CN111110683B

CN111110683B - Soponaine taste masking composition and preparation method thereof

Info

Publication number: CN111110683B
Application number: CN201911028974.XA
Authority: CN
Inventors: 汪志辉; 黄心; 游劲松; 黄芳芳
Original assignee: Guangdong HEC Pharmaceutical
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2018-10-31
Filing date: 2019-10-28
Publication date: 2023-08-15
Anticipated expiration: 2039-10-28
Also published as: CN111110683A

Abstract

The invention belongs to the field of pharmaceutical preparations, and mainly relates to a solifenacin taste masking composition and a preparation method thereof. The composition contains solifenacin and cyclodextrin or a derivative thereof, wherein the cyclodextrin or the derivative thereof is as follows: beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin or mixtures thereof. The pharmaceutical composition can be further added with other pharmaceutically acceptable auxiliary materials to prepare granules, chewable tablets, orally disintegrating tablets and the like. The composition has the advantages of no influence on drug dissolution, good taste, stable quality, simple and feasible preparation process, etc.

Description

Soponaine taste masking composition and preparation method thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a solifenacin taste masking composition and a preparation method thereof.

Background

Solifenacin is the first line drug currently used to treat overactive bladder. The solifenacin succinate bulk drug has obvious tingling, and can be rapidly dissolved in the oral cavity due to high water solubility, so that a good taste masking effect is difficult to realize by a common taste masking technology.

The most common and effective method of masking the unpleasant taste of a drug is to establish a physical barrier that can achieve the effect of masking the unpleasant taste of the drug by retarding the dissolution of the active ingredient in the oral cavity. Although this technique can better mask the bad taste of the drug, it does not guarantee the normal release of the drug in the gastrointestinal tract, and therefore there is a risk of decreasing the bioavailability. The patent application TW200539902A of the pharmaceutical group company of Talc, japanese An Si, originally developed, mentions an oral disintegrating tablet of solifenacin based on a salting-out taste masking technique, which can better mask the bad taste of solifenacin succinate, but has complicated process operation, high technical requirements and can affect the dissolution of the drug. Patent application CN103585123A discloses an orally disintegrating tablet containing solifenacin succinate, which is prepared by adopting wet granulation, dividing an adhesive and a disintegrating agent into an inner part and an outer part, granulating and drying the inner part by adding materials, and uniformly mixing the inner part and the outer part with auxiliary materials. The bad taste of solifenacin succinate of the disintegrating tablet is still obvious. Patent application CN 105919963a discloses that solifenacin succinate is mixed with cyclodextrin (weight ratio of 1:1-1:1.6) and other pharmaceutical excipients to prepare Cheng Suoli solifenacin composition, which cannot achieve the effect of masking the bad taste of solifenacin succinate, and the bad taste of the drug is obvious. Patent application US20100137358A1 discloses the preparation of stable amorphous inclusion compounds by cyclodextrin inclusion of cyclodextrin with solifenacin succinate (in a weight ratio of 1:1 or 1:0.5), which cannot achieve the effect of masking the bad taste of solifenacin succinate, and the inclusion compound adopts an organic solvent dissolution preparation process, which is environment-friendly and has high production cost. Therefore, in order to obtain the solifenacin composition with good taste, the problem that the prior art cannot mask the strong tingling taste of solifenacin succinate is solved, and a simple and easy method for preparing the solifenacin taste-masking composition is explored, so that the solifenacin composition is a technical problem to be solved by pharmaceutical workers.

Disclosure of Invention

Summary of The Invention

The application was made based on the inventors' findings of the following problems and facts:

the solifenacin succinate has relatively high solubility (12.9 mg/mL) in water relative to the molecular weight 480.55, and the high solubility leads to rapid dissolution of the medicine in the oral cavity, has obvious bad taste and tingling taste, lasts for a long time, and brings great difficulty to development of medicine dosage forms with taste masking requirements such as granules, orally disintegrating tablets and the like. Based on this, the present invention proposes a solifenacin taste masking composition, the taste masking material being capable of masking the unpleasant taste of solifenacin succinate with cyclodextrin or its derivative.

In a first aspect of the invention, the invention provides a solifenacin taste masking composition.

In some embodiments, the solifenacin taste-masking composition comprises solifenacin or a salt thereof, cyclodextrin or a derivative thereof, wherein the mass ratio of the solifenacin or salt thereof to the cyclodextrin or derivative thereof is from 1:3 to 1:60. The cyclodextrin can mask the bad taste of solifenacin succinate in the dosage range, the medicine dissolution is not affected, and when the mass ratio of solifenacin or salt thereof to cyclodextrin or derivative thereof is more than 1:3, the taste masking effect is poor; when the mass ratio of solifenacin or salt thereof to cyclodextrin or derivative thereof is less than 1:60, the amount of auxiliary materials is too large, so that the subsequent preparation is difficult to mold. Preferably, the mass ratio of the solifenacin succinate to the cyclodextrin is 1:7-1:30, and after the solifenacin succinate and the cyclodextrin are physically mixed, the cyclodextrin can well mask the bad taste of the solifenacin succinate and does not influence the dissolution of the medicine. It is further preferable that the mass ratio of the solifenacin succinate to the cyclodextrin is 1:7-1:15, and after the solifenacin succinate and the cyclodextrin are physically mixed, the cyclodextrin can well mask the bad taste of the solifenacin succinate and does not influence the dissolution of the medicine.

The inventor finds that the solifenacin taste masking composition prepared from one or a mixture of beta-cyclodextrin (beta-CD), hydroxypropyl-beta-cyclodextrin (HP-beta-CD) can mask the bad taste of solifenacin succinate better than alpha-cyclodextrin (alpha-CD), gamma-cyclodextrin (gamma-CD), sulfobutyl-beta-cyclodextrin (SBE-beta-CD) and other cyclodextrin derivatives.

According to the embodiment of the invention, the solifenacin or the salt thereof and the cyclodextrin or the derivative thereof are physically mixed to obtain the solifenacin taste masking composition, and the taste masking effect is better than that of the inclusion compound.

The term "physical mixing" as used herein means the physical and thorough mixing of two or more materials, which do not undergo chemical reaction with each other, and which do not affect the crystal structure of the pharmaceutically active ingredient such as solifenacin or a salt thereof.

Clathrate refers to an inclusion body formed by embedding one (drug) molecule in the hole structure of another (constituting) substance molecule, or referred to as a "molecular capsule". The most common steps of the preparation method of the cyclodextrin inclusion compound are that guest molecules or a solution thereof and cyclodextrin water-soluble solution (cold or warm; neutral or acidic) are stirred or shaken, water in the cyclodextrin water-soluble solution is removed by a freeze drying method, a spray drying method or other proper methods after the cyclodextrin inclusion compound is balanced, or mother liquor is separated by filtration, so that amorphous inclusion compound is obtained. The technical scheme of the invention is that any solvent is not needed to be added, so that the degradation of the medicine is reduced, and the cost for preparing the composition is reduced.

In some embodiments, solifenacin or a salt thereof is physically mixed with cyclodextrin alone or with a derivative thereof (without the addition of other excipients such as fillers, disintegrants, lubricants, etc.), the cyclodextrin can mask the unpleasant taste of solifenacin succinate well without affecting drug dissolution.

In some embodiments, the physical mixing time of solifenacin, or a salt thereof, and cyclodextrin, or a derivative thereof, is no less than 20 minutes. The taste masking effect of the composition prepared by fully mixing solifenacin with cyclodextrin or the derivative thereof is better than that of the clathrate compound.

In some embodiments, the solifenacin taste-masking composition, optionally, contains a filler, a disintegrant, a flavoring agent, and/or a lubricant.

According to an embodiment of the present invention, the filler may be microcrystalline cellulose, mannitol, lactose, or a mixture thereof; the disintegrating agent can be cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose or a mixture thereof; the flavoring agent can be acesulfame potassium, aspartame, sucralose, citric acid monohydrate, tartaric acid, essence or mixture thereof; the lubricant can be micropowder silica gel, sodium stearate, magnesium stearate or their mixture. The inventor finds that under the precondition of the preferable mass ratio of solifenacin to cyclodextrin and certain physical mixing mode and physical mixing time, the third auxiliary material is added, the mixing sequence of all auxiliary materials has no influence on the taste masking effect of the cyclodextrin, for example, solifenacin succinate and cyclodextrin are mixed firstly, or one or more other necessary pharmaceutically acceptable auxiliary materials, such as filler microcrystalline cellulose, mannitol, lactose and the like, are added, for example, disintegrating agents with quick disintegration performance, such as cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and the like, for example, one or more than two of flavoring agents, acesulfame, aspartame, sucralose, citric acid monohydrate, tartaric acid and essence are added, and after being mixed for a certain time, the taste masking effect is not adversely affected.

According to embodiments of the present invention, the solifenacin taste-masking composition may be further prepared into granules, chewable tablets or orally disintegrating tablets.

In a second aspect of the present invention, the present invention provides a method of preparing a solifenacin taste-masking composition. The composition prepared by the preparation method does not influence the dissolution of the medicine, has good taste masking effect, is simple and feasible, can be used in industrial production, and has very wide application prospect.

According to an embodiment of the present invention, a method for preparing a taste-masked composition of solifenacin comprises physically mixing solifenacin or a salt thereof, cyclodextrin or a derivative thereof for not less than 20 minutes to obtain a taste-masked composition of solifenacin.

According to an embodiment of the present invention, the preparation method comprises adding solifenacin or a salt thereof, cyclodextrin or a derivative thereof, and optionally, a filler, a disintegrant and/or a flavoring agent, and then physically mixing for not less than 20 minutes, and optionally, adding a lubricant, to obtain a solifenacin taste-masking composition.

According to embodiments of the present invention, physical mixing means include, but are not limited to, vortex mixing, high shear granulation mixing, granulator mixing, mixing barrel mixing, mill mixing, and comminuting mixing. The solifenacin succinate has good water solubility, and the inventor adopts X-ray powder diffraction (XRD) pattern analysis to prove that the solifenacin taste masking composition prepared by the invention does not form inclusion compound.

In the context of the present invention, when used or whether or not the word "about" or "about" is used, means within 10%, suitably within 5%, particularly within 1% of a given value or range. Alternatively, the term "about" or "approximately" means within an acceptable standard error of the average value to one of ordinary skill in the art. Whenever a number is disclosed having a value of N, any number within the values of N+/-1%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8% or N+/-10% will be explicitly disclosed, where "+/-" means plus or minus.

Definition of terms

In the present invention, DEG C represents degrees Celsius, mg represents milligrams, μL represents microliters, μm represents micrometers, mL represents milliliters, mmol/L represents millimoles/liter, s represents seconds, min represents minutes, and h represents hours.

Drawings

FIG. 1 is a flow chart of detection of an electronic tongue;

FIG. 2 is an XRD pattern of solifenacin taste masking compositions of varying milling physical mixing times;

FIG. 3 is the XRD patterns of the solifenacin taste-masked lyophilisates of comparative example 3, comparative example 4, comparative example 5 and comparative example 6;

figure 4 is an XRD pattern for solifenacin succinate drug substance (API).

Detailed Description

In order to better understand the technical solution of the present invention, the following non-limiting examples are further disclosed for further details of the present invention.

The reagents used in the present invention are all commercially available or can be prepared by the methods described herein.

Unless otherwise stated, the invention has the analysis conditions of X-ray powder diffraction (XRD) of 3-40 degrees of scanning range and 0.0168 degrees of scanning step length, and the scanning speed is as follows: 10 seconds/step.

Examples 1 to 16

Examples 1-16 solifenacin taste masking compositions were prepared according to table 1.

Table 1:

the preparation method comprises the following steps: according to the prescription proportion and the treatment method in the table 1, a predetermined amount of solifenacin succinate and cyclodextrin are weighed and mixed for a certain time to obtain the solifenacin succinate taste masking composition.

Example 17: preparation of solifenacin succinate taste-masking orally disintegrating tablet

Table 2:

the preparation method comprises the following steps: according to the prescription proportion of the table 2, the optimal mass ratio of the solifenacin succinate to the cyclodextrin (the mass ratio is 1:13), and a certain mixing mode and mixing time, adding a third auxiliary material, specifically, adding the solifenacin succinate, beta-cyclodextrin, microcrystalline cellulose, mannitol, low-substituted hydroxypropyl cellulose, croscarmellose sodium, citric acid monohydrate, aspartame and orange essence into a mixing barrel together for physical mixing for 2 hours, then adding the micro powder silica gel and sodium stearate of the prescription amount, mixing for 5 minutes, and tabletting to obtain the orally disintegrating tablet. The elution results are shown in Table 6.

Example 18: preparation of solifenacin succinate taste-masking orally disintegrating tablets

Table 3:

component (A)	Prescription dose (mg)
		EXAMPLE 8 solifenacin taste masking composition	35.00
Microcrystalline cellulose	40.38
		Mannitol (mannitol)	12.46
Low substituted hydroxypropyl cellulose	9.04
		Croscarmellose sodium	3.10
Citric acid monohydrate	1.40
		Aspartame	5.06
Orange essence	0.52
		Micro powder silica gel	0.90
Stearic acid sodium fumarate	0.52

The preparation method comprises the following steps: according to the prescription proportion of Table 3, predetermined amounts of solifenacin taste masking composition prepared according to the method described in example 8, as well as microcrystalline cellulose, mannitol, low-substituted hydroxypropyl cellulose, croscarmellose sodium, citric acid monohydrate, aspartame, orange essence and silica gel micropowder were mixed for 10 minutes, then sodium fumarate in the prescribed amount was added, mixed for 10 minutes, and tabletted to prepare an orally disintegrating tablet. The dissolution data are shown in Table 6.

Comparative examples 1 to 8

Comparative examples 1-8 solifenacin compositions were prepared according to table 4.

Table 4:

wherein comparative example 2 prepared the composition according to the procedure prescribed in patent application CN 105919963a and comparative examples 3-4 prepared the composition according to the procedure prescribed in patent application US20100137358A 1.

Comparative example 9: preparation of solifenacin succinate orally disintegrating tablet

Table 5:

the preparation method comprises the following steps: according to the process of the prescription of the patent application CN103585123A (Table 5), solifenacin succinate, microcrystalline cellulose PH102 and crospovidone XL-10 in the prescription are weighed, mixed for 3 times by a 80-mesh sieve, added with water after being uniformly mixed, ground by a mortar and uniformly mixed, and granulated by a 24-mesh sieve. Oven drying at 50deg.C for 2 hr, sieving with 30 mesh sieve, measuring and calculating the actual content of dry particles, adding the converted microcrystalline cellulose PH102, crosslinked povidone XL-10, mixing for 3min, adding the converted silicon dioxide and magnesium stearate, and tabletting to obtain orally disintegrating tablet.

Example 19: taste evaluation

19.1 sensory panel evaluation

Examples 1-5, 8, 12-18, comparative example 1, comparative examples 5-9 were tested for mouthfeel, with the mouthfeel being evaluated as a score based on how and whether there is bitter taste. Before taste evaluation, the food should be fasted for not less than 0.5h. During the period, the food with the pungent taste such as sweet taste, salty taste, bitter taste, spicy taste and spicy taste cannot be eaten, and the food should be drunk normally, so that enough water intake is kept, and the influence of other factors such as food on the taste sense is avoided.

10 volunteers were tested, and before commencing taste evaluation, the volunteers were rinsed with not less than 100mL of water, and each volunteer was rinsed with water (not less than 50mL in volume) before taste evaluation to infiltrate the mouth and throat, and taste feelings of the volunteers were recorded by placing the equal-specification powders of examples 1 to 5, examples 8 to 12 to 16, comparative example 1, and comparative examples 5 to 8 into the mouth, and rinsing with water after about 1 minute. In addition, the orally disintegrating tablets of example 17, the orally disintegrating tablet of example 18 and the orally disintegrating tablet of comparative example 9, which were respectively prepared in equal specifications, were placed on the tongue part, and after disintegration was completed, the mouth was rinsed with water, and the taste sensation of volunteers was recorded. And scoring in a table according to corresponding standards during evaluation, and carrying out average score statistics, wherein the results are shown in Table 6 respectively.

Tingling scoring criteria: 1, the method comprises the following steps: very tingling, unacceptable; 2, the method comprises the following steps: hemp, not acceptable; 3, the method comprises the following steps: some tingling, but acceptable; 4, the following steps: does not cause tingling.

Bitter scoring criteria: 1, the method comprises the following steps: very bitter and unacceptable; 2, the method comprises the following steps: bitter, not acceptable; 3, the method comprises the following steps: is slightly bitter but acceptable; 4, the following steps: is not bitter.

In the process of establishing the taste model, statistics show that the scoring difference between the same tastes is more than or equal to 0.5 time sharing, namely the obvious taste difference is shown.

Table 6: taste evaluation tables of examples 1 to 5, example 8, examples 12 to 18, comparative example 1, comparative examples 5 to 9

The taste evaluation result shows that: 1. compared with the solifenacin composition disclosed in patent application CN103585123A, the solifenacin succinate taste masking composition disclosed by the invention can mask the bad tingling taste of solifenacin succinate well and has more obvious cyclodextrin taste masking effect along with the increase of the dosage of cyclodextrin; 2. when cyclodextrin (the dosage mass ratio is 1:30) is adopted to mask the taste of the rosuvastatin calcium and the acotiamide hydrochloride respectively, the cyclodextrin has no taste masking effect, and the rosuvastatin calcium and the acotiamide hydrochloride have obvious bitter taste; 3. when cyclodextrin or the derivative thereof is used as a taste masking material, the physical mixing ratio inclusion mode has good taste masking effect; 4. the taste masking effect of the solifenacin taste masking compositions of different physical mixing modes is not greatly different under the preferable physical mixing time.

19.2 Japanese INSENT electronic tongue (Japanese INSENT Co., model: SA-402B) detection

The electronic tongue is specifically designed for taste analysis technology, and its analysis principle is completely similar to human taste.

According to the invention, a Japanese INSENT intelligent taste analysis system, namely an electronic tongue is adopted to quantitatively analyze taste indexes, and the taste analysis of software can be utilized to directly give out the difference of each taste of a sample.

The analysis uses the bulk drug sample as a reference sample, and the final taste index value can be compared with the data obtained by the sensory panel, and the specific test flow is shown in figure 1.

The experiment uses a crude drug sample as a reference sample, and judges the difference between the comprehensive flavor of other samples and the crude drug according to the relative distance between the crude drug sample and the crude drug sample.

Solifenacin INSENT electronic tongue detection:

in the experimental process, a proper amount of solifenacin raw material medicine and samples of examples 1, examples 5-12, comparative examples 2-6 and comparative example 9 are respectively weighed, 50mL of 10mmol/L potassium chloride (10 mmol/L KCl) is added to prepare 0.4mg/mL solution, the solution is timely filtered by a filter head after uniform dispersion, and the filtrate is placed in a special beaker (25 mL) for INSENT electronic tongue to be tested. The results are shown in tables 7 to 9. Solifenacin is a weak alkaline drug, and the alkaline bitter taste value is detected to evaluate the taste masking effect; the higher the bitterness value, the more bitter the taste. The bitterness of the blank KCl solution is 0, and the bitter value of the crude drug solution is 109.56. In the process of establishing a Japanese INSENT electronic tongue model, when the basic bitter taste value (B-bitterness 2) of the solifenacin composition is reduced by 20 percent in combination with a taste test, the solifenacin composition has a better taste masking effect, when the basic bitter taste value (B-bitterness 2) is reduced by 30 percent, the taste masking effect is considered to be more obvious, and further, when the basic bitter taste value (B-bitterness 2) is reduced by 40 percent, the solifenacin composition is considered to have a remarkable taste masking effect. The basic bitter taste value reduction calculation formula is as follows:

wherein CV% is the base bitter taste (B-bitterless 2) reduction value, W is the base bitter taste value of the raw material medicine, and W _t The base bitter number of the taste masking sample.

Table 7: solifenacin succinate drug substance, example 1, example 5, example 8, example 12, and comparative example 9 taste index value

Test sample	B-bitterness2
		10mmol/LKCl	0
Bulk drug	109.56
		Example 1	83.24
Example 5	70.67
		Example 8	65.22
Implementation of the embodimentsExample 12	59.27
		Comparative example 9	98.05

Electronic tongue detection data display: 1. as the cyclodextrin proportion increases, the bitterness value of the solifenacin taste-masking composition decreases; 2. the bitterness value of the solifenacin taste-masking composition was significantly lower than that of the orally disintegrating tablet produced according to the method of patent application CN103585123 a.

Table 8: solifenacin succinate as a drug substance, example 12, comparative examples 2 to 6 taste index values

Electronic tongue detection data display: the taste masking composition of solifenacin succinate prepared according to the mass ratio of 1:30 has better taste masking effect on bulk drugs (APIs) by physical mixing of solifenacin succinate and cyclodextrin compared with the composition prepared according to the patent application CN 105919963A and the patent application US20100137358A 1.

Table 9: bulk drug of solifenacin succinate, examples 6-11 taste index values

Test sample	B-bitterness2
		10mmol/LKCl	0
Bulk drug	109.56
		Example 6	92.24
Example 7	89.85
		Example 8	65.22
Example 9	64.91
		Example 10	63.79
Example 11	61.89

As can be seen from Table 9, the bitterness values of the solifenacin taste-masking compositions (5 min/10min/20min/30min/40min/60 min) prepared by different mixing barrel physical mixing times were examined. Electronic tongue detection data display: in the same physical mixing mode, the mixing time has an effect on the solifenacin taste-masking composition. When the mixing time is more than or equal to 20 minutes in combination with taste evaluation data, the cyclodextrin has better taste masking effect on the API.

Rosuvastatin calcium INSENT electronic tongue experiment:

and respectively weighing a proper amount of rosuvastatin calcium bulk drug and a comparative example 7 sample, adding 50mL of distilled water, dispersing at a constant speed, filtering with filter paper in time after 60s, and placing the filtrate into a beaker (25 mL) special for INENT electronic tongue to be tested. The results are shown in Table 10.

Table 10: rosuvastatin calcium drug substance and comparative example 7 taste index value

Test sample	B-bitterness2
		10mmol/LKCl	0
Bulk drug	5.53
		Comparative example 7	6.82

When the rosuvastatin calcium is masked by adopting a cyclodextrin scheme, the alkaline bitter value is not reduced compared with the bulk drug, which indicates that the cyclodextrin has no taste masking effect on the rosuvastatin calcium.

Acotiamide hydrochloride INSENT electronic tongue experiment:

respectively weighing a proper amount of acotiamide hydrochloride bulk drug and a comparative example 8 sample, adding 50mL of distilled water, dispersing at a constant speed, filtering with filter paper in time after 60s, and placing the filtrate into a beaker (25 mL) special for INENT electronic tongue to be tested. The results are shown in Table 11.

Table 11: acotiamide hydrochloride drug substance and comparative example 8 taste index value

Test sample	B-bitterness2
		10mmol/LKCl	0
Bulk drug	12.47
		Comparative example 8	11.07

When the acotiamide is masked by cyclodextrin, the alkaline bitter value is not reduced compared with the bulk drug, which indicates that the cyclodextrin has no taste masking effect on the acotiamide.

The above experimental results show that the bad taste of the drug can be masked when not all the drug is physically mixed with cyclodextrin or its derivative, for example, the mass ratio of rosuvastatin calcium or acotiamide hydrochloride to cyclodextrin is 1:3-1:60, and the bad taste of rosuvastatin calcium (comparative example 7) or acotiamide hydrochloride (comparative example 8) cannot be masked by the cyclodextrin under the same operation when the physical mixing time is 30min or more.

From the above-mentioned evaluation results of the electronic tongue taste in tables 6 to 11, it can be seen that: 1. the solifenacin taste masking composition prepared by the invention can mask the bad taste of solifenacin succinate well; 2. along with the extension of the mixing time, cyclodextrin has better taste masking effect on the API, and the mixing time is preferably longer than 20 minutes (20 minutes); 3. not all drugs may be taste masked by cyclodextrin or its derivatives.

Example 20: solid state analysis XRD investigation of the form of solifenacin succinate present

The specific operation steps are as follows: the preparation method comprises the steps of weighing the solifenacin succinate and the beta-cyclodextrin according to the mass ratio of 1:3, and examining by preparing solifenacin succinate taste masking compositions (0 min/10min/30min/50 min) with different grinding physical mixing times, wherein an X-ray powder diffraction (XRD) spectrum is shown in figure 2, and the result shows that the crystal structure of solifenacin succinate is not influenced by different grinding physical mixing times.

Analysis of the XRD patterns of comparative example 3 (see FIG. 3) and comparative example 4 (see FIG. 3), in combination with the characteristic peaks of the crystal forms in the XRD patterns of the API (see FIG. 4), showed that the freeze-drying process altered the crystal of solifenacin succinate and the API was amorphous and formed into inclusion compounds. By analyzing the XRD patterns of comparative example 5 (see FIG. 3) and comparative example 6 (see FIG. 3), the results also show that the freeze-drying process would alter the crystalline form of solifenacin succinate, and that the API is amorphous.

Example 21: dissolution data determination

The sample and reference preparation (solifenacin succinate orally disintegrating tablet, source: an Si Talc pharmaceutical group, japan) of example 18 were taken, and 900mL of phosphate buffer solution with pH of 6.8 was used as dissolution medium, respectively, in accordance with the dissolution examination method (paddle method) of the Chinese pharmacopoeia and United states pharmacopoeia, the rotation speed was 50 revolutions per minute, and appropriate amounts of solutions were taken at 5, 10, 15, 20, 30, 45 and 60 minutes while supplementing the blank medium with the same temperature and the same volume. The obtained solution was filtered through a 0.45 μm aqueous microporous membrane, and the subsequent filtrate was taken as a sample solution. And dissolving appropriate amount of solifenacin succinate reference substance in dissolution medium to obtain reference substance solution. And precisely measuring 20 mu L of each of the reference substance solution and the test substance solution, injecting into a high performance liquid chromatograph, calculating the concentration of solifenacin succinate in the test substance according to an external standard method, and calculating the leaching amount of each tablet, wherein the result is shown in Table 12.

Table 12: EXAMPLE 18 dissolution data for orally disintegrating tablets and reference orally disintegrating tablets

The usual physical taste masking coatings are capable of achieving the effect of masking the unpleasant taste of the drug by retarding the dissolution of the active ingredient in the oral cavity, these taste masking modes generally reducing drug dissolution. The solifenacin succinate is highly soluble in different media, and the reference preparation (orally disintegrating tablet) cannot be rapidly dissolved in the medium with the pH of 6.8, and the dissolution amount of 15min is only 50% of that of a dissolution platform. Compared with a reference preparation (orally disintegrating tablet), the solifenacin succinate taste masking composition prepared by the invention can mask the bad taste of solifenacin succinate better, has no obvious inhibition effect on the dissolution rate and dissolution platform of active ingredients, and can be dissolved out rapidly.

In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.

While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims

1. A solifenacin taste-masking composition comprising solifenacin or a salt thereof, and a cyclodextrin, wherein the mass ratio of solifenacin or a salt thereof to cyclodextrin is 1:3-1:60.

2. The composition of claim 1, wherein the mass ratio of solifenacin or a salt thereof to the cyclodextrin is 1:7-1:30.

3. The composition of claim 1, wherein the cyclodextrin is selected from beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, or a mixture thereof.

4. The composition of claim 1, wherein the solifenacin, or a salt thereof, and the cyclodextrin are physically mixed to provide the composition.

5. The composition of claim 4, wherein the physical mixing time of the solifenacin or salt thereof and the cyclodextrin is not less than 20 minutes.

6. The composition of any one of claims 1-5, wherein the composition optionally contains a filler, a disintegrant, a flavoring agent, and/or a lubricant.

7. The composition of claim 6, wherein the filler is microcrystalline cellulose, mannitol, lactose, or a mixture thereof; the disintegrating agent is cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose or a mixture thereof; the flavoring agent is acesulfame potassium, aspartame, sucralose, citric acid monohydrate, tartaric acid, essence or a mixture thereof; the lubricant is micropowder silica gel, sodium stearate, magnesium stearate or their mixture.

8. The composition of claim 7, wherein the composition is further formulated as granules, chewable tablets, or orally disintegrating tablets.

9. A process for preparing a taste-masked composition of solifenacin, wherein the process comprises physically mixing solifenacin or a salt thereof, cyclodextrin for not less than 20 minutes to obtain the composition.

10. A process according to claim 9, wherein the process comprises adding solifenacin or a salt thereof, cyclodextrin, and optionally fillers, disintegrants and/or flavouring agents, and obtaining the composition by physical mixing for not less than 20 minutes, optionally adding lubricants.