CN116554239A

CN116554239A - Arabinose granule and preparation method and application thereof

Info

Publication number: CN116554239A
Application number: CN202210101531.4A
Authority: CN
Inventors: 石国良; 林卫军; 蔡许彬; 王羽娟; 肖永成; 萧舜之
Original assignee: Thomson Biotech Xiamen Pte Ltd
Current assignee: Thomson Biotech Xiamen Pte Ltd
Priority date: 2022-01-27
Filing date: 2022-01-27
Publication date: 2023-08-08

Abstract

The invention relates to an L-arabinose granule and a preparation process thereof, wherein the preparation of the granule comprises the following steps: (1) Dissolving L-arabinose raw material in water, adding active carbon for filtering, removing the active carbon to obtain filtered sugar solution, (2) taking 40% -55% (v%) of the filtered sugar solution obtained in the step (1), evaporating the filtered sugar solution until the sugar solution sugar degree reaches 55-65% Brix, adding a proper amount of L-arabinose raw material as seed crystal, beginning to feed the rest filtered sugar solution, and continuing concentrating after the feeding is finished. In the process of preparing the arabinose granules, no auxiliary materials are needed, and meanwhile, no complex granulating and processing process is needed, so that the obtained product has good fluidity in the packing and filling processes, has proper particle size distribution, and can meet the particle size and quality requirements of the current pharmacopoeia on the granules.

Description

Arabinose granule and preparation method and application thereof

Technical Field

The invention relates to the field of pharmaceutical chemicals, in particular to an arabinose granule, a preparation method and application thereof.

Background

L-arabinose (C) ₅ H ₁₀ O ₅ ) Is an aldopentose, also known as L (+) -aldoarabinose. Initially the monosaccharides were isolated from gum arabic. Free L-arabinose is rarely present in nature, and is usually present in the form of heteropolysaccharides in gums, hemicelluloses, bacterial polysaccharides and certain glycosides in combination with other monosaccharides, and is found only in the core of conifer trees. L-arabinose is increasingly used in the fields of foods, medicines and the like. The research shows that the L-arabinose has the effects of assisting in reducing blood sugar and assisting in losing weight and good bowel relaxing function, but the product development of the L-arabinose applied to the pharmaceutical preparation in the prior art has more problems, for example, the arabinose needs to be matched with other auxiliary materials for administration, so that the safety risk is increased when the large-dose preparation is taken, for example, the preparation is difficult to meet the pharmacopoeia quality standard or has complex process, has high cost and is not suitable for industrial production and the like.

The granule is a dry granular preparation with a certain granularity prepared by mixing the raw material medicines with proper auxiliary materials. The particle size range specified in the Chinese pharmacopoeia (2020) is such that the sum of coarse particles which cannot pass through a No. 1 sieve (10 mesh, 2000 um) and coarse particles which can pass through a No. 5 sieve (80 mesh, 180um pore size) cannot exceed 15%.

The Chinese patent application with publication number of CN111202244A discloses granular arabinose, the preparation method is that an arabinose solution is used as a binder, so that no additional binder is needed, the granulated arabinose powder is granulated in the presence of the binder, but the lower 80-mesh part of the obtained arabinose granule still has 38-78% inequality, which does not meet the general requirements of pharmacopoeia granules, and in the application, the obtained granular arabinose still needs to be compounded and mixed with other auxiliary materials such as sweetener to further prepare granules and capsules.

Therefore, it is necessary to develop an L-arabinose granule which meets the quality standard of the preparation and is suitable for industrial production and a process thereof.

Disclosure of Invention

In order to solve the problems in the prior art, on the one hand, the invention provides a preparation method of L-arabinose granules, which comprises the following steps:

(1) Dissolving L-arabinose raw material in water, adding active carbon for filtration, and removing the active carbon to obtain filtered sugar solution;

(2) Taking 40% -55% (v%) of the filtered sugar solution obtained in the step (1), evaporating until the sugar solution has a sugar degree of 55-65% Brix, adding a proper amount of L-arabinose raw material as seed crystal, beginning to feed the rest filtered sugar solution, and continuing concentrating after the feeding is finished.

According to an embodiment of the present invention, the L-arabinose starting material as seed is 40-200 mesh, for example 40, 60, 80 mesh, 100 mesh, preferably 80-100 mesh. It will be appreciated by those skilled in the art that the seed crystals may be obtained from the L-arabinose starting material after grinding and sieving, for example, by conventional industrial sieves (40-200 mesh) or pharmacopoeia standard sieves (No. three, no. four, no. five, no. six, no. seven, no. eight, no. nine), for example, by pharmacopoeia standard sieves No. 5, no. 6; in some embodiments, the L-arabinoside feedstock is milled through pharmacopoeia standard sieves No. 5 and No. 6, and the fraction that passes through sieve No. 5 but cannot pass through sieve No. 6 is taken as seed crystals.

According to the embodiment of the invention, the adding amount of the seed crystal can be 0.05% -1% of the input mass of the L-arabinose raw material; for example, the amount of the L-arabinose is 0.05%,0.1%,0.2%,0.3%,0.4%,0.5%,0.6%,0.7%,0.8%,0.9% and 1% of the charged mass.

According to an embodiment of the invention, in step (1) of the process, 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; the mass ratio of the raw material to the activated carbon is 1:0.0005-0.01, preferably 1:0.0005-0.0015, for example 0.001; preferably, the activated carbon can be removed by vacuum filtration with a microporous filter membrane, or by plate-frame filtration or plate microfiltration membrane filtration; the microporous filter membrane can sequentially select 25 mu m and 0.45 mu m; preferably, the activated carbon is added at 50-70℃and, after the addition of activated carbon, may be stirred at 50-70℃for 20-40 minutes, for example 30 minutes.

In step (2), it is preferable to evaporate to a sugar solution sugar degree of 55-60% Brix, for example, 56, 57, 58, 59% Brix; after the feeding is finished, continuing to concentrate for 1-2 hours; preferably, the evaporation temperature is 55-70 ℃, more preferably, the evaporation temperature is 58-65 ℃, e.g. 60, 61, 62, 63, 64, 65 ℃; preferably, the time from the seeding to the discharging is about 10 to 15 hours, for example about 14 hours; preferably, stirring is started during evaporation, and the stirring speed is 90-110rpm; in some embodiments, the stirring mode can be selected from double-layer stirring (the lower layer is of a two-half crescent type, the upper layer is of a three-leaf propulsion type) or single-layer 3-6-leaf propulsion type assisted by forced circulation; preferably, the run-up time is from 6 to 24 hours, such as 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 hours, and in some preferred embodiments, from 8 to 15 hours; in the feeding process, the supersaturation degree of the sugar solution is controlled between 1.01 and 1.19, preferably between 1.01 and 1.10, and more preferably between 1.03 and 1.08.

According to embodiments of the present invention, the evaporation may be under reduced pressure conditions, as will be appreciated by those skilled in the art.

According to an embodiment of the invention, the method further comprises the steps of:

(3) After the feeding is finished, continuing evaporating until the concentration of the sugar cake is 75-85%, discharging and centrifuging;

(4) Drying to obtain granule.

According to an embodiment of the invention, in said step (3), the evaporation time is 1-3 hours, for example 2 hours; preferably, the evaporation is to a sugar cake concentration of 75% -80%, for example 75, 76, 77, 78, 79, 80%.

In some embodiments, the drying may be selected from one or more of ebullated drying, fluidized bed drying, reduced pressure drying.

In some embodiments, the step (4) is specifically:

(4i) Boiling and drying, and then drying by a fluidized bed to obtain the granule. Preferably, the boiling drying adopts air temperature of 90-105 ℃ and material temperature of 60-80 ℃; the fluidized bed is dried and gradually cooled, preferably, the air is fed at 40-50 ℃, cold and dry air is fed at low temperature (such as 15-25 ℃), and finally, the fluidized bed is cooled to normal temperature.

According to an embodiment of the present invention, in the step (4 i), back-mixed bed boiling drying may be employed; in the drying process, a star-shaped feeder or a rotary feeder can be adopted for feeding, and preferably, vibration is assisted in the feeding process.

In some embodiments, the step (4) is specifically: and (5) adopting manual spreading, and drying in a drying oven under reduced pressure and vacuum.

According to an embodiment of the invention, the method further comprises step (5): and (5) packaging. Preferably, in the packaging process, a vibration blanking mode is adopted, and the packaging process is subjected to linear weighing and quantitative measurement.

According to an embodiment of the invention, the method optionally comprises the steps of: the dried granules were further sieved.

According to an embodiment of the invention, the arabinose is β -L- (+) -arabinose.

In yet another aspect, the invention also provides the L-arabinose granules obtained by the preparation method.

According to an embodiment of the invention, the average particle size of the L-arabinose particles is in the range of 100-600um, preferably 100-300um, for example 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290um. The L-arabinose particles have a D10 of 40-200. Mu.m, preferably 40-100. Mu.m, for example 40, 50, 60, 70, 80, 90, 100. Mu.m; the L-arabinose particles have a D50 of from 80 to 200. Mu.m, preferably from 90 to 150. Mu.m, for example from 90, 100, 110, 120, 130, 140, 150. Mu.m; the L-arabinose particles have a D90 of from 150 to 300. Mu.m, preferably from 200 to 250. Mu.m, for example 200, 210, 220, 230, 240, 250. Mu.m.

According to embodiments of the present invention, the granules may be in unit dosage form or in multi-dosage form. In some embodiments, the granule is in unit dosage form, contains 1-100g L-arabinose, for example, contains 1, 5, 10, 20, 30, 40, 50, 60g L-arabinose. In some embodiments, the granule is used in a single daily dose of 20-75g; in other embodiments, the granule is administered in a single daily dose of 3 to 20g.

In yet another aspect, the invention also provides methods of using the L-arabinose granules for bowel cleansing and/or bowel preparation, weight control, and improvement and/or treatment of constipation. In some embodiments, when the granule is used for bowel cleansing and/or bowel preparation, 20g-60g of the L-arabinose granule may be administered per time, for example 20, 30, 40, 50, 60g per time; in some embodiments, one bowel cleansing and/or bowel preparation is completed and the total dose of L-arabinose granules administered is 20-75g; in other embodiments, the L-arabinose granule is administered in an amount of 3-20g per day when the granule is used for weight control, amelioration and/or treatment of constipation.

In yet another aspect, the invention also provides the use of the L-arabinose granules for the preparation of a medicament for the cleaning and/or preparation of the intestinal tract, weight control and amelioration and/or treatment of constipation.

Advantageous effects

The process of the invention does not need to add any auxiliary materials in the process of preparing the arabinose granules, and does not need complex granulating and processing processes, and the obtained product has good fluidity in the packing and filling processes and proper granularity distribution, and can meet the granularity quality requirements of the current pharmacopoeia on the granules.

Drawings

FIG. 1 is a graph showing the saturation curve and crystallization curve of arabinose

Detailed Description

The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.

Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.

The L-arabinose starting materials used in the following examples: the product is purchased from Xiaotong biotechnology (Xiamen) limited company, and the purity is more than or equal to 99 percent (accords with the L-arabinose national standard QB/T4321-2012).

Example 1 preparation of L-arabinose particles

1.1 Experimental procedure

1kg of L-arabinose raw material was taken, 1.2kg of pure water was added to dissolve at 60℃and after the solution was completely clarified, 1g of activated carbon (1% by mass of L-arabinose) was added. The mixture was incubated at 60℃for 30min, and then activated carbon was removed by vacuum filtration through a 25 μm and 0.45 μm filter in sequence, resulting in a filtered sugar liquid volume of approximately 1800ml. Taking about 800ml of the filtered sugar solution to a three-mouth bottle, regulating the temperature of a water bath to 62 ℃, stirring, decompressing and evaporating until the sugar solution sugar degree is 58-60% Brix, adding a proper amount of L-arabinose as seed crystals (different seed crystal specifications are selected from 40-60 meshes, 16.5g, 60-80 meshes, 6g, 80-100 meshes and 1.5g as shown in the following table 1-1), starting stirring (stirring type is double-layer, lower layer is two half crescent, upper layer is three-leaf pushing type), stirring speed is 90-110rpm until the seed crystals are completely dispersed, starting the operation of feeding sugar solution, and feeding time is 12/18h. And after the end of the feeding, continuing to concentrate for 1-2 hours. The time from seeding to discharging was about 14 hours.

It will be appreciated by those skilled in the art that the term "fed-batch" is one of the conventional operations of evaporative crystallization, i.e., the continuous replenishment of the sugar liquor while evaporating the water, maintains the liquid concentration of the sugar liquor in the system relatively constant. In the feeding process, the supersaturation degree of the sugar solution is controlled within the range of 1.01-1.10.

According to the experimental results in Table 1-1, the specific surface area of the seed crystal with 80-100 meshes is smaller than that of the seed crystal with other specifications (as shown in Table 1-2), but the thickness distribution of the sample obtained by the experiment is more uniform, the proportion of 20-80 meshes reaches more than 89.7%, and the maximum proportion exceeds 90%, thus completely meeting the requirements of the current pharmacopoeia (2020 Chinese pharmacopoeia) on granules: the sum of the inability to pass through sieve No. 1 (10 mesh, pore size 2000 um) and the ability to pass through sieve No. 5 (80 mesh, 180um pore size) cannot exceed 15%.

TABLE 1-1 Effect of seed Specification on sample particle size distribution (Standard Screen)

TABLE 1-2 seed parameters

Remarks: the specific surface area and the particle number of the seed crystal are detected by a dynamic image particle size particle type analysis system.

Example 2L-arabinose Single Crystal culture and characterization

The L-arabinose product was prepared using example 1 and identified as beta-L- (+) -arabinose by single crystal diffractometer. Through single crystal cultivation. Culturing the L-arabinose monocrystal by adopting an interface diffusion method: 40g of the prepared L-arabinose is weighed and dissolved in 40ml of deionized water, 80ml of ethanol is added along the inner wall of a beaker after the L-arabinose is completely dissolved and cooled to room temperature, and the solution is prevented from shaking as much as possible in the ethanol adding process and the sealing process by using a preservative film for sealing to prevent ethanol evaporation. Placing the beaker into a constant-temperature water bath kettle, and setting the temperature to be 30 DEG CAfter about 15 days, an L-arabinose single crystal was obtained. The crystal is orthorhombic, and the space group is P2 ₁ 2 ₁ 2 ₁ 。

Table 2-1 size of single crystal crystals (length of cultivation 15×24=360 h)

Remarks: 10 crystals were randomly selected from the grown single crystals, and when the crystals were selected, part of the crystals were broken, so that the actual length was slightly longer than this value.

Example 3 preparation of L-arabinose granules

Taking 8000 kgL-arabinose raw material, adding 8800 kg pure water, heating and stirring until dissolution is complete, adding 4kg active carbon at the solution temperature of 60 ℃, keeping the temperature and stirring for 30min, removing active carbon by filtration to obtain filtered clear liquid, adding about 8400kg (about 7200L) of the filtered clear liquid into an evaporation crystallizer for evaporation, wherein the temperature of the evaporated sugar liquid is 60-65 ℃; evaporating and concentrating the sugar solution to 59.4% Brix, adding 80-100 mesh seed crystal, feeding at 64.9deg.C with flow acceleration of 600L/h for 12h, and evaporating under reduced pressure for crystallization; after the feeding is finished, the mixture is evaporated for about 2 hours, and when the concentration of the sugar cake is 81%, the mixture is discharged and centrifuged. Adopting a screw continuous feeding back mixing bed boiling drying (air temperature 90-105 ℃ and material temperature 60-80 ℃), then drying by a fluidized bed, gradually cooling (air inlet 40-50 ℃ and cold dry air feeding at low temperature 15-25 ℃), cooling to normal temperature and packaging.

Those skilled in the art will appreciate that "sugar cake" is a solid-liquid mixture of arabinose crystals and sugar liquid, and that "sugar cake concentration" is the concentration of arabinose in the solid-liquid mixture.

TABLE 3 preparation process parameters

Example 4 preparation of L-arabinose granules

Taking 30kg of L-arabinose raw material, adding 33 kg of pure water, heating and stirring until the L-arabinose raw material is completely dissolved, adding 15.2g of active carbon at the solution temperature of 60 ℃, keeping the temperature and stirring for 30min, filtering to remove the active carbon to obtain filtered clear liquid, adding about 32kg of filtered clear liquid into a reaction kettle for reduced pressure evaporation, wherein the temperature of the evaporated sugar liquid is 60-65 ℃; evaporating and concentrating the sugar solution to 57.6% Brix, adding 45g of 80-100 mesh seed crystal, wherein the seed casting temperature is 61.5 ℃, the flow acceleration is 2-2.3L/h, and the flow adding time is 12h; and (3) after the fed-batch is finished, evaporating for about 2 hours, discharging and centrifuging when the concentration of the sugar cake is 78%, and drying by using a manual spreading oven.

Example 5 preparation of L-arabinose granules

Taking 40kg of L-arabinose raw material, adding 44 kg of pure water, heating and stirring until the L-arabinose raw material is completely dissolved, adding 20.2g of active carbon at the solution temperature of 60 ℃, keeping the temperature and stirring for 30min, filtering to remove the active carbon to obtain filtered clear liquid, adding about 32kg of filtered clear liquid into a reaction kettle for reduced pressure evaporation, wherein the temperature of the evaporated sugar liquid is 60-65 ℃; evaporating and concentrating the sugar solution to 57.6% Brix, adding 60g of 80-100 mesh seed crystal, wherein the seed casting temperature is 61.5 ℃, the flow acceleration is 2-2.3L/h, and the flow adding time is 12h; after the feeding is finished, the mixture is evaporated for about 2 hours, and when the concentration of the sugar cake is 78%, the mixture is discharged and centrifuged, and is dried by a manual spreading oven (reduced pressure vacuum drying).

Table 5 preparation process parameters

EXAMPLE 6 results of the granule Performance test of the invention

TABLE 6-1 flowability test results (particle and powder characterization analyzer, FT-102D)

TABLE 6-2 finished particle size distribution (quantity distribution) (BT-2900 image particle size shape analysis System)

Example 7

The process according to example 3 was operated with the alternative of a star feeder, and correspondingly, the height of the back-mixed bed ebullated dried mat was reduced to less than about 1/3, i.e. the mat thickness was less than 16cm (about 50cm of the original height).

TABLE 7

EXAMPLE 8L-arabinose saturation Curve and crystallization Curve

The round bottom flask was placed in a temperature-controllable incubator, a certain amount of ionized water was added to the three-necked round bottom flask (one neck was plugged with a rubber plug as a sampling port, one neck was placed as a stirring paddle, and one neck was placed as a temperature probe port), and excess L-arabinose crystals (prepared as in example 3) were added, and stirred at 40, 49, 53, 58 and 65℃for 3 hours, respectively, and allowed to stand for 4 hours, allowing undissolved L-arabinose crystals to settle sufficiently, and then the supernatant was filtered with a microporous filter membrane (for use in a small-sized syringe in the incubator to exclude the effect of temperature variations), and the concentration was measured with the supernatant obtained by filtration. Drawing an arabinose saturation curve: y=0.5927x+23.089 (correlation coefficient R ² =0.99) (see fig. 1 and table 7-1). Preparing a clarified L-arabinose sugar solution with corresponding mass concentration, slowly cooling (1 ℃/h), uniformly cooling (stirring at 100 rpm), and observing and recording crystallization temperatures of sugar solutions with different mass concentrations. Drawing an arabinose crystallization curve: y=0.4163x+40.413 (correlation coefficient R ² =1) (see fig. 1 and table 7-1), as can be seen from table 7-1If the crystallization temperature is 65 ℃, the concentration of the sugar solution exceeds 67.47% (the supersaturation exceeds 1.1) in the process of feeding, a large amount of powder crystals appear, the number of crystals increases sharply, and the crystal size cannot be increased continuously, namely the crystallization fails, and the system needs to be heated and dissolved for recrystallization.

TABLE 8 data on arabinose saturation Curve and devitrification Curve

Temperature (DEG C)	Saturated mass concentration%	Concentration of devitrified mass%	Supersaturation coefficient
				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

EXAMPLE 9L-arabinose granule packaging

Packaging with the L-arabinose finished product prepared in example 7 at a packaging speed of 15-40 bags/min, and checking air tightness and filling amount in a single-channel packaging process to meet production requirements. In the packaging process of the packaging machine, a vibration blanking mode is adopted, and the obtained L-arabinose granules are linearly weighed and quantified, so that the requirements of the pharmacopoeia 2020 edition on the granularity and the loading amount of the granules are met.

Equipment model: MK-600

TABLE 9

Remarks: the current selected packaging specification of the model equipment is 1-30 g, the packaging specification is 5g, and the size of the preparation bag is 65mm x 85mm;20 g, formulation pouch size 65 mm.130 mm. Such as 31-100 g, the bag making device and the forming device can be replaced according to the size of the preparation bag.

The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A preparation method of L-arabinose granules comprises the following steps:

2. The process according to claim 1, wherein the seed crystals of the L-arabinose starting material are 40 to 200 mesh.

3. The preparation method according to claim 1 or 2, wherein the seed crystal is added in an amount of 0.05% -1% of the input mass of the L-arabinose raw material.

4. A process according to any one of claims 1 to 3, wherein in step (1), the mass ratio of raw materials to water is 1:0.5-3.

5. The process according to any one of claims 1 to 4, wherein in the step (2), the sugar solution is evaporated to a sugar degree of 55 to 60% Brix.

6. The process according to any one of claims 1 to 5, wherein the evaporation temperature is 55 to 70 ℃; the feeding time is 6-24 h.

7. The method according to any one of claims 1 to 6, wherein the supersaturation degree of the sugar solution is controlled to be 1.01 to 1.19 in the fed-batch process.

8. The method according to any one of claims 1 to 6, wherein the method further comprises the steps of:

(4) Drying to obtain granule.

9. The method according to claim 8, wherein the drying is one or more selected from the group consisting of boiling drying, fluidized bed drying and reduced pressure drying.

10. The method according to claim 8 or 9, wherein a star feeder or a rotary feeder is used for feeding during the drying process.