CN104645336B - A kind of composite auxiliary material and its preparation method and application - Google Patents

Abstract

The invention provides a composite auxiliary material, which is spherical or quasi-spherical particles obtained by co-crystallizing mannitol and cross-linked povidone. The fluidity, compressibility and other properties of the composite auxiliary material all meet the requirements of the direct tableting process. The present invention also provides a preparation method of a composite auxiliary material, comprising the following steps: adding the crospovidone suspension into a saturated solution of mannitol, and mixing the mannitol and the crospovidone in an ice-water bath and stirring state. Co-crystallization of polyvidone, after the crystallization of mannitol is completed, suction filtration, drying, grinding and sieving, the composite auxiliary material is obtained, and the composite auxiliary material is obtained by co-crystallization of mannitol and crospovidone spherical or quasi-spherical particles. The preparation method of the composite auxiliary material has simple process and low cost, and is beneficial to industrialized production. The compound auxiliary material prepared by the invention is used to prepare orally disintegrating tablets, and the disintegration time of the prepared tablets is all within 1 min.

Description

A kind of composite auxiliary material and its preparation method and application

technical field

The invention relates to the field of medicine, in particular to a composite auxiliary material and its preparation method and application.

Background technique

As a traditional dosage form, tablet has become one of the most commonly used dosage forms at present because of its stable properties, convenient carrying and use, high degree of manufacturing mechanization, low cost, high output, and accurate dosage. However, because the tablet needs to be pressurized, the disintegration is slow, the bioavailability is low, and it is difficult for the elderly, children, and mental patients to swallow, so the popularization and use of the tablet is limited to a certain extent. Therefore, in the research of solid preparations, various immediate-release preparations have gradually become a hot spot in the development of new drugs in recent years, especially orally disintegrating tablets. Orally disintegrating tablet is a tablet that can disintegrate or dissolve in the oral cavity without water. It has the advantages of fast absorption, high bioavailability, no need to take water, easy to take, less intestinal residue, low side effects, and Advantages such as reducing the first-pass effect of the liver. Disintegrants commonly used in commonly used orally disintegrating tablets, such as sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and crospovidone, all have a heavy grainy feel after disintegration, and the taste is not good. The fluidity of the solution is not good, and it is difficult to mix evenly with the main drug and other excipients, which leads to quality problems such as large differences in tablet weight and large differences in the disintegration time of the finished product when directly compressed.

In order to solve this problem, the invention with the publication number CN101829333 provides a new multifunctional auxiliary material, which is processed from mannitol, isosorbide and crospovidone, although the fluidity and disintegration ability of the prepared auxiliary material Improve to some extent, but use spray-drying method to prepare auxiliary material, method is comparatively complicated, and spray equipment occupies a large area, and production cost is higher; Also need to add isosorbide as binder in the preparation process, further improved production cost.

Contents of the invention

In order to solve the above problems, the present invention provides a composite auxiliary material and its preparation method and application. The composite auxiliary material provided by the invention is obtained by the co-crystallization of mannitol and crospovidone, the preparation method is simple, no large-scale equipment is needed in the preparation process, the cost is low, and it is beneficial to industrial production, which solves the problem of the prior art composite auxiliary material Preparation method complicates the issue.

The first aspect of the present invention provides a composite auxiliary material, which is spherical or quasi-spherical particles obtained by co-crystallization of mannitol and crospovidone.

The composite auxiliary material is spherical or quasi-spherical particles, the particles of the composite auxiliary material are round and have good sphericity, which can improve the fluidity of the composite auxiliary material.

Preferably, the mannitol and the crospovidone are co-crystallized at a mass ratio of 98-40:2-60. At this ratio, the mixing effect of mannitol and crospovidone is better, and the fluidity and compressibility of the prepared compound excipients can meet the needs of direct tablet compression, which overcomes the disadvantage of crospovidone alone as a disintegrant. defect.

More preferably, the mannitol and the crospovidone are co-crystallized at a mass ratio of 98-75:2-25.

Further preferably, the mannitol and the crospovidone are co-crystallized at a mass ratio of 90-75:10-25.

The composite excipient provided by the first aspect of the present invention is obtained by co-crystallization of mannitol and crospovidone, wherein mannitol has the advantages of low hygroscopicity, high stability, high tolerance, low calorie and pure sweetness, etc. Orally disintegrating tablets mainly function as excipients and flavoring agents. At present, most of the excipients used in the preparation of tablets in the prior art are lactose, which makes patients suffering from lactose intolerance, especially children whose gastrointestinal function is not fully developed, cause certain troubles when taking medicine. The composite auxiliary material of the present invention fundamentally solves this problem. Crospovidone is a commonly used disintegrant in orally disintegrating tablets, with a good taste and no sandy feeling. The fluidity and compressibility of the composite excipient prepared by co-crystallization of mannitol and crospovidone can meet the requirements of the direct compression process. A small amount of water in the mouth can make it swell and disintegrate quickly and taste good.

The second aspect of the present invention provides a kind of preparation method of composite auxiliary material, comprises the following steps:

Add the crospovidone suspension into the saturated mannitol solution, and in the state of ice-water bath and stirring, make the mannitol and the crospovidone co-crystallize, and after the mannitol crystallization is completed, suction filter After drying, grinding and sieving, the composite auxiliary material is obtained, and the composite auxiliary material is a spherical or quasi-spherical particle obtained by co-crystallizing mannitol and crospovidone.

The composite auxiliary material is a spherical or quasi-spherical granular particle with rounded shape and good sphericity, which can improve the fluidity of the composite auxiliary material.

Preferably, the mannitol saturated solution is placed in an ice-water bath and stirred until crystallization begins, then the cross-linked povidone suspension is added, and the stirring is continued to make the mannitol and the cross-linked polyvinyl alcohol Vitone co-crystallized.

Preferably, the mannitol and the crospovidone are co-crystallized at a mass ratio of 98-40:2-60.

More preferably, the mannitol and the crospovidone are co-crystallized at a mass ratio of 98-75:2-25.

Further preferably, the mannitol and the crospovidone are co-crystallized at a mass ratio of 90-75:10-25.

Preferably, the crospovidone is uniformly dispersed in one or more of water, ethanol and ethyl acetate to obtain the crospovidone suspension.

More preferably, the crospovidone is uniformly dispersed in water to obtain the crospovidone suspension.

Preferably, in the crospovidone suspension, the concentration of the crospovidone is 0.4 g/mL˜0.8 g/mL.

Preferably, the mannitol is dissolved in one or more of water, ethanol and ethyl acetate to obtain a saturated mannitol solution.

More preferably, the mannitol is added into hot water at 80-90° C. and stirred to completely dissolve to obtain the saturated mannitol solution.

Preferably, the drying temperature is 65°C.

Preferably, the sieving is carried out with a 65-mesh sieve.

In the preparation method of the composite auxiliary material provided by the second aspect of the present invention, the composite auxiliary material can be obtained by co-crystallizing the mannitol and the crospovidone, and the obtained composite auxiliary material has fluidity and The compressibility is better, the tablet prepared by using the composite auxiliary material has a certain hardness, the surface is smooth and clean, the adhesion between the composite auxiliary materials is good, and the tablet made by pressing the tablet does not have tablet powder falling off. Using the composite auxiliary material The prepared orally disintegrating tablet disintegrates quickly and tastes good. The preparation method provided by the invention is simple and easy to operate, does not require large instruments and equipment, has low cost, and is beneficial to industrialized production. The method solves the problems in the prior art that the compound auxiliary material is prepared by the spray drying method, the method is complicated, the auxiliary material is wasted, and the cost is high.

The third aspect of the present invention provides the use of a composite excipient for preparing orally disintegrating tablets.

The prepared compound excipient provided by the third aspect of the present invention can be used to prepare orally disintegrating tablets, and the disintegration time of the prepared orally disintegrating tablets is all within 1 minute, disintegrates quickly, has a good taste, and has no gritty feeling. And it has suitable hardness, suitable for transportation and storage, and the difference in tablet weight is small.

In summary, the beneficial effects of a composite auxiliary material provided by the present invention and its preparation method and use include the following aspects:

(1), properties such as fluidity, compressibility of described composite auxiliary material all can reach the requirement of direct tableting process;

(2), the preparation method process of described composite auxiliary material is simple, and cost is low, is conducive to industrialized production;

(3) Orally disintegrating tablets are prepared by using the compound excipients, and the disintegration time of the prepared orally disintegrating tablets is all within 1 min.

Description of drawings

Fig. 1 is the scanning electron micrograph of the product of comparative example 1～3 and the composite auxiliary material that embodiment 1 makes;

Fig. 2 is the differential scanning calorimetry (DSC) collection of illustrative plates of the product of comparative example 1～3 and the composite auxiliary material that embodiment 1 makes;

Fig. 3 is the X-ray powder diffraction (XRD) curve of the product of comparative example 1～3 and the composite auxiliary material that embodiment 1 makes;

Fig. 4 is the infrared spectrum (FT-IR) spectrogram of the products of Comparative Examples 1-3 and the composite auxiliary material prepared in Example 1.

detailed description

The following description is a preferred embodiment of the present invention, it should be pointed out that for those skilled in the art, without departing from the principle of the present invention, some improvements and modifications can also be made, and these improvements and modifications are also considered Be the protection scope of the present invention.

Example 1:

A preparation method of composite auxiliary material, comprising the following steps:

Weigh 20g of crospovidone and place it in a beaker, add water to make a suspension of crospovidone with a concentration of 0.8g/mL; weigh 80g of mannitol and place it in a beaker, add 80°C hot water and stir to make it Dissolve completely to make a saturated mannitol solution, place the saturated mannitol solution in an ice-water bath to cool down and stir until crystallization begins to precipitate in the beaker, add the cross-linked povidone suspension, and make the mannitol Alcohol and crospovidone are co-crystallized. After the crystallization of mannitol is completed, the substance in the beaker is suction-filtered, dried at 65°C, ground, and sieved through a 65-mesh sieve to obtain the compound auxiliary material.

Example 2:

A preparation method of composite auxiliary material, comprising the following steps:

Weigh 15g of crospovidone and put it in a beaker, add water to make a suspension of crospovidone with a concentration of 0.6g/mL; weigh 85g of mannitol and put it in a beaker, add 90°C hot water and stir to make it Dissolve completely to make a saturated mannitol solution, place the saturated mannitol solution in an ice-water bath to cool down and stir until crystallization begins to precipitate in the beaker, add the cross-linked povidone suspension, and make the mannitol Alcohol and crospovidone are co-crystallized. After the crystallization of mannitol is completed, the substance in the beaker is suction-filtered, dried at 65°C, ground, and sieved through a 65-mesh sieve to obtain the compound auxiliary material.

Example 3:

A preparation method of composite auxiliary material, comprising the following steps:

Weigh 10g of crospovidone and put it in a beaker, add water to make a suspension of crospovidone with a concentration of 0.4g/mL; weigh 90g of mannitol and put it in a beaker, add 80°C hot water and stir to make it Dissolve completely to make a saturated mannitol solution, place the saturated mannitol solution in an ice-water bath to cool down and stir until crystallization begins to precipitate in the beaker, add the cross-linked povidone suspension, and make the mannitol Alcohol and crospovidone are co-crystallized. After the crystallization of mannitol is completed, the substance in the beaker is suction-filtered, dried at 65°C, ground, and sieved through a 65-mesh sieve to obtain the compound auxiliary material.

Example 4:

A preparation method of composite auxiliary material, comprising the following steps:

Weigh 2 g of crospovidone and place it in a beaker, add water to make a crospovidone suspension with a concentration of 0.4 g/mL; weigh 98 g of mannitol and place it in a beaker, add 80°C hot water and stir to make it Dissolve completely to make a saturated mannitol solution, place the saturated mannitol solution in an ice-water bath to cool down and stir until crystallization begins to precipitate in the beaker, add the cross-linked povidone suspension, and make the mannitol Alcohol and crospovidone are co-crystallized. After the crystallization of mannitol is completed, the substance in the beaker is suction-filtered, dried at 65°C, ground, and sieved through a 65-mesh sieve to obtain the compound auxiliary material.

Example 5:

A preparation method of composite auxiliary material, comprising the following steps:

Weigh 40g of crospovidone and place it in a beaker, add water to make a suspension of crospovidone with a concentration of 0.8g/mL; weigh 60g of mannitol and place it in a beaker, add 80°C hot water and stir to make it Dissolve completely to make a saturated mannitol solution, place the saturated mannitol solution in an ice-water bath to cool down and stir until crystallization begins to precipitate in the beaker, add the cross-linked povidone suspension, and make the mannitol Alcohol and crospovidone are co-crystallized. After the crystallization of mannitol is completed, the substance in the beaker is suction-filtered, dried at 65°C, ground, and sieved through a 65-mesh sieve to obtain the compound auxiliary material.

Embodiment 6:

A preparation method of composite auxiliary material, comprising the following steps:

Weigh 25g of crospovidone and put it in a beaker, add water to make a crospovidone suspension with a concentration of 0.6g/mL; weigh 75g of mannitol and put it in a beaker, add 80°C hot water and stir to make it Dissolve completely to make a saturated mannitol solution, place the saturated mannitol solution in an ice-water bath to cool down and stir until crystallization begins to precipitate in the beaker, add the cross-linked povidone suspension, and make the mannitol Alcohol and crospovidone are co-crystallized. After the crystallization of mannitol is completed, the substance in the beaker is suction-filtered, dried at 65°C, ground, and sieved through a 65-mesh sieve to obtain the compound auxiliary material.

Embodiment 7:

Experts from the United States Pharmacopoeia Committee pointed out in an article on compound excipients published in the United States Pharmacopoeia Forum that the single components used to prepare excipients should be clearly identifiable in the state of physical mixing, and in the process of co-processing, the single excipients cannot be separated. A chemical reaction occurs, so the combination mechanism and characterization state of the composite auxiliary materials prepared by the present invention are studied and explained.

Comparative Example 1: A single mannitol (indicated by A) was weighed for testing.

Comparative example 2: Weigh a single crospovidone (indicated by B) for testing.

Comparative example 3: Weigh 80 g of mannitol and 20 g of crospovidone, and mix them uniformly to make a physical mixing auxiliary material (indicated by C) for testing.

The products of Comparative Examples 1-3 and the composite auxiliary material (indicated by D) prepared in Example 1 were comparatively analyzed. The specific analysis is as follows.

1. Scanning electron microscope analysis

Get the product of comparative examples 1～3 and the composite auxiliary material that embodiment 1 makes and carry out the combination mechanism and characterization research between auxiliary materials:

Adopt gold-spraying method to observe surface structure, sample (being respectively mannitol (A), crospovidone (B), mannitol and above-mentioned crospovidone physical mixture (C), the compound auxiliary material that embodiment 1 makes (D)) is placed in a glass dish, and the surface structure of the sample is observed by SEM after ion sputtering, and the accelerating voltage is 25.0kV.

Fig. 1 is a scanning electron microscope image of the products of Comparative Examples 1-3 and the composite auxiliary material prepared in Example 1. It can be seen from Figure 1A that Comparative Example 1 has an obvious crystal form of mannitol as a single auxiliary material; Figure 1B is the structure of the cross-linked povidone in Comparative Example 2; Figure 1C is the physically mixed auxiliary material prepared in Comparative Example 3, and mannitol can be observed Individual characterization of alcohol and crospovidone. Figure 1D is the composite excipient obtained in Example 1. The composite excipient obtained after co-crystallization of mannitol and crospovidone is a whole particle with a spherical or quasi-spherical appearance, and no obvious crystal form of the single excipient of mannitol is observed and the individual characteristics of single crospovidone, the two combine well. While the physical mixing of excipients can observe the individual characteristics of mannitol and crospovidone, the two do not combine well together. It shows that the preparation method of the present invention can well combine mannitol and crospovidone together, not simply mixing, which further explains the reason for the improvement of the advantages of the physical properties of the composite auxiliary material.

2. Differential calorimetry scanning (DSC) analysis

The mannitol and cross-linked povidone composite auxiliary material (D) that appropriate amount of mannitol (A), crospovidone (B), mannitol and crospovidone physical mixture (C), embodiment 1 make are placed respectively In an aluminum pot, using an empty aluminum crucible as a reference, the heating rate: 10.00°C·min ^-1 ; the heating range: 0-500°C, respectively record the differential calorimetry scanning curves of the samples. Figure 2 is Comparative Example 1 The differential scanning calorimetry (DSC) spectrum of the product of ~ 3 and the composite auxiliary material that embodiment 1 makes.

As can be seen from Figure 2, comparing the DSC spectra of the mixed excipient (C) and the compound excipient (D), it can be seen that mannitol and crospovidone in the compound excipient do not produce new endothermic peaks, indicating that there is no chemical group in the compound excipient. change in score.

3. X-ray powder diffraction (XRD) analysis

Appropriate amount of mannitol (A), crospovidone (B), mannitol and crospovidone physical mixture (C), mannitol and crospovidone composite excipients (D) were analyzed by X-ray powder diffraction . The test conditions are Cu target (40kV, 40mV); step scan: 0.02°/step; scan range: 5°～60°; scan speed: 0.02°·min ^-1 . Record the X-ray powder diffraction curves of the samples respectively, see accompanying drawing 3.

Fig. 3 is the X-ray powder diffraction (XRD) curve of the product of comparative example 1～3 and the composite auxiliary material that embodiment 1 makes; As can be seen from Fig. 3, mannitol has multiple strong in the scope of 10 °～50 ° Crystalline characteristic diffraction peaks; cross-linked povidone is a non-crystalline compound without obvious diffraction peaks; mannitol still has crystallization diffraction peaks in the spectrum lines of mixed excipients, and the intensity is weakened, indicating that the crystal form of mannitol has not changed, and the chemical group However, part of the mannitol crystallization diffraction peaks existed in the spectral line of the composite excipients, which may be due to the fact that part of the mannitol was dispersed in the composite excipients in an amorphous or molecular state during the crystallization process.

4. Infrared spectroscopy (FT-IR) analysis

Respectively the mannitol and cross-linked povidone composite auxiliary material (D) that appropriate amount of mannitol (A), crospovidone (B), mannitol and crospovidone physical mixture (C), embodiment 1 make are mixed with After KBr was mixed and made into tablets in a dry environment, the infrared spectrum was measured in the range of 400-4000 cm ^-1 , and Figure 4 was obtained.

Fig. 4 is the infrared spectrum (FT-IR) spectrogram of the products of Comparative Examples 1-3 and the composite auxiliary material prepared in Example 1. It can be seen from Figure 4 that the characteristic peaks of the spectrum of the mixed excipients are the simple superposition of mannitol and crospovidone. Comparing the spectral lines of the compound excipients with those of the mixed excipients, no new absorption peaks were seen in the spectral lines of the compound excipients, presumably no new chemical bonds were formed between mannitol and crospovidone.

In summary, by co-crystallizing mannitol and cross-linked povidone, the composite excipient obtained is a whole particle with uniform particle size dispersion and a spherical or quasi-spherical appearance, and no separate characteristics of mannitol and cross-linked povidone are observed , the chemical composition of compound excipients has not changed compared with simple physical mixing excipients, and no new chemical bonds have been formed between mannitol and crospovidone.

Effect Example 1

The pharmaceutical excipients prepared in Examples 1-3 were subjected to performance tests on powder fluidity, compressibility and other aspects.

Powder fluidity: The fluidity of powder has a great influence on the weight difference of granules, capsules, tablets and other preparations, and it is an important link to ensure product quality. The preparation of tablets by direct compression has specific requirements on the fluidity of the powder. Angle of Repose (Angle of Repose) refers to the largest angle formed by the free slope of the powder accumulation layer and the horizontal plane, and is an index commonly used to express the fluidity of powder. It is generally believed that the smaller the angle of repose, the smaller the friction between particles and the better the fluidity. When the angle of repose is less than or equal to 35°, it can meet the fluidity requirements in the production process. The composite auxiliary materials obtained in Examples 1 to 3 were used to measure the angle of repose by the fixed cone bottom method, and the results are shown in Table 1.

Bulk density, tap density, Karl's index: Karl's index reflects the compressibility and filling performance of powder. A powder with a large Karnofsky index has good compressibility, but poor fluidity; a powder with a small Karnofsky index has good filling and fluidity,

But compressibility is poor. Generally, when the Karnofsky index is between 15% and 25%, the fluidity and compressibility of the powder can meet the requirements of direct tableting of powder by a rotary tablet press. The bulk density, tap density, and Carr index of the composite auxiliary materials obtained in Examples 1 to 3 were measured, and the results are shown in Table 1.

Table 1 The powder properties of composite auxiliary materials

The results in Table 1 show that the angle of repose and the Carr index of the composite auxiliary material prepared by the present invention all meet the requirements of the direct compression method for auxiliary materials.

Comparing the fluidity of the composite auxiliary material prepared in Example 2 with the products of Comparative Examples 1-3, the results are shown in Table 2.

Table 2 The powder properties of single excipients, physical mixtures and composite excipients

The result of table 2 shows, the compound auxiliary material powder physical properties that the present invention makes is better than its single auxiliary material and the auxiliary material that simple physical mixing obtains, illustrates that the performance of the composite auxiliary material that the present invention makes is not the simple addition of the performance of two kinds of single auxiliary materials. And, the powder properties of the composite auxiliary material of the present invention are more advantageous.

Effect Example 2

The compound excipients obtained in Examples 1-3 were pressed without additional excipients to make a blank orally disintegrating tablet, and the hardness, disintegration time limit, mouthfeel, surface finish and friability of the blank orally disintegrating tablet were measured. Each item was measured in three groups. The results are shown in Table 3:

Disintegration time: As a special dosage form, orally disintegrating tablets, one of the technical points is to control the disintegration time of the tablet in the oral cavity. Tianda Tianfa KB-1 oral disintegration instrument was used for determination. The specific measurement process is as follows: add 900mL of distilled water at 37°C to the dissolution cup, put the orally disintegrating tablet into the disintegration basket, click start, shake the disintegration basket up and down, and record the period from when the tablet is put in until there is basically no residue on the screen Time is the disintegration time of the orally disintegrating tablet.

Taste: compare the taste with volunteer experiments. Select 6 healthy volunteers, including 3 males and 3 females, aged between 18 and 36, and adopt three evaluation grades, A: good; B: average; C: poor.

Surface gloss: visual observation.

Friability: Measured according to the friability determination method of "Chinese Pharmacopoeia".

Table 3 Study on the characteristics of the blank orally disintegrating tablets made of compound excipients

Results: The blank orally disintegrating tablets prepared with the compound excipients had a smooth surface, good taste, no sandy feeling, and the disintegration time was within 1 min, and had a certain hardness, which was suitable for transportation and storage.

Application Example 1

Prepare ibuprofen orally disintegrating tablets with the compound auxiliary material that embodiment 2 makes, and preparation method is as follows:

Get 18g of ibuprofen, add 27g of the composite auxiliary material obtained in the above embodiment 2, finally add an appropriate amount of magnesium stearate, mix evenly, adopt the powder direct compression method to prepare, press and form with an 8mm die, each tablet is 0.2g, and the hardness is controlled at 70 ～80N, made 200 ibuprofen orally disintegrating tablets.

The ibuprofen orally disintegrating tablets prepared above were tested: the test results showed that the obtained tablets were complete and smooth, with uniform color, tablet hardness of 70-80N, disintegration time within 40s, slightly sweet taste, no sandy feeling, Good taste. The tablet weight difference is controlled within 0.75%.

Application Example 2

Prepare vitamin C orally disintegrating tablets with the composite auxiliary material obtained in Example 3, the preparation method is as follows:

Take 6g of vitamin C, add 56g of the composite auxiliary material obtained in Example 3 above, and finally add an appropriate amount of magnesium stearate, mix well, prepare it by powder direct compression method, press it with an 8mm die, each tablet is 0.2g, and the hardness is controlled at 70~ 80N, made 260 vitamin C orally disintegrating tablets.

The vitamin C orally disintegrating tablets prepared above were tested: the test results showed that the obtained tablets were complete and smooth, with uniform color, tablet hardness of 70-80N, disintegration time within 40s, slightly sweet taste, no sandy feeling, and taste good. The tablet weight difference is controlled within 0.75%.

In summary, the performance of the composite excipients prepared by the simple co-crystallization method in the examples of the present invention is better than that of the excipients obtained by simple physical mixing of the two excipients, and its fluidity, compressibility and other properties can reach direct tableting Process requirements; the disintegration time of the orally disintegrating tablet prepared by using the composite auxiliary material of the present invention is all within 1 min. The compound excipient can be mixed evenly with other excipients and the main drug. After direct tableting, the weight difference of the obtained tablet is small. In addition, the orally disintegrating tablet has a smooth surface, good taste, no sandy feeling, and has a certain hardness. , suitable for transportation and storage.

The above-mentioned embodiments only express several implementation modes of the present invention, and the description thereof is relatively specific and detailed, but should not be construed as limiting the patent scope of the present invention. It should be pointed out that those skilled in the art can make several modifications and improvements without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent for the present invention should be based on the appended claims.

Claims (8)

1. a kind of composite auxiliary material, it is characterised in that it by mannitol and PVPP is 98 in mass ratio that the composite auxiliary material, which is, ~40:2~60 in the mixed solvents formed in water or at least one of ethanol and ethyl acetate with water are tied jointly The spherical or spherical particle that crystalline substance is obtained.

2. a kind of preparation method of composite auxiliary material, it is characterised in that comprise the following steps：

PVPP suspension is added in mannitol saturated solution, under ice-water bath and stirring, makes the mannitol It is 98~40 in mass ratio with the PVPP:2~60 in water or at least one of ethanol and ethyl acetate with The in the mixed solvent of water formation carries out cocrystallization, treats after the completion of crystallization of mannitol, suction filtration is dried, ground after sieving, produces institute Composite auxiliary material is stated, the composite auxiliary material is to carry out spherical or spherical that cocrystallization is obtained by mannitol and PVPP Grain.

3. the preparation method of composite auxiliary material as claimed in claim 2, it is characterised in that the mannitol and the poly- dimension of the crosslinking Ketone is 98~75 in mass ratio:2~25 carry out cocrystallization.

4. the preparation method of composite auxiliary material as claimed in claim 3, it is characterised in that the mannitol and the poly- dimension of the crosslinking Ketone is 90~75 in mass ratio:10~25 carry out cocrystallization.

5. the preparation method of composite auxiliary material as claimed in claim 2, it is characterised in that be placed in the mannitol saturated solution In ice-water bath and stir to when beginning with crystallization and separating out, add the PVPP suspension, continue to stir, make the sweet dew Alcohol carries out cocrystallization with the PVPP.

6. the preparation method of composite auxiliary material as claimed in claim 2, it is characterised in that the PVPP is dispersed One or more in water, ethanol and ethyl acetate obtain the PVPP suspension.

7. the preparation method of composite auxiliary material as claimed in claim 2, it is characterised in that be dissolved in water the mannitol To the mannitol saturated solution.

8. a kind of purposes of composite auxiliary material, it is characterised in that be combined made from the preparation method as described in claim any one of 2-7 Auxiliary material is used to prepare oral disnitegration tablet.