An orally disintegrating granule and its preparation method

Abstract

The present invention discloses an orally disintegrating granule and its preparation method, as well as the use of an antiviral orally disintegrating granule and xylitol as an excipient in the preparation of an orally disintegrating preparation. The orally disintegrating granule prepared by the present invention using xylitol can be directly taken under anhydrous conditions and completely dissolved within 2 - 10 seconds after entering the mouth, overcoming the drawback of traditional granules that need to be taken with boiling water, making it more convenient for patients to take. It solves the problems that some varieties of rapidly disintegrating powders are prone to dust flying during taking, which is likely to cause choking cough, and ordinary granules must be taken with hot water, and the lower the water temperature, the slower the dissolution and the more precipitation.

Description

Technical Field

[0001] The present invention specifically relates to an orally disintegrating granule and a preparation method thereof. Background Art

[0002] Orally disintegrating preparations are one of the research directions of current oral solid preparations. Their characteristics of oral rapid dissolution and taking medicine without water practice the dosage form design concept of "patient-centered", greatly improving the convenience and compliance of patients taking medicine. In recent years, a new type of oral solid preparation - orally disintegrating tablets (including orally disintegrating tablets and freeze-dried foams) has developed rapidly. Since most of them use water-soluble excipients, most of them can dissolve after encountering saliva and quickly turn into a solution state, with good taste, no gritty feeling, convenient to take, fast onset, high bioavailability, etc., providing convenience for the elderly, children, patients with poor swallowing function and inconvenient access to water. Therefore, orally disintegrating tablets are more and more popular among patients because of their unique advantages. However, there is currently no orally disintegrating granule for therapeutic purposes.

[0003] Generally speaking, for orally disintegrating granules, the larger the amount of excipients used, the better the oral rapid dissolution effect. However, increasing the amount of excipients will lead to an increase in the dosage. Due to the relatively fixed volume of the human oral cavity and the limited amount of saliva secreted in the oral cavity (about 10 ml in the eating state), how to dissolve a large number of granules with a limited amount of saliva secretion is a huge technical challenge. According to actual research and exploration, the direct one-time dosage of traditional Chinese medicine granules placed in the oral cavity without dissolution should not exceed 4 g, otherwise it will seriously affect the oral rapid dissolution effect.

[0004] For traditional Chinese medicine orally disintegrating granules, there are three major technical challenges to simultaneously achieve granule forming, rapid dissolution, and taste correction within a relatively limited excipient space range, create and adopt a suitable granulation technology, and ensure that the rapid dissolution effect is not reduced during the granulation process: First, the proportion of extract in traditional Chinese medicine preparations is high, and the amount of excipients available for rapid dissolution is limited, which will affect the oral rapid dissolution effect. Second, many drugs have obvious bitterness or other bad tastes, and the oral cavity is the main organ for taste perception. Simultaneously achieving rapid granule dissolution and creating a good taste in the oral cavity is a technical contradiction. Third, the challenge in granulation technology is that since the rapid dissolution excipients are mainly water-soluble, the traditional wet granulation process will cause the dissolution of excipients during the granulation process, the crystal structure is damaged, and the rapid dissolution effect is reduced. Using the dry granulation process will result in low porosity of the granules due to strong extrusion and poor rapid dissolution effect. Therefore, it is urgent to explore a new granulation process method suitable for the forming requirements of orally disintegrating granules. Therefore, for traditional Chinese medicine orally disintegrating granules, it is necessary to simultaneously achieve granule forming, rapid dissolution, and taste correction within a relatively limited excipient space range, create and adopt a suitable granulation technology, and ensure that the rapid dissolution effect is not reduced during the granulation process. Summary of the Invention

[0005] To solve the above problems, the present invention provides a welding granulation method, which is characterized in that it comprises the following steps:

[0006] a. Take raw materials and auxiliary materials for compounding;

[0007] b. Take the compound obtained in step a, weld it until it is formed, cool it, and pulverize it to obtain the product.

[0008] Among them, the temperature of the welding in step b is 5 - 20°C lower than the melting point of the specified auxiliary material, the humidity is not more than 50%, the welding is carried out until the surface is slightly melted and the powder mass is bonded; the cooling is to room temperature; the pulverization is into particles.

[0009] Among them, the raw materials include natural plant extract powder or raw powder, purified product or synthetic product, classic traditional Chinese medicine formula or empirical formula, and traditional Chinese patent medicine formula.

[0010] Among them, the traditional Chinese patent medicine formula includes: antiviral granules, Lianhua Qingwen granules.

[0011] The present invention also provides an orally disintegrating granule prepared, which contains water-soluble orally ingestible sugar alcohol crystals.

[0012] Among them, the water-soluble orally ingestible sugar alcohol crystals include one or more of xylitol, sucrose or glucose in combination.

[0013] The orally disintegrating granule of the present invention contains natural plant extract powder or raw powder, purified product or synthetic product, and one or more of xylitol, sucrose or glucose in combination. Among them, the mass ratio of the natural plant extract powder or raw powder to xylitol, sucrose or glucose is 10:5 - 100.

[0014] The present invention provides a preparation method of an orally disintegrating granule, which comprises the following steps:

[0015] 1) Take natural plant extract powder or raw powder, purified product or synthetic product, and compound it with a mixture of one or more of xylitol, sucrose or glucose; among them, the mass ratio of the natural plant extract powder or raw powder, purified product or synthetic product to the mixture of one or more of xylitol, sucrose or glucose is 10:5 - 100;

[0016] The d0.95 of the natural plant extract powder or raw powder ≤ 30μm; the water content is lower than 3%;

[0017] The d0.95 of the mixture of one or more of xylitol, sucrose or glucose ≤ 5μm;

[0018] 2) Take the compound prepared in step 1), add pharmaceutically or food-acceptable auxiliary materials or adjuvants, compound them, and carry out welding granulation according to the method described in claim 1) to obtain the product.

[0019] The present invention provides an antiviral orally-dissolvable granule, which is a granule prepared by the described method. Among them, the natural plant extract powder or the raw powder is prepared from the medicinal powders of Isatis root, Forsythia suspensa, Gypsum, Anemarrhena asphodeloides, Phragmites communis, Rehmannia glutinosa, Pogostemon cablin, Acorus tatarinowii and Curcuma aromatica, or the extract solution with water or an organic solvent.

[0020] The present invention provides the use of water-soluble and orally-administered sugar alcohol crystals as excipients in the preparation of orally-dissolvable preparations.

[0021] Among them, the water-soluble and orally-administered sugar alcohol crystals include xylitol, glucose and sucrose.

[0022] Among them, the total water content of the excipients in the preparation does not exceed 6% w / w.

[0023] Among them, the total water content of the excipients in the preparation does not exceed 4% w / w.

[0024] Among them, the total water content of the excipients in the preparation is 2%-4% w / w.

[0025] Among them, the preparation is a granule, a powder or a microcapsule.

[0026] "Welding" as described in the present invention refers to controlled and uniform heating.

[0027] "Micro-melting" as described in the present invention means that the surface of the powder mass begins to dissolve.

[0028] The welding granulation of the present invention is a vivid description of a macroscopic phenomenon, and micro-melting is the microscopic basis of welding granulation. First, due to controlled heating, the surface of the powder mass undergoes micro-melting under the condition of being lower than the melting point of xylitol, which will cause the powder masses to adhere to each other due to surface micro-melting (similar to welding), laying a structural foundation for granule preparation.

[0029] The effects achieved by the present invention are as follows:

[0030] 1. The orally-dissolvable granule prepared by the present invention can be directly taken under anhydrous conditions and completely dissolved within 2-10 seconds after entering the mouth, overcoming the disadvantage that traditional granules need to be taken with boiling water, making it more convenient for patients to take.

[0031] 2. Compared with some currently available instant powders that are prone to dust flying during taking, which is likely to cause choking cough and is not conducive to accurate dose packaging, the oral experience of the present invention is more comfortable.

[0032] 3. Compared with ordinary granules that must be taken with hot water, the lower the water temperature, the slower the dissolution and the more precipitation, the orally-dissolvable granule of the present invention has a better taste when taking medicine, can be taken directly without water, and realizes oral instant dissolution.

[0033] Obviously, based on the above content of the present invention, according to the common general technical knowledge and conventional means in the art, without departing from the above basic technical idea of the present invention, various other forms of modifications, substitutions or changes can be made.

[0034] The following is a further detailed description of the above content of the present invention through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. Description of the Drawings

[0035] Figure 1 It is a preparation flow chart Detailed Description of the Invention

[0036] Example 1. Preparation of the orally disintegrating granules of the present invention

[0037] 1) Take the traditional Chinese medicine extract with a water content of less than 3% and crush it to D95 of 10 - 30 μm, and then take 50% of xylitol based on the amount of the traditional Chinese medicine extract powder and crush it to D95 of 2 - 5 μm; first place the xylitol powder in a vibrating fine grinder, and then add the traditional Chinese medicine extract powder, and crush them together for 10 s - 3 min to form a composite powder mass with the adjuvant on the surface of the extract powder.

[0038] 2) Take the composite powder mass obtained in step 1), add aspartame (the amount of aspartame accounts for 3 / 1000 - 3 / 200 of the weight of the traditional Chinese medicine extract powder), mix well, and weld it to the surface of the composite powder mass until it is slightly melted under the conditions of a temperature 5 - 20 °C lower than the melting point of xylitol and a humidity not exceeding 50%, so that the powder mass generates adhesion. After cooling to room temperature, a loose agglomerated form is formed, and after crushing, the orally disintegrating granules are obtained.

[0039] Example 2. Preparation of the orally disintegrating granules of the present invention

[0040] 1) Take the traditional Chinese medicine extract with a water content of less than 3% and crush it to D95 of 10 - 30 μm, and then take 100% of xylitol based on the amount of the traditional Chinese medicine extract powder and crush it to D95 of 2 - 5 μm; first place the xylitol powder in a vibrating fine grinder, and then add the traditional Chinese medicine extract powder, and crush them together for 10 s - 3 min to form a composite powder mass with the adjuvant on the surface of the extract powder.

[0041] 2) Take the composite powder mass obtained in step 1), add neotame (the amount of neotame accounts for 1 / 10000 - 1 / 5000 of the weight of the traditional Chinese medicine extract powder), mix well, and weld it to the surface of the composite powder mass until it is slightly melted under the conditions of a temperature 5 - 20 °C lower than the melting point of xylitol and a humidity not exceeding 50%, so that the powder mass generates adhesion. After cooling to room temperature, a loose agglomerated form is formed, and after crushing, the orally disintegrating granules are obtained.

[0042] Example 3. Preparation of the orally disintegrating granules of the present invention

[0043] 1) Take the traditional Chinese medicine extract with a water content of less than 3% and crush it to D95 of 10 - 30 μm. Then take xylitol at 500% of the amount of the traditional Chinese medicine extract powder and crush it to D95 of 2 - 5 μm. First place the xylitol powder in a vibrating fine grinder, and then add the traditional Chinese medicine extract powder, and crush them together for 10 s - 3 min to form a composite powder mass with the adjuvant on the surface of the extract powder.

[0044] 2) Take the composite powder mass from step 1), add stevioside at 1 / 50 - 1 / 100 of the weight of the traditional Chinese medicine extract powder and mix evenly. Under the conditions that the temperature is 5 - 20 °C lower than the melting point of xylitol and the humidity does not exceed 50%, weld it until the surface of the composite powder mass is slightly melted, the powder mass generates adhesion, and after cooling to room temperature, a loose caked form is formed. After crushing, the orally disintegrating granules are obtained.

[0045] Example 4 Preparation of the orally disintegrating granules of the present invention

[0046] 1) Take the traditional Chinese medicine extract with a water content of less than 3% and crush it to D95 of 10 - 30 μm. Then take xylitol at 1000% of the amount of the traditional Chinese medicine extract powder and crush it to D95 of 2 - 5 μm. First place the xylitol powder in a vibrating fine grinder, and then add the traditional Chinese medicine extract powder, and crush them together for 10 s - 3 min to form a composite powder mass with the adjuvant on the surface of the extract powder.

[0047] 2) Take the composite powder mass from step 1), add malic acid at 1 / 50 - 1 / 100 of the weight of the traditional Chinese medicine extract powder and mix evenly. Under the conditions that the temperature is 5 - 20 °C lower than the melting point of xylitol and the humidity does not exceed 50%, weld it until the surface of the composite powder mass is slightly melted, the powder mass generates adhesion, and after cooling to room temperature, a loose caked form is formed. After crushing, the orally disintegrating granules are obtained.

[0048] Example 5 Preparation of the orally disintegrating granules of the present invention

[0049] 1) Take the traditional Chinese medicine extract with a water content of less than 3% and crush it to D95 of 10 - 30 μm. Then take xylitol at 143% of the amount of the traditional Chinese medicine extract powder and crush it to D95 of 2 - 5 μm. First place the xylitol powder in a vibrating fine grinder, and then add the traditional Chinese medicine extract powder, and crush them together for 10 s - 3 min to form a composite powder mass with the adjuvant on the surface of the extract powder.

[0050] 2) Take the composite powder mass from step 1), add aspartame (aspartame accounts for 3 / 1000 - 3 / 200 of the weight of the traditional Chinese medicine extract powder) and mix evenly. Under the conditions that the temperature is 5 - 20 °C lower than the melting point of xylitol and the humidity does not exceed 50%, weld it until the surface of the composite powder mass is slightly melted, the powder mass generates adhesion, and after cooling to room temperature, a loose caked form is formed. After crushing, the orally disintegrating granules are obtained.

[0051] The beneficial effects of the present invention are further illustrated by the following test examples:

[0052] The raw materials and equipment used in this experiment were obtained through commercial purchases. Among them, the antiviral granule extract was purchased from Sichuan Guangda Pharmaceutical Co., Ltd., and its medicinal flavor components include Isatis Root, Forsythia Fruit, Gypsum, Anemarrhena Rhizome, Reed Root, Rehmannia Root, Pogostemon Herb, Acorus Tatarinowii Rhizome, and Curcuma Aromatica Salisb.

[0053] Experimental Example 1

[0054] 1. Instant granule formula:

[0055] 1.4 g of antiviral granule extract, 0.7 g of xylitol, 0.02 g of aspartame, 0.04 g of silicon dioxide, and 0.036 ml of aromatic oil.

[0056] 2. Process steps:

[0057] First step: Mix and adsorb silicon dioxide and aromatic oil according to the prescription ratio, that is, gradually drip the aromatic oil into the silicon dioxide and stir to make it evenly mixed, and use the porous structure of silicon dioxide to adsorb the aromatic oil.

[0058] Second step: Crush the antiviral granule extract to D95 of 10 - 30 μm, with the moisture content of the extract being less than 3%, and crush 50% of the xylitol excipient in the extract powder to D95 of 2 - 5 μm.

[0059] Third step: Take the antiviral granule extract and aspartame in proportion and add them to a vibration mill, mix for 1 min. Discharge the material to obtain the oral fast-dissolving powder for standby.

[0060] Fourth step: Mix the prepared oral fast-dissolving powder, xylitol, and silicon dioxide adsorbed with aromatic oil evenly, spread them evenly on a metal tray (with a thickness of about 5 mm), place them in a heating box for heating, the heating temperature is 70 °C, the heating time is 10 min, and the humidity does not exceed 50%. At this time, the material is in a caked state. The temperature is selected to make the fine xylitol slightly melt first, and other materials do not melt, so that the caked state can be loose, easy to crush by extrusion. If the heating time is too long, the melting is excessive, the caking is serious, and the fast-dissolving property decreases.

[0061] Fifth step: Directly granulate the caked material taken out from the heating box through a swing granulator, and package it to obtain the finished product. ( Figure 1 )

[0062] 3. Effect test

[0063] The prepared antiviral orally disintegrating granules were compared with antiviral granules (commercial products) in terms of their dissolution properties. 4 g of antiviral granules (the minimum package quantity of antiviral granules) and 4 g of antiviral orally disintegrating granules were taken respectively, and the oral dissolution time under anhydrous oral administration conditions, the dissolution time in hot water at 100 °C, and the dissolution time in water at 25 °C were measured respectively. The results are shown in Table 1. It was found from the test results that the orally disintegrating granules were significantly superior to the antiviral granules under several conditions, demonstrating the superiority of the quality of the orally disintegrating granules.

[0064] Table 1 Comparison results of dissolution effect

[0065]

[0066] In summary, the orally disintegrating granules prepared by the present invention can be directly taken under anhydrous conditions and completely dissolve within 2 - 10 seconds after entering the mouth, overcoming the drawback that traditional granules need to be taken with boiling water, making it more convenient for patients to take and having practical value for popularization and application.

Claims

1. A welding granulation method, characterized in that: It includes the following steps: a. Take raw materials and auxiliary materials for compounding; b. Take the compound obtained in step a, weld it into shape, cool it, and pulverize it to obtain the product; The temperature of the welding in step b is 5 - 20°C lower than the melting point of the specified auxiliary material, and the humidity is not more than 50%. The welding is carried out until the surface is slightly melted and the powder mass is bonded; it is cooled to room temperature; it is pulverized into particles; the specified auxiliary materials include xylitol, sucrose or glucose.

2. The welding granulation method according to claim 1, wherein: The raw materials include natural plant extract powder or raw powder, purified product or synthetic product, classic traditional Chinese medicine formula or empirical formula, and traditional Chinese patent medicine formula.

3. The welding granulation method according to claim 2, wherein: The traditional Chinese patent medicine formula includes: antiviral granules, Lianhua Qingwen granules.

4. An orally disintegrating granule prepared by the method according to any one of claims 1-3, characterized in that: It contains water-soluble and orally administrable sugar alcohol crystals.

5. The orally disintegrating granule according to claim 4, wherein: The water-soluble and orally administrable sugar alcohol crystals include one or a combination of two or more of xylitol, sucrose or glucose.

6. The orally disintegrating granule according to claim 4 or 5, characterized in that: It contains natural plant extract powder or raw powder, purified product or synthetic product, and one or a combination of two or more of xylitol, sucrose or glucose. Among them, the mass ratio of natural plant extract powder or raw powder to xylitol, sucrose or glucose is 10:5 - 100.

7. A preparation method of orally disintegrating granules, characterized in that: It includes the following steps: 1) Take natural plant extract powder or raw powder, purified product or synthetic product, and compound it with a mixture of one or a combination of two or more of xylitol, sucrose or glucose; among them, the mass ratio of natural plant extract powder or raw powder, purified product or synthetic product to the mixture of one or a combination of two or more of xylitol, sucrose or glucose is 10:5 - 100; The natural plant extract powder or raw powder has d0.95 ≤ 30μm and a water content lower than 3%; The mixture of one or a combination of two or more of xylitol, sucrose or glucose has d0.95 ≤ 5μm; 2) Take the compound prepared in step 1), add pharmaceutically or food-acceptable auxiliary materials or auxiliary components, compound them, and granulate by welding according to the method of step b in claim 1 to obtain the product.

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