 125 μm to 250 μm.
10. 根据技术方案 7~9的任一项所述的聚乙二醇电解质颗粒制剂的制造 方法， 其中， 所述润湿剂为乙醇浓度为 80体积％以上的乙醇水溶液。  The method for producing a polyethylene glycol electrolyte granule preparation according to any one of claims 7 to 9, wherein the wetting agent is an aqueous ethanol solution having an ethanol concentration of 80% by volume or more.
11.根据技术方案 7~10的任一项所述的聚乙二醇电解质颗粒制剂的制造 方法，其中，相对于聚乙二醇和电解质的总量，润湿剂的用量为 5 ~20重量％。  The method for producing a polyethylene glycol electrolyte granule preparation according to any one of claims 7 to 10, wherein the wetting agent is used in an amount of 5 to 20% by weight based on the total amount of the polyethylene glycol and the electrolyte. .
12.根据技术方案 7~11的任一项所述的聚乙二醇电解质颗粒制剂的制造 方法， 其中， 聚乙二醇与电解质的重量比为 80~98： 20~2。 12. The manufacture of a polyethylene glycol electrolyte particle preparation according to any one of claims 7 to 11. The method wherein the weight ratio of the polyethylene glycol to the electrolyte is 80 to 98: 20 to 2.
13.根据技术方案 7~12的任一项所述的聚乙二醇电解质颗粒制剂的制造 方法， 其中， 干燥时的温度为 10°C ~ 60°C。  The method for producing a polyethylene glycol electrolyte granule preparation according to any one of claims 7 to 12, wherein the temperature at the time of drying is from 10 ° C to 60 ° C.
14.通过技术方案 7~13的任一项所述的制造方法制造得到的聚乙二醇电 解质颗粒制剂。  The polyethylene glycol electrolyte granule preparation produced by the production method according to any one of claims 7 to 13.
发明效果  Effect of the invention
本发明的聚乙二醇电解质颗粒制剂的质量可控， 口感好， 使用筒便， 疗 效确切也更安全可靠， 并可保证其完全等渗溶液， 保持结肠内水分不被吸收， 降低了聚乙二醇电解质散剂在使用中存在的弊端及副作用发生的几率， 提供 了一种效果更好的通便及清肠药物及其制造方法。 另外， 不需要包装成多种 小包装， 因此可以筒化生产工序。  The polyethylene glycol electrolyte granule preparation of the invention has the controllable quality, good mouthfeel, and the use of the tube, the curative effect is safer and more reliable, and the completely isotonic solution can be ensured, the moisture in the colon is not absorbed, and the polyethylation is lowered. The disadvantages of the use of diol electrolyte powder in the use and the incidence of side effects provide a better laxative and intestinal drug and its manufacturing method. In addition, there is no need to pack into a variety of small packages, so the production process can be completed.
具体实施方式 detailed description
以下对本发明进行详细说明。  The invention is described in detail below.
本发明提供一种聚乙二醇电解质颗粒制剂， 其特征在于， 包括聚乙二醇 电解质颗粒， 所述聚乙二醇电解质颗粒含有平均分子量为 3000~4000的聚乙 二醇和电解质，所述聚乙二醇电解质颗粒的粒径是 180~850μηι,更优选为 250 〜 550μηι„  The present invention provides a polyethylene glycol electrolyte particle preparation, comprising: polyethylene glycol electrolyte particles, the polyethylene glycol electrolyte particles comprising polyethylene glycol having an average molecular weight of 3000 to 4000 and an electrolyte, the polymerization The particle diameter of the ethylene glycol electrolyte particles is from 180 to 850 μm, more preferably from 250 to 550 μm.
聚乙二醇电解质颗粒的粒径大小对聚乙二醇电解质颗粒制剂的流动性、 装量准确性、 溶解速度、 渗透压等都有影响， 颗粒过大， 则干燥时间较长， 会造成碳酸氢根离子含量变化， 而且服用时溶解时间较长； 颗粒过小， 则流 动性较差， 装量差异较大， 而且服用时 ^艮难倒干净， 造成渗透压偏低。 通过 使聚乙二醇电解质颗粒的粒径在本发明 180~850μηι的范围内， 可以使聚乙二 醇电解质颗粒制剂兼具优良的流动性、 装量准确性、 溶解速度、 渗透压。  The particle size of the polyethylene glycol electrolyte particles has an influence on the fluidity, the loading accuracy, the dissolution rate, the osmotic pressure, etc. of the polyethylene glycol electrolyte particle preparation. If the particles are too large, the drying time is long, which causes carbonation. The content of hydrogen ion ions changes, and the dissolution time is longer when taken; when the particles are too small, the fluidity is poor, the difference in the loading is large, and the osmotic pressure is low when the dosage is taken. By making the particle diameter of the polyethylene glycol electrolyte particles in the range of 180 to 850 μm of the present invention, the polyethylene glycol electrolyte particle preparation can have excellent fluidity, charge accuracy, dissolution rate, and osmotic pressure.
本发明的聚乙二醇电解质颗粒制剂中， 聚乙二醇优选为聚乙二醇 4000, 相对于聚乙二醇电解质颗粒制剂 100重量份来说， 聚乙二醇的含量为 80~98 重量份， 优选为 92~98重量份， 电解质是选自碳酸氢钠、 氯化钠、 氯化钾、 硫酸钠中的两种以上的电解质的混合物， 电解质的含量为 2~20重量份， 优选 为 2~6重量份。 电解质优选为碳酸氢钠、 氯化钠和氯化钾的混合物， 并且， 相对于聚乙二醇电解质颗粒制剂 100重量份来说， 碳酸氢钠优选为 1~1.5重 量份， 氯化钠优选为 2~3重量份， 氯化钾优选为 0.2~0.5重量份。 通过选用上述的聚乙二醇和电解质， 并将各自含量控制在上述范围内， 可以获得良好的通便和清肠的效果。 In the polyethylene glycol electrolyte granule preparation of the present invention, the polyethylene glycol is preferably polyethylene glycol 4000, and the polyethylene glycol content is 80 to 98 weights relative to 100 parts by weight of the polyethylene glycol electrolyte granule preparation. Preferably, the mixture is 92 to 98 parts by weight, and the electrolyte is a mixture of two or more electrolytes selected from the group consisting of sodium hydrogencarbonate, sodium chloride, potassium chloride, and sodium sulfate, and the content of the electrolyte is 2 to 20 parts by weight, preferably 2 to 6 parts by weight. The electrolyte is preferably a mixture of sodium hydrogencarbonate, sodium chloride and potassium chloride, and the sodium hydrogencarbonate is preferably 1 to 1.5 weights relative to 100 parts by weight of the polyethylene glycol electrolyte particle preparation. The amount of sodium chloride is preferably 2 to 3 parts by weight, and the potassium chloride is preferably 0.2 to 0.5 parts by weight. By selecting the above polyethylene glycol and electrolyte, and controlling the respective contents within the above range, a good laxative and bowel effect can be obtained.
本发明的聚乙二醇电解质颗粒中可以含有甜味剂， 该甜味剂的种类没有 限定， 可以使用药学上通常用作的甜味剂的物质， 例如可以是安赛蜜、 糖精 钠、 阿斯帕坦、 三氯蔗糖。 本发明的聚乙二醇电解质颗粒制剂中还可以含有 和矫味剂， 该矫味剂的种类没有限定， 可以使用药学上通常用作的矫味剂的 物质， 例如可以是樱桃味香精、 菠萝味香精、 柠檬味香精、 橘味香精。 至于 甜味剂和矫味剂的含量， 相对于本发明的聚乙二醇电解质颗粒制剂 100重量 份来说， 甜味剂可以为 0.05~1.5重量份， 优选为 0.05~0.15重量份， 矫味剂可 以为 0.2~1重量份， 优选为 0.5~1重量份。  The polyethylene glycol electrolyte granule of the present invention may contain a sweetener, and the type of the sweetener is not limited, and a pharmaceutically acceptable sweetener may be used, and for example, acesulfame, sodium saccharin, or arsenic may be used. Spartan, sucralose. The polyethylene glycol electrolyte granule preparation of the present invention may further contain a flavoring agent, and the type of the flavoring agent is not limited, and a pharmaceutically acceptable flavoring agent may be used, and for example, it may be a cherry flavored flavor or a pineapple. Flavor, lemon flavor, orange flavor. The content of the sweetener and the flavoring agent may be 0.05 to 1.5 parts by weight, preferably 0.05 to 0.15 parts by weight, based on 100 parts by weight of the polyethylene glycol electrolyte particle preparation of the present invention. The agent may be 0.2 to 1 part by weight, preferably 0.5 to 1 part by weight.
通过加入上述的甜味剂和矫味剂， 可以改善制剂的口感， 使患者更易接 受。 尤其是对于幼儿患者来说， 在临床上是很有实用价值的。 进一步， 使甜 味剂和矫味剂各自的含量在上述范围内， 其口感更佳。  By adding the above-mentioned sweeteners and flavoring agents, the mouthfeel of the preparation can be improved, making the patient more acceptable. Especially for young children, it is very practical in clinical practice. Further, the content of each of the sweetener and the flavoring agent is within the above range, and the texture is better.
本发明的聚乙二醇电解质颗粒制剂 13.08g~14.45g用 40°C~50°C的水配成 125ml溶液时渗透压在 280~330mOsmol/kg的范围内。  The polyethylene glycol electrolyte granule preparation of the invention 13.08g~14.45g is immersed in a range of 280-330 mOsmol/kg when formulated into a 125 ml solution with water at 40 ° C to 50 ° C.
本发明的聚乙二醇电解质颗粒制剂的聚乙二醇电解质颗粒中所包含的钠 离子、 钾离子、 氯离子、 碳酸氢根离子含量均匀度均为 ± 15%。  The content of sodium ion, potassium ion, chloride ion and hydrogencarbonate ion contained in the polyethylene glycol electrolyte particles of the polyethylene glycol electrolyte particle preparation of the present invention is ± 15%.
本发明的聚乙二醇电解质颗粒制剂的聚乙二醇电解质颗粒中所包含的钠 离子、 钾离子、 氯离子、 碳酸氢根离子均为标示量的 95-105%。  The sodium ion, potassium ion, chloride ion, and hydrogencarbonate ion contained in the polyethylene glycol electrolyte particle of the polyethylene glycol electrolyte particle preparation of the present invention are 95-105% of the labeled amount.
本发明的聚乙二醇电解质颗粒制剂适于用作通便及清肠药物， 其可以在 临用前用水配成溶液以口服方式给药。 关于给药剂量， 本领域技术人员可以 根据具体的实际情况来确定， 例如可以是将本发明的聚乙二醇电解质颗粒制 剂 13.8g溶于 125ml温水中形成溶液， 成人每次服用该溶液 125ml。  The polyethylene glycol electrolyte granule preparation of the present invention is suitable for use as a laxative and enteric medicine, which can be administered orally in a solution with water before use. Regarding the dose to be administered, those skilled in the art can determine the specific conditions, for example, 13.8 g of the polyethylene glycol electrolyte granule preparation of the present invention can be dissolved in 125 ml of warm water to form a solution, and the adult takes 125 ml of the solution each time.
以下对本发明的聚乙二醇电解质颗粒制剂的制造方法进行说明。  Hereinafter, a method for producing the polyethylene glycol electrolyte particle preparation of the present invention will be described.
本发明的聚乙二醇电解质颗粒制剂的制造方法的特征在于， 将聚乙二醇 和电解质分别粉碎成细粒， 将这些细粒混合后， 加入润湿剂制软材， 然后进 行制粒， 干燥， 形成粒径 180μηι ~850μηι的聚乙二醇电解质颗粒。 另外， 也 可以在所述电解质中混入甜味剂， 将电解质和甜味剂一起粉碎。 另外， 还可 以在干燥后进行整粒。 The method for producing a polyethylene glycol electrolyte granule preparation of the present invention is characterized in that polyethylene glycol and an electrolyte are separately pulverized into fine granules, and the fine granules are mixed, and a softener is added to a soft material, followed by granulation and drying. , forming polyethylene glycol electrolyte particles having a particle diameter of 180 μm to 850 μm. Further, a sweetener may be mixed in the electrolyte to pulverize the electrolyte together with the sweetener. In addition, it can also To granulate after drying.
本发明中， 聚乙二醇和电解质根据各自的粒径大小不同， 流动性、 形态 也发生变化， 直接影响聚乙二醇和电解质的混合均匀性及剂量准确性， 因此 控制聚乙二醇和电解质的粒径是保证混合效果的关键。  In the present invention, the polyethylene glycol and the electrolyte vary according to the respective particle sizes, and the fluidity and morphology also change, directly affecting the mixing uniformity and the dose accuracy of the polyethylene glycol and the electrolyte, thereby controlling the particles of the polyethylene glycol and the electrolyte. The diameter is the key to ensuring the mixing effect.
本发明的制造方法中， 优选将聚乙二醇粉碎成粒径 150μηι ~250μηι的细 粒，其粒径更优选为 180μηι ~250μηι;优选将电解质粉碎成粒径 125μηι ~250μηι 的细粒， 其粒径更优选为 150μηι ~250μηι, 进一步优选为 180μηι~250μηι。  In the production method of the present invention, it is preferred to pulverize polyethylene glycol into fine particles having a particle diameter of 150 μm to 250 μm, and the particle diameter thereof is more preferably 180 μm to 250 μm; preferably, the electrolyte is pulverized into fine particles having a particle diameter of 125 μm to 250 μm. The diameter is more preferably 150 μηι to 250 μηι, further preferably 180 μηι to 250 μηι.
通过将聚乙二醇和电解质粉碎成粒径在上述范围内的细粒， 在细粒混合 时， 可以避免飞尘、 结块、 分层， 能够均匀地进行混合， 因此能够保证制得 的聚乙二醇电解质颗粒中聚乙二醇和电解质的含量均勾， 从而保证最终的聚 乙二醇电解质制剂能够形成符合要求的等渗溶液，能够实现更好的治疗效果。  By pulverizing polyethylene glycol and an electrolyte into fine particles having a particle diameter within the above range, when fine particles are mixed, fly ash, agglomeration, and delamination can be avoided, and mixing can be performed uniformly, thereby ensuring the obtained polyethylene The content of polyethylene glycol and electrolyte in the diol electrolyte particles is checked to ensure that the final polyethylene glycol electrolyte preparation can form an isotonic solution which meets the requirements, and a better therapeutic effect can be achieved.
本发明中所说的粒径是指粒径（D90 ), 意思是累积粒度分布达到 90%时 所对应的粒径。 它的物理意义是小于该粒径的粒子占总粒子的 90%。  The particle diameter referred to in the present invention means the particle diameter (D90), which means the particle diameter corresponding to the cumulative particle size distribution of 90%. Its physical meaning is that particles smaller than this particle size account for 90% of the total particles.
本发明中， 粒径是通过筛分法来测定的。 本发明中使用的筛子是 GB/T 15602-2008 工业用筛标准的药筛。  In the present invention, the particle size is determined by a sieving method. The sieve used in the present invention is a chemical sieve of GB/T 15602-2008 industrial sieve standard.
本发明中， 制备聚乙二醇电解质颗粒制剂时， 通过选择合适的润湿剂， 可以更好地改善颗粒的流动性， 增大物料的密度， 避免聚乙二醇和电解质分 层及细粉飞扬， 使产品含量均匀准确， 并以性状色泽、 含量均匀度、 粒径的 大小及溶解速度等各项指标来研究润湿剂的不同浓度对制粒影响。  In the present invention, when preparing a polyethylene glycol electrolyte granule preparation, by selecting a suitable wetting agent, the fluidity of the granule can be better improved, the density of the material can be increased, and delamination of polyethylene glycol and electrolyte and fine powder can be avoided. To make the product content uniform and accurate, and to study the effect of different concentrations of wetting agent on granulation by various indicators such as color tone, content uniformity, particle size and dissolution rate.
本发明的制造方法中， 所述润湿剂选自 80体积％以上的乙醇水溶液， 优 选 90~95体积％的乙醇水溶液， 例如可以是 91、 92、 93、 94、 95、 96、 97、 98、 99、 100体积％；其用量相对于聚乙二醇细粒和电解质细粒的总量为 5 ~20 重量％, 优选为 8 ~16重量％, 例如可以是 6、 7、 8、 9、 10、 11、 12、 13、 14、 15、 16、 17、 18、 19、 20重量％。  In the production method of the present invention, the wetting agent is selected from the group consisting of 80% by volume or more of an aqueous ethanol solution, preferably 90 to 95% by volume of an aqueous ethanol solution, and may be, for example, 91, 92, 93, 94, 95, 96, 97, 98. 99, 100% by volume; the amount thereof is 5 to 20% by weight, preferably 8 to 16% by weight, based on the total amount of the polyethylene glycol fine particles and the electrolyte fine particles, and may be, for example, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20% by weight.
通过选择上述润湿剂及其用量范围， 可以更好地改善聚乙二醇和电解质 细粒的流动性， 避免聚乙二醇和电解质分层及细粉飞扬， 使聚乙二醇和电解 质细粒混合后的含量均匀准确， 并且可以使最终的制剂具有良好的含量均匀 度等优异的性质。  By selecting the above wetting agent and its dosage range, the fluidity of polyethylene glycol and electrolyte fine particles can be better improved, and the polyethylene glycol and electrolyte layering and fine powder flying can be avoided, and polyethylene glycol and electrolyte fine particles can be mixed. The content is uniform and accurate, and the final formulation can have excellent properties such as good content uniformity.
本发明中使用的聚乙二醇优选是平均分子量 3000~4000的聚乙二醇， 电 解质优选是选自碳酸氢钠、 氯化钠、 氯化钾、 硫酸钠中的两种以上的电解质 的混合物， 更优选是碳酸氢钠、 氯化钠和氯化钾的混合物， The polyethylene glycol used in the present invention is preferably polyethylene glycol having an average molecular weight of 3,000 to 4,000, and electricity. The detoxification is preferably a mixture of two or more electrolytes selected from the group consisting of sodium hydrogencarbonate, sodium chloride, potassium chloride, and sodium sulfate, more preferably a mixture of sodium hydrogencarbonate, sodium chloride, and potassium chloride.
所述聚乙二醇细粒和电解质细粒混合时， 调整其混合比例使得聚乙二醇 与电解质的重量比为 80~98： 20~2。 所述干燥可以在 10 °C ~ 60°C的温度下进 行。  When the polyethylene glycol fine particles and the electrolyte fine particles are mixed, the mixing ratio thereof is adjusted so that the weight ratio of the polyethylene glycol to the electrolyte is 80 to 98: 20 to 2. The drying can be carried out at a temperature of from 10 ° C to 60 ° C.
更具体地， 本发明优选实施方式的聚乙二醇电解质颗粒制剂的制造方法 可以包括以下步骤：  More specifically, the method for producing a polyethylene glycol electrolyte granule formulation according to a preferred embodiment of the present invention may comprise the following steps:
1 )将平均分子量 3000~4000 的聚乙二醇粉碎， 过筛， 制成粒径 150μηι ~250μηι的细粒；  1) pulverizing and sieving polyethylene glycol having an average molecular weight of 3000 to 4000 to prepare fine particles having a particle diameter of 150 μm to 250 μm;
2 )将电解质粉碎， 过筛， 制成粒径为 125μηι ~250μηι的细粒；  2) pulverizing the electrolyte and sieving it to form fine particles having a particle diameter of 125 μm to 250 μm;
3 )将上述聚乙二醇细粒与上述电解质细粒以聚乙二醇与电解质的重量比 为 80~98： 20~2的比例混合均匀后， 加入润湿剂制软材， 制粒， 在 10°C ~ 60 °C干燥， 整粒， 制成粒径为 180μηι ~850μηι的聚乙二醇电解质颗粒。  3) mixing the above polyethylene glycol fine particles and the above electrolyte fine particles in a ratio of polyethylene glycol to electrolyte at a ratio of 80 to 98:20 to 2, and then adding a wetting agent to make a soft material, granulating, The mixture was dried at 10 ° C to 60 ° C and granulated to prepare polyethylene glycol electrolyte particles having a particle diameter of 180 μm to 850 μm.
上述方法中的步骤 2 )也可以是以下的步骤： 2 )将电解质和甜味剂以重 量比为 20~2： 0.05-1.5的比例混合后，粉碎，过筛，制成粒径为 125μηι ~250μηι 的细粒。  Step 2) in the above method may also be the following steps: 2) mixing the electrolyte and the sweetener in a weight ratio of 20 to 2: 0.05-1.5, pulverizing, sieving, and preparing the particle size to 125 μηι ~ 250μηι fine particles.
本发明中， 混合的方法和设备没有限定， 可以采用药学上常用的方法、 设备， 但聚乙二醇细粒与电解质细粒混合时， 优选采用等量递加法来进行混 合。 本发明中所说的 "等量递加法" 是指， 将聚乙二醇 4000取出一部分与电 解质等量混合均匀 , 再取一部分聚乙二醇 4000与以上混合物等量混合均匀， 如此倍量增加聚乙二醇 4000直至全部混匀。  In the present invention, the method and apparatus for mixing are not limited, and methods and equipment which are commonly used in pharmacy may be employed. However, when the polyethylene glycol fine particles are mixed with the electrolyte fine particles, it is preferred to carry out mixing by an equal amount of addition. The "equal amount addition method" as used in the present invention means that a part of the polyethylene glycol 4000 is taken out and mixed with the electrolyte in an equal amount, and a part of the polyethylene glycol 4000 is uniformly mixed with the above mixture, and the amount is increased. Polyethylene glycol 4000 until all is mixed.
本发明中， 制粒和干燥的方法、 设备也没有限定， 可以采用药学上常用 的方法、 设备， 干燥时优选使用流化床进行干燥， 制粒时优选采用挤压制粒 法， 例如可以采用摇摆制粒机等制粒设备， 但不限于此。  In the present invention, the method and equipment for granulating and drying are not limited, and methods and equipment which are commonly used in pharmacy may be employed. When drying, it is preferred to use a fluidized bed for drying, and granulation is preferably carried out by granulation, for example, it may be employed. A granulation device such as a swing granulator, but is not limited thereto.
本发明中， 制得的聚乙二醇电解质颗粒可以直接作为聚乙二醇电解质颗 粒制剂， 也可以进一步与矫味剂混合， 作为聚乙二醇电解质颗粒制剂。  In the present invention, the obtained polyethylene glycol electrolyte particles may be directly used as a polyethylene glycol electrolyte particle preparation, or may be further mixed with a flavoring agent as a polyethylene glycol electrolyte particle preparation.
更具体地， 本发明优选实施方式的聚乙二醇电解质颗粒制剂的制造方法 可以包括以下步骤：  More specifically, the method for producing a polyethylene glycol electrolyte granule formulation according to a preferred embodiment of the present invention may comprise the following steps:
1 )将平均分子量 3000~4000 的聚乙二醇粉碎， 过筛， 制成粒径 125μηι ~250μηι的聚乙二醇细粒； 1) The polyethylene glycol with an average molecular weight of 3000~4000 is pulverized and sieved to a particle size of 125 μm. ~250μηι polyethylene glycol fine particles;
2 )将电解质和甜味剂以重量比为 20~2： 0.05~1.5的比例混合后， 粉碎， 过筛， 制成粒径为 125μηι ~250μηι的电解质细粒；  2) mixing the electrolyte and the sweetener in a weight ratio of 20 to 2: 0.05 to 1.5, pulverizing, and sieving to prepare an electrolyte fine particle having a particle diameter of 125 μm to 250 μm;
3 )将上述聚乙二醇细粒与上述电解质细粒以聚乙二醇与电解质的重量比 为 80~98： 20~2的比例按等量递加法混合均匀后， 加入润湿剂制软材， 制粒， 用流化床在 10 °C ~ 60°C沸腾干燥， 整粒， 制成粒径为 180μηι ~850μηι的聚乙 二醇电解质颗粒；  3) mixing the above polyethylene glycol fine particles with the above electrolyte fine particles in a weight ratio of polyethylene glycol to electrolyte of 80 to 98: 20 to 2, and uniformly adding the same amount, and adding a wetting agent to make the soft particles. , granulating, boiled and dried at 10 ° C to 60 ° C in a fluidized bed, and formed into polyethylene glycol electrolyte particles having a particle diameter of 180 μm to 850 μm;
4 )加入矫味剂， 混合均匀， 制成聚乙二醇电解质颗粒制剂。  4) Adding a flavoring agent and mixing uniformly to prepare a polyethylene glycol electrolyte particle preparation.
本发明中， 矫味剂的添加量为， 相对于聚乙二醇电解质颗粒制剂 100重 量份为 0.2~1重量份。  In the present invention, the flavoring agent is added in an amount of 0.2 to 1 part by weight based on 100 parts by weight of the polyethylene glycol electrolyte granule preparation.
通过本发明的上述方法， 可以制造出能够实现本发明技术效果的聚乙二 醇电解质颗粒制剂。  By the above method of the present invention, a polyethylene glycol electrolyte particle preparation capable of realizing the technical effects of the present invention can be produced.
实施例  Example
以下， 通过实施例具体地说明本发明， 但本发明不限于这些实施例的内 容。  Hereinafter, the present invention will be specifically described by way of examples, but the invention is not limited by the examples.
制备例 1  Preparation example 1
聚乙二醇电解质颗粒制剂的制备：  Preparation of polyethylene glycol electrolyte particle preparation:
称取 13125 g聚乙二醇 4000粉碎，过 60目筛，得到粒径（ D90 )为 250μηι 的聚乙二醇 4000细粒。 分别称取碳酸氢钠 178.5g、 氯化钠 350.7g、 氯化钾 46.6g、 安赛蜜 10g混合， 粉碎， 过 80 目筛， 得到粒径（D90 ) 为 180μηι的 电解质细粒。将上述得到的聚乙二醇 4000细粒与电解质细粒按等量递加法混 合均匀后， 用 95体积％乙醇水溶液约 1371g制软材， 然后用 40目筛制粒， 流化床 10°C~60°C沸腾干燥 20分钟， 用 40 目筛整粒， 制成粒径（D90 ) 为 380μηι的聚乙二醇电解质颗粒。将上述制得的颗粒与橘味香精 100g混合均匀， 即得到本发明的聚乙二醇电解质颗粒制剂。  13125 g of polyethylene glycol 4000 was weighed and passed through a 60 mesh sieve to obtain polyethylene glycol 4000 fine particles having a particle diameter (D90) of 250 μm. Separately, 178.5 g of sodium hydrogencarbonate, 350.7 g of sodium chloride, 46.6 g of potassium chloride, and 10 g of acesulfame-milk were weighed, pulverized, and sieved through an 80-mesh sieve to obtain an electrolyte fine particle having a particle diameter (D90) of 180 μm. The polyethylene glycol 4000 fine particles obtained above and the electrolyte fine particles were uniformly mixed by an equal amount, and then about 1371 g of a 95% by volume aqueous solution of ethanol was used to prepare a soft material, and then granulated with a 40 mesh sieve, and the fluidized bed was 10 ° C. The mixture was boiled and dried at ~60 ° C for 20 minutes, and granulated with a 40 mesh sieve to prepare polyethylene glycol electrolyte particles having a particle diameter (D90) of 380 μm. The granules obtained above were uniformly mixed with 100 g of orange flavor to obtain a polyethylene glycol electrolyte granule preparation of the present invention.
制备例 2〜制备例 6  Preparation Example 2 to Preparation Example 6
按照表 1 , 改变制备聚乙二醇电解质颗粒制剂的各组成及其用量， 以及 所使用的筛的型号， 按照与制备例 1相同的操作步骤， 制造制备例 2〜制备例 6的聚乙二醇电解质颗粒制剂。 表 1 According to Table 1, the composition and the amount of the preparation of the polyethylene glycol electrolyte granule preparation, and the type of the sieve used were changed, and the polyethylene glycol of Preparation Example 2 to Preparation Example 6 was produced in the same manner as in Preparation Example 1. Alcohol electrolyte particle preparation. Table 1
Figure imgf000010_0001
Figure imgf000010_0001
以下， 通过试验例对本发明的聚乙二醇电解质颗粒制剂及其制造方法的 技术效果进行进一步说明。 Hereinafter, the technical effects of the polyethylene glycol electrolyte particle preparation of the present invention and a method for producing the same will be further described by way of test examples.
本发明中， 流动性 (休止角）的评价方法如下。  In the present invention, the evaluation method of fluidity (rest angle) is as follows.
<流动性 (；休止角） >  <liquidity (; angle of repose) >
取样品颗粒， 从固定的小漏斗中流入圓形的表面亚中， 直到得到最高的 圓锥体， 量取圓锥体高度 H和半径 R, 按下式计算休止角 α。 休止角越大， 巟动 <1 "生越差。  Take the sample particles, flow from the fixed small funnel into the circular surface sub-region until the highest cone is obtained, measure the cone height H and the radius R, and calculate the angle of repose α as follows. The larger the angle of repose, the worse the incitement <1 ".
tana=H/R  Tana=H/R
试验例 1 关于聚乙二醇电解质颗粒的粒径  Test Example 1 Regarding the particle size of the polyethylene glycol electrolyte particles
除了在制软材后分别用 14、 16、 18、 20、 30、 40、 60、 80、 100 目筛制 粒以外， 按照与制备例 1相同的操作制备聚乙二醇电解质颗粒。 将上述制备 好的颗粒按每袋 13.8g进行分装， 考察颗粒的流动性、 装量差异、 溶解时限、 渗透压及口感的各项指标。 结果见表 2。  Polyethylene glycol electrolyte particles were prepared in the same manner as in Preparation Example 1, except that the pellets were sieved with 14, 16, 18, 20, 30, 40, 60, 80, and 100 mesh, respectively. The prepared granules were dispensed at 13.8 g per bag, and the indexes of the fluidity, the difference in the amount of the granules, the dissolution time, the osmotic pressure and the mouthfeel were examined. The results are shown in Table 2.
表 2 ： 聚乙二醇电解质颗粒的不同粒径比较  Table 2: Comparison of different particle sizes of polyethylene glycol electrolyte particles
目数 休止角 装量差异 溶解时限 渗透压及口感  Number of angles of repose angle, difference in loading, dissolution time, osmotic pressure and taste
14 40° 士 8.5% 6分 38秒 336mOsmol/kg药液澄清， 有沙石乐感。  14 40° ± 8.5% 6 minutes 38 seconds 336mOsmol / kg liquid clarification, there is a sense of sand.
16 38° 士 7.8% 6分 3秒 333mOsmol/kg药液澄清， 有沙石乐感。  16 38°士 7.8% 6分 3秒 333mOsmol/kg liquid clarified, with a sense of sand and stone.
18 37° 士 8.0ο/ο 5分 41秒 328mOsmol/kg药液澄清， 有沙石乐感。 18 37° 8.0 ο / ο 5 minutes 41 seconds 328mOsmol / kg liquid clarification, there is a sense of sand.
20 36° 士 4.5% 3分 22秒 308mOsmol/kg药液澄清, 口感好。  20 36° ± 4.5% 3 minutes 22 seconds 308mOsmol / kg liquid clarification, good taste.
30 38° 士 4.5% 2分 39秒 312mOsmol/kg药液澄清 , 口感好。  30 38° ± 4.5% 2 minutes 39 seconds 312mOsmol / kg liquid clarification, good taste.
40 36° ± 3.8% 1分 21秒 307mOsmol/kg药液澄清, 口感好。  40 36° ± 3.8% 1 minute 21 seconds 307mOsmol/kg liquid clarified, good taste.
60 39° 士 4.4% 1分 18秒 294mOsmol/kg药液澄清, 口感好。  60 39° 4.4% 1 minute 18 seconds 294mOsmol/kg liquid clarified, good taste.
80 42° 士 4.8% 1分 12秒 286mOsmol/kg药液澄清, 口感好。  80 42°士 4.8% 1 minute 12 seconds 286mOsmol/kg liquid clarified, good taste.
100 51° 士 8.3% 1分 08秒 27 ImOsmol/kg药液澄清 , 口感好。  100 51°士 8.3% 1 minute 08 seconds 27 ImOsmol/kg liquid is clear and tastes good.
根据表 2的试验结果可知， 目数为 18目以下时， 装量准确性差， 溶解速 度慢， 渗透压不符合治疗要求； 目数为 100 目时， 虽然溶解速度快， 但装量 准确性差、 渗透压不符合治疗要求， 而且流动性很差。 聚乙二醇电解质颗粒 的粒径在 20 目 （ 850μηι )到 80 目 （180μηι ) 的范围内时， 在流动性、 装量 准确性、 溶解速度、 渗透压各方面综合来看， 都具有良好的效果。  According to the test results in Table 2, when the mesh number is 18 mesh or less, the accuracy of the loading is poor, the dissolution rate is slow, and the osmotic pressure does not meet the treatment requirements. When the mesh number is 100 mesh, although the dissolution rate is fast, the loading accuracy is poor. The osmotic pressure does not meet the treatment requirements and the fluidity is poor. When the particle size of the polyethylene glycol electrolyte particles is in the range of 20 mesh (850 μηι) to 80 mesh (180 μηι), it has a good combination of fluidity, charge accuracy, dissolution rate, and osmotic pressure. effect.
试验例 2 关于聚乙二醇细粒的粒径和电解质细粒的粒径  Test Example 2 Regarding the particle diameter of the polyethylene glycol fine particles and the particle diameter of the electrolyte fine particles
除了将聚乙二醇和电解质粉碎成表 3记载的各组粒径以外， 进行与制备 例 1相同的操作。 对聚乙二醇细粒和电解质细粒混合后制软材前的含量均匀 度进行测定， 并目测评价它们的混合结果。 评价结果见表 3。 Except for pulverizing polyethylene glycol and electrolyte into the particle diameters of each group described in Table 3, preparation and preparation Example 1 the same operation. The content uniformity of the polyethylene glycol fine particles and the electrolyte fine particles before mixing the soft materials was measured, and the mixing results thereof were visually evaluated. The evaluation results are shown in Table 3.
含量均匀度的测定方法如下。  The method for determining the content uniformity is as follows.
I. 钾离子的含量均匀度  I. Potassium ion content uniformity
将混合后制软材前的聚乙二醇细粒和电解质细粒按每袋 13.8g进行分装， 作为样品。 取 10袋样品， 测定每袋中钾离子的含量， 10袋中钾离子的含量 测定值与平均值相比较。  The polyethylene glycol fine particles and the electrolyte fine particles before mixing the soft materials were packed at 13.8 g per bag to prepare a sample. Take 10 bags of samples and measure the content of potassium ions in each bag. The measured values of potassium ions in 10 bags are compared with the average value.
具体测定方法：  Specific measurement method:
对照品溶液的制备： 取氯化钾对照品约 25mg, 精密称定， 置 200ml量瓶 中，加去离子水适量，振摇使溶解，另称取聚乙二醇约 5.63g、氯化钠约 0.15g、 碳酸氢钠约 76mg、 安赛蜜约 5.6mg、 香精约 21.4mg, 精密称定， 置上述量瓶 中， 振摇使溶解， 加去离子水稀释至刻度， 摇匀。 精密量取 0.6、 0.8、 1.0、 1.2、 1.4ml, 分别置 100ml量瓶中， 分别配置成含钾离子约 0.39、 0.52、 0.66、 0.78、 0.92 g/ml的溶液， 作为对照品溶液。  Preparation of the reference solution: Take about 25mg of potassium chloride reference substance, accurately weighed, placed in a 200ml volumetric flask, add deionized water to the amount, shake to dissolve, otherwise called polyethylene glycol about 5.63g, sodium chloride About 0.15g, sodium bicarbonate about 76mg, acesulfame about 5.6mg, flavor about 21.4mg, accurately weighed, placed in the above measuring flask, shake to dissolve, add deionized water to dilute to the mark, shake. Precisely weighed 0.6, 0.8, 1.0, 1.2, and 1.4 ml, and placed them in a 100 ml volumetric flask, respectively, and arranged a solution containing potassium ions of about 0.39, 0.52, 0.66, 0.78, and 0.92 g/ml as a reference solution.
样品溶液的制备： 取一袋样品， 置 200ml量瓶中， 加去离子水适量， 振 摇使溶解， 加去离子水稀释至刻度， 摇匀。 精密量取 2ml置 100ml量瓶中， 加去离子水稀释至刻度， 摇勾， 作为样品溶液。  Preparation of sample solution: Take a bag of sample, place it in a 200ml volumetric flask, add deionized water to the appropriate amount, shake to dissolve, add deionized water to dilute to the mark, and shake well. Precisely measure 2ml into a 100ml volumetric flask, dilute with deionized water to the mark, and shake the hook as a sample solution.
测定法： 取对照品溶液与样品溶液， 按照火焰光度法（中国药典 2005年 版二部附录 IV F )测定， 用标准曲线法计算得到钾离子的含量。  Determination method: Take the reference solution and the sample solution, and determine the content of potassium ions by the flame curve method (Chinese Pharmacopoeia 2005 edition two appendix IV F).
II. 碳酸氢根离子的含量均匀度  II. Content uniformity of bicarbonate ions
将混合后制软材前的聚乙二醇细粒和电解质细粒按每袋 13.8g进行分装， 作为样品。 取 10袋样品， 测定每袋中碳酸氢根离子的含量， 10袋中碳酸氢 根离子的含量测定值与平均值相比较。  The polyethylene glycol fine particles and the electrolyte fine particles before mixing the soft materials were packed at 13.8 g per bag to prepare a sample. Take 10 bags of samples and measure the content of bicarbonate ions in each bag. The measured values of bicarbonate ions in 10 bags are compared with the average.
具体测定方法： 取一袋样品， 加水 50ml使溶解， 加曱基红 -溴曱酚绿混 合指示液 1滴， 用盐酸滴定液（0.1mol/L )滴定至溶液由绿色变为暗紫色， 煮 沸 2分钟， 冷却至室温， 继续滴定至溶液由绿色转变为暗色。 每 lml的盐酸 滴定液（ 0.1mol/L )相当于 6.10mg的碳酸氢根离子。 表 3： 聚乙二醇细粒和电解质细粒的不同粒径比较 Specific determination method: Take a bag of samples, add 50ml of water to dissolve, add 1 drop of hydrazine red-bromophenol phenol green mixed indicator solution, titrate with hydrochloric acid titration solution (0.1mol/L) until the solution changes from green to dark purple, boil 2 In minutes, cool to room temperature and continue titration until the solution changes from green to dark. Each 1 ml of hydrochloric acid titration solution (0.1 mol/L) corresponds to 6.10 mg of bicarbonate ions. Table 3: Comparison of different particle sizes of polyethylene glycol fine particles and electrolyte fine particles
Figure imgf000013_0001
Figure imgf000013_0001
表 3中， 优： 混合均匀， 不分层， 不产尘； 一般： 基本混合均匀， 振动时稍有分层； 差： 明显分层， 混合不均匀， 产尘  In Table 3, excellent: uniform mixing, no delamination, no dust generation; general: basic mixing is uniform, slightly stratified when vibrating; poor: distinct stratification, uneven mixing, dust production
表 3的结果表明： 第 1组〜第 6组， 即聚乙二醇的粒径在 150μηι~250μηι ( 60目〜 100目 )且电解质的粒径在 125μηι~250μηι ( 60目〜 120目 )时， 混合 时不分层或振动时稍有分层， 不产尘， 能够均勾混合， 并且混合后制软材前 的钾离子和碳酸氢根离子的含量均匀度均在 ± 10%以下， 即聚乙二醇和电解 质的含量均匀； 特别是第 1 组〜第 3组， 即聚乙二醇的粒径在 60 目〜 80 目 ( 180μηι~250μηι )且电解质的粒径在 150μηι~180μηι ( 80目〜 100目 ） 时， 上 述效果更好。其中， 第 1组中，将聚乙二醇粉碎过筛（ 60目 ）制成粒径（ D90 ) 为 250μηι的细粒， 将电解质粉碎过筛（ 80目）制成粒径（ D90 )为 180μηι的 细粒时， 混合效果最好， 振动也不分层。  The results in Table 3 indicate that: Group 1 to Group 6, ie, the particle size of polyethylene glycol is 150 μηι to 250 μηι (60 mesh to 100 mesh) and the particle size of the electrolyte is 125 μηι to 250 μηι (60 mesh to 120 mesh). When mixing, there is no delamination or slight stratification when vibrating, no dust is produced, and it can be mixed and mixed, and the content of potassium ions and hydrogencarbonate ions before mixing the soft materials is less than ± 10%, that is, The content of polyethylene glycol and electrolyte is uniform; especially the first group to the third group, that is, the diameter of polyethylene glycol is 60 mesh to 80 mesh (180μηι~250μηι) and the particle size of the electrolyte is 150μηι~180μηι (80 mesh). When the ~100 mesh), the above effect is better. Among them, in the first group, polyethylene glycol was pulverized and sieved (60 mesh) to prepare fine particles having a particle diameter (D90) of 250 μm, and the electrolyte was pulverized (80 mesh) to have a particle diameter (D90) of 180 μm. When the fine particles are used, the mixing effect is the best and the vibration is not delaminated.
试验例 3 润湿剂的浓度及配比  Test Example 3 Concentration and ratio of wetting agent
除了以不同浓度和用量的乙醇作为润湿剂以外， 按照与制备例 1相同的 组成、 配比和操作， 制备聚乙二醇电解质颗粒。 将制备好的聚乙二醇电解质 颗粒， 按每袋 13.8g进行分装， 作为样品。  Polyethylene glycol electrolyte particles were prepared in the same composition, ratio, and operation as in Preparation Example 1, except that ethanol was used as a wetting agent in various concentrations and amounts. The prepared polyethylene glycol electrolyte particles were dispensed at 13.8 g per bag to prepare a sample.
目测评价颗粒性状、 样品中细粉状态； 通过测定休止角来评价样品颗粒 的流动性； 除了将试验例 2的样品改为本试验例的样品以外， 按照与试验例 2相同的操作， 测定钾离子和碳酸氢根离子的含量均匀度。 结果见表 4。 表 4 ： 润湿剂浓度配比 The particle properties and the fine powder state in the sample were visually evaluated; the fluidity of the sample particles was evaluated by measuring the angle of repose; the potassium was measured in the same manner as in Test Example 2 except that the sample of Test Example 2 was changed to the sample of the test example. The content uniformity of ions and bicarbonate ions. The results are shown in Table 4. Table 4: Wetting agent concentration ratio
Figure imgf000014_0001
Figure imgf000014_0001
本试验例中，休止角 40° ~50。 为流动性一般， 30° ~40。 为流动性好; 含量均匀度 ± 10% ~ ± 15%为一般， ±5%~ ±10%为好， 小于 ±5%为优。  In this test example, the angle of repose is 40° to 50°. For general mobility, 30 ° ~ 40. It is good for fluidity; content uniformity ± 10% ~ ± 15% is normal, ± 5% ~ ± 10% is good, less than ± 5% is excellent.
上述试验结果表明， 80体积％ ~ 100体积％的乙醇水溶液作为润湿剂在颗 粒形状、 颗粒中细粉状态、 颗粒流动性、 含量均勾度方面具有很好的效果， 特别是 90体积％~95体积％乙醇水溶液的效果更加优异。 至于乙醇水溶液的 用量， 相对于聚乙二醇和电解质的总量为 5 ~20重量％时， 在颗粒性状、颗粒 中细粉状态、 颗粒流动性、 含量均匀度方面具有很好的效果， 特别是用量为 8-16重量％时的效果更加优异。 The above test results show that 80% by volume to 100% by volume of aqueous ethanol solution has a good effect as a wetting agent in particle shape, fine powder state, particle fluidity and content. In particular, the effect of 90% by volume to 95% by volume of the aqueous ethanol solution is more excellent. The amount of the aqueous ethanol solution is 5 to 20% by weight based on the total amount of the polyethylene glycol and the electrolyte, and has a good effect on the particle properties, the fine powder state of the particles, the fluidity of the particles, and the uniformity of the content, especially The effect is more excellent when the amount is from 8 to 16% by weight.
试验例 4 甜味剂和矫味剂的添加  Test Example 4 Addition of sweeteners and flavoring agents
在使用聚乙二醇电解质制剂前有 57%的患儿需要住院治疗， 26%的患儿 需要进行特殊的家庭护理。 服用口感好的聚乙二醇电解质制剂可减轻护理工 作的时间及难度， 同时也改善了医护关系。  Before the use of polyethylene glycol electrolyte preparations, 57% of patients required hospitalization and 26% needed special home care. Taking a good taste polyethylene glycol electrolyte preparation can reduce the time and difficulty of nursing work, and also improve the medical relationship.
目前已上市聚乙二醇电解质散剂口感都不好， 溶液盐味重， 患者不易接 受， 为了改善聚乙二醇电解质制剂的口感， 提高患者用药的依从性， 本发明 的乙二醇电解质颗粒制剂添加了多种口味的甜味剂和矫味剂。  At present, the polyethylene glycol electrolyte powder has been badly tasted, the salt of the solution is heavy, and the patient is not easy to accept. In order to improve the mouthfeel of the polyethylene glycol electrolyte preparation and improve the compliance of the patient, the ethylene glycol electrolyte particle preparation of the invention A variety of flavors of sweeteners and flavorings have been added.
试验方法： 分别称取处方聚乙二醇 4000粉碎， 过 60目筛备用， 碳酸氢 钠、 氯化钠、 氯化钾、 甜味剂混合粉碎过 80 目筛备用； 而后将处方量的聚 乙二醇 4000 与电解质按等量递加法混合均匀， 用配制好的乙醇水溶液制软 材， 用 40 目筛制粒， 流化床沸腾干燥， 整粒,将上述制好的颗粒加入多种口 味矫味剂， 混合均匀， 检验合格后， 每袋分装 13.8g, 装盒， 分别评价口感， 结果见表 5。 其中的用量为相对于聚乙二醇电解质颗粒 100重量份的用量。  Test method: Weigh the prescription polyethylene glycol 4000 separately, pass 60 mesh sieve for use, sodium bicarbonate, sodium chloride, potassium chloride, sweetener mixture and crushed through 80 mesh sieve for use; then the prescription amount of polyethylene The diol 4000 and the electrolyte are uniformly mixed by the equal amount, and the soft material is prepared by using the prepared ethanol aqueous solution, and the granules are sieved by a 40 mesh sieve, and the fluidized bed is boiled and dried, and the whole granules are added to the various flavors. The scented agent was evenly mixed. After the test was passed, 13.8 g of each bag was dispensed and packed, and the taste was evaluated separately. The results are shown in Table 5. The amount used is the amount relative to 100 parts by weight of the polyethylene glycol electrolyte particles.
表 5 ： 不同调味剂的添加  Table 5: Addition of different flavors
组号 矫味剂 用量（重量份） Hi— 用量 （重量份） 口感评价 Group No. Flavoring agent Dosage (parts by weight) Hi - Dosage (parts by weight) Taste evaluation
1 橘味 0.8重量份 安赛密 0.1重量份 药液澄清， 口感好。 1 Orange flavor 0.8 parts by weight Anselmi 0.1 parts by weight The liquid is clear and tastes good.
2 菠萝味 0.6重量份 糖精钠 0.08重量份 药液澄清， 口感好。2 Pineapple flavor 0.6 parts by weight Sodium saccharin 0.08 parts by weight The liquid is clear and tastes good.
3 柠檬味 0.5重量份 阿斯帕坦 0.12重量份 药液澄清， 口感好。3 Lemon flavor 0.5 parts by weight Aspartame 0.12 parts by weight The liquid is clear and tastes good.
4 樱桃味 1重量份 三氯蔗糖 0.09重量份 药液澄清， 口感好。 4 Cherry flavor 1 part by weight Sucralose 0.09 parts by weight The liquid is clear and tastes good.
表 5的试验结果表明， 加入甜味剂和矫味剂的聚乙二醇电解质制剂， 口 感明显比先前好， 和没有加甜味剂和矫味剂的聚乙二醇电解质制剂比较， 患 者更易被接受味道和口感， 且临床效果很理想。  The test results in Table 5 show that the polyethylene glycol electrolyte preparations to which the sweetener and the flavoring agent are added have a better taste than before, and the patient is easier to compare with the polyethylene glycol electrolyte preparation without the sweetener and the flavoring agent. It is taste and taste, and the clinical effect is ideal.
试验例 5 制剂稳定性试验  Test Example 5 Preparation Stability Test
将制备例 1的聚乙二醇电解质颗粒制剂用复合薄膜包装后置于 25 °C、 相 对湿度为 60%的恒温恒湿箱中， 放置 24个月， 分别于第 12、 24月取样考察， 测定其试验前后的外观性状、 聚乙二醇 4000、 钠离子、 钾离子、 氯离子、 碳 酸氢根离含量及溶解时间， 测定结果见表 6。 The polyethylene glycol electrolyte granule preparation of Preparation Example 1 was packaged in a composite film and placed in a constant temperature and humidity chamber at 25 ° C and a relative humidity of 60%, and left for 24 months, and sampled in the 12th and 24th months, respectively. Determination of appearance properties before and after the test, polyethylene glycol 4000, sodium ion, potassium ion, chloride ion, carbon The acid hydrogen radical content and dissolution time are shown in Table 6.
表 6: 稳定性试验考察结果  Table 6: Results of the stability test
时间 （月） 0 12 24 外观性状 白色均匀颗粒 白色均匀颗粒 白色均匀颗粒 溶解时间与澄清度 1分 20秒， 澄清 1分 20秒， 澄清 1分 20秒， 澄清 钾离子含量均匀度（％) < 士 15% < 士 15% < 士 15% 碳酸氢根离子含量均匀度（％ ) < 士 15% < 士 15% < 士 15%  Time (month) 0 12 24 Appearance trait white uniform granule white uniform granule white uniform granule dissolution time and clarity 1 minute 20 seconds, clarification 1 minute 20 seconds, clarification 1 minute 20 seconds, clarified potassium ion content uniformity (%) < 15% < 士 15% < 士 15% bicarbonate ion content uniformity (%) < 士15% < 士15% < 士15%
聚乙二醇 4000含量（％) 99.8 99.9 100.1 碳酸氢钠含量（％ ) 100.2 99.7 99.8 钠离子含量（％) 100.6 100.4 100.7 钾离子含量（％) 101.4 101.1 101.3 氯离子含量（％) 100.7 100.2 100.5  Polyethylene glycol 4000 content (%) 99.8 99.9 100.1 Sodium hydrogencarbonate content (%) 100.2 99.7 99.8 Sodium ion content (%) 100.6 100.4 100.7 Potassium ion content (%) 101.4 101.1 101.3 Chloride ion content (%) 100.7 100.2 100.5
pH值 8.09 8.00 8.03 从表 6的结果可以看出： 试验前后本发明的颗粒制剂在外观性状、 溶解 时间与澄清度、 钾与碳酸氢根离子含量均匀度、 含量、 pH值等方面均无明显 变化， 说明本发明的聚乙二醇电解质颗粒制剂 4艮稳定。  pH 8.09 8.00 8.03 It can be seen from the results in Table 6: The granule preparation of the present invention has no obvious appearance, dissolution time and clarity, uniformity of potassium and bicarbonate ion content, content, pH value, etc. before and after the test. The change indicates that the polyethylene glycol electrolyte particle preparation of the present invention is stable.
试验例 6 治疗效果  Test Example 6 Treatment effect
分别使用本发明制备例 1 的聚乙二醇电解质颗粒制剂和作为对照品的聚 乙二醇电解质散剂 （商品名舒泰清， 舒泰神（北京） 药业有限公司生产）进 行以下对照试验。  The following control test was carried out using the polyethylene glycol electrolyte granule preparation of Preparation Example 1 of the present invention and the polyethylene glycol electrolyte powder (trade name: Shu Taiqing, Shu Tai Shen (Beijing) Pharmaceutical Co., Ltd.) as a control, respectively.
功能性便秘患者对照性临床研究：  Controlled clinical study of patients with functional constipation:
56 例功能性便秘患者口服聚乙二醇电解质颗粒制剂 （ 13.8g/次， 溶于 125ml温水中成溶液， 2次 /天）后， 均表现出排便次数逐渐增加， 治疗后第 1、 2周排便次数明显高于治疗前。 治疗 2~4周后大便次数和性状恢复正常。 同时腹痛腹胀、 食欲不振等症状明显改善。 在治疗过程中， 未发生不良反应。  56 patients with functional constipation were treated with oral polyethylene glycol electrolyte granules (13. 8g/time, dissolved in 125ml warm water, 2 times/day), and the number of bowel movements increased gradually. The first and second weeks after treatment The number of bowel movements was significantly higher than before treatment. The number of stools and traits returned to normal after 2 to 4 weeks of treatment. At the same time, abdominal pain, bloating, loss of appetite and other symptoms improved significantly. No adverse reactions occurred during the treatment.
48例功能性便秘患者口服聚乙二醇电解质散剂 （商品名舒泰清， 舒泰神 (北京）药业有限公司生产）（13.8g/次， 溶于 125ml温水中成溶液， 2次 /天） 后， 47例表现出排便次数逐渐增加， 1例无明显改善。 治疗 3~4周后大便次 数和性状恢复正常。 在治疗过程中， 1例发生轻度不良反应。  48 patients with functional constipation oral polyethylene glycol electrolyte powder (trade name Shu Taiqing, Shu Tai Shen (Beijing) Pharmaceutical Co., Ltd.) (13.8g / time, dissolved in 125ml warm water into a solution, 2 times / day) 47 cases showed a gradual increase in the number of bowel movements, and 1 case showed no significant improvement. The number of stools and traits returned to normal after 3 to 4 weeks of treatment. During the course of treatment, 1 patient developed mild adverse reactions.
由上述试验结果可以看出， 聚乙二醇电解质颗粒制剂可有效改善功能性 便秘患者的排便次数和大便性状， 其作用优于聚乙二醇电解质散剂。  It can be seen from the above test results that the polyethylene glycol electrolyte granule preparation can effectively improve the frequency of defecation and stool characteristics in patients with functional constipation, and its effect is superior to that of polyethylene glycol electrolyte powder.
肠道清洁患者对照性临床研究： 82例需要肠道清洁患者分为 2组， 聚乙二醇电解质颗粒制剂组（41人） 和聚乙二醇电解质散剂组（41 人）， 分别口服聚乙二醇电解质颗粒制剂和聚 乙二醇电解质散剂。 服用方法为， 27.6g/次， 溶于 250ml温水中成溶液， 每隔 10~15分钟服用一次， 直到排出水样清便。 Controlled clinical study of intestinal cleansing patients: 82 patients requiring intestinal cleansing were divided into 2 groups, polyethylene glycol electrolyte particle preparation group (41 persons) and polyethylene glycol electrolyte powder group (41 persons), respectively, oral polyethylene glycol electrolyte particle preparation and polyethylene glycol Alcohol electrolyte powder. Take the method, 27.6g / time, dissolve in 250ml warm water into a solution, take it every 10~15 minutes, until the water sample is clear.
聚乙二醇电解质颗粒制剂组（41人）， 总有效率为 97.56%, 其中清肠效 果达到优、 良级者分别为 63.42%和 34.15%, 出现明显不良反应者 2.5% ( 1 人）。  In the polyethylene glycol electrolyte particle preparation group (41 persons), the total effective rate was 97.56%, of which 63.42% and 34.15% were good and good, and 2.5% (1) were obvious adverse reactions.
聚乙二醇电解质散剂组（41人）， 总有效率为 92.69%, 其中清肠效果达 到优、 良级者分别为 56.10%和 36.59%, 出现明显不良反应者 7.4% ( 3人）。  In the polyethylene glycol electrolyte powder group (41 persons), the total effective rate was 92.69%, of which the effect of clearing the intestine was 56.10% and 36.59%, and those with obvious adverse reactions were 7.4% (3 persons).
试验表明， 聚乙二醇电解质颗粒制剂组清肠效果优于聚乙二醇电解质散 剂对照组， 同时， 不良反应低于对照组。  The test showed that the effect of clearing the intestine of the polyethylene glycol electrolyte granule preparation group was better than that of the polyethylene glycol electrolyte powder control group, and the adverse reaction was lower than that of the control group.
本发明的优点是： 解决了聚乙二醇和电解质生产混合不均， 重量不可控， 使用繁瑣， 药粉粒径不均， 流动性不好及稳定性差等问题， 提供了一种聚乙 二醇和电解质混合均匀的颗粒制剂， 其质量可控， 口感好， 使用筒便， 疗效 确切， 安全可靠， 并其形成的等渗溶液， 能够保持结肠内水分不被吸收。 该 制备方法降低了聚乙二醇电解质散剂在使用中存在的上述弊端及聚乙二醇电 解质散剂副作用发生的几率， 提供了一种效果更好的通便及清肠药物， 其中 的技术进步是毋庸置疑的。  The invention has the advantages of: solving the problem of uneven mixing of polyethylene glycol and electrolyte production, uncontrollable weight, cumbersome use, uneven particle size, poor fluidity and poor stability, and providing a polyethylene glycol and electrolyte The uniformly mixed granule preparation has controllable quality, good mouthfeel, convenient use, safe and reliable use, and an isotonic solution formed thereof, which can keep the moisture in the colon from being absorbed. The preparation method reduces the above disadvantages of the polyethylene glycol electrolyte powder and the occurrence of side effects of the polyethylene glycol electrolyte powder, and provides a better laxative and intestinal medicine, wherein the technical progress is Undoubtedly.

Claims

权利 要求 书 Claim
1. 聚乙二醇电解质颗粒制剂， 其特征在于， 包括聚乙二醇电解质颗粒， 所述聚乙二醇电解质颗粒含有平均分子量为 3000~4000 的聚乙二醇和电解 质， 所述聚乙二醇电解质颗粒的 D90粒径是 180~850μηι。 A polyethylene glycol electrolyte granule preparation, comprising: polyethylene glycol electrolyte particles, the polyethylene glycol electrolyte particles comprising polyethylene glycol having an average molecular weight of 3000 to 4000 and an electrolyte, the polyethylene glycol The D90 particle size of the electrolyte particles is 180 to 850 μm.
2. 根据权利要求 1所述的聚乙二醇电解质颗粒制剂， 其中， 所述聚乙二 醇的平均分子量为 4000, 所述电解质为选自碳酸氢钠、 氯化钠、 氯化钾、 硫 酸钠中的两种以上电解质的混合物。  The polyethylene glycol electrolyte granule preparation according to claim 1, wherein the polyethylene glycol has an average molecular weight of 4000, and the electrolyte is selected from the group consisting of sodium hydrogencarbonate, sodium chloride, potassium chloride, and sulfuric acid. a mixture of two or more electrolytes in sodium.
3. 根据权利要求 1或 2所述的聚乙二醇电解质颗粒制剂， 其中， 相对于 聚乙二醇电解质颗粒制剂 100重量份， 所述聚乙二醇为 80~98重量份， 所述 电解质为 2~20重量份。  The polyethylene glycol electrolyte granule preparation according to claim 1 or 2, wherein the polyethylene glycol is 80 to 98 parts by weight, based on 100 parts by weight of the polyethylene glycol electrolyte particle preparation, the electrolyte It is 2 to 20 parts by weight.
4. 根据权利要求 1~3的任一项所述的聚乙二醇电解质颗粒制剂， 所述电 解质为碳酸氢钠、 氯化钠和氯化钾的混合物， 相对于所述聚乙二醇电解质颗 粒制剂 100重量份， 碳酸氢钠为 1~2重量份， 氯化钠为 1.5~3重量份， 氯化 钾为 0.2~1.2重量份。  The polyethylene glycol electrolyte granule preparation according to any one of claims 1 to 3, wherein the electrolyte is a mixture of sodium hydrogencarbonate, sodium chloride and potassium chloride, relative to the polyethylene glycol electrolyte The granule preparation is 100 parts by weight, sodium hydrogencarbonate is 1 to 2 parts by weight, sodium chloride is 1.5 to 3 parts by weight, and potassium chloride is 0.2 to 1.2 parts by weight.
5. 根据权利要求 1~4的任一项所述的聚乙二醇电解质颗粒制剂， 其中， 还含有甜味剂和 /或矫味剂，相对于所述聚乙二醇电解质颗粒制剂 100重量份， 所述甜味剂为 0.05~1.5重量份， 所述矫味剂为 0.2~1重量份。  The polyethylene glycol electrolyte granule preparation according to any one of claims 1 to 4, further comprising a sweetener and/or a flavoring agent, 100 parts by weight relative to the polyethylene glycol electrolyte granule preparation The sweetener is 0.05 to 1.5 parts by weight, and the flavoring agent is 0.2 to 1 part by weight.
6. 根据权利要求 1~5的任一项所述的聚乙二醇电解质颗粒制剂， 其中， 所述聚乙二醇电解质颗粒制剂 13.08g~14.45g用 40°C~50°C的水配成 125ml溶 液时， 渗透压在 280~330mOsmol/kg的范围内。  The polyethylene glycol electrolyte granule preparation according to any one of claims 1 to 5, wherein the polyethylene glycol electrolyte granule preparation 13.08 g to 14.45 g is mixed with water at 40 ° C to 50 ° C. When the solution is 125 ml, the osmotic pressure is in the range of 280 to 330 mOsmol/kg.
7. 聚乙二醇电解质颗粒制剂的制造方法， 其包括以下步骤： 将平均分子 量为 3000~4000的聚乙二醇和电解质分别粉碎成细粒， 将这些细粒混合后， 加入润湿剂制软材， 然后进行制粒， 干燥， 形成 D90粒径 180μηι ~850μηι的 聚乙二醇电解质颗粒。  A method for producing a polyethylene glycol electrolyte granule preparation, comprising the steps of: pulverizing polyethylene glycol having an average molecular weight of 3,000 to 4,000 into fine particles, mixing the fine particles, and adding a wetting agent to make a soft The material was then granulated and dried to form polyethylene glycol electrolyte particles having a D90 particle size of 180 μm to 850 μm.
8. 根据权利要求 7所述的聚乙二醇电解质颗粒制剂的制造方法， 其中， 在所述电解质中混入甜味剂后进行粉碎。  The method for producing a polyethylene glycol electrolyte granule preparation according to claim 7, wherein the electrolyte is mixed with a sweetener and then pulverized.
9. 根据权利要求 7或 8所述的聚乙二醇电解质颗粒制剂的制造方法， 其 中， 在粉碎时， 将聚乙二醇粉碎成 D90粒径为 150μηι ~250μηι的细粒， 将电 解质粉碎成 D90粒径为 125μηι ~250μηι的细粒。 The method for producing a polyethylene glycol electrolyte granule preparation according to claim 7 or 8, wherein, in the pulverization, the polyethylene glycol is pulverized into fine particles having a D90 particle diameter of 150 μm to 250 μm, and electricity is charged. The solution was pulverized into fine particles having a D90 particle size of 125 μm to 250 μm.
10. 根据权利要求 7~9的任一项所述的聚乙二醇电解质颗粒制剂的制造 方法， 其中， 所述润湿剂为乙醇浓度为 80体积％以上的乙醇水溶液。  The method for producing a polyethylene glycol electrolyte granule preparation according to any one of claims 7 to 9, wherein the wetting agent is an aqueous ethanol solution having an ethanol concentration of 80% by volume or more.
11.根据权利要求 7~10的任一项所述的聚乙二醇电解质颗粒制剂的制造 方法，其中，相对于聚乙二醇和电解质的总量，润湿剂的用量为 5 ~20重量％。  The method for producing a polyethylene glycol electrolyte granule preparation according to any one of claims 7 to 10, wherein the wetting agent is used in an amount of 5 to 20% by weight based on the total amount of the polyethylene glycol and the electrolyte. .
12.根据权利要求 7~11的任一项所述的聚乙二醇电解质颗粒制剂的制造 方法， 其中， 聚乙二醇与电解质的重量比为 80~98： 20~2。  The method for producing a polyethylene glycol electrolyte granule preparation according to any one of claims 7 to 11, wherein a weight ratio of the polyethylene glycol to the electrolyte is 80 to 98: 20 to 2.
13.根据权利要求 7~12的任一项所述的聚乙二醇电解质颗粒制剂的制造 方法， 其中， 干燥时的温度为 10°C ~ 60°C。  The method for producing a polyethylene glycol electrolyte granule preparation according to any one of claims 7 to 12, wherein the temperature at the time of drying is from 10 ° C to 60 ° C.
14.通过权利要求 7~13的任一项所述的制造方法制造得到的聚乙二醇电 解质颗粒制剂。  A polyethylene glycol electrolyte granule preparation produced by the production method according to any one of claims 7 to 13.
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