Vildagliptin double-release preparation and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a vildagliptin double-release preparation and a preparation method thereof. The invention aims to provide a double-release preparation which has two curative effects of taking effect quickly and persistently on diabetics. The vildagliptin double-release preparation comprises a drug-containing quick-release part and a drug-containing slow-release part, the drug-containing quick-release part comprises a first vildagliptin active component and a slow-release auxiliary material, and the weight of the first vildagliptin active component is 1-20% of the total weight of the drug-containing quick-release part; the drug-containing sustained-release part comprises a second vildagliptin active component and a sustained-release auxiliary material, and the weight of the second vildagliptin active component is 1-15% of the total weight of the drug-containing sustained-release part; the weight ratio of the first vildagliptin active component to the second vildagliptin active component is 1: (1-15). The invention further provides a method for preparing the vildagliptin double-release preparation.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and more specifically, to a vildagliptin dual-release preparation and a preparation method thereof. Background Art

[0002] The number of adult patients with diabetes (20-79 years old) in the world has nearly tripled from 151 million in 2000 to 425 million in 2017. It is estimated that by 2045, the number of patients with diabetes may reach 629 million. The number of people with diabetes is increasing rapidly, and prevention of diabetes is particularly important. However, there are few high-end preparations circulating in the market, and ordinary oral preparations are the main ones.

[0003] Novartis's Vildagliptin tablets were launched in 2007, with global sales reaching US$181 million in 2009, US$1.2 billion in 2013, US$1.224 billion in 2014, US$1.140 billion in 2015, US$1.193 billion in 2016, and US$1.233 billion in 2017. Vildagliptin inhibits the activity of DPP-4 by binding to it to form a DPP-4 complex, while increasing the concentration of GLP-1 and prompting pancreatic B cells to produce insulin, it reduces the concentration of glucagon, thereby lowering blood sugar, and has no significant effect on body weight.

[0004] The prior art has many studies on the preparation method or dosage form of vildagliptin, for example:

[0005] Patent document WO2007019255 records that vildagliptin is extremely unstable to moisture and heat, so during the production process, dry granulation or direct powder compression is often used. Although this can avoid the loss of API components, the uniformity of the preparation is insufficient.

[0006] Patent document CN105193752A provides a vildagliptin tablet and a preparation method thereof, which only provides a quick-release preparation of vildagliptin and cannot meet the requirement of long-term effect on patients.

[0007] Patent document CN102846567A discloses the preparation of xanthan gum vildagliptin gastric retention floating sustained-release tablets, which uses xanthan gum as the skeleton and adds some additives to help reduce the density of the preparation; and prevent the hydration of the skeleton. The main problem to be solved is to control the release rate, release the drug by the dissolution mechanism of the skeleton, and optimize the drug release characteristics of the prescription to meet the Higuichi equation, thereby improving its bioavailability and prolonging the duration of action. This patent only provides a sustained-release preparation of vildagliptin, which cannot achieve the purpose of rapid onset of action on patients.

[0008] Patent document CN103040759A discloses a sustained-release oral solid preparation with vildagliptin as the active ingredient, which adopts a wet granulation process. To ensure the stability of vildagliptin, anhydrous ethanol and isopropanol are used as the solvent or dispersed phase of vildagliptin. The granulation process of this patent requires the use of ethanol, which poses a safety hazard and increases the granulation cost.

[0009] Patent document CN114010612B provides a method for preparing a sitagliptin metformin double-layer sustained-release tablet. The preparation method of the dual-release preparation in this patent is complicated, and the premixed excipients need to be spray-dried first and then wet granulated, and organic solvents are used for granulation, which has high safety risks.

[0010] It can be seen that the prior art preparation method and preparation of vildagliptin still have many deficiencies. Summary of the invention

[0011] The present invention aims to overcome at least one defect of the above-mentioned prior art and provide a vildagliptin dual-release preparation and a preparation method thereof, so as to achieve both rapid onset and long-lasting therapeutic effects on diabetic patients.

[0012] The first aspect of the present invention is to provide a vildagliptin dual-release preparation, comprising a drug-containing immediate-release portion and a drug-containing sustained-release portion, wherein the drug-containing immediate-release portion comprises a first vildagliptin active ingredient and an immediate-release excipient, wherein the weight of the first vildagliptin active ingredient is equivalent to 1-20%, preferably 2-15% of the total weight of the drug-containing immediate-release portion;

[0013] The drug-containing sustained-release portion comprises a second vildagliptin active ingredient and a sustained-release excipient, wherein the weight of the second vildagliptin active ingredient is equivalent to 1-15%, preferably 2-10% of the total weight of the drug-containing sustained-release portion;

[0014] The weight ratio of the first vildagliptin active ingredient to the second vildagliptin active ingredient is 1:(1-15).

[0015] Furthermore, the rapid-release excipient includes a first filler, a first lubricant and a disintegrant.

[0016] Preferably, the drug-containing immediate-release portion comprises the following components in parts by weight:

[0017] 1-20 parts of the first vildagliptin active ingredient,

[0018] 55-99 parts of the first filler,

[0019] 0.2-10 parts of the first lubricant,

[0020] 1-15 parts of disintegrant.

[0021] Furthermore, the sustained-release excipients include a second filler, a second lubricant, an adhesive, a glidant and a sustained-release material, wherein the weight of the sustained-release material is equivalent to 10-80%, preferably 20-50%, of the total weight of the drug-containing sustained-release portion.

[0022] Preferably, the drug-containing sustained-release portion comprises the following components in parts by weight:

[0023] 1-15 parts of the second vildagliptin active ingredient,

[0024] 10-55 parts of the second filler,

[0025] 0.2-10 parts of the second lubricant,

[0026] 0.1-10 parts of adhesive,

[0027] 0.2-10 parts of flow aid,

[0028] 10-80 portions of sustained-release material.

[0029] Furthermore, the sustained-release material is selected from any one or more of hydroxypropylmethylcellulose, xanthan gum, sodium alginate, carbomer or polyoxyethylene.

[0030] Furthermore, the glidant is a hydrophobic glidant.

[0031] Optionally, the glidant is selected from any one or more of hydrophobic colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, paraffin, glyceryl monostearate, glyceryl behenate, and glyceryl monopalmitate; preferably, it is hydrophobic colloidal silicon dioxide.

[0032] The second aspect of the present invention is to provide a method for preparing a vildagliptin dual-release preparation, comprising:

[0033] The components of the drug-containing immediate-release part are mixed and compressed by powder direct compression to obtain drug-containing immediate-release total mixed granules, and the components of the drug-containing sustained-release part are wet granulated, dried and mixed to obtain drug-containing sustained-release total mixed granules;

[0034] The drug-containing rapid-release total mixed granules and the drug-containing sustained-release total mixed granules are tableted to prepare the vildagliptin dual-release preparation.

[0035] Furthermore, the components of the drug-containing sustained-release part are wet granulated, dried, and mixed to obtain the drug-containing sustained-release total mixed granules, which include:

[0036] The second filler and part of the sustained-release material are wet granulated, and dry granules are obtained after drying. The remaining part of the sustained-release material is mixed with the second vildagliptin active ingredient and the binder, and then added to the dry granules for remixing, and then the second lubricant is added for lubrication to obtain the drug-containing sustained-release total mixed granules.

[0037] Preferably, the moisture content of the dry whole granules is ≤2.0%.

[0038] Compared with the prior art, the present invention has the following beneficial effects: the drug-containing rapid-release portion of the vildagliptin dual-release preparation provided by the present invention can be rapidly released in vivo, and can quickly take effect within 1 hour to achieve a hypoglycemic effect; the drug-containing sustained-release portion can be sustained-released in vivo and maintain an effective blood drug concentration for more than 16 hours, thereby achieving both rapid release effects and prolonged release time, reducing the number of daily doses, and improving medication safety and patient compliance; the drug-containing sustained-release portion of the present invention is granulated with a wet method for some excipients, and then the vildagliptin active ingredient therein is added externally, thereby avoiding moisture and heat from reducing the activity of the active ingredient, and also reducing the impurity content of the final product preparation, thereby improving stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 This is the dissolution curve of the vildagliptin dual-release preparation of Example 1.

[0040] Figure 2 This is the dissolution curve of the vildagliptin dual-release preparation of Example 2.

[0041] Figure 3 This is the dissolution curve of the vildagliptin dual-release preparation of Example 3.

[0042] Figure 4 This is the dissolution curve of the vildagliptin dual-release preparation of Example 4.

[0043] Figure 5 This is the dissolution curve of the vildagliptin dual-release preparation of Example 5.

[0044] Figure 6 This is the dissolution curve of the vildagliptin dual-release preparation of Comparative Example 1.

[0045] Figure 7 This is the dissolution curve of the vildagliptin dual-release preparation of Comparative Example 2.

[0046] Figure 8 This is the dissolution curve of the vildagliptin dual-release preparation of Comparative Example 3.

[0047] Fig. 9 This is the dissolution curve of the vildagliptin dual-release preparation of Comparative Example 4.

[0048] Fig.10 This is the dissolution curve of the vildagliptin dual-release preparation of Comparative Example 5.

[0049] Fig.11 This is the dissolution curve of the vildagliptin dual-release preparation of Comparative Example 6. DETAILED DESCRIPTION

[0050] The first aspect of the present invention is to provide a vildagliptin dual-release preparation, comprising a drug-containing immediate-release portion and a drug-containing sustained-release portion, wherein the drug-containing immediate-release portion comprises a first vildagliptin active ingredient and an immediate-release excipient, and the weight of the first vildagliptin active ingredient is equivalent to 1-20% of the total weight of the drug-containing immediate-release portion;

[0051] The drug-containing sustained-release portion comprises a second vildagliptin active ingredient and a sustained-release excipient, wherein the weight of the second vildagliptin active ingredient is equivalent to 1-15% of the total weight of the drug-containing sustained-release portion;

[0052] The weight ratio of the first vildagliptin active ingredient to the second vildagliptin active ingredient is 1:(1-15).

[0053] In specific implementation, the first vildagliptin active ingredient and the second vildagliptin active ingredient of the present invention can be vildagliptin or a pharmaceutically acceptable salt thereof. The vildagliptin dual-release formulation of the present invention can be implemented in a multi-layer tablet, more specifically, a double-layer tablet.

[0054] Research tests have shown that by setting the weight of the first vildagliptin active ingredient to 1-20% of the total weight of the drug-containing immediate-release portion, setting the weight of the second vildagliptin active ingredient to 1-15% of the total weight of the drug-containing sustained-release portion, and making the weight ratio of the first vildagliptin active ingredient to the second vildagliptin active ingredient 1:(1-15), the vildagliptin solubility of the vildagliptin dual-release preparation can reach 20-50% at 1 hour, which can meet the requirement of rapid onset of effect for patients. In addition, the release time of the remaining part of the vildagliptin can be delayed, and the solubility at 12 hours can reach more than 80%, which meets the purpose of long-lasting effect on patients. The study also showed that when the weight ratio of the first vildagliptin active ingredient to the second vildagliptin active ingredient is greater than 1:1, it causes excessive dissolution of vildagliptin in a short period of time, posing a safety hazard to patients; when the weight ratio of the first vildagliptin active ingredient to the second vildagliptin active ingredient is less than 1:15, the dissolution rate of vildagliptin slows down, and the solubility in 1h and 12h are both lower than the standard requirements, making it impossible to provide effective treatment for patients.

[0055] In a preferred embodiment, the weight of the first vildagliptin active ingredient is equivalent to 2-15% of the total weight of the immediate-release drug-containing portion, for example, 2%, 3%, 4%, 5%, 5.5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, etc.

[0056] In a preferred embodiment, the weight of the second vildagliptin active ingredient is equivalent to 2-10% of the total weight of the drug-containing sustained-release portion, for example, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 8.4%, 8.9%, 9%, 10%, etc.

[0057] In a preferred embodiment, the weight ratio of the first vildagliptin active ingredient to the second vildagliptin active ingredient is 1:(1-10), for example, 1:2, 1:2.33, 1:3, 1:4, 1:5, 1:5.25, 1:6, 1:7, 1:8, 1:8.09, 1:9, 1:10 and the like.

[0058] In a specific implementation, the rapid-release excipient includes a first filler, a first lubricant and a disintegrant.

[0059] Preferably, the drug-containing immediate-release portion comprises the following components in parts by weight:

[0060] 1-20 parts of the first vildagliptin active ingredient,

[0061] 55-99 parts of the first filler,

[0062] 0.2-10 parts of the first lubricant

[0063] 1-15 parts of disintegrant.

[0064] The sustained-release excipients include a second filler, a second lubricant, an adhesive, a glidant and a sustained-release material, wherein the weight of the sustained-release material is equivalent to 10-80% of the total weight of the drug-containing sustained-release portion, preferably 20-50%, such as 20%, 25%, 30%, 35%, 40%, 45%, 50%, etc. Studies have shown that when the weight of the sustained-release material accounts for less than 10% of the total weight of the drug-containing sustained-release portion, the dissolution rate of vildagliptin is accelerated, resulting in excessive dissolution in a short period of time, which poses a safety hazard to the user, and may also result in insufficient concentration of vildagliptin in the sustained-release portion, and an effective blood drug concentration cannot be maintained; when the weight of the sustained-release material accounts for more than 85% of the total weight of the drug-containing sustained-release portion, the dissolution rate of vildagliptin decreases significantly, and an effective blood drug concentration cannot be maintained, resulting in a decrease in efficacy.

[0065] Preferably, the drug-containing sustained-release portion comprises the following components in parts by weight:

[0066] 1-15 parts of the second vildagliptin active ingredient,

[0067] 10-55 parts of the second filler,

[0068] 0.2-10 parts of the second lubricant,

[0069] 0.1-10 parts of adhesive,

[0070] 0.2-10 parts of flow aid,

[0071] 10-80 portions of sustained-release material.

[0072] In a specific implementation, the first filler and / or the second filler is selected from any one or more of lactose, microcrystalline cellulose, mannitol, starch or pregelatinized starch, preferably any one or two of microcrystalline cellulose and lactose. The supplier of microcrystalline cellulose can be any one or more of Anhui Shanhe, JRS, Jiangsu Xidian, Zhuhai Dongchen and Roquette.

[0073] The first lubricant and / or the second lubricant are selected from any one or more of talc, hydrogenated vegetable oil, sodium stearyl fumarate or magnesium stearate, preferably magnesium stearate.

[0074] The disintegrant is selected from any one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone and partially pregelatinized starch, preferably sodium carboxymethyl starch.

[0075] The binder is selected from any one or more of hydroxypropyl methylcellulose, polyvinyl pyrrolidone, hydroxypropyl methylcellulose or hydroxypropyl cellulose: polyvinyl pyrrolidone is preferred.

[0076] The glidant is preferably a hydrophobic glidant, for example, any one or more selected from hydrophobic colloidal silica, talc, stearic acid, magnesium stearate, calcium stearate, paraffin, glyceryl monostearate, glyceryl behenate, and glyceryl monopalmitate; more preferably, hydrophobic colloidal silica.

[0077] The sustained-release material is selected from any one or more of hydroxypropylmethylcellulose, xanthan gum, sodium alginate, carbomer or polyoxyethylene. In particular, the hydroxypropylmethylcellulose is preferably a combination of HPMC K100M and HPMC K200M.

[0078] The second aspect of the present invention is to provide a method for preparing a vildagliptin dual-release preparation, comprising:

[0079] The components of the drug-containing immediate-release part are mixed and compressed by powder direct compression to obtain drug-containing immediate-release total mixed granules, and the components of the drug-containing sustained-release part are wet granulated, dried and mixed to obtain drug-containing sustained-release total mixed granules;

[0080] The drug-containing rapid-release total mixed granules and the drug-containing sustained-release total mixed granules are tableted to prepare the vildagliptin dual-release preparation.

[0081] In a preferred embodiment, the components of the drug-containing sustained-release part are wet granulated, dried, and mixed to obtain the drug-containing sustained-release total mixed granules, which include:

[0082] The second filler and part of the sustained-release material are wet granulated, and dry granules are obtained after drying. The remaining part of the sustained-release material is mixed with the second vildagliptin active ingredient and the binder, and then added to the dry granules for mixing, and then the second lubricant is added for lubrication to obtain the drug-containing sustained-release total mixed granules.

[0083] In a preferred embodiment, the moisture content of the dry whole granules is ≤2.0%. Studies have shown that when the moisture content of the dry whole granules is greater than 2.0%, the obtained vildagliptin dual-release preparation has increased impurities and decreased stability.

[0084] Example 1

[0085] This embodiment provides a vildagliptin dual-release preparation, the formula of which is shown in Table 1:

[0086] Table 1. Example 1 Vildagliptin dual-release formulation formula

[0087]

[0088]

[0089] The preparation method of Example 1 is as follows:

[0090] S1. Preparation of drug-containing immediate-release total mixed granules: The API, filler, lubricant and disintegrant of the drug-containing immediate-release part are mixed and tableted by a powder direct compression method to prepare drug-containing immediate-release total mixed granules;

[0091] S2. Preparation of drug-containing sustained-release total mixed granules: wet granulate the filler of the drug-containing sustained-release part and the first part of the sustained-release materials in the sustained-release materials, namely HPMC K100M, HPMC K200M and sodium alginate, and obtain dry granules after drying. The moisture content of the dry granules is 1.5%. Take the second part of the sustained-release materials, namely carbomer, mix it with API and binder, sieve it, add it to the dry granules and mix it again, and then add lubricant to lubricate it, so as to obtain drug-containing sustained-release total mixed granules.

[0092] S3. Tablet the drug-containing immediate-release mixed granules of step S1 and the drug-containing sustained-release mixed granules of step S2 to prepare the vildagliptin dual-release preparation.

[0093] It should be pointed out that the order of step S1 and step S2 can be swapped; the supplier of microcrystalline cellulose (MCCPH102) is JRS.

[0094] Example 2

[0095] This embodiment provides a vildagliptin dual-release preparation, the formula of which is shown in Table 2:

[0096] Table 2. Example 2 Vildagliptin dual-release formulation formulation

[0097]

[0098]

[0099] Preparation method: The preparation method of Example 2 is the same as that of Example 1.

[0100] Example 3

[0101] This embodiment provides a vildagliptin dual-release preparation, the formula of which is shown in Table 3:

[0102] Table 3. Example 3 Vildagliptin dual-release formulation formula

[0103]

[0104] Preparation method: The preparation method of Example 3 is the same as that of Example 2.

[0105] Example 4

[0106] This embodiment provides a vildagliptin dual-release preparation, the formula of which is shown in Table 4:

[0107] Table 4. Example 4 Vildagliptin dual-release formulation formula

[0108]

[0109]

[0110] Preparation method: The difference between the preparation method of Example 4 and that of Example 1 is that in step S2, xanthan gum and sodium alginate are used as the first part of the sustained-release material, and polyoxyethylene N80 is used as the second part of the sustained-release material; and the moisture content of the dried whole granules in step S2 is 0.8%. The rest is the same as in Example 1.

[0111] Example 5

[0112] This embodiment provides a vildagliptin dual-release preparation, the formula of which is shown in Table 5:

[0113] Table 5. Example 5 Vildagliptin dual-release formulation formula

[0114]

[0115] Preparation method: The preparation method of Example 6 differs from that of Example 1 in that in step S2, hydroxypropyl methylcellulose is used as the first part of the sustained-release material, and the moisture content of the dry whole granules is 1.7%. The other steps are the same as those of Example 1.

[0116] Example 6

[0117] This example provides a vildagliptin dual-release preparation, the formulation components and preparation method are exactly the same as those in Example 3, the only difference being that the supplier of microcrystalline cellulose (MCC PH102) in the formulation is changed to Roquette.

[0118] Example 7

[0119] This embodiment provides a vildagliptin dual-release preparation, and the preparation method is the same as that of Example 3, except that the glidant in the formulation is replaced by stearic acid.

[0120] Comparative Example 1

[0121] This comparative example provides a vildagliptin dual-release preparation. Compared with Example 1, the speed-slow ratio of the API active ingredient is adjusted to 2:1. The formula is shown in Table 6.

[0122] Table 6. Comparative Example 6 Vildagliptin dual-release formulation formula

[0123]

[0124] Comparative Example 1 Preparation method: exactly the same as Example 2.

[0125] Comparative Example 2

[0126] This comparative example provides a vildagliptin dual-release preparation. Compared with Example 1, the speed-slow ratio of the API active ingredient is adjusted to 1:19. The formula is shown in Table 7.

[0127] Table 7. Comparative Example 2 Vildagliptin dual-release formulation formula

[0128]

[0129]

[0130] Comparative Example 1 Preparation method: exactly the same as Example 1.

[0131] Comparative Example 3

[0132] This comparative example provides a vildagliptin dual-release preparation. The only difference between this comparative example and Example 3 is that in step S2 of the preparation method, the moisture content of the dried whole granules is 3.5%. Apart from this, the formula and other preparation steps are exactly the same as those of Example 3.

[0133] Comparative Example 4

[0134] This comparative example provides a vildagliptin dual-release preparation. The only difference between this comparative example and Example 1 is that the sustained-release material is completely replaced by glyceryl behenate. Correspondingly, in step S2 of the preparation method of this comparative example, the first part of the sustained-release material is glyceryl behenate with the same amount as the total amount of HPMC and sodium alginate in Example 1, and the second part of the sustained-release material is glyceryl behenate with the same amount as the carbomer in Example 1. In addition, the other formula components and preparation steps are the same as those in Example 1.

[0135] Comparative Example 5

[0136] This comparative example provides a vildagliptin dual-release preparation. Compared with Example 5, the amount of sustained-release material is adjusted. The formulation of this comparative example is shown in Table 8.

[0137] Table 8. Comparative Example 5 Vildagliptin dual-release formulation formula

[0138]

[0139]

[0140] Preparation method: The preparation method of this comparative example is exactly the same as that of Example 5.

[0141] Comparative Example 6

[0142] This comparative example provides a vildagliptin dual-release preparation. Compared with Example 5, this comparative example only adjusts the amount of sustained-release material. The formula of this comparative example is shown in Table 9

[0143] Table 9. Comparative Example 6 Vildagliptin dual-release formulation formula

[0144]

[0145] Preparation method: The preparation method of this comparative example is exactly the same as that of Example 5.

[0146] Comparative Example 7

[0147] This comparative example provides a vildagliptin dual-release preparation. The only difference between this comparative example and Example 3 is that the supplier of microcrystalline cellulose (MCC PH102) is changed to DuPont, and the other components and preparation method are exactly the same as those in Example 3.

[0148] Comparative Example 8

[0149] This comparative example provides a vildagliptin dual-release preparation. The vildagliptin dual-release preparation in this comparative example differs from Example 3 only in that the glidant is replaced by polyethylene glycol, and the other components and preparation method are exactly the same as those in Example 3.

[0150] Test Case

[0151] 1. API Dissolution Test

[0152] 1.1 Dissolution standard: 1 hour, dissolution 20%-50%; 12 hours, dissolution ≥80%.

[0153] 1.2 Dissolution method: pH 1.2 medium, basket method, rotation speed 100 rpm, medium volume 900 mL, sampling volume 1.5 mL.

[0154] Table 10. Summary of dissolution of Examples 1-5, Comparative Examples 1-2, 4-6

[0155]

[0156] Refer to Table 10 for a summary of dissolution profiles and Figure 1-11 From the dissolution curve, we can see that:

[0157] Compared with Examples 1-3, the formulations and preparation methods of Comparative Examples 1 and 2 are exactly the same, and the only difference is that the API content in the immediate-release layer and the sustained-release layer is adjusted. Among them, in Comparative Example 1, the vildagliptin content in the immediate-release layer is increased to 33%, exceeding the upper limit of 1-20% required by the embodiment, and the API rapid-to-slow ratio is increased to 2:1, exceeding the upper limit of 1:(1-15) required by the embodiment, resulting in a significant increase in the dissolution rate of vildagliptin, resulting in a dissolution rate of 1h exceeding the qualified requirement value, which has safety concerns for patients. The invention discloses a novel method for treating vildagliptin in an instant-release layer and a sustained-release layer, which is a potential risk for the whole body, and also fails to achieve the therapeutic requirement of sustained effect due to the excessively rapid dissolution. In comparative example 2, the contents of vildagliptin in the immediate-release layer and the sustained-release layer are respectively adjusted. Although the contents of vildagliptin in the immediate-release layer and the sustained-release layer are respectively within the range of 1-20% and 1:15 required in the embodiment, the API rapid-to-slow ratio is 1:19, which is lower than the lower limit of 1:(1-15) required in the embodiment, resulting in a slow dissolution rate of vildagliptin. The dissolution rates at 1h and 12h are both lower than the standard requirements, and the patient cannot be effectively treated.

[0158] Compared with Examples 1-3, the only difference in Comparative Example 4 is that the sustained-release material is changed to single behenic acid glyceryl ester, and other formula components and preparation methods are exactly the same. As a result, the dissolution rate in 12 hours does not meet the qualified standard requirements.

[0159] Compared with Example 5, the difference of Comparative Example 5 is only that the weight proportion of the sustained-release material in the sustained-release layer is lowered to 5%, which is lower than the lower limit of 10-80% required by the embodiment. As a result, the dissolution rate of the dual-release preparation in 1 hour exceeds the qualified standard requirements, and there is a potential safety hazard for patients; the difference of Comparative Example 6 is only that the weight proportion of the sustained-release material in the sustained-release layer is increased to 85%, which is higher than the upper limit of 10-80% required by the embodiment. As a result, the dissolution rate of the dual-release preparation in 12 hours is lower than the qualified standard requirements, and cannot meet the requirements of long-lasting medication for patients.

[0160] 2. Stability Test

[0161] 2.1 Method: The impurity content of vildagliptin dual-release preparation was carefully evaluated by testing.

[0162] 2.2 Evaluation criteria: known impurity content ≤ 1.0%; maximum single impurity content ≤ 1.0%; total impurity content ≤ 3.5%.

[0163] Table 11. Summary of impurity contents in Examples 1-7 and Comparative Examples 1-8

[0164]

[0165]

[0166] Referring to the summary table of impurity content in Table 11, it can be seen that:

[0167] Compared with Example 3, the formula and preparation method of Comparative Example 3 are the same, the only difference is that in step S2 of the preparation method, the moisture content of the dried whole granules is 3.5%, resulting in an increase in impurities in the prepared vildagliptin dual-release preparation and the stability does not meet the qualified standard requirements.

[0168] Compared with Example 3, the only difference in Comparative Example 7 is that the supplier of microcrystalline cellulose (MCC PH102) is changed to DuPont, resulting in that the impurity data of the prepared vildagliptin dual-release preparation all exceed the qualified standard requirements.

[0169] Compared with Example 3, the only difference of Comparative Example 8 is that the glidant is replaced by polyethylene glycol, resulting in the maximum single impurity content of the prepared vildagliptin dual-release preparation exceeding the qualified standard requirements and failing to meet the stability requirements.

[0170] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the technical solution of the present invention, and are not intended to limit the specific implementation methods of the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the claims of the present invention shall be included in the protection scope of the claims of the present invention.

Claims

1. A vildagliptin dual-release preparation, comprising a drug-containing immediate-release portion and a drug-containing sustained-release portion, characterized in that: The drug-containing immediate-release portion comprises a first vildagliptin active ingredient and an immediate-release excipient, wherein the weight of the first vildagliptin active ingredient is equivalent to 1-20% of the total weight of the drug-containing immediate-release portion; The drug-containing sustained-release portion comprises a second vildagliptin active ingredient and a sustained-release excipient, wherein the weight of the second vildagliptin active ingredient is equivalent to 1-15% of the total weight of the drug-containing sustained-release portion; The weight ratio of the first vildagliptin active ingredient to the second vildagliptin active ingredient is 1:(1-15).

2. The vildagliptin dual-release preparation according to claim 1, characterized in that The rapid-release excipients include a first filler, a first lubricant and a disintegrant; Preferably, the drug-containing immediate-release portion comprises the following components in parts by weight: 1-20 parts of the first vildagliptin active ingredient, 55-99 parts of the first filler, 0.2-10 parts of the first lubricant, 1-15 parts of disintegrant.

3. The vildagliptin dual-release preparation according to claim 1, characterized in that The sustained-release auxiliary material comprises a second filler, a second lubricant, an adhesive, a glidant and a sustained-release material, wherein the weight of the sustained-release material is equivalent to 10-80% of the total weight of the drug-containing sustained-release part.

4. The vildagliptin dual-release preparation according to claim 3, characterized in that The drug-containing sustained-release portion includes the following components in parts by weight: 1-15 parts of the second vildagliptin active ingredient, 10-55 parts of the second filler, 0.2-10 parts of the second lubricant, 0.1-10 parts of adhesive, 0.2-10 parts of flow aid, 10-80 portions of sustained-release material.

5. The vildagliptin dual-release preparation according to claim 3 or 4, characterized in that: The sustained-release material is selected from any one or more of hydroxypropylmethylcellulose, xanthan gum, sodium alginate, carbomer or polyoxyethylene.

6. The vildagliptin dual-release preparation according to claim 3 or 4, characterized in that: The glidant is a hydrophobic glidant.

7. The vildagliptin dual-release preparation according to claim 6, characterized in that The hydrophobic glidant is selected from any one or more of hydrophobic colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, paraffin, glyceryl monostearate, glyceryl behenate, and glyceryl monopalmitate.

8. A method for preparing the vildagliptin dual-release preparation according to any one of claims 2 to 7, characterized in that: The components of the drug-containing immediate-release part are mixed and compressed by powder direct compression to obtain drug-containing immediate-release total mixed granules, and the components of the drug-containing sustained-release part are wet granulated, dried and mixed to obtain drug-containing sustained-release total mixed granules; The drug-containing rapid-release total mixed granules and the drug-containing sustained-release total mixed granules are tableted to prepare the vildagliptin dual-release preparation.

9. The method according to claim 8, characterized in that The components of the drug-containing sustained-release part are wet granulated, dried, and mixed to obtain the drug-containing sustained-release total mixed granules, which include: The second filler and part of the sustained-release material are wet granulated, and dry granules are obtained after drying. The remaining part of the sustained-release material is mixed with the second vildagliptin active ingredient and the binder, and then added to the dry granules for remixing, and then the second lubricant is added for lubrication to obtain the drug-containing sustained-release total mixed granules.

10. The method according to claim 9, characterized in that The moisture content of the dry whole granules is ≤2.0%.

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