WO2023130594A1 - 一种阿拉伯糖及其制剂和用途 - Google Patents

一种阿拉伯糖及其制剂和用途 Download PDF

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WO2023130594A1
WO2023130594A1 PCT/CN2022/083083 CN2022083083W WO2023130594A1 WO 2023130594 A1 WO2023130594 A1 WO 2023130594A1 CN 2022083083 W CN2022083083 W CN 2022083083W WO 2023130594 A1 WO2023130594 A1 WO 2023130594A1
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arabinose
preparation
raw material
activated carbon
crystal
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PCT/CN2022/083083
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English (en)
French (fr)
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石国良
林卫军
蔡许彬
王羽娟
肖永成
萧舜之
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唐传生物科技（厦门）有限公司
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Priority claimed from CN202210010286.6A external-priority patent/CN116444584A/zh
Priority claimed from CN202210101531.4A external-priority patent/CN116554239A/zh
Application filed by 唐传生物科技（厦门）有限公司 filed Critical 唐传生物科技（厦门）有限公司
Priority to EP22799828.3A priority Critical patent/EP4230635A4/en
Priority to US17/998,902 priority patent/US20230406876A1/en
Priority to JP2022577570A priority patent/JP7531240B2/ja
Publication of WO2023130594A1 publication Critical patent/WO2023130594A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/02—Monosaccharides
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification

Definitions

  • the invention relates to the field of medicine and chemical industry, in particular to arabinose and its preparation and application.
  • colonoscopy has been widely used clinically and has become one of the main means of diagnosis and treatment of various intestinal diseases.
  • Colonoscopy is largely affected by bowel preparation, and it is extremely important to make adequate bowel preparation before surgery to improve the image quality of colonoscopy to improve the detection rate of colonic diseases.
  • L-arabinose (L-arabinose, C 5 H 10 O 5 ) is an aldopentose, also known as L(+)-aldoglucanose. Originally a monosaccharide isolated from gum arabic. Free L-arabinose rarely exists in nature. It is usually combined with other monosaccharides and exists in gum, hemicellulose, bacterial polysaccharides and some glycosides in the form of heteropolysaccharides. Free L-arabinose is only found in Coniferaceae Found in the corewood of trees. L-arabinose is more and more widely used in food, medicine and other fields. Studies have found that L-arabinose has the effect of assisting in lowering blood sugar and assisting weight loss, as well as a good laxative function. Research on the preparation process of production is not enough.
  • the Chinese patent document with publication number CN102146102A discloses the extraction of L-arabinose from gum arabic. After acid catalyzed hydrolysis, alkali neutralization and concentration, extraction with ketones, alcohols and ethers, a large amount of organic solvents are used in the process, which seriously pollutes the environment.
  • the Chinese patent document whose publication number is CN1373135A discloses a method for extracting arabinose from gum arabic by a two-column method. After the method is hydrolyzed with an inorganic acid, it is neutralized with alkali and extracted with alcohol. The mixture of rhamnose and arabinose obtained is then passed through For column separation, a large amount of organic solvents such as n-butanol, ethyl acetate, isopropanol and acetic acid are used as the column developer. Although the purity reaches 99.5%, the process is complicated, and the organic solvent is easy to pollute the environment, so it is not an environmentally friendly process.
  • the Chinese patent document with the publication number CN104744525A discloses a method for extracting arabinose from gum arabic.
  • the raw material undergoes hydrolysis, alkali neutralization, adsorption decolorization, electrodialysis desalination, adsorption separation to remove impurities and crystallization, and the purity reaches 98%.
  • the aforementioned process is more environmentally friendly, but the crystallization process also uses organic solvents such as methanol/ethanol to melt, and the cooling crystallization takes 24 to 72 hours to obtain L-arabinose powder.
  • L-arabinose products have good application prospects in bowel cleansers, but they still face a series of problems when they are further developed into pharmaceutical preparations: for example, arabinose needs to be formulated with other excipients for administration, which leads to large doses When the preparation is taken, the increase in the introduction of impurities will lead to an increase in safety risks. For example, the preparation is difficult to meet the quality standards of the Pharmacopoeia or the process is complicated, the cost is high, and it is not suitable for industrial production.
  • Granules refer to dry granule preparations with a certain particle size made by mixing raw materials and suitable auxiliary materials.
  • the particle size range stipulated in "Chinese Pharmacopoeia” (2020) is that the sum of coarse particles that cannot pass through No. 1 sieve (10 mesh, 2000um) and No. 5 sieve (80 mesh, 180um aperture) cannot exceed 15%.
  • the Chinese patent application with the publication number CN111202244A discloses a granular arabinose.
  • the preparation method used is to use the arabinose solution as a binder so that no additional binder is added, so that the arabinose powder is in the presence of the binder
  • the granulation is completed, but the obtained arabinose granules still have 38-78% under 80 mesh, which does not meet the requirements of the general principles of pharmacopoeia granules, and in this application, the obtained granulated arabinose still needs to be combined with other sweeteners
  • Flavoring agents and other auxiliary materials are compounded and mixed to further make granules and capsules.
  • the present invention provides an L-arabinose, and the arabinose is ⁇ -L-(+)-arabinose.
  • the L-arabinose has the following crystal structure (single crystal),
  • the crystal structure is orthorhombic
  • the space group is P2 1 2 1 2 1 ,
  • the unit cell parameters are:
  • the crystal of L-arabinose uses Cu-K ⁇ radiation, and the X-ray powder diffraction represented by 2 ⁇ angle is at 14.416 ⁇ 0.20°, 16.450 ⁇ 0.20°, 20.556 ⁇ 0.20°, 27.443 ⁇ 0.20 °, 27.828 ⁇ 0.20°, 33.161 ⁇ 0.20° have characteristic peaks.
  • the crystal of L-arabinose uses Cu-K ⁇ radiation, and the X-ray powder diffraction in 2 ⁇ angle is 14.416 ⁇ 0.20°, 16.450 ⁇ 0.20°, 20.556 ⁇ 0.20°, 22.943 ⁇ 0.20°, 27.443 ⁇ There are characteristic peaks at 0.20°, 27.828 ⁇ 0.20°, and 33.161 ⁇ 0.20°.
  • the crystal has a powder X-ray diffraction pattern substantially as shown in FIG. 1 .
  • the crystal has an infrared spectrum substantially as shown in FIG. 2 .
  • the average particle size of the L-arabinose ranges from 100-600um, preferably 100-300um, such as 110, 120, 130, 140, 150, 160, 170, 180, 190 , 200, 210, 220, 230, 240, 250, 260, 270, 280, 290um.
  • the L-arabinose contains ⁇ 0.04% galactose, preferably, the L-arabinose contains ⁇ 0.01% galactose; more preferably, contains 0.005% galactose.
  • the present invention also provides a method for preparing the L-arabinose.
  • the preparation method adopts scheme one, comprising the following steps:
  • step (2) Take about half of the filtered sugar solution obtained in step (1) into an evaporation crystallization tank, evaporate until the sugar content reaches 55-65% Brix, add an appropriate amount of L-arabinose raw material as a seed crystal, and start feeding the remaining About half of the filtrated sugar solution, after the end of feeding, continued to concentrate.
  • the L-arabinose raw material is ground and sieved evenly as a seed crystal.
  • a conventional industrial sieve 40-200 mesh
  • a pharmacopoeia standard sieve No. 3, No. 4, No. 5, No. 6, No. 7, No. 8, and No. 9 sieves
  • No. 5 and No. 6 pharmacopoeia standard sieves for example, No. 5 and No. 6 pharmacopoeia standard sieves
  • the L-arabinose raw material is ground through No. 5 and No. 6 Pharmacopoeia standard sieve, take the part that can pass through No. 5 but cannot pass through No. 6 sieve.
  • the mass ratio of raw material to water is 1:0.5-3, preferably 1:1-1.5, for example 1:1.1, 1:1.2; raw material
  • the mass ratio to activated carbon is 1:0.0005-0.01, preferably 1:0.0005-0.0015, for example 1:0.0005, 1:0.001;
  • the feeding time is 6-24 hours, such as 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 hours, preferably, the feeding time is 6-12 hours ;
  • the supersaturation of the sugar solution is controlled between 1.01-1.19, preferably between 1.01-1.10, more preferably between 1.03-1.08.
  • step (2) it is preferred to evaporate until the sugar content of the sugar solution is 55-60% Brix, such as 56, 57, 58, 59% Brix, more preferably 58-60% Brix; 2 hours; preferably, the time from adding the seed crystal to discharging is 10-15 hours, for example, about 14 hours.
  • the sugar content of the sugar solution is 55-60% Brix, such as 56, 57, 58, 59% Brix, more preferably 58-60% Brix; 2 hours; preferably, the time from adding the seed crystal to discharging is 10-15 hours, for example, about 14 hours.
  • the preparation method adopts scheme two, including the following steps:
  • the obtained material is put into a reaction kettle for concentration.
  • concentration is 55-65% Brix
  • an appropriate amount of L-arabinose raw material is added as a seed crystal, and the temperature is lowered at a rate of 0.5-2° C. per hour.
  • the seed crystal used in the second scheme is the same as that used in the first scheme.
  • the mass ratio of raw material to water is 1:0.5-3, preferably 1:1-1.5, such as 1:1-1.2; raw material and activated carbon
  • the mass ratio of the activated carbon is 1:0.0005-0.01, for example, 1:0.0005; the temperature for activated carbon adsorption is 55-70°C, and the adsorption time is 20-60min.
  • step (2) it is preferred to concentrate until the sugar content of the sugar solution is 58-60% Brix; the preferred cooling rate is 0.5-1.5° C. per hour, for example, 1° C. per hour.
  • the present invention also provides L-arabinose obtained by the preparation method.
  • the present invention also provides a preparation containing the L-arabinose.
  • the formulations may be presented in unit dose form or in multiple dose form.
  • the preparation is in unit dosage form, containing 1-100g L-arabinose, preferably containing 20g-60g L-arabinose, for example containing 20, 30, 40, 50, 60g L-arabinose.
  • the single daily dosage is 20-75g.
  • the preparation is an aqueous solution of the L-arabinose, and in the aqueous solution, the concentration of the L-arabinose is 0.1-0.6 g/ml (calculated in grams of L-arabinose in ml of water) ), preferably 0.2-0.5 g/ml, for example 0.2, 0.3, 0.4 g/ml.
  • the present invention provides a granule of L-arabinose.
  • the L-arabinose granule contains the L-arabinose described in the first aspect above, or the L-arabinose obtained according to the preparation process in the third aspect above.
  • the present invention provides a method for preparing the L-arabinose granule, comprising the following steps:
  • step (2) Take 40%-55% (v%) of the filtered sugar solution obtained in step (1), evaporate it until the sugar content reaches 55-65% Brix, and add an appropriate amount of L-arabinose raw material as a seed crystal , start to add the remaining filtered sugar solution, after the end of the addition, continue to concentrate.
  • the L-arabinose raw material used as a seed crystal is 40-200 mesh, such as 40, 60, 80 mesh, 100 mesh, preferably 80-100 mesh.
  • the seed crystals can be obtained by grinding and sieving the L-arabinose raw material, for example, conventional industrial sieves (40-200 mesh) or pharmacopoeia standard sieves (No. No. 5, No. 6, No. 7, No. 8, and No. 9 sieves), for example, obtained by using No. 5 and No. 6 pharmacopoeia standard sieves; in some embodiments, the L-arabinose raw material is ground through No. 5 and No. 6 Pharmacopoeia standard sieve, take the part that can pass through No. 5 but cannot pass through No. 6 sieve as seed crystal.
  • the amount of the seed crystal can be 0.05%-1% of the input mass of the L-arabinose raw material; for example, 0.05%, 0.1%, 0.2% of the input mass of the L-arabinose raw material, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%.
  • the mass ratio of the raw material to water is 1:0.5-3, preferably 1:1-1.5, such as 1:1.1, 1:1.2; the raw material and The mass ratio of activated carbon is 1:0.0005-0.01, preferably 1:0.0005-0.0015, such as 1:0.0005, 1:0.001; preferably, microporous membrane vacuum filtration, or plate and frame filtration or plate microfiltration can be used Membrane filtration to remove activated carbon; the microporous membrane can be selected in sequence of 25 ⁇ m and 0.45 ⁇ m; preferably, activated carbon is added at 50-70 ° C, after adding activated carbon, it can be stirred at 50-70 ° C for 20-40 minutes, such as stirring for 30 minute.
  • step (2) it is preferred to evaporate until the sugar content of the sugar solution is 55-60% Brix, such as 56, 57, 58, 59% Brix; -70°C, more preferably, the evaporation temperature is 58-65°C, such as 60, 61, 62, 63, 64, 65°C; preferably, the time from adding the seed crystal to discharging is 10-15 hours, such as About 14 hours; Preferably, start agitation during the evaporation process, and the agitation speed is 90-110rpm; type) or single-layer 3-6 blade propulsion type supplemented by forced circulation; preferably, the feeding time is 6 to 24 hours, such as 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , 20h, in some preferred embodiments, feeding time is 8-15h; In described feeding process, the degree of supersaturation of sugar solution is controlled between 1.01-1.19, is preferably controlled between 1.01-1.10, more The preferred control is between 1.03-1.08.
  • the evaporation can adopt a reduced pressure condition.
  • the method further includes the steps of:
  • the evaporation time is 1-3 hours, such as 2 hours; preferably, the concentration of the sugar cake is evaporated to 75%-80%, such as 75, 76, 77, 78, 79, 80%.
  • the drying may be selected from one or more of boiling drying, fluidized bed drying, and reduced pressure drying.
  • the step (4) is specifically:
  • boiling drying adopts wind temperature of 90-105°C and material temperature of 60-80°C; in the fluidized bed drying, the temperature is gradually lowered, preferably, the inlet air is 40-50°C, and the temperature is low (such as 15-25°C). Air-cooled and air-blown, and finally cooled to room temperature.
  • boiling drying in a back-mixed bed can be used; in the drying process, a star feeder or a rotary feeder can be used for feeding, preferably, the feeding The feeding process is supplemented by vibration.
  • the step (4) specifically includes: adopting artificial paving, and vacuum drying in an oven under reduced pressure.
  • the method further includes step (5): packaging.
  • step (5) packaging.
  • a vibrating blanking method is used, and the amount is quantified through linear weighing.
  • the method optionally includes the step of further sieving the dried particles.
  • the arabinose is ⁇ -L-(+)-arabinose.
  • the L-arabinose granules contain the L-arabinose described in the first aspect above, or the L-arabinose obtained according to the preparation process in the third aspect above.
  • the present invention also provides the L-arabinose granules obtained by the preparation method.
  • the average particle size of the L-arabinose particles is in the range of 100-600um, preferably 100-300um, such as 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290um.
  • the D10 of the L-arabinose particles is 40-200 ⁇ m, preferably 40-100 ⁇ m, such as 40, 50, 60, 70, 80, 90, 100 ⁇ m;
  • the D50 of the L-arabinose particles is 80- 200 ⁇ m, preferably 90-150 ⁇ m, such as 90, 100, 110, 120, 130, 140, 150 ⁇ m;
  • the D90 of the L-arabinose particles is 150-300 ⁇ m, preferably 200-250 ⁇ m, such as 200, 210, 220, 230, 240, 250um.
  • the granules may be in unit dose form or in multi-dose form.
  • the granules are in unit dose form, containing 1-100 g of L-arabinose, for example containing 1, 5, 10, 20, 30, 40, 50, 60 g of L-arabinose.
  • the single daily dose of the granules is 20-75g; in other embodiments, the single daily dose of the granules is 3-20g.
  • the present invention also provides the aforementioned L-arabinose and its preparations (including the L-arabinose and its preparations involved in the first, third, fourth, fifth, and seventh aspects) for bowel cleansing and/or bowel preparation Methods.
  • 20g-60g of the L-arabinose and the preparation can be administered each time, for example, 20, 30, 40, 50, 60g each time; complete once For bowel cleansing and/or bowel preparation, the total dosage of the L-arabinose and preparations given is 20-75g.
  • the present invention provides the L-arabinose granules for use in methods of bowel cleansing and/or bowel preparation, weight management, and improvement and/or treatment of constipation.
  • 20g-60g of the L-arabinose granules can be administered each time, such as 20, 30, 40, 50, 60g each time; in some implementations
  • the total dose of the L-arabinose granules administered is 20-75g after completing one bowel cleansing and/or bowel preparation; in other embodiments, when the granules are used for weight control, improvement and /or when treating constipation, 3-20 g of the L-arabinose granule is administered daily.
  • the present invention also provides the L-arabinose and its preparations (including the L-arabinose and its preparations involved in the first, third, fourth, fifth, and seventh aspects) for preparing bowel cleansing and/or bowel preparation use of the drug.
  • the present invention provides the use of the L-arabinose granules for preparing medicines for bowel cleansing and/or bowel preparation, weight control, and improvement and/or treatment of constipation.
  • the L-arabinose product prepared by the present invention is identified as a single ⁇ crystal form after single crystal cultivation.
  • the L-arabinose product prepared by the present invention can be directly applied as an intestinal cleanser drug without adding other adjuvants, has good fluidity, is safe and effective, and greatly improves the taste and taste of the intestinal preparation drug and the range of doses that can be taken.
  • Significantly enhanced patient compliance reduced the resistance of most patients to drinking traditional intestinal preparation drugs, and was comprehensively superior to traditional clinically recommended drugs such as magnesium sulfate and PEG, and also had certain advantages over sorbitol hypertonic solution.
  • the preparation process adopted in the present invention is simple and easy, and the crystallization process does not require the use of organic solvents, which is environmentally safe and easy to control the particle size range of the product.
  • the purity of the obtained product can reach more than 99.6%, and the single impurity is controlled within the limit of 0.05%, which can meet the standard of high-quality intestinal preparation raw materials.
  • the process of the present invention can control the fructose content in the product to 0.5%. Lactose content is controlled at 0.01-0.04%, which can reduce or avoid the unnecessary impact and burden on patients caused by the absorption of fructose and galactose impurities, and is especially suitable for those who are fructose intolerant to take the product safely.
  • the present invention does not need to add any auxiliary materials, and does not need complicated granulation process. The particle size and quality requirements of granules in the current Pharmacopoeia.
  • Fig. 1 is the powder X-ray diffraction pattern of L-arabinose of the present invention
  • Fig. 2 is the infrared spectrogram of L-arabinose of the present invention
  • Figure 3 schematically shows the single crystal diffraction structure of L-arabinose
  • Figure 4 shows the saturation curve and crystallization curve of arabinose.
  • L-arabinose raw material used in the following examples purchased from Tang Chuan Biotechnology (Xiamen) Co., Ltd., with a purity of ⁇ 99% (in line with the national standard for L-arabinose QB/T 4321-2012).
  • fed-feeding is one of the conventional operations of evaporative crystallization, that is, water is evaporated while continuously supplementing the sugar solution to keep the liquid concentration of the sugar solution in the system relatively constant.
  • the supersaturation of the sugar solution is not more than 1.10.
  • the crystal of the L-arabinose uses Cu-K ⁇ radiation, and the X-ray powder diffraction represented by 2 ⁇ angle adopts a testing instrument that is a D8 advance (Bruker) X-ray diffractometer, and the instrument parameters are as follows:
  • Termination angle 40°(2-theta);
  • the L-arabinose product prepared in Example 1 was identified as ⁇ -L-(+)-arabinose by single crystal diffractometer after single crystal cultivation.
  • the L-arabinose single crystal is cultivated by the interfacial diffusion method: Weigh 20g of the prepared L-arabinose and dissolve it in 20ml of deionized water. After it is completely dissolved and cooled to room temperature, add 40ml of ethanol along the inner wall of the beaker And seal with plastic wrap to prevent ethanol from evaporating, and try to avoid solution shaking during the process of adding ethanol and sealing.
  • the beaker was placed in a constant temperature water bath, and the temperature was set at 30°C, and L-arabinose single crystal was obtained after about one month.
  • the crystal is orthorhombic, the space group is P2 1 2 1 2 1 , and the unit cell parameters are:
  • Sugar dissolving Add 25L of water and 22kg of L-arabinose raw material into the sugar dissolving tank, start stirring when adding L-arabinose raw material, after heating and dissolving completely, add 22g of activated carbon, and keep it at 55-70°C for 20-60min for adsorption. After the active carbon is filtered and removed, the material is added to the reaction kettle for concentration. When the concentration is 60% Brix, an appropriate amount of L-arabinose raw material is added as a seed crystal (the seed crystal is the L-arabinose raw material that is ground and sieved (5 ⁇ No. 6 Pharmacopoeia standard sieve) powder, take the part that can pass through No. 5 but cannot pass through No. 6 sieve), and the seeding temperature is 60°C.
  • the stirring rate was adjusted to 50 rpm, and the cooling program was executed.
  • the initial cooling temperature was 60° C., and the cooling rate was about 1° C./h.
  • the liquid chromatographic results are shown in the table below (% purity is calculated by the area normalization method, i.e. the ratio of the components to be measured to account for the total peak area of the sample):
  • Example 2 After testing, the product of Example 2 does not contain D-arabinose (document (Higaki S, et al., Journal of the Food Hygienic Society of Japan, 2018, 59(3): 114-120) records that D-arabinose Arabinose is toxic and has food safety hazards) and furfural.
  • embodiment 3 The operation of embodiment 3 is basically the same as that of embodiment 2, the cooling rate is increased to about 2° C./h, and the crystallization period is shortened to 16 hours, which is close to the crystallization period of evaporative feeding crystallization.
  • the yield of crystallized product is 40.8%.
  • the average particle size is 125um
  • D50 109um
  • D90 232um.
  • SPF mice were randomly divided into blank control group, positive control group and test group, 20 in each group, half male and half male.
  • the dosage of each group is shown in Table 1 below.
  • Administration method the animals in each group were fasted at 22:00 the night before the test, and were given 1/3 of the calculated dose at 7:00, 9:00, and 11:00 on the day of the test (gastric administration), and at 12:00 and 13:00 At 14:00 and 14:00, respectively, 0.1 mL of pure water was given by intragastric administration, and the animals were dissected 3.5 hours after the last administration.
  • the subjects had an empty stomach in the morning and drank water normally after getting up;
  • the whole process consumes about 1L of water and takes 3 and a half hours.
  • the L-arabinose product prepared by the present invention can be directly taken with water, the taking process is convenient, the dosage is appropriate, and it can effectively meet the needs of preoperative bowel cleansing preparation or colonoscopy and other intestinal cleansing preparations.
  • Osmotic pressure A and Osmotic pressure B respectively represent the results of parallel testing of samples with the same number.
  • the average osmolality is the average value of the osmolality A and the osmolality B.
  • the osmotic pressure of L-arabinose with the same mass concentration is 22.8% higher than that of sorbitol hypertonic solution, which shows that after oral administration of the L-arabinose solution of the present invention, the osmotic pressure effect based on the solution itself , can enhance the intestinal osmotic pressure, which has certain advantages compared with sorbitol hypertonic solution.
  • fed-feeding is one of the conventional operations of evaporative crystallization, that is, water is evaporated while continuously supplementing the sugar solution to keep the liquid concentration of the sugar solution in the system relatively constant.
  • the supersaturation of the sugar solution is controlled within the range of 1.01-1.10.
  • the specific surface area and particle number of the seed crystal are detected by the dynamic image particle size and particle type analysis system.
  • the L-arabinose product was prepared by using Example 8, which was identified as ⁇ -L-(+)-arabinose by single crystal diffractometer. grown in single crystals. Cultivate L-arabinose single crystal by interfacial diffusion method: Weigh 40g of the prepared L-arabinose and dissolve it in 40ml of deionized water. After it is completely dissolved and cooled to room temperature, add 80ml of ethanol along the inner wall of the beaker and seal it with plastic wrap to prevent ethanol. Avoid shaking the solution as much as possible during evaporation, ethanol addition and sealing. The beaker was placed in a constant temperature water bath, and the temperature was set at 30°C. After about 15 days, a single crystal of L-arabinose was obtained. The crystal is orthorhombic, and the space group is P2 1 2 1 2 1 .
  • Half of the filtrated supernatant was fed at a speed of about 600L/h, and the feeding time was 12 hours, and then evaporated and crystallized under reduced pressure; after the feeding was completed, the evaporation was continued for about 2 hours, and when the sugar cake concentration was 81%, the material was centrifuged.
  • Use the auger to continuously feed the material back to the mixed bed for boiling drying (air temperature 90-105°C, material temperature 60-80°C), then fluidized bed drying and gradually lowering the temperature (inlet air 40-50°C, low temperature 15-25°C for lyophilization) wind blowing), pack after cooling to normal temperature.
  • sucgar cake refers to the solid-liquid mixture of arabinose crystals and sugar liquid
  • sucgar cake concentration refers to the concentration of arabinose in the solid-liquid mixture
  • superscript a means that the sample is dried by auger feeding in the drying process-returning mixed bed drying method
  • superscript b means that the sample is sampled after centrifugation-artificial spreading in an oven drying method.
  • Half of the filtered clear liquid is fed at a rate of 2-2.3L/h, and the feeding time is 12 hours; after the feeding is completed, continue to evaporate for about 2 hours, and when the sugar cake concentration reaches 78%, the material is centrifuged and passed through a manual spreading oven dry.
  • Half of the filtered clear liquid is fed at a rate of 2-2.3L/h, and the feeding time is 12 hours; after the feeding is completed, continue to evaporate for about 2 hours, and when the sugar cake concentration reaches 78%, the material is centrifuged and passed through a manual spreading oven Dry (vacuum drying under reduced pressure).
  • Embodiment 13 Granule performance test result of the present invention
  • Example 10 The first batch Example 10 The second batch Example 11 Example 12 Mobility (Angle of Repose) better better better better Liquidity (Hausnaby) good good passable good Hausnaby 1.2 1.2 1.3 1.3 Compression 17.1 15.9 23.1 24.4 Karl Liquidity Index 100.5 102.5 102.0 99 Jetness index 75.0 75.0 75.0 75.0 angle of repose 40.01 30.95 34.29 39.74 Tap density 0.85 0.81 0.65 0.64 loose density 0.7 0.68 0.5 0.48
  • the superscript a means that the sample adopts the auger feeding-return mixed bed drying method; the superscript b means that the sample adopts the centrifuged sampling-artificial spreading oven drying method.
  • Example 10 Operate with reference to the technique of Example 10, only replace the feeding mode to be a star feeder, and correspondingly, reduce the material spreading height of the back-mixing bed boiling drying to below about 1/3, that is, the material spreading thickness is less than 16cm (original height about 50cm).
  • Example 14 80 ⁇ 100 mesh/15kg 12 hours 94.3% 89%
  • the superscript a means that the sample is sampled after centrifugation-artificial spreading in an oven drying method; the superscript c means that the sample is fed by a star valve-back mixed bed drying.
  • the round-bottomed flask was placed in a temperature-controllable incubator, and in a three-neck round-bottomed flask (one bottle mouth was plugged with a rubber stopper as a sampling port, one bottle mouth was used as a stirring paddle placement port, and the other bottle mouth was used as a temperature probe port)
  • Add a certain amount of ionized water and add excess L-arabinose crystals (prepared according to the method in Example 10), stir at 40°C, 49°C, 53°C, 58°C and 65°C for 3 hours, and then let stand for 4h , so that the undissolved L-arabinose crystals fully settle, and then take the supernatant and filter it with a microporous membrane (used for filtering a small sample needle in a thermostat to exclude the influence of temperature changes), and use the filtered clear liquid to measure the concentration .
  • a microporous membrane used for filtering a small sample needle in a thermostat to exclude the influence of temperature changes
  • the L-arabinose finished product prepared in Example 14 is used for packaging, the packaging speed is 15-40 bags/min, single channel, and the airtightness and filling capacity are checked during the packaging process to meet the production requirements.
  • the vibrating feeding method is adopted, and the obtained L-arabinose granules meet the requirements of the 2020 Pharmacopoeia for particle size and loading volume after linear weighing and quantification.
  • the packaging specification currently selected for this type of equipment is 1-30 grams, the packaging specification is 5 grams, and the size of the preparation bag is 65mm*85mm; for 20 grams, the size of the preparation bag is 65mm*130mm. If the packaging capacity is 31-100 grams, it is only necessary to replace the equipment bag maker and former according to the size of the preparation bag.

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Abstract

本发明涉及一种L-阿拉伯糖及其制剂和用途，所述L-阿拉伯糖及其制剂通过如下工艺制备：(1)将L-阿拉伯糖原料溶解于水中，加入活性炭过滤，除去活性炭，得到滤清的糖液，(2)取步骤(1)得到的滤清糖液的40％-55％(v％)，将其蒸发至糖液糖度至55-65％Brix，加入适量L-阿拉伯糖原料作为晶种后，开始流加剩余的滤清糖液，流加结束后，继续浓缩。所述阿拉伯糖及其制剂在制备过程中，无需添加任何辅料，同时也不需要复杂的制粒加工过程，所得产品可直接应用为肠道清洁剂药物，粒径范围可控，安全有效，适于制剂吸收，极大提高了肠道准备药物的口感口味和可服用剂量范围，明显增强了患者依从性，降低大部分患者喝传统肠道准备药物的抵触心理，全面优于传统的临床推荐用药。

Description

一种阿拉伯糖及其制剂和用途
本申请要求2022年1月6日向中国国家知识产权局提交的，专利申请号为202210010286.6，发明名称为“一种L-阿拉伯糖及其制备方法和用途”以及2022年1月27日向中国国家知识产权局提交的，专利申请号为202210101531.4，发明名称为“一种阿拉伯糖颗粒剂及其制备方法和用途”的两件在先申请的优先权。所述两件申请的全文通过引用的方式结合于本申请中。
技术领域
本发明涉及医药化工领域，具体涉及一种阿拉伯糖及其制剂和用途。
背景技术
随着内镜技术的发展，肠镜检查在临床得到广泛应用，成为诊治各种肠道疾病的主要手段之一。肠镜检查在很大程度上受到肠道准备影响，术前做好充分的肠道准备以提高结肠镜图像质量对于提高结肠疾病检出率是极其重要的。
同时，传统肠道清洁的过程中，硫酸镁，PEG等的口感让许多人难以接受，再加上口服剂量大，导致患者服用困难，服用量没有遵照遗嘱执行，依从性下降，是清肠不彻底的重要因素。
L-阿拉伯糖(L-arabinose，C 5H 10O 5)是一种戊醛糖，又称L(+)-树胶醛糖。最初是从阿拉伯树胶中分离得到的单糖。自然界极少存在游离态L-阿拉伯糖，它通常是与其它单糖结合，以杂多糖的形式存在于胶质、半纤维素、细菌多糖及某些糖苷中，游离态L-阿拉伯糖只在松柏科树木的芯材中被发现过。L-阿拉伯糖在食品，医药等领域的应用越来越广泛。研究发现，L-阿拉伯糖具有辅助降血糖和辅助减肥的功效以及良好的润肠通便功能，但现有技术中对于L-阿拉伯糖药用产品的开发以及关于其利于药用安全、规模化生产的制备工艺方面的研究尚不足够。
公开号为CN102146102A的中国专利文献公开了以阿拉伯胶为原料提取L-阿拉伯糖。用酸催化水解后，碱中和浓缩后用酮、醇和醚类萃取，工艺过程用到大量有机溶剂，严重污染环境。
公开号为CN1373135A的中国专利文献公开了通过两柱法从阿拉伯胶提取阿拉伯糖的方法，该法用无机酸水解后，碱中和，醇萃取，所得的鼠李糖和阿拉伯糖的混合物再经过柱分离，柱展开剂用的是正丁醇、乙酸乙酯、异丙醇和乙酸等大量有机溶剂，虽然纯度达到99.5％，但是工序复杂，而且有机溶剂容易污染环境，不是环境友好型工艺。
公开号为CN104744525A的中国专利文献公开了从阿拉伯胶提取阿拉伯糖的方法，原料经过水解、碱中和、吸附脱色、电渗析脱盐，吸附分离去杂质和结晶，纯度达到98％。前述工艺过程比较环保，但是其结晶过程也用到了甲醇/乙醇等有机溶剂热溶，冷却结晶时长24到72小时，才得到L-阿拉伯糖粉末。
L-阿拉伯糖产品在清肠剂方面具有较好的应用前景，但其在进一步开发为可药用制剂时仍然面临一系列问题：如阿拉伯糖需要与其他辅料配伍制剂以便服用，进而导致大剂量制剂服用时由于杂质引入增加而导致安全性风险增加，如制剂难以符合药典质量标准或工艺复杂、成本高进而不适用于工业化生产等。
颗粒剂系指原料药物与适宜的辅料混合制成具有一定粒度的干燥颗粒状制剂。《中国药典》(2020年)规定的粒度范围是不能通过1号筛(10目，2000um)的粗粒和能通过5号筛(80目，180um孔径)之和不能超过15％。
公开号为CN111202244A的中国专利申请公开了一种颗粒状阿拉伯糖，所使用的制备方法是利用阿拉伯糖溶液作为粘合剂从而不必额外加入粘合剂，使得阿拉伯糖粉末在该粘合剂存在下完成制粒，但其所得的阿拉伯糖颗粒剂80目下部分仍有38-78％不等，不符合药典颗粒剂通则的要求，且该申请中，所得到的颗粒状阿拉伯糖仍需与其他甜味剂等辅料复配混合以进一步制作颗粒剂、胶囊剂。
因此，研究人员需要通过对L-阿拉伯糖的性质、制备工艺以及制剂性能进行研究，以便得到能够有效提高清肠过程中患者依从性，从而提高肠道准备质量的L-阿拉伯糖产品，并进一步得到其符合药用质量标准的制剂，以及研发有利于工业化、安全环保、可行的制备工艺。
发明内容
为解决现有技术中存在的问题，第一方面，本发明提供一种L-阿拉伯糖，所述阿拉伯糖为β-L-(+)-阿拉伯糖。
根据本发明的实施方案，所述L-阿拉伯糖具有如下晶体结构(单晶)，
所述晶体结构是正交斜方晶系，
空间群是P2 12 12 1，
晶胞参数是：
Figure PCTCN2022083083-appb-000001
Figure PCTCN2022083083-appb-000002
Figure PCTCN2022083083-appb-000003
α＝90°，β＝90°，γ＝90°，
Figure PCTCN2022083083-appb-000004
Z＝4，F(000)＝320.0。
根据本发明的实施方案，所述L-阿拉伯糖的晶体使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在14.416±0.20°、16.450±0.20°、20.556±0.20°、27.443±0.20°、27.828±0.20°、33.161±0.20°处具有特征峰。优选的，所述L-阿拉伯糖的晶体使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在14.416±0.20°、16.450±0.20°、20.556±0.20°、22.943±0.20°、27.443±0.20°、27.828±0.20°、33.161±0.20°处具有特征峰。
根据本发明的实施方案，所述晶体具有基本如图1所示的粉末X射线衍射图。
根据本发明的实施方案，所述晶体具有基本如图2所示的红外光谱图。
根据本发明的实施方案，所述L-阿拉伯糖的平均粒径范围为100-600um，优选的，为100-300um，例如为110，120，130，140，150，160，170，180，190，200，210，220，230，240，250，260，270，280，290um。
根据本发明的实施方案，所述L-阿拉伯糖含有≤0.04％的半乳糖，优选的，所述L-阿拉伯糖含有≤0.01％的半乳糖；更优选的，含有0.005％的半乳糖。
根据本发明的实施方案，所述L-阿拉伯糖含有≤0.05％的果糖；更优选的，所述L-阿拉伯糖中不含果糖(即果糖含量＝0％)。
第二方面，本发明还提供了所述L-阿拉伯糖的制备方法。
在一些实施方式中，所述制备方法采用方案一，包括如下步骤：
(1)将L-阿拉伯糖原料溶解于水中，加入活性炭过滤，除去活性炭，得到滤清的糖液；
(2)取步骤(1)得到的滤清糖液约一半至蒸发结晶罐中，蒸发至糖液糖度至55-65％Brix，加入适量L-阿拉伯糖原料作为晶种后，开始流加剩余约一半的滤清糖液，流加结束后，继续浓缩。
根据本发明的实施方案，所述L-阿拉伯糖原料研磨过筛均匀后作为晶种，本领域技术人员可以理解，可以采用常规的工业筛(40-200目)或药典标准筛(三号、四号、五号、六号、七号、八号、九号筛)，例如，采用5号、6号药典标准筛；在一些实施方案中，将L-阿拉伯糖原料研磨过5号和6号药典标准筛，取能过5号但不能过6号筛的部分。
根据本发明的实施方案，所述方案一的步骤(1)中，原料与水的质量比为1：0.5-3，优选为1:1-1.5，例如为1:1.1，1:1.2；原料和活性炭的质量比为1:0.0005-0.01，优选为1:0.0005-0.0015，例如为1:0.0005，1:0.001；
步骤(2)中，流加时间为6～24h，例如为9，10，11，12，13，14，15，16，17，18，19，20h，优选的，流加时间为6～12h；所述流加过程中，糖液的过饱和度控制在1.01-1.19之间，优选控制在1.01-1.10之间，更优选的控制在1.03-1.08之间。
步骤(2)中，优选蒸发至糖液糖度为55-60％Brix，例如为56，57，58，59％Brix，更优 选的为58-60％Brix；流加结束后，继续浓缩1～2小时；优选的，从加入晶种到出料用时为10～15小时，例如为14小时左右。
在另一些实施方式中，所述制备方法采用方案二，包括如下步骤：
(1)加入水和L-阿拉伯糖原料，加入L-阿拉伯糖原料同时开启搅拌，加热溶解完全后，加入活性炭吸附；
(2)将活性炭过滤去除后，所得物料加入反应釜进行浓缩，待浓缩至糖度55～65％Brix时，加入适量L-阿拉伯糖原料作为晶种，以0.5-2℃每小时的速度降温。
根据本发明的实施方案，所述方案二采用的晶种与方案一相同。
根据本发明的实施方案，所述方案二的步骤(1)中，原料与水的质量比为1：0.5-3，优选为1:1-1.5，例如为1:1-1.2；原料和活性炭的质量比为1:0.0005-0.01，例如为1:0.0005；活性炭吸附的温度为55-70℃，吸附时间为20～60min。
步骤(2)中，优选浓缩至糖液糖度为58-60％Brix；优选降温速度为0.5-1.5℃每小时，例如为1℃每小时。
第三方面，本发明还提供了所述制备方法得到的L-阿拉伯糖。
第四方面，本发明还提供了一种制剂，含有所述L-阿拉伯糖。所述制剂可以为单位剂量形式或多剂量形式。在一些实施方案中，所述制剂为单位剂量形式，含有1-100g L-阿拉伯糖，优选含有20g-60g L-阿拉伯糖，例如含有20、30、40、50、60g L-阿拉伯糖。根据本发明的实施方案，所述制剂应用于肠道准备时，单日使用剂量为20-75g。
根据本发明的实施方案，所述制剂为所述L-阿拉伯糖的水溶液，所述水溶液中，L-阿拉伯糖的浓度为0.1-0.6g/ml(以ml水中L-阿拉伯糖的克数计)，优选为0.2-0.5g/ml，例如为0.2，0.3，0.4g/ml。
第五方面，本发明提供了一种L-阿拉伯糖的颗粒剂。根据本发明的实施方案，所述L-阿拉伯糖的颗粒剂，含有前文第一方面所述L-阿拉伯糖，或前文第三方面根据所述制备工艺得到的L-阿拉伯糖。
第六方面，本发明提供所述L-阿拉伯糖颗粒剂的制备方法，包括如下步骤：
(1)将L-阿拉伯糖原料溶解于水中，加入活性炭过滤，除去活性炭，得到滤清的糖液；
(2)取步骤(1)得到的滤清糖液的40％-55％(v％)，将其蒸发至糖液糖度至55-65％Brix，加入适量L-阿拉伯糖原料作为晶种后，开始流加剩余的滤清糖液，流加结束后，继续浓缩。
根据本发明的实施方案，作为晶种的L-阿拉伯糖原料为40-200目，例如为40、60、80目、100目，优选为80-100目。本领域技术人员可以理解，所述晶种可以由L-阿拉伯糖原料经研磨过筛后获得，例如，可以采用常规的工业筛(40-200目)或药典标准筛(三号、四号、 五号、六号、七号、八号、九号筛)获得，例如，采用5号、6号药典标准筛获得；在一些实施方案中，将L-阿拉伯糖原料研磨过5号和6号药典标准筛，取能过5号但不能过6号筛的部分作为晶种。
根据本发明的实施方案，所述晶种的加入量可以为L-阿拉伯糖原料投入质量的0.05％-1％；例如，为L-阿拉伯糖原料投入质量的0.05％，0.1％，0.2％，0.3％，0.4％，0.5％，0.6％，0.7％，0.8％，0.9％，1％。
根据本发明的实施方案，所述方法的步骤(1)中，原料与水的质量比为1:0.5-3，优选为1:1-1.5，例如为1:1.1，1:1.2；原料和活性炭的质量比为1:0.0005-0.01，优选为1:0.0005-0.0015，例如为1:0.0005，1:0.001；优选的，可以采用微孔滤膜真空抽滤、或者板框过滤或平板微滤膜过滤来除去活性炭；所述微孔滤膜可以依次选用25μm、0.45μm；优选的，在50-70℃加入活性炭，加入活性炭后，可以在50-70℃搅拌20-40分钟，例如搅拌30分钟。
步骤(2)中，优选蒸发至糖液糖度为55-60％Brix，例如为56，57，58，59％Brix；流加结束后，继续浓缩1～2小时；优选的，蒸发温度为55-70℃，更优选的，蒸发温度为58-65℃，例如为60，61，62，63，64，65℃；优选的，从加入晶种到出料用时为10～15小时，例如为14小时左右；优选的，在蒸发过程中开启搅拌，搅拌速度为90-110rpm；在一些实施方式中，所述搅拌方式可选自双层搅拌(下层为两半月牙型，上层为三叶推进型)或者单层3-6叶推进型辅以强制循环；优选的，流加时间为6～24h，例如为9，10，11，12，13，14，15，16，17，18，19，20h，在一些优选的实施方式中，流加时间为8-15h；所述流加过程中，糖液的过饱和度控制在1.01-1.19之间，优选控制在1.01-1.10之间，更优选的控制在1.03-1.08之间。
根据本发明的实施方案，本领域技术人员可以理解，所述蒸发可以采用减压条件。
根据本发明的实施方案，所述方法进一步包括如下步骤：
(3)流加结束后，继续蒸发至糖糕浓度为75-85％，出料离心；
(4)干燥，制得颗粒剂。
根据本发明的实施方案，所述步骤(3)中，蒸发时间为1-3小时，例如为2小时；优选的，蒸发至糖糕浓度为75％-80％，例如为75，76,，77，78，79，80％。
在一些实施方案中，所述干燥可以选自沸腾干燥，流化床干燥，减压干燥中的一种或几种。
在一些实施方案中，所述步骤(4)具体为：
(4i)沸腾干燥，然后经流化床干燥，制得颗粒剂。优选的，所述沸腾干燥采用风温90-105℃，料温60-80℃；所述流化床干燥中逐步降温，优选的，进风40-50℃，低温(如15-25℃)冷干风风送，最后冷却至常温。
根据本发明的实施方案，所述步骤(4i)中，可以采用回混床沸腾干燥；所述干燥过程中，可以采用星型下料器或者旋转供料器喂料，优选的，所述喂料过程中辅以振动。
在一些实施方案中，所述步骤(4)具体为：采用人工铺料，烘箱减压真空干燥。
根据本发明的实施方案，所述方法进一步包括步骤(5)：包装。优选的，所述包装过程中，采用振动下料方式，经过线性称定量。
根据本发明的实施方案，所述方法任选包括如下步骤：将干燥所得颗粒进一步筛分。
根据本发明的实施方案，所述阿拉伯糖为β-L-(+)-阿拉伯糖。在一些实施方案中，所述L-阿拉伯糖的颗粒剂，含有前文第一方面所述L-阿拉伯糖，或前文第三方面根据所述制备工艺得到的L-阿拉伯糖。
第七方面，本发明还提供了所述制备方法得到的L-阿拉伯糖颗粒剂。
根据本发明的实施方案，所述L-阿拉伯糖颗粒的平均粒径范围为100-600um，优选的，为100-300um，例如为100，110，120，130，140，150，160，170，180，190，200，210，220，230，240，250，260，270，280，290um。所述L-阿拉伯糖颗粒的D10为40-200μm，优选的，为40-100μm，例如为40，50，60，70，80，90，100um；所述L-阿拉伯糖颗粒的D50为80-200μm，优选的，为90-150μm，例如为90，100，110，120，130，140，150um；所述L-阿拉伯糖颗粒的D90为150-300μm，优选的，为200-250μm，例如为200，210，220，230，240，250um。
根据本发明的实施方案，所述颗粒剂可以为单位剂量形式或多剂量形式。在一些实施方案中，所述颗粒剂为单位剂量形式，含有1-100g L-阿拉伯糖，例如含有1、5、10、20、30、40、50、60g L-阿拉伯糖。在一些实施方案中，所述颗粒剂单日使用剂量为20-75g；在另一些实施方案中，所述颗粒剂单日使用剂量为3-20g。
第八方面，本发明还提供前文所述L-阿拉伯糖和制剂(包括第一、三、四、五、七方面涉及的L-阿拉伯糖及其制剂)用于清肠和/或肠道准备的方法。根据本发明的实施方案，在清肠和/或肠道准备时，可以每次给予所述L-阿拉伯糖和制剂20g-60g，例如每次给予20、30、40、50、60g；完成一次清肠和/或肠道准备，给予所述L-阿拉伯糖和制剂的总剂量为20-75g。在一些实施方案中，本发明提供所述L-阿拉伯糖颗粒剂用于清肠和/或肠道准备、体重控制以及改善和/或治疗便秘的方法。当所述颗粒剂用于清肠和/或肠道准备时，可以每次给予所述L-阿拉伯糖颗粒剂20g-60g，例如每次给予20、30、40、50、60g；在一些实施方案中，完成一次清肠和/或肠道准备，给予所述L-阿拉伯糖颗粒剂的总剂量为20-75g；在另一些实施方案中，当所述颗粒剂用于体重控制、改善和/或治疗便秘时，每日给予所述L-阿拉伯糖颗粒剂3-20g。
第九方面，本发明还提供所述L-阿拉伯糖和制剂(包括第一、三、四、五、七方面涉及的L-阿拉伯糖及其制剂)用于制备清肠和/或肠道准备的药物的用途。在一些实施方案中，本发明提供所述L-阿拉伯糖颗粒剂用于制备清肠和/或肠道准备、体重控制以及改善和/或治疗便秘的药物的用途。
有益效果
1)本发明制备得到的L-阿拉伯糖产品，经过单晶培养后，鉴定为单一β晶型。本发明制备得到的L-阿拉伯糖产品可以直接应用为肠道清洁剂药物，无需添加其他辅剂，流动性好，安全有效，极大提高了肠道准备药物的口感口味和可服用剂量范围，明显增强了患者依从性，降低大部分患者喝传统肠道准备药物的抵触心理，全面优于传统的临床推荐用药硫酸镁和PEG，且相对于山梨醇高渗液也具有一定的优势。
2)本发明采用的制备工艺简单易行，结晶过程无需使用有机溶剂，环保安全，易于控制产品粒径范围。所得产品纯度可达99.6％以上，单个杂质均控制在0.05％限度范围内，能够满足高质量肠道准备原料药的标准，特别的，本发明的工艺，将产品中果糖含量控制为0，半乳糖含量控制为0.01-0.04％，可以减少或避免果糖和半乳糖杂质吸收给患者带来不必要的影响和负担，且尤其适合果糖不耐者安全服用产品。3)本发明在制备阿拉伯糖颗粒剂的过程中，无需添加任何辅料，同时也不需要复杂的制粒加工过程，所得产品在包装充填过程中流动性良好，且具有合适的粒度分布，能够满足现行药典对颗粒剂的粒度质量要求。
附图说明
图1为本发明的L-阿拉伯糖的粉末X射线衍射图；
图2为本发明的L-阿拉伯糖的红外光谱图；
图3示意为L-阿拉伯糖的单晶衍射结构；
图4示意为阿拉伯糖的饱和曲线和析晶曲线。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
以下实施例中采用的L-阿拉伯糖原料：购自唐传生物科技(厦门)有限公司，纯度≥99％(符合L-阿拉伯糖国标QB/T 4321-2012)。
实施例1 蒸发流加结晶法制备L-阿拉伯糖
取30kgL-阿拉伯糖原料，加33kg纯净水在60℃下溶解；加入30g活性炭。60℃下保温40-60min，过滤去除活性炭，得到滤清的糖液。
取以上滤清糖液约一半至蒸发结晶罐中，蒸发至糖液糖度58-60％Brix，加入适量L-阿拉伯糖原料作为晶种后(所述晶种为L-阿拉伯糖原料经研磨过筛(5～6号药典标准筛)后的粉末，取能过5号但不能过6号筛的部分)，开始流加剩余约一半的滤清糖液，流加速度为1.5～4.0L/h，流加时间10～12h。流加结束后，继续浓缩1～2小时。从投晶种到出料用时在14小时左右。
本领域技术人员可以理解，术语“流加”为蒸发结晶的常规操作之一，即一边持续性补充加入糖液一边将水蒸发，保持体系内糖液的液体浓度相对固定。如上述流加过程中，糖液的过饱和度不超过1.10。
Figure PCTCN2022083083-appb-000005
所述L-阿拉伯糖的晶体使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射采用的测试仪器为D8 advance(Bruker)X射线衍射仪，仪器参数如下：
辐射:Cu K(λ＝1.54056)；
工作电流:40mA；
工作电压:40KV；
探测器:PSD；
起始角度:4°(2-theta)；
终止角度:40°(2-theta)；
扫描步长:0.05°/step；
扫描速度:1sec/step。
所测结果如图1所示，2θ角度误差范围±0.20°。
实施例1制备得到L-阿拉伯糖，经粒度粒形分析测定，平均粒径为149um，粒径分布为D10＝49um，D50＝138um，D90＝261um，跨距＝0.985。
实施例1制备得到L-阿拉伯糖产品，经过单晶培养后，单晶衍射仪鉴定为β-L-(+)-阿拉伯糖。在具体实施过程中，采用界面扩散法培养L-阿拉伯糖单晶：称取20g制备得到的L-阿拉伯糖溶于20ml去离子水中，待全部溶解后并冷却至室温后沿烧杯内壁加入40ml乙醇并用保鲜膜密封防止乙醇蒸发，乙醇添加过程和密封过程中尽量避免溶液晃动。将烧杯置于恒温水浴锅中，温度设定为30℃，约1个月后得到L-阿拉伯糖单晶。所述晶体是正交斜方晶系，空间群是P2 12 12 1，晶胞参数是：
Figure PCTCN2022083083-appb-000006
Figure PCTCN2022083083-appb-000007
Figure PCTCN2022083083-appb-000008
α＝90°，β＝90°，γ＝90°，
Figure PCTCN2022083083-appb-000009
Z＝4，F(000)＝320.0。
实施例2 降温结晶制备L-阿拉伯糖
溶糖：在溶糖罐中加入25L水和22kgL-阿拉伯糖原料，加L-阿拉伯糖原料时开启搅拌，加热溶解完全后，加入22g的活性炭，在55～70℃中保温吸附20～60min。活性炭过滤去除后，将物料加入反应釜进行浓缩，待浓缩至糖度为60％Brix时，加入适量L-阿拉伯糖原料作为晶种(所述晶种为L-阿拉伯糖原料经研磨过筛(5～6号药典标准筛)后的粉末，取能过5号但不能过6号筛的部分)，投种温度60℃。搅拌速率调为50rpm，执行降温程序，起始降温温度为60℃，降温速率约1℃/h。经液相色谱测定结果如下表所示(％纯度以面积归一法，即待测成分占样品总峰面积的比例计算)：
类别 液相纯度(％) 结晶周期 半乳糖％ 果糖％ 成品收率％
L-阿拉伯糖原料 99.1   0.095 0.05 -
实施例2产品 99.68 36h 0.03 0 43.1
实施例3产品 99.63 16h 0.04 0 40.8
经检测，实施例2的产品中不含有D-阿拉伯糖(文献(Higaki S，et al.，Journal of the Food Hygienic Society of Japan,2018,59(3):114-120)中记载了D-阿拉伯糖存在毒性，具有食用安全性隐患)以及糠醛。
实施例2制备得到L-阿拉伯糖产品，经鉴定，与实施例1的产品具有相同的晶型形态，经 粒度粒形分析测定，平均粒径为189um，粒径分布为D10＝82um，D50＝182um，D90＝299um。
实施例3
实施例3与实施例2操作基本相同，把降温速率提高到约2℃/h，结晶周期缩短到16h，接近蒸发流加结晶的结晶周期。结晶成品收率40.8％。经粒度粒形分析测定，平均粒径为125um，粒径分布为D10＝43um，D50＝109um，D90＝232um。
实施例4 L-阿拉伯糖的粒径参数和粉末特性(数量分布)
表4-1 粒径参数测试结果(BT-2900图像粒度粒形分析系统)
Figure PCTCN2022083083-appb-000010
表4-2 流动性测试结果(颗粒和粉末特性分析仪，FT-102D)
Figure PCTCN2022083083-appb-000011
实施例5 本发明制备的L-阿拉伯糖对小鼠的肠道清洁准备
5.1实验动物及其饲养：SPF级小鼠，无特定病原体(Specific pathogen Free，SPF)级别，6 周龄；普通饲料为D12450-B饲料：碳水化合物67.35wt％、粗蛋白19.2wt％、脂肪4.3wt％。自房间温度保持在24～26℃，湿度40～60％。
5.2实验方法和过程：
SPF级小鼠随机分成空白对照组、阳性对照组和试验组，每组20只，雌雄各半。各组给药剂量如下表1所示。给药方法：各组动物试验前一晚22点禁食不禁水，试验当天早7点、9点和11点分别给予计算药量的1/3(灌胃给药)，12点、13点和14点分别灌胃给予0.1mL纯水，末次给药后3.5h解剖。
表5-1
Figure PCTCN2022083083-appb-000012
备注：各给药组受试物均分三次给予。
5.3实验结果：
(1)阳性对照组和试验组在解剖前均观察到水样便和稀便。
(2)阳性对照组和试验组在解剖后，观察直结肠内已经没有残渣残留，清肠效果良好。显然，L-阿拉伯糖试验组的使用剂量只有阳性对照组的38％，就可以达到同样的效果，服用剂量的优势明显。
实施例6 本发明制备的L-阿拉伯糖对人体的肠道清洁准备
给药样品：实施例1制备的L-阿拉伯糖
受试者：男，41岁，体重73kg
给药方案：
受试者早上空腹，起床后正常喝水；
10：06用30gL-阿拉伯糖溶解于约100～150ml矿泉水，5分钟左右喝完，
10：42约40分钟后补水约350ml后，上洗手间稀便，
11:11过25分钟再补完100ml水后，第二次上洗手间，水样便，
11:34再过约15min,再喝掉250ml水
11:55上第三次洗手间，水样便，很少渣
12：10喝200ml水
13：27分上第四次洗手间，淡黄色水样便，无渣。
整个过程用水量约1L水，时间，耗时3个半小时。
由此可见，本发明制备的L-阿拉伯糖产品可以直接配水服用，服用过程方便，剂量合适，能够有效满足术前肠道清洁准备或者肠镜及其它检查前的肠道清洁准备之需求。
实施例7 本发明制备的L-阿拉伯糖体外渗透压试验
实验仪器：Vapro pressure osmometer蒸汽渗透压仪
实验材料：L-阿拉伯糖(根据实施例1的方法制备)；山梨醇(市售国药试剂)
实验过程：将4个编号的溶液按照表2所示物料配比分别配置好，搅拌至溶液完全澄清透明后，开始逐一检测，检测结果如下表7-1所示。
表7-1 山梨醇高渗液和L-阿拉伯糖溶液渗透压比较
Figure PCTCN2022083083-appb-000013
备注：渗透压A和渗透压B分别代表同样编号的样品进行平行测试的结果。平均渗透压是渗透压A和渗透压B的平均值。
从上表可知，同等质量浓度的L-阿拉伯糖和山梨醇高渗液相比，渗透压高出22.8％，这表明，口服本发明的L-阿拉伯糖溶液后，基于溶液本身的渗透压作用，即可增强肠道渗透压，相比山梨醇高渗液具有一定优势。
实施例8 L-阿拉伯糖颗粒制备
1.1实验过程
取1kg L-阿拉伯糖原料，加1.2kg纯水在60℃下溶解，待溶液完全澄清后，加入1g活性炭(L-阿拉伯糖质量的1‰)。60℃下保温30min，而后依次用25μm，0.45μm的滤膜真空抽滤除去活性炭，所得滤清糖液体积大约1800ml。取以上滤清糖液约800ml至三口瓶中，调节水浴温度为62℃，搅拌减压蒸发至糖液糖度58-60％Brix，加入适量的L-阿拉伯糖做晶种(如下表8-1所示，选用不同晶种规格：40-60目，16.5g；60-80目，6g；80-100目，1.5g)，开启搅拌(搅拌类型为双层，下层为两半月牙型，上层为三叶推进型)，搅拌速度90-110rpm，至 晶种完全分散开，开启流加糖液操作，流加速度为50-100ml/h，流加时间为12/18h。流加结束后，继续浓缩1～2小时。从投晶种到出料用时在14小时左右。
本领域技术人员可以理解，术语“流加”为蒸发结晶的常规操作之一，即一边持续性补充加入糖液一边将水蒸发，保持体系内糖液的液体浓度相对固定。如上述流加过程中，控制糖液的过饱和度控制在1.01-1.10范围之内。
根据表8-1的实验结果可知，所投80-100目晶种相对于其他规格的晶种的比表面积比较少(如表8-2所示)，但是实验所得样品粗细分布较为均匀，20～80目所占比例达到89.7％以上，最大超过90％，完全符合现行药典(《2020中国药典》)对于颗粒剂的要求：不能通过1号筛(10目，孔径2000um)和能通过5号筛(80目，180um孔径)之和不能超过15％。
表8-1 晶种规格对样品粒度分布(标准筛)的影响
Figure PCTCN2022083083-appb-000014
表8-2 晶种参数
Figure PCTCN2022083083-appb-000015
备注：晶种比表面积和颗粒数为动态图像粒度粒型分析系统检测。
实施例9 L-阿拉伯糖单晶培养以及鉴定
采用实施例8制备得到L-阿拉伯糖产品，单晶衍射仪鉴定为β-L-(+)-阿拉伯糖。经过单 晶培养。采用界面扩散法培养L-阿拉伯糖单晶：称取40g制备得到的L-阿拉伯糖溶于40ml去离子水中，待全部溶解后并冷却至室温后沿烧杯内壁加入80ml乙醇并用保鲜膜密封防止乙醇蒸发，乙醇添加过程和密封过程中尽量避免溶液晃动。将烧杯置于恒温水浴锅中，温度设定为30℃，约15天后得到L-阿拉伯糖单晶。所述晶体是正交斜方晶系，空间群是P2 12 12 1。
表9-1 单晶晶体的尺寸(培养时长15*24＝360h)
晶体编号 长mm 宽mm
1 4.2 1.5
2 8.8 2.1
3 5.5 1.8
4 7.3 2.7
5 6.1 1.2
6 6.3 1.3
7 4.0 2.0
8 6.0 2.0
9 7.8 2.5
10 8.5 2.3
范围 4000um-8800um 1200um-2700um
备注：从培养的单晶中随机挑了10个，挑取晶体时，部分晶体会断，因此实际的长度会比此数值略长。
实施例10 L-阿拉伯糖颗粒剂制备
取8000kgL-阿拉伯糖原料，加入8800公斤纯水，加热搅拌待溶解完全后，在溶液温度60℃加入4kg活性炭，保温搅拌30min，后用过滤去除活性炭，得到过滤清液，将约8400kg(约7200L)过滤清液加入蒸发结晶器进行蒸发，蒸发的糖液温度为60-65℃；将糖液蒸发浓缩至59.4％Brix，加入80-100目晶种，投种温度64.9℃，用剩余的另一半过滤清液以约600L/h速度进行流加，流加时间为12h，进行减压蒸发结晶；流加结束后，继续蒸发约2h，至糖糕浓度81％时，出料离心。采用绞龙持续喂料回混床沸腾干燥(风温90-105℃，料温60-80℃)，然后流化床干燥并逐步降温(进风40-50℃，低温15-25℃冷干风风送)，冷却至常温后进行包装。
本领域技术人员可以理解，“糖糕”即阿拉伯糖晶体和糖液的固液混合物，“糖糕浓度”即阿拉伯糖在固液混合物中的浓度。
表10-1 制备过程参数
批号 晶种目数/重量 流加时间 样品 a 20-80目比例％ 样品 b 20-80目比例％
第1批次 80～100目/12kg 12h 66.4 93.0
第2批次 80～100目/9kg 12h 79.8 96.4
备注：上标a代表样品采用干燥过程中绞龙喂料-回混床干燥方式；上标b代表样品采用离心后取样-人工铺料烘箱干燥方式。
实施例11 L-阿拉伯糖颗粒剂制备
取30kg L-阿拉伯糖原料，加入33公斤纯水，加热搅拌待溶解完全后，在溶液温度60℃加入15.2g活性炭，保温搅拌30min，后用过滤去除活性炭，得到过滤清液，将约32kg过滤清液加入反应釜进行减压蒸发，蒸发的糖液温度为60-65℃；将糖液蒸发浓缩至57.6％Brix，加入45g 80-100目晶种，投种温度61.5℃，用剩余的另一半过滤清液以2-2.3L/h的速度进行流加，流加时间为12h；流加结束后，继续蒸发约2h，至糖糕浓度78％时，出料离心，经人工铺料烘箱干燥。
实施例12 L-阿拉伯糖颗粒剂制备
取40kg L-阿拉伯糖原料，加入44公斤纯水，加热搅拌待溶解完全后，在溶液温度60℃加入20.2g活性炭，保温搅拌30min，后用过滤去除活性炭，得到过滤清液，将约32kg过滤清液加入反应釜进行减压蒸发，蒸发的糖液温度为60-65℃；将糖液蒸发浓缩至57.6％Brix，加入60g 80-100目晶种，投种温度61.5℃，用剩余的另一半过滤清液以2-2.3L/h的速度进行流加，流加时间为12h；流加结束后，继续蒸发约2h，至糖糕浓度78％时，出料离心，经人工铺料烘箱干燥(减压真空干燥)。
表12-1 制备过程参数
产品 晶种目数/重量 流加时间 样品20-80目比例％
实施例11 80～100目/45g 12h 90.6
实施例12 80～100目/60g 12h 93.57
备注：此实施例均为人工铺料烘箱干燥方式。
实施例13 本发明颗粒剂性能测试结果
表13-1 流动性测试结果(颗粒和粉末特性分析仪，FT-102D)
产品 实施例10 第1批次 实施例10 第2批次 实施例11 实施例12
流动性(休止角) 较好 较好 较好 较好
流动性(豪斯那比) 良好 良好 尚可 良好
豪斯那比 1.2 1.2 1.3 1.3
压缩度 17.1 15.9 23.1 24.4
卡尔流动性指数 100.5 102.5 102.0 99
喷流性指数 75.0 75.0 75.0 75.0
休止角 40.01 30.95 34.29 39.74
振实密度 0.85 0.81 0.65 0.64
松散密度 0.7 0.68 0.5 0.48
备注：测流动性实施例10两批次样品均为绞龙喂料-回混床干燥方式。
表13-2 成品粒度分布(数量分布)(BT-2900图像粒度粒形分析系统)
Figure PCTCN2022083083-appb-000016
备注：上标a代表样品采用绞龙喂料-回混床干燥方式；上标b代表样品采用离心后取样-人工铺料烘箱干燥方式。
实施例14
参照实施例10的工艺进行操作，仅替换喂料方式为星型下料器，相应的，将回混床沸腾干燥的铺料高度降至约1/3以下，即铺料厚度小于16cm(原高度约50cm)。
表14-1
产品 晶种目数/重量 流加时间 样品 a20-80目比例％ 样品 c20-80目比例％
实施例14 80～100目/15kg 12h 94.3％ 89％
备注：上标a代表样品采用离心后取样-人工铺料烘箱干燥方式；上标c代表样品采用星型阀下料-回混床干燥。
实施例15 L-阿拉伯糖饱和曲线和析晶曲线
圆底烧瓶放置在可温控的恒温箱中，在三口圆底烧瓶中(一个瓶口用胶塞塞着作为取样口，一个瓶口作为搅拌桨放置口，一个瓶口作为温度探头口)加入一定量的离子水，并加入过量的L-阿拉伯糖晶体(按照实施例10的方法制备所得)，分别在40℃，49℃，53℃，58℃和65℃搅拌3小时，再静置4h，使未溶解的L-阿拉伯糖晶体充分沉降，然后取上清以微孔滤膜过滤(用于小型进样针于恒温箱中过滤，以排除温度变化影响)，用过滤所得清液测浓度。绘制阿拉伯糖饱和曲线：y＝0.5927x+23.089(相关系数R 2＝0.99)(参见图4)。配置溶解相应质量浓度的澄清L-阿拉伯糖糖液，然后缓慢降温(1℃/h)，匀速降温(搅拌100rpm)，观察并记录不同质量浓度糖液的析晶温度。绘制阿拉伯糖析晶曲线：y＝0.4163x+40.413(相关系数R 2＝1)(参见图4和表15-1)，由表15-1可知，如果结晶温度是65℃，此时流加的过程中糖液的浓度超过67.47％(过饱和度超过1.1)，那就会出现大量的粉晶，晶体数量急剧增加，而导致晶体尺寸无法继续增长，即结晶失败，需要把体系升温溶解，重新结晶。
表15-1 阿拉伯糖饱和曲线和析晶曲线数据
温度℃ 饱和质量浓度％ 析晶质量浓度％ 过饱和系数
40 46.3 57.07 1.233
49 52.7 60.81 1.154
53 55.1 62.48 1.134
58 56.9 64.56 1.135
65 61.5 67.47 1.097
实施例16 L-阿拉伯糖颗粒剂包装
用实施例14制备的L-阿拉伯糖成品进行包装，包装速度15-40袋/min，单通道，包装过程进行气密性和装量检查以符合生产要求。经过本包装机包装的过程中，采用振动下料方式，经过线性称定量，所得L-阿拉伯糖颗粒剂符合2020版药典对颗粒剂粒度和装量的要求。
设备型号：MK-600
表16-1
Figure PCTCN2022083083-appb-000017
Figure PCTCN2022083083-appb-000018
备注：本型号设备目前选择的包装规格是1-30克，包装规格为5克，制剂袋子尺寸65mm*85mm；20克，制剂袋子尺寸65mm*130mm。如包装31-100克装量，只要根据制剂袋的尺寸更换设备制袋器和成型器即可。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (16)

  1. 一种L-阿拉伯糖的制备方法，其特征在于，所述制备方法包括如下步骤：
    (1)将L-阿拉伯糖原料溶解于水中，加入活性炭过滤，除去活性炭，得到滤清的糖液；
    (2)取步骤(1)得到的滤清糖液约一半至蒸发结晶罐中，蒸发至糖液糖度至55-65％Brix，加入适量L-阿拉伯糖原料作为晶种后，开始流加剩余约一半的滤清糖液，流加结束后，继续浓缩；
    优选的，步骤(1)中，原料与水的质量比为1：0.5-3，更优选为1:1-1.5；
    优选的，原料和活性炭的质量比为1:0.0005-0.01；流加时间为6～12h；流加结束后，继续浓缩1～2小时；
    优选的，从加入晶种到出料用时为10～15小时。
  2. 根据权利要求1所述的制备方法，其特征在于，所述L-阿拉伯糖为β-L-(+)-阿拉伯糖，具有如下晶体结构：
    所述晶体结构是正交斜方晶系，
    空间群是P2 12 12 1，
    晶胞参数是：
    Figure PCTCN2022083083-appb-100001
    Figure PCTCN2022083083-appb-100002
    Figure PCTCN2022083083-appb-100003
    α＝90°，β＝90°，γ＝90°，
    Figure PCTCN2022083083-appb-100004
    Z＝4，F(000)＝320.0。
  3. 根据权利要求2所述的制备方法，其特征在于，所述L-阿拉伯糖的晶体使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在14.416±0.20°、16.450±0.20°、20.556±0.20°、27.443±0.20°、27.828±0.20°、33.161±0.20°处具有特征峰；
    优选的，所述L-阿拉伯糖的晶体使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在14.416±0.20°、16.450±0.20°、20.556±0.20°、22.943±0.20°、27.443±0.20°、27.828±0.20°、33.161±0.20°处具有特征峰；更优选的，所述晶体具有基本如图1所示的粉末X射线衍射图。
  4. 根据权利要求1-3任一项所述的制备方法，其特征在于，所述L-阿拉伯糖的平均粒径范围为100-600um。
  5. 根据权利要求1-4任一项所述的制备方法，其特征在于，所述L-阿拉伯糖含有≤0.04％的半乳糖；所述L-阿拉伯糖含有≤0.05％的果糖。
  6. 根据权利要求1所述的制备方法，其特征在于，所述L-阿拉伯糖制备为颗粒剂，包括 如下步骤：
    (1)将L-阿拉伯糖原料溶解于水中，加入活性炭过滤，除去活性炭，得到滤清的糖液；
    (2)取步骤(1)得到的滤清糖液的40％-55％(v％)，将其蒸发至糖液糖度至55-65％Brix，加入适量L-阿拉伯糖原料作为晶种后，开始流加剩余的滤清糖液，流加结束后，继续浓缩；
    优选的，作为晶种的L-阿拉伯糖原料为40-200目；所述晶种的加入量为L-阿拉伯糖原料投入质量的0.05％-1％；步骤(1)中，原料与水的质量比为1：0.5-3；
    步骤(2)中，蒸发至糖液糖度为55-60％Brix。
  7. 根据权利要求6所述的制备方法，其特征在于，蒸发温度为55-70℃；流加时间为6～24h。
  8. 根据权利要求6所述的制备方法，其特征在于，所述流加过程中，糖液的过饱和度控制在1.01-1.19之间。
  9. 根据权利要求6所述的制备方法，其特征在于，所述制备方法进一步包括如下步骤：
    (3)流加结束后，继续蒸发至糖糕浓度为75-85％，出料离心；
    (4)干燥，制得颗粒剂。
  10. 根据权利要求9所述的制备方法，其特征在于，所述干燥可以选自沸腾干燥，流化床干燥，减压干燥的一种或几种。
  11. 根据权利要求9或10所述的制备方法，其特征在于，所述干燥过程中，可以采用星型下料器或者旋转供料器喂料。
  12. 根据权利要求6-11任一项所述制备方法得到的L-阿拉伯糖颗粒剂。
  13. 一种L-阿拉伯糖的制备方法，其特征在于，所述制备方法包括如下步骤：
    (1)加入水和L-阿拉伯糖原料，加入L-阿拉伯糖原料同时开启搅拌，加热溶解完全后，加入活性炭吸附；
    (2)将活性炭过滤去除后，所得物料加入反应釜进行浓缩，待浓缩至糖度55～65％Brix时，加入适量L-阿拉伯糖原料作为晶种，以0.5-2℃每小时的速度降温；
    优选的，所述方案二的步骤(1)中，原料与水的质量比为1：0.5-3；原料和活性炭的质量比为1:0.0005-0.01；活性炭吸附的温度为55-70℃，吸附时间为20～60min；步骤(2)中蒸发至糖液糖度为58-60％Brix；降温速度为0.5-1.5℃每小时。
  14. 根据权利要求13所述的制备方法，其特征在于，所述L-阿拉伯糖为β-L-(+)-阿拉伯糖，具有如下晶体结构：
    所述晶体结构是正交斜方晶系，
    空间群是P2 12 12 1，
    晶胞参数是：
    Figure PCTCN2022083083-appb-100005
    Figure PCTCN2022083083-appb-100006
    Figure PCTCN2022083083-appb-100007
    α＝90°，β＝90°，γ＝90°，
    Figure PCTCN2022083083-appb-100008
    Z＝4，F(000)＝320.0。
  15. 根据权利要求13所述的制备方法，其特征在于，所述L-阿拉伯糖的晶体使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在14.416±0.20°、16.450±0.20°、20.556±0.20°、27.443±0.20°、27.828±0.20°、33.161±0.20°处具有特征峰；
    优选的，所述L-阿拉伯糖的晶体使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在14.416±0.20°、16.450±0.20°、20.556±0.20°、22.943±0.20°、27.443±0.20°、27.828±0.20°、33.161±0.20°处具有特征峰；更优选的，所述晶体具有基本如图1所示的粉末X射线衍射图。
  16. 根据权利要求1-5、13-15任一项所述制备方法得到的L-阿拉伯糖或权利要求6-11任一项所述制备方法得到的L-阿拉伯糖颗粒剂用于制备清肠和/或肠道准备的药物的用途。
PCT/CN2022/083083 2022-01-06 2022-03-25 一种阿拉伯糖及其制剂和用途 WO2023130594A1 (zh)

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