KR20180038622A - Pharmaceutical Composition Containing Linagliptin and Preparing Method Thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising linalglyptin and a process for producing the same. The pharmaceutical composition according to the present invention overcomes the disadvantages of the wet granulation method, which is a conventional method for the production of linagliptin, and provides an economical composition by realizing the preparation by direct tableting method. In addition, the present invention provides an optimal embodiment regarding stabilization of linagliptin, which is an active ingredient, so as to stabilize a pharmaceutical composition by significantly reducing the amount of a substance to be produced.

Description

FIELD OF THE INVENTION The present invention relates to a pharmaceutical composition containing linagliptin,

The present invention relates to a pharmaceutical composition comprising linalglyptin and a process for producing the same.

Rinagliptin (molecular formula: C25H28N8O2, molecular weight: 472.54) represented by the following formula 1 is a DPP-IV inhibitor and is effective for the treatment of diabetes and is widely used for the treatment of diabetes.

[Chemical Formula 1]

Medicines can also break down over time or create by-products that harm the patient. Therefore, there is a great demand in the art for the development of formulations that can minimize the occurrence of non-medically permissible substances that are not decomposed by long-term storage, and many inventions have been registered with the patent Korea Patent No. 1526825, No. 1217526, No. 1406265, etc.).

In Korean Patent No. 1478983, DPP-IV inhibitors have been observed to exhibit incompatibility, deterioration problems or extraction problems with many conventional excipients, and in particular the contact contact provided in the tablet and the impurity of the excipient at high excipient / ≪ / RTI >

Accordingly, it is considered to be very important to a person skilled in the art to provide a stable pharmaceutical composition of linagliptin, which is a kind of DPP-IV inhibitor.

Methods for preparing conventional pharmaceutical solid oral formulations include direct compression (also referred to as direct tableting, direct method) and granular compression. The direct compression method is to prepare a solid oral formulation by directly kneading a homogeneous dry mixture prepared by mixing additives or additives such as excipients, binders and disintegrants into crystals or powders of active ingredients, It is a method of preparing granules by mixing of additives and then tableting.

However, the granulation method is more complicated than the direct compression method, requires a lot of time and equipment, and is highly likely to decompose the active ingredient during the granulation process. Therefore, Korean Patent Registration No. 10-1033975 discloses that direct compression is considered to be economical and ideal in the production of pharmaceutical compositions.

In particular, the dry granule compression method is disadvantageous in that it requires economical efficiency because it requires expensive new equipment called a roller compactor, and if it is not densified by a uniform compressive force, reproducibility of drug elution from the granules may be deteriorated. The method of preparing pharmaceutical compositions of linagliptin, which is currently known, is limited to the wet granulation method (Korean Patent No. 1478983).

Therefore, the present inventors have been studying stable excipients in order to avoid problems of incompatibility with linalglyptin and excipients, deterioration of linaloglyptin, etc., and it is possible to prepare tablets by direct tableting method, The present invention relates to a pharmaceutical composition and a method for preparing the same.

Korean Patent Publication No. 10-2009-0009226

The present invention provides a pharmaceutical composition comprising linagliptin or a salt thereof as an active ingredient, mannitol as a diluent, hydroxypropylcellulose as a binder, low-substituted hydroxypropylcellulose as a disintegrant, and magnesium stearate as a lubricant .

In addition,

a. Preparing a first mixture by adding linalglyptin or its salt, hydroxypropylcellulose and low-substituted hydroxypropylcellulose to a mixer, firstly dewaxing and mixing the mixture;

b. Adding 25 to 35% by weight of total mannitol to the first mixture into a mixer, subjecting the mixture to second-order brewing and mixing to prepare a second mixture;

c. Adding 65 to 75% by weight of total mannitol to the secondary mixture into a mixer, subjecting the mixture to tertiary bombardment and mixing to prepare a tertiary mixture;

d. Adding magnesium stearate to the tertiary mixture to prepare a fourth mixture; And

e. And directly titrating said quaternary mixture.

It is an object of the present invention to provide a method for producing a pharmaceutical composition.

In addition,

a. Preparing a first mixture by firstly charging and mixing linalglytin or its salt, pregelatinized starch, hydroxypropylcellulose and low-substituted hydroxypropylcellulose into a mixer;

b. Adding 25 to 35% by weight of total mannitol to the first mixture into a mixer, subjecting the mixture to second-order brewing and mixing to prepare a second mixture;

c. Adding 65 to 75% by weight of total mannitol to the secondary mixture into a mixer, subjecting the mixture to tertiary bombardment and mixing to prepare a tertiary mixture;

d. Adding magnesium stearate to the tertiary mixture to prepare a fourth mixture; And

e. And directly titrating said quaternary mixture.

It is an object of the present invention to provide a method for producing a pharmaceutical composition comprising linalooligin.

In order to achieve the object to be solved by the present invention, the present invention provides a pharmaceutical composition comprising as an active ingredient linagliptin or a salt thereof, mannitol as a diluent, hydroxypropylcellulose as a binder, low-substituted hydroxypropylcellulose as a disintegrant, There is provided a pharmaceutical composition comprising magnesium stearate.

In addition,

a. Preparing a first mixture by adding linalglyptin or its salt, hydroxypropylcellulose and low-substituted hydroxypropylcellulose to a mixer, firstly dewaxing and mixing the mixture;

b. Adding 25 to 35% by weight of total mannitol to the first mixture into a mixer, subjecting the mixture to second-order brewing and mixing to prepare a second mixture;

c. Adding 65 to 75% by weight of total mannitol to the secondary mixture into a mixer, subjecting the mixture to tertiary bombardment and mixing to prepare a tertiary mixture;

d. Adding magnesium stearate to the tertiary mixture to prepare a fourth mixture; And

e. And directly titrating said quaternary mixture.

A method for preparing a pharmaceutical composition is provided.

In addition,

a. Preparing a first mixture by firstly charging and mixing linalglytin or its salt, pregelatinized starch, hydroxypropylcellulose and low-substituted hydroxypropylcellulose into a mixer;

b. Adding 25 to 35% by weight of total mannitol to the first mixture into a mixer, subjecting the mixture to second-order brewing and mixing to prepare a second mixture;

c. Adding 65 to 75% by weight of total mannitol to the secondary mixture into a mixer, subjecting the mixture to tertiary bombardment and mixing to prepare a tertiary mixture;

d. Adding magnesium stearate to the tertiary mixture to prepare a fourth mixture; And

e. And directly titrating said quaternary mixture.

The present invention also provides a method for preparing a pharmaceutical composition comprising linalooligin.

The present invention provides an optimal embodiment for the stabilization of linagliptin, which is an active ingredient, so as to stabilize the pharmaceutical composition by significantly reducing the amount of the generated substance.

Further, the pharmaceutical composition according to the present invention overcomes the disadvantages of the wet granulation method, which is a conventional method for producing linalglyptin, and provides an economical composition by realizing the preparation by direct tableting method.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a diagram showing an elution pattern of the pharmaceutical composition of the present invention. FIG.
2 is a graph showing the content of a sample after the acid hydrolysis reaction of the pharmaceutical composition of the present invention.
FIG. 3 is a graph showing the content of a substance after acid hydrolysis in the pharmaceutical composition of the present invention. FIG.
4 is a graph showing the content of a sample after the base hydrolysis reaction of the pharmaceutical composition of the present invention.
FIG. 5 is a graph showing the content of a soft substance after a base hydrolysis reaction of the pharmaceutical composition of the present invention. FIG.
6 is a graph showing the content of a sample in water hydrolysis conditions of the pharmaceutical composition of the present invention.
FIG. 7 is a graph showing the content of a soft substance in water hydrolysis conditions of the pharmaceutical composition of the present invention. FIG.
8 is a graph showing the content of a sample under the experimental conditions of thermal stability of the pharmaceutical composition of the present invention.
FIG. 9 is a graph showing the content of a flexible substance under the experimental conditions of thermal stability of the pharmaceutical composition of the present invention. FIG.

Hereinafter, the present invention will be described in more detail.

It will be appreciated by those of ordinary skill in the art that in the development of pharmaceutical compositions, due to differences in the chemical nature between the individual agents, they may be inactivated progressively at different rates and under different conditions during the storage period. That is, the kind and amount of the additive to be added in addition to the active substance vary depending on the type of the active substance, and when the same excipient is used for different compounds, the properties of the desired active ingredient It may show different or unexpected effects because it is changed or decomposed to generate a flexible substance or its concentration changes

In addition, those skilled in the art will appreciate that in the development of pharmaceutical compositions, the method of preparation varies depending on the type of each excipient or additive, and in particular, direct compression (or direct compression method, hereinafter referred to as direct method) It will be appreciated that the application is not easy because the binding force is not predictable.

If the binding force of each component between the pharmaceutical compositions is not sufficient, the tablets may not be formed upon compression with the tablet, or capping or laminating may occur. Even if tablets are formed, the tablets may be worn or broken in a subsequent process such as coating and packaging, resulting in loss of commercial value. Thus, the binding force between the pharmaceutical compositions in a solid oral formulation can be a very important factor to be directly linked to the final market.

The present invention provides a pharmaceutical composition with improved stability over commercially available preparations for the active ingredient linagliptin or its salts in the development of such unpredictable pharmaceutical compositions.

The present invention relates to a pharmaceutical composition comprising linagliptin or a salt thereof as an active ingredient, mannitol as a diluent, hydroxypropylcellulose as a binder, low-substituted hydroxypropylcellulose as a disintegrant, and magnesium stearate as a lubricant . The composition may further comprise pregelatinized starch.

According to one embodiment of the present invention, the pharmaceutical composition of the present invention has a higher content of active ingredient than that of the commercial formulation after the acid hydrolysis reaction, and the generation of the flexible substance is remarkably low (see Table 5, 3).

In addition, according to one embodiment of the present invention, the pharmaceutical composition of the present invention has a higher content of the active ingredient than that of the commercial formulation even after the basic hydrolysis reaction, 4 and 5).

In addition, according to one embodiment of the present invention, the pharmaceutical composition of the present invention has substantially the same amount of active ingredient as that of the commercial formulation even after the water hydrolysis reaction, And 7).

According to one embodiment of the present invention, the pharmaceutical composition of the present invention has substantially the same amount of active ingredient as the commercially available preparation even after the heat-stress condition test, Reference).

The term " pharmaceutical composition " of the present invention means an article used for diagnosis, treatment, alleviation, treatment or prevention of a disease of a human or an animal, and any composition necessary for maintaining, improving or improving the health of an animal or a human. do.

The salt of linalglyptin contained in the pharmaceutical composition according to the present invention may be a physiologically acceptable salt with an inorganic acid, an organic acid, an inorganic base or an organic base.

Examples of the inorganic acid include hydrochloric acid, bromic acid, sulfuric acid and phosphoric acid. The organic acids include citric acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid ), Oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid or aspartic acid.

The pharmaceutical composition of the present invention comprises 0.1 to 10% by weight of linagliptin or a salt thereof as a diluent, 10 to 95% by weight of mannitol as a diluent, 1 to 15% by weight of hydroxypropylcellulose as a binder, 1 to 20% by weight of low-substituted hydroxypropylcellulose as a disintegrant, and 0.5 to 5% by weight of magnesium stearate as a lubricant. Such a particular composition is optimized for elution and stabilization of the active ingredient, and when administered in amounts less than or greater than the above composition, the elution and stabilization of the pharmaceutical composition may be adversely affected.

In the present invention, the term "weight%" refers to the weight of the pharmaceutical composition in terms of the total weight thereof, unless otherwise specified.

When the pharmaceutical composition of the present invention contains pregelatinized starch, the amount thereof is 1 to 10% by weight based on the total weight of the pharmaceutical composition. If the pregelatinized starch is administered in a smaller or larger amount than the above composition, the elution and stabilization of the pharmaceutical composition may be adversely affected.

The mannitol contained in the pharmaceutical composition of the present invention preferably has a diameter of 60 to 360 탆, and preferably has a diameter of 100 to 250 탆. When the diameter of mannitol is lower than 60 占 퐉 or higher than 250 占 퐉, there is a possibility that the defective rate may be increased in the production method of the pharmaceutical composition of the present invention, that is, in the production by the direct method.

The pharmaceutical composition of the present invention can be prepared into a dosage form of capsules, tablets or film-coated tablets, but is not limited thereto.

The shape of the tablet is not particularly limited. For example, it may be an uncoated tablet having a shape such as a circle, an ellipse, a rectangle, or a coated tablet of the above shape.

When the pharmaceutical composition of the present invention is formulated into film-coated tablets, the film coating may comprise from 1 to 5% by weight of the film coating, based on the total weight of the pharmaceutical composition prepared before film coating.

Film coatings that may be provided in the pharmaceutical compositions of the present invention include hypromellose and / or polyethylene glycol. 0.1 to 1% by weight of the total weight of the pharmaceutical composition prepared before coating the film when the hyperpropulse is included, 0.01 to 0.1% by weight of the total weight of the pharmaceutical composition prepared before coating the film when the polyethylene glycol is included, ≪ / RTI >

As described above, the pharmaceutical composition of the present invention can be produced by the direct method. As described above, since it is unnecessary to add unnecessary excipients to the case of manufacturing by the direct method, it is possible to minimize the number of patients causing a side reaction (so-called allergy) to a specific substance, and the use of additional excipients The corresponding cost reduction can be induced.

In addition, significant economic benefits can be achieved in the formulation process since the use of additional equipment or equipment required for dry granulation methods is not required.

According to one embodiment of the present invention, the dissolution pattern of the pharmaceutical composition prepared by the direct tableting method has almost the same or improved effect as the dissolution pattern of the pharmaceutical composition prepared by the commercial formulation method or the wet granulation method (FIG. 1 Reference).

The pharmaceutical composition of the present invention can be prepared by the following method.

a. Preparing a first mixture by adding linalglyptin or its salt, hydroxypropylcellulose and low-substituted hydroxypropylcellulose to a mixer, firstly dewaxing and mixing the mixture;

b. Adding 25 to 35% by weight of total mannitol to the first mixture into a mixer, subjecting the mixture to second-order brewing and mixing to prepare a second mixture;

c. Adding 65 to 75% by weight of total mannitol to the secondary mixture into a mixer, subjecting the mixture to tertiary bombardment and mixing to prepare a tertiary mixture;

d. Adding magnesium stearate to the tertiary mixture to prepare a fourth mixture; And

e. Directly titrating the quaternary mixture.

The pharmaceutical composition of the present invention can also be produced by the following method.

a. Preparing a first mixture by firstly charging and mixing linalglytin or its salt, pregelatinized starch, hydroxypropylcellulose and low-substituted hydroxypropylcellulose into a mixer;

b. Adding 25 to 35% by weight of total mannitol to the first mixture into a mixer, subjecting the mixture to second-order brewing and mixing to prepare a second mixture;

c. Adding 65 to 75% by weight of total mannitol to the secondary mixture into a mixer, subjecting the mixture to tertiary bombardment and mixing to prepare a tertiary mixture;

d. Adding magnesium stearate to the tertiary mixture to prepare a fourth mixture; And

e. Directly titrating the quaternary mixture.

Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example

Example 1. Preparation of pharmaceutical composition by wet granulation method

A pharmaceutical composition according to the wet granulation method was prepared according to the composition shown in Table 1 below and the following preparation method.

- Manufacturing method

The active ingredient and hydroxypropylcellulose were dissolved in purified water at room temperature to prepare a granulating liquid. Mannitol, pregelatinized starch, and low-substituted hydroxypropylcellulose were mixed and wetted with the granulating liquid prepared above and subsequently granulated. The wet granules were dried in a suitable dryer at about 55 캜 to reduce the residual moisture content by 2 to 5% during drying. The dried granules were arbitrarily sieved through a sieve having a mesh size of 0.5 to 2.0 mm. And magnesium stearate was added to the above granules and mixed. The thus-prepared final granules were compressed and pressed to prepare tablets. For film coating of the tablets, hypromellose, titanium oxide, talc, polyethylene glycol and red iron oxide were suspended in purified water to prepare a coating suspension. The tablets were coated with a coating suspension such that the weight of the tablets was increased by 1 to 5 wt% to prepare film-coated tablets.

ingredient %/refine Active ingredient 2.7 Mannitol 75 Pregelatinized starch 6 Hydroxypropylcellulose 5 Low-substituted hydroxypropylcellulose 9.3 Magnesium stearate 2 Purified water Sum 100 Hi Prom Melose 0.75 Titanium oxide 0.375 Talc 0.2625 Polyethylene glycol 0.075 Red iron oxide 0.0375 Sum 101.5

Example 2. Preparation of pharmaceutical compositions according to direct tableting method 1

A pharmaceutical composition according to the wet granulation method was prepared according to the composition shown in Table 2 below and the following manufacturing method.

- Manufacturing method

The active ingredient, pregelatinized starch, hydroxypropylcellulose and low-substituted hydroxypropylcellulose were arbitrarily sieved through a sieve having a mesh size of 0.5 to 2.0 mm, and then blended and mixed. After thoroughly mixing, mannitol was added and the mixture was twice blended and mixed. Finally, magnesium stearate was added to the above mixture and mixed. The resulting final mixture was compressed and tableted to prepare tablets. The film suspension was prepared by suspending hypromellose, titanium oxide, talc, polyethylene glycol and red iron oxide in purified water to prepare a coating suspension. The tablets were coated with a coating suspension such that the weight of the tablets was increased by 1 to 5 wt% to prepare film-coated tablets.

ingredient %/refine Active ingredient 2.7 Mannitol 75 Pregelatinized starch 6 Hydroxypropylcellulose 5 Low-substituted hydroxypropylcellulose 9.3 Magnesium stearate 2 Sum 100 Hi Prom Melose 0.75 Titanium oxide 0.375 Talc 0.2625 Polyethylene glycol 0.075 Red iron oxide 0.0375 Sum 101.5

Example 3. Preparation of pharmaceutical compositions by direct tableting 2

A pharmaceutical composition according to the wet granulation method was prepared according to the composition shown in Table 3 below and the following manufacturing method.

- Manufacturing method

The active ingredient, hydroxypropylcellulose and low-substituted hydroxypropylcellulose were arbitrarily sieved through a sieve having a mesh size of 0.5 to 2.0 mm, and then blended and mixed. After thoroughly mixing, mannitol was added and the mixture was twice blended and mixed. Finally, magnesium stearate was added to the above mixture and mixed. The resulting final mixture was compressed and tableted to prepare tablets. The film suspension was prepared by suspending hypromellose, titanium oxide, talc, polyethylene glycol and red iron oxide in purified water to prepare a coating suspension. The tablets were coated with a coating suspension such that the weight of the tablets was increased by 1 to 5 wt% to prepare film-coated tablets.

ingredient %/refine Active ingredient 2.7 Mannitol 75 Hydroxypropylcellulose 5 Low-substituted hydroxypropylcellulose 14.3 Magnesium stearate 3 Sum 100 Hi Prom Melose 0.75 Titanium oxide 0.375 Talc 0.2625 Polyethylene glycol 0.075 Red iron oxide 0.0375 Sum 101.5

Experimental Example 1 Elution test of film-coated tablets

The elution tests were carried out according to the USP dissolution test method No. 2 (paddle method) for the film-coated tablets and commercial tablets prepared in Examples 1, 2 and 3. The dissolution test solution was 300 mL artificial gastric juice. The temperature of the test solution was set to 37 ± 0.5 ° C., and the rotation speed of the paddle was set to 50 rpm. Samples were taken at 5, 10, 15, and 30 minutes after the start of the test, 5 mL was taken from the dissolution test solution, and the resultant was filtered with a 10 μm pore filter. The filtrate was analyzed by HPLC and the results are shown in FIG.

As can be seen from FIG. 1, the elution results of the film-coated tablets prepared in Examples 1, 2, and 3 and the commercial product according to the present invention showed that elution of all the active ingredients in the artificial gastric juice within 30 minutes It was completed.

Experimental Example 2 Severe condition Initial sample analysis

In order to confirm the degradation products under severe conditions, the content and purity of the initial samples were tested. The content of the initial sample was 101.0% for the commercial product, 99.8% for Example 1, 100.5% for Example 2, and 99.7% for Example 3. In the case of the commercial products, two softeners of 0.14 and 0.20% were detected, and the total amount of the softeners was 0.34%. In Examples 1, 2 and 3, 4).

Experimental Example 3 Acid hydrolysis (1N-HCl) test

Experiments were carried out under acid hydrolysis conditions to confirm the degradation products of the commercial product and Examples 1, 2 and 3, and the degradation products were confirmed by the content and purity test methods. In order to decompose about 10% of the main component, the reaction was carried out for 4 hours. However, the commercial product was 97.1% lower than the initial content by 3%, and in Examples 1, 2 and 3, 98.1 ~ 98.7% Little decomposition occurred. The amount of decomposition product (softening substance) was detected more in the commercial product than in the examples, and the total amount of the flexible substance was 3.30% for the commercial product, 2.52% for Example 1, 2.31% for Example 3 and 1.99% for Example 3 It was confirmed that it was the least detected in Example 3 (see Table 5).

Experimental Example 4 Basic hydrolysis (1N-NaOH) test

Experiments were carried out under basic hydrolysis conditions to confirm the decomposition products of the commercial product and Examples 1, 2 and 3, and the decomposition products were confirmed by the content and purity test methods. As a result of the reaction under basic hydrolysis conditions, it was confirmed that the content of the commercial product was 88.8%, and the contents of Examples 1, 2 and 3 were 88.6 ~ 89.0%, which was about 11% lower than that of the initial sample. The total amount of the flexible substance of the commercial product was 7.30%, that of Example 1 was 6.51%, that of Example 2 was 5.33%, that of Example 3 was 4.63%, and that of the commercial product and 12 of Examples 1 and 2 were 12 , And in Example 3, it was confirmed that ten flexible substances were detected. The detection method of the suppositories showed a tendency to be more stable than that of the wet granulation method, and it was confirmed that the formulation of Example 3 was more stable than those of Examples 1 and 2 in the basic hydrolysis conditions (see Table 6).

Experimental Example 5 Water hydrolysis test

Experiments were carried out under water hydrolysis conditions to confirm the decomposition products of commercial products and Examples 1, 2 and 3, and the products of decomposition were determined by the content and purity test methods. As a result of the reaction under water hydrolysis conditions, there was no change in the content of the commercial product in 98.2%, Examples 1, 2 and 3, 98.4 to 99.9% The seafood was identified as 0.51%. In the case of Examples 1, 2 and 3, it was confirmed that decomposition products were not detected, and in the hydrolysis conditions using water, it was confirmed that both the commercial product and the examples were very stable (see Table 7).

Experimental Example 6 Thermal Harsh Condition Test

In order to confirm the decomposition product of the commercial product and Examples 1, 2 and 3, the experiment was conducted under the heat-harsh condition, and the decomposition products were confirmed by the content and purity test method. The tablets were powdered to block the light, and the thermal stability was confirmed for 48 hours. As a result, the content of the commercial product was 99.5% and the content of the example was 98.0%. It was confirmed that there was no decomposition products specifically detected except for the initially detected suppositories, and no decomposition product was found to increase. It was confirmed that the commercial product and the example had a similar decomposition product profile, and the total amount of the flexible substance (%) was 0.80% for the commercial product, 0.58% for Example 1 and 0.48% for Examples 2 and 3 ).

Claims (13)

Linagliptin or its salt as an active ingredient;
Mannitol as a diluent;
Hydroxypropylcellulose as a binder;
Low-substituted hydroxypropylcellulose as a disintegrant; And
A pharmaceutical composition comprising magnesium stearate as a lubricant.
The method according to claim 1,
0.1 to 10% by weight of the above-mentioned linagliptin or its salt;
10 to 95% by weight of the above mannitol;
1 to 15% by weight of the hydroxypropyl cellulose;
1 to 20% by weight of the low-substituted hydroxypropyl cellulose; And
And 0.5 to 5% by weight of the magnesium stearate.
The method according to claim 1,
The mannitol is a pharmaceutical composition having a diameter of 60 to 360 mu m
The method according to claim 1,
The mannitol is a pharmaceutical composition having a diameter of 100 to 250 mu m
3. The method of claim 2,
≪ / RTI > wherein said composition further comprises pregelatinized starch.
6. The method of claim 5,
And 1 to 10% by weight of the total pregelatinized starch.
The method according to claim 1,
Wherein said pharmaceutical composition is a dosage form of capsule, tablet or film-coated tablet.
8. The method according to any one of claims 1 to 7,
1 to 5% by weight of a film coating for said composition.
9. The method of claim 8,
Wherein the film coating comprises hypromellose and polyethylene glycol.
10. The method of claim 9,
0.1 to 1% by weight of the highrommelose and 0.01 to 0.1% by weight of the polyethylene glycol.
The method according to claim 1,
Wherein said composition is prepared by direct tabletting.
a. Preparing a first mixture by adding linalglyptin or its salt, hydroxypropylcellulose and low-substituted hydroxypropylcellulose to a mixer, firstly dewaxing and mixing the mixture;
b. Adding 25 to 35% by weight of total mannitol to the first mixture into a mixer, subjecting the mixture to second-order brewing and mixing to prepare a second mixture;
c. Adding 65 to 75% by weight of total mannitol to the secondary mixture into a mixer, subjecting the mixture to tertiary bombardment and mixing to prepare a tertiary mixture;
d. Adding magnesium stearate to the tertiary mixture to prepare a fourth mixture; And
e. And directly titrating said quaternary mixture.
A method for preparing a pharmaceutical composition according to claim 1.
a. Preparing a first mixture by firstly charging and mixing linalglytin or its salt, pregelatinized starch, hydroxypropylcellulose and low-substituted hydroxypropylcellulose into a mixer;
b. Adding 25 to 35% by weight of total mannitol to the first mixture into a mixer, subjecting the mixture to second-order brewing and mixing to prepare a second mixture;
c. Adding 65 to 75% by weight of total mannitol to the secondary mixture into a mixer, subjecting the mixture to tertiary bombardment and mixing to prepare a tertiary mixture;
d. Adding magnesium stearate to the tertiary mixture to prepare a fourth mixture; And
e. And directly titrating said quaternary mixture.
A method for preparing a pharmaceutical composition according to claim 5.

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