WO2021234430A1

WO2021234430A1 - Modified release dosage form comprising vildagliptin and process for manufacturing the same

Info

Publication number: WO2021234430A1
Application number: PCT/IB2020/054661
Authority: WO
Inventors: Jaya Abraham; On Hwang; Vijender Gupta; Pankaj Ranjan KARN; KiYun HONG; Hyesuk Hong; Yoonjung Lee; Dohyung Kim
Original assignee: Lotus International Pte. Ltd.
Priority date: 2020-05-17
Filing date: 2020-05-17
Publication date: 2021-11-25

Abstract

The present invention relates to a modified-release formulation, preferably a bilayer tablet formulation comprising an immediate-release part comprising vildagliptin and a rapid-acting excipient to enable immediate drug release and a sustained-release part comprising vildagliptin and a release controlling agent to consistently maintain the pharmacological activity, and a process for manufacturing the same. The preparation according to the present invention can improve the patient's medication compliance even with once daily administration to satisfy both the rapid expression of pharmacological activity and the consistent pharmacological activity compared to the conventional vildagliptin formulation which is administered twice a day.

Description

Modified release dosage form comprising vildagliptin and process for manufacturing the same

TECHNICAL FIELD

The present invention relates to a modified release formulation comprising vildagliptin or a pharmaceutically acceptable salt thereof, and a process for manufacturing the same. Particularly, the present invention relates to a modified release oral formulation comprising an immediate-release part including vildagliptin and a rapid-acting excipient to enable immediate drug release, and a sustained-release part including vildagliptin and a release controlling agent to consistently release the drug and maintain the pharmacological activity, and a process for manufacturing the same.

BACKGROUND

Vildagliptin is known as l-[{(3-hydroxy-l-adamantyl) amino] acetyl] -2-cyano(s)- pyrrolidine, and has a structure of the following Formula 1.

[Formula 1]

Vildagliptin compound and process for manufacturing the same are disclosed in International Publication No. W02000/034241, and an improved process for manufacturing the same is disclosed in International Publication No. W02004/092127.

Vildagliptin is known as a dipeptidyl peptidase IV (DPP-IV) inhibitor. Since DPP- IV inactivates glucagon-like peptide- 1 (GLP-1) which is one of the main stimulants for secretion of insulin from pancreas, it exhibits an effect on the treatment of a disease such as non-insulin dependent diabetes mellitus (NIDDM, type II diabetes mellitus) by inhibiting DPP-IV.

Thus, vildagliptin, alone or in combination with other anti-diabetic agents, is prescribed as an adjuvant therapy to diet and exercise for improving the control of blood sugar of a patient with type II diabetes mellitus in many clinical conditions. Vildagliptin is commercially available in the form of tablet under the product name GALVUS^® by Novartis AG. The product is an immediate-release formulation including 50 mg of vildagliptin per tablet, and is administered at a single dose of 50 mg in the morning and a single dose of 50 mg in the evening when administered at a recommended daily dose of 100 mg, but there have not been commercialized any modified-release formulations thereof yet.

The existing vildagliptin formulation described above is a formulation administered orally twice daily. It has a disadvantage in deteriorating patients’ compliance, in decreased therapeutic effect due to low susceptibility to the drug that is caused by rapid change in blood drug concentration every repeated administration thereof, and an increased risk of side effects when vildagliptin formulation is repeatedly administered in an amount exceeding the effective blood concentration.

For the above reasons, it is desirable to develop a modified-release formulation which contains the daily unit dose of vildagliptin and releases the drug for a longer period. Within the framework of the present invention, the inventors developed a modified-release formulation simultaneously having the immediate-release and sustained-release characteristics achieved by modified release of Vildagliptin from a dosage form. The immediate-release portion helps to achieve the desired blood plasma concentration immediately after administration, followed by release of the drug in a sustained manner to minimize drug-blood level fluctuations, thereby improving the therapeutic benefits.

PRIOR ART REFERENCES - PATENTS

(Patent Document 0001) International Publication No. W02000/034241

(Patent Document 0002) International Publication No. W02004/092127

SUMMARY OF THE INVENTION

PROBLEMS TO BE SOLVED

The present invention overcomes the disadvantages of the conventional formulation as discussed above, and provides a modified-release formulation containing vildagliptin and process for manufacturing the same. The inventive modified-release formulation is capable of improving patients’ medication compliance by simultaneously satisfying rapid expression of pharmacological activity and sustained maintenance of pharmacological activity only by once-daily administration. SOLUTIONS OF THE PROBLEMS

The present invention provides a modified-release formulation comprising an immediate-release part including vildagliptin or a pharmaceutically acceptable salt thereof and a rapid-acting excipient; and a sustained-release part including vildagliptin or a pharmaceutically acceptable salt and a release controlling agent.

The immediate-release part serves to reach therapeutically effective vildagliptin blood concentration by immediate release of vildagliptin, and the sustained-release part serves to maintain the therapeutically effective vildagliptin blood concentration for a long period.

In this case, the modified release formulation contains vildagliptin or a pharmaceutically acceptable salt thereof in an amount from 10 to 60 wt%, preferably from 20 to 40 wt%, in the immediate-release part and from 40 to 90 wt%, preferably from 60 to 80 wt%, in the sustained-release part, respectively, based on the total weight of vildagliptin or pharmaceutically acceptable salt thereof in the formulation, in order to simultaneously achieve rapid release of vildagliptin through the immediate-release part and sustained-release of vildagliptin through the sustained-release part.

In the present invention, it was confirmed that a modified-release formulation separately comprising vildagliptin in the immediate-release part and the sustained-release part as described above exhibits the ability to inhibit a DPP-IV enzyme early, which is like that of the commercially available vildagliptin immediate-release tablet, by sufficiently releasing vildagliptin at the early stage of the initiation of dissolution. Further, the pharmacological activity of the drug is sustained by adjusting of the amount of released drug from the sustained-release part to about 10% or less per hour, and therefore complete release of the drug takes 10 hours or more, based on the amount and physical characteristics of the used sustained-release agents.

The release controlling agent utilized in the sustained-release part of the modified- release formulation is one or more agents selected from the group consisting of hydroxypropyl methyl cellulose (HPMC), polyethylene oxide (PEO), hydroxypropyl cellulose (HPC), sodium carboxymethyl cellulose, and hydroxyethyl cellulose, and is preferably hydroxypropyl methyl cellulose or polyethylene oxide.

The amount of the release controlling agent is from 10 to 70 wt%, preferably from 20 to 50 wt% based on a total weight of the sustained-release part. In a preferred embodiment the release controlling agent is hydroxypropyl methyl cellulose having viscosity from 150,000 to 250,000 cp and hydroxypropyl methyl cellulose having viscosity from 2,000 to 6,000 cp, and it is preferred that these hydroxypropyl methyl celluloses are included at a weight ratio of 1 : 0.2 to 1 : 1. In a further preferred embodiment the release controlling agent is polyethylene oxide having an average molecular weight from 6 million to 8 million and polyethylene oxide having an average molecular weight from 800,000 to 1 million, and it is preferred that these polyethylene oxides are included at a weight ratio of 1 : 0.1 to 1 : 0.5.

In a preferred embodiment hydroxypropyl methyl cellulose preferably has methoxy group substitution degree from 18 to 24% and hydroxypropyl group substitution degree from 6 to 10%, to achieve a better release control, but hydroxypropyl methyl cellulose is not limited thereto.

Specifically, the modified-release formulation according to the present invention can precisely control the dissolution rate of vildagliptin by selecting hydroxypropyl methyl cellulose with specific viscosity, content, and substitution degree.

The rapid-acting excipient included in the immediate-release part is one or more agents selected from the group consisting of sugar alcohols such as xylitol, sorbitol, mannitol, and mixtures thereof, polyethylene glycol, sodium starch glycolate, crospovidone, low- substituted hydroxypropyl cellulose, carboxymethylcellulose calcium, gelatinized starch, croscarmellose sodium, an ion exchange resin, corn starch, microcrystalline cellulose, lactose and anhydrous lactose, and mixtures thereof.

The rapid-acting excipient may be granulated by dry granulation, wet granulation, fluid bed, or used as such, and then used in a mixture with a disintegrating agent and a lubricant accepted in the art.

With respect to the total amount of the rapid-acting excipient, it is preferred that the rapid-acting excipient is used within a range of 300 to 500 parts by weight based on 100 parts by weight of vildagliptin used in the immediate-release part. When the amount of rapid-acting excipient used is less than 300 parts by weight, there is a problem with tableting in the form of a bilayer tablet due to the insufficient tableting weight, and when the amount thereof is more than 500 parts by weight, there is a problem in that the size of the tablet is excessively increased.

In some embodiments, the composition of the immediate-release part of the formulation preferably has the following composition: - 10-50 wt.%, preferably 15-35 wt.% of vildagliptin or a pharmaceutically acceptable salt thereof,

- 20-88 wt.%, preferably 50-80 wt.% of at least one pharmaceutical diluent, preferably selected from lactose and microcrystalline cellulose,

- 1-10 wt.%, preferably 3-6 wt.% of at least one disintegrant,

- 1-10 wt.%, preferably 3-6 wt.% of at least one binder,

- 0.1-5 wt.%, preferably 0.5-3 wt.% of at least one lubricant.

In some embodiments, the composition of the sustained-release part of the formulation preferably has the following composition:

- 10-50 wt.%, preferably 15-35 wt.% of vildagliptin or a pharmaceutically acceptable salt thereof,

- 20-80 wt.%, preferably 40-60 wt.% of at least one pharmaceutical diluent, preferably selected from lactose and microcrystalline cellulose,

- 20-60 wt.%, preferably 25-50 wt.% of at least one release controlling agent, wherein the release controlling agent preferably includes hydroxypropyl methyl cellulose with nominal viscosity of 2000 to 200000 cp and/or polyethylene oxide with molecular weight of 600000 to 7000000,

- 2-10 wt.%, preferably 3-6 wt.% of at least one binder,

- 0.1-5 wt.%, preferably 1-3 wt.% of at least one lubricant,

- optionally 2-10 wt.%, preferably 3-6 wt.% of at least one disintegrant,

- optionally 0.1-2 wt.% of at least one antioxidant.

The modified-release formulation described in the present invention is manufactured according to the following process:

- preparing an immediate-release part by mixing vildagliptin or a pharmaceutically acceptable salt thereof and a rapid-acting excipient;

- preparing a sustained-release part by preparing dry granules from a mixture comprising vildagliptin or a pharmaceutically acceptable salt thereof, and a release controlling agent; and

- filling the immediate-release part and the sustained-release part into capsules or tableting the immediate-release part and the sustained-release part by using a bilayer tableting machine.

According to the preferred embodiment of the present invention the modified- release formulation is a multilayer tablet, preferably a bilayer tablet containing an immediate- release part and a sustained-release part, and it is prepared by performing a tableting of the immediate-release part as a first layer, and then filling the first layer with the sustained-release part to perform a bilayer tableting. In this case, it is not always necessary to tablet the sustained-release part after tableting the immediate-release part, and it is also possible to perform the tableting by first tableting the sustained-release part, and then filling the sustained-release part with granules of the immediate-release part. Further, it is also possible to perform the tableting once by filling the immediate-release part and the sustained-release part sequentially or reversely, respectively.

EFFECTS OF THE INVENTION

The advantage of the modified-release formulation according to the present invention is reduction of the dosing frequency and side effects, as the minimum effective therapeutic vildagliptin blood plasma concentration is reached by immediately released vildagliptin from the immediate-release part, and effective blood concentration for a constant time is reached by slowly released vildagliptin from the sustained-release part of the composition.

The modified-release formulation according to the present invention, containing an immediate-release part enabling immediate release of a drug and a sustained-release part, allows for consistently maintaining the pharmacological activity and enabling optimization of blood concentration of vildagliptin, thus resulting in reduction of vildagliptin side effects such as hepatotoxicity. Accordingly, since only once-daily administration satisfies both the sufficient initial blood concentration of vildagliptin and the consistent maintenance of an effective blood concentration of vildagliptin, patients’ medication compliance is remarkably improved compared to the existing formulations administered twice daily.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a graph illustrating a comparison and evaluation of dissolution rates of vildagliptin with respect to the tablets prepared in Examples 1 and 2, Comparative Example 1 and the reference drug (50 mg of Galvus^® tablet).

Fig. 2 is a graph illustrating a comparison and evaluation of the dissolution rates of vildagliptin with respect to the tablets prepared in Example 3, Comparative Example 2 and the reference drug (50 mg of Galvus^® tablet). DETAILED DESCRIPTION OF THE INVENTION

The following is a detailed description of the present invention using specific examples to specifically elaborate the present invention. However, the examples according to the present invention could be modified in many other ways are not intended to be limiting the scope of the present invention. The examples are provided to illustrate the present invention more fully to a person of ordinary skill in the art.

Examples

Preparation of vildagliptin bilayer tablet including immediate-release part and sustained-release part

Preparation Method 1

Preparation of immediate-release part

1) Blending

Vildagliptin, anhydrous lactose, microcrystalline cellulose, sodium starch glycolate, and hydroxypropyl cellulose are sieved using appropriate screen, introduced into a blender, and then blended.

2) Lubrication

After the blending, magnesium stearate is added to the blender, and the mixture is blended.

Preparation of sustained-release part

1) Blending

Vildagliptin, hydroxypropyl methyl cellulose (HPMC), microcrystalline cellulose, hydroxypropyl cellulose, and magnesium stearate are sieved using appropriate screen, introduced into a blender, and then blended.

2) Dry granulation

The resulting blend is passed through the roller compactor and dry granules are formed.

3) Lubrication

The prepared granules, magnesium stearate and light anhydrous silicic acid are put into a blender, and then blended.

Tableting

When the immediate-release part and sustained-release part granules are completely prepared, tableting is performed by using a bilayer tableting machine.

Capsule filling

The immediate-release and sustained release parts are individually compressed into tablets using a compression machine, and both tablets are further filled into a hard 00-size hard gelatin capsule shell.

Example 1

A bilayer tablet comprising vildagliptin-containing immediate -release part and vildagliptin-containing sustained-release part including HPMC with viscosity 200,000 cp and HPMC with viscosity 4,000 cp together as release controlling agents was prepared by the above preparation method. Specific ingredients and contents are shown in the following Table 1.

Table 1

Example 2

A bilayer tablet comprising vildagliptin-containing immediate-release part and a vildagliptin-containing sustained-release part including HPMC with viscosity 200,000 cp as a release controlling agent was prepared by the same preparation method as in Example 1. Specific ingredients and contents are shown in the following Table 2.

Table 2

Example 3

A hard gelatin capsule comprising vildagliptin-containing immediate-release part and vildagliptin-containing sustained-release part including HPMC with viscosity 200,000 cp and HPMC with viscosity 4,000 cp together as release controlling agents was prepared using above preparation methods of immediate and sustained release parts followed by capsule filling. Specific ingredients and contents are shown in the following Table 3.

Table 3

Comparative example 1

Preparation of vildagliptin tablet except for immediate-release part

A vildagliptin tablet including HPMC having viscosity of 200,000 cp was prepared by the same process as the process for manufacturing a sustained-release part in the Examples 1 and 2. Specific ingredients and contents are shown in the following Table 3.

Table 3

Test example 1

Evaluation of dissolution characteristics Tablets prepared in Example 1, Example 2, Example 3, the Comparative Example 1, and the reference drug (Galvus^® Tab. 50 mg) were subjected to dissolution testing in accordance with the following dissolution test conditions.

5 <Test Conditions>

Specimen: four tablets of each of Examples 1 and 2 and the Comparative Example, and the reference drug (Galvus^® Tab. 50 mg)

Dissolution tester: Hanson Vision^® G2 Elite 8, Agilent 708-DS Dissolution conditions: USP (II) - paddle method, 50 rpm 0 Test solution: 0.1 N HC1 solution 900 ml, pH 1.2

Test temperature: 37°C

Sampling time point: 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 16 hours

<Test Result> 5 The results of the dissolution tests are shown in Table 4 and Fig. 1.

Table 4

The results, presented in Table 4 and Fig. 1, confirm that bilayer tablets prepared in Examples 1 and 2, including in total 100 mg of vildagliptin separately in the immediate- release part and the sustained-release part, released about 50% of vildagliptin within 1 hour after initiation of dissolution testing, and the amount of drug released within 1 hour at the early stage was similar as the release from the reference drug Galvus^® tablet (50 mg of vildagliptin). Accordingly, it was confirmed that when the described vildagliptin modified- release tablets were administered orally, they ability to inhibit DPP-4 enzyme is similar as the activity of the commercially available vildagliptin immediate-release tablets. The initial release rate of capsule in Example 3 was slightly lower than the tablets in Example 1 and 2 because the dissolution of the capsule shell adds an additional step to the release and results in a lag time for drug release.

On the contrary, it was confirmed that the tablet described in the Comparative Example 1, which does not contain immediate-release part to express rapid therapeutic effect immediately after oral administration is not suitable because the dissolution failed to reach 30% within 1 hour.

The dissolution test results show that 1 hour after starting dissolution, the amount of drug was consistently released from the sustained-release part of each of the tablets prepared according to Examples 1 and 2, and release was adjusted to about 10% or less than 10% per hour, and complete release of the drug took from 10 to 12 hours. Accordingly, it was confirmed that tablets described in Examples 1 and 2 could maintain the effect of the drug for a long period of time.

From observation of the difference in dissolution rates exhibited in the tablets of Examples 1 and 2 including HPMCs having different viscosities and contents as the release controlling agents, it was confirmed that dissolution could be more precisely controlled by adjusting the viscosity and content of HPMC.

In conclusion, the modified-release composition according to the present invention which is preferably a bilayer tablet including an immediate-release part and a sustained- release part could remarkably improve patients’ medication convenience and safety. The bilayer tablet described above is suitable for satisfying both the high initial blood concentration of the drug and the consistent maintenance of effective blood concentration of the drug.

Preparation Method 2

Preparation of immediate-release part

1) Blending

Vildagliptin, anhydrous lactose, microcrystalline cellulose, sodium starch glycolate, and hydroxypropyl cellulose are sieved by using appropriate screen, introduced into a blender, and then blended.

2) Lubrication

Preparation of sustained-release part

1) 1^st Blending

Butyl hydroxy toluene and isomalt are sieved using appropriate screen, introduced into a blender, and then blended.

2) 2^nd Blending

Vildagliptin and polyethylene oxide are sieved using appropriate screen, introduced into a blender, and then blended.

3) 3^rd Blending

Hydroxypropyl cellulose and magnesium stearate are introduced into a blender, and then blended.

4) Dry granulation

5) Lubrication

The prepared granules and magnesium stearate are put into a blender, and then blended.

Tableting

When the immediate-release part and sustained-release part granules are completely prepared, tableting is performed using a bilayer tableting machine. Example 4

A bilayer tablet comprising vildagliptin-containing immediate-release part, and sustained-release part, containing vildagliptin and polyethylene oxide with an average molecular weight 7 million (PEO 7M, WSR 303) and polyethylene oxide with an average molecular weight of 900,000 (PEO 900K, WSR 1105) together as release controlling agents, was prepared by the above preparation method. Specific ingredients and contents are shown in the following Table 5. Table 5

Comparative example 2

Preparation of vildagliptin tablet except for immediate-release part

A vildagliptin tablet comprising polyethylene oxide with an average molecular weight 7 million (PEO 7M, WSR 303) and polyethylene oxide with an average molecular weight 900,000 (PEO 900K, WSR 1105) together was prepared by the same process as the process for manufacturing a sustained-release part in the Example 4 above. Specific ingredients and contents are shown in the following Table 6. Table 6

Test example 2

Evaluation of dissolution characteristics

Tablets prepared in Example 4, in Comparative Example 2 and the reference drug (Galvus^® Tab. 50 mg) was subjected to dissolution testing in accordance with the following dissolution test conditions. <Test Conditions>

Specimen: four tablets of each of the Example and the Comparative Example, and the reference drug (Galvus® Tab. 50 mg)

Dissolution tester: Hanson Vision® G2 Elite 8, Agilent 708-DS Dissolution conditions: USP (II) - paddle method, 50 rpm

Test solution: 0.1 N HC1 solution 900 ml, pH 1.2 Test temperature: 37°C

Sampling time point: 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 16 hours <Test Result>

The results of the dissolution test are shown in Table 7 and Fig. 2.

Table 7

The results, presented in Table 7 and Fig. 2, confirm that bilayer tablets prepared in Example 4, including in total 100 mg of vildagliptin separately in the immediate-release part and the sustained-release part, released about 50% of vildagliptin within 1 hour after initiation of dissolution testing, and the amount of drug released within 1 hour at the early stage was similar as the release from the reference drug Galvus^® tablet (50 mg of vildagliptin). Accordingly, it was confirmed that when the described vildagliptin modified-release tablets were administered orally, they ability to inhibit DPP-4 enzyme is similar as the activity of the commercially available vildagliptin immediate-release tablets.

On the contrary, it was confirmed that the tablet described in the Comparative Example 2, which does not contain immediate-release part to express rapid therapeutic effect immediately after oral administration, is not suitable because the dissolution failed to reach 30% within 1 hour.

The dissolution test results show that 1 hour after starting dissolution, the amount of drug was consistently released from the sustained-release part of each of the tablets prepared according to Example 4, and release was adjusted to about 10% or less than 10% per hour, and complete release of the drug took from 10 to 12 hours. Accordingly, it was confirmed that tablets described in Example 4 could maintain the effect of the drug for a long period of time.

In conclusion, the modified-release composition according to the present invention, which is preferably a bilayer tablet including an immediate-release part and a sustained- release part, could remarkably improve patients’ medication convenience and safety. The bilayer tablet described above is suitable for satisfying both the high initial blood concentration of the drug and the consistent maintenance of effective blood concentration of the drug.

Example 5. Oral comparative bioavailability study in human subjects

The pharmacokinetics studies were conducted to assess the bioavailability of Vildagliptin SR 100 mg test drug described in Example 1 with reference drug, Galvus^® Tab 50 mg, an immediate release product. The total number of human subjects for this study was 32 for each fasting and fed conditions. The details of the study were following:

Study title: An open label, randomized, balanced, four-treatment, four-period, four- sequence, crossover, pilot, oral relative bioavailability study of test product of Vildagliptin 100 mg SR tablet and Galvus^® tab 50 mg from Novartis Korea in healthy, adult, human subjects under fasting and fed conditions.

Objectives: To characterize the rate and extent of Vildagliptin absorption after oral administration and to assess the relative bioavailability of Vildagliptin 100 mg SR tablets test product 1 (Example 1 given once a day) with reference product Galvus^® tab 50 mg (b.i.d.) in healthy, adult, human subjects under fasting and fed conditions and to assess the safety and tolerability of the formulation on the basis of clinical and laboratory examination, documentation of the Adverse Events (AEs) and/or Adverse Drug Reactions (ADRs).

Study design: An open label, randomized, balanced, four-treatment, four-period, four- sequence, crossover, pilot, oral relative bioavailability study with a washout period of at least 05 days in healthy, adult, human subjects under fasting and fed conditions.

Investigational drugs: Test product 1 (as described in Example 1): Vildagliptin 100 mg SR tablets

Reference product (R): Galvus 50 mg tablets, Manufactured by Novartis Pharma Stein AG.

Pharmacokinetics Results: All pharmacokinetic parameters are expressed in geometric means ratio (90% Confidence Interval, %). Reference drug used was Galvus^® Tab 50 mg from Novartis Korea.

Table 8. Comparative bioavailability analysis results of Test 1 Vs Reference in fed condition

The Test 1 (Example 1) product Vildagliptin 100 mg Sustained-Release Tablets demonstrated a comparable extent of absorption of vildagliptin to the reference product (B.I.D) Galvus 50 mg Immediate-Release Tablets.

Table 9. Comparative bioavailability analysis results of Test 1 Vs Reference in fasting condition

By comparing the bioavailability of Test 1 (Vildagliptin 100 mg sustained-release tablets example 1; administered once daily) to reference Treatment (Galvus 50 mg Tablets administered two times daily (BID) with 12 hours interval) under fasting conditions, results showed that Test 1 (Example 1) demonstrated comparable extent (GMR of AUC_t and AUC_mf approx. 84%) and a comparable rate of vildagliptin absorption (GMR of C_max approx. 103%) compared to the reference Treatment.

Claims

CLAIMS:

1. A modified-release formulation comprising: an immediate-release part comprising vildagliptin or a pharmaceutically acceptable salt thereof and a rapid-acting excipient; and a sustained-release part comprising vildagliptin or a pharmaceutically acceptable salt thereof and a release controlling agent.

2. A modified-release formulation according to claim 1, which is a capsule or a multilayer tablet.

3. A modified-release formulation according to claim 2, which is a bilayer tablet.

4. A modified-release formulation according to any of the preceding claims, wherein the immediate-release part of the formulation contains from 10 to 60 wt%, preferably from 20 to 40 wt% of vildagliptin or pharmaceutically acceptable salt thereof, and the sustained-release part contains from 40 to 90 wt%, preferably from 60 to 80 wt% of vildagliptin, based on the total weight of vildagliptin or the pharmaceutically acceptable salt thereof.

5. A modified-release formulation according to any of the preceding claims, wherein the release controlling agent is one or more selected from the group consisting of hydroxypropyl methyl cellulose, polyethylene oxide, hydroxypropyl cellulose, sodium carboxymethyl cellulose, and hydroxyethyl cellulose.

6. A modified-release formulation according to claim 5, wherein the formulation contains as release controlling agent hydroxypropyl methyl cellulose or polyethylene oxide in an amount from 20 to 50 wt% based on the total weight of the sustained-release part.

7. A modified-release formulation according to claim 6, wherein viscosity of hydroxypropyl methyl cellulose is from 150,000 to 250,000 cp.

8. A modified-release formulation according to claim 5 to 7, wherein the formulation contains hydroxypropyl methyl cellulose having viscosity from 150,000 to 250,000 cp and hydroxypropyl methyl cellulose having viscosity from 2,000 to 6,000 cp.

9. A modified-release formulation according to claim 8, wherein the formulation contains hydroxypropyl methyl cellulose having viscosity from 150,000 to 250,000 cp and hydroxypropyl methyl cellulose having a viscosity of 2,000 to 6,000 cp in a weight ratio from 1:0.2 to 1:1.

10. A modified-release formulation according to claims 5 to 9, wherein the formulation comprises hydroxypropyl methyl cellulose having methoxyl group substitution degree from 18 to 24% and hydroxypropoxyl group substitution degree from 6 to 10%.

11. A modified-release formulation according to claim 5, wherein polyethylene oxide comprises both polyethylene oxide having an average molecular weight of 6 million to 8 million and polyethylene oxide having an average molecular weight of 800,000 to 1 million.

12. A modified-release formulation according to claim 5 and 11, wherein polyethylene oxide having an average molecular weight of 6 million to 8 million and polyethylene oxide having an average molecular weight of 800,000 to 1 million are comprised at a weight ratio of 1:0.1 to 1:0.5.

13. A modified-release formulation according to any of the preceding claims, wherein the formulation comprises as rapid-acting excipient one or more agent selected from the group consisting of sugar alcohols, polyethylene glycol, sodium starch glycolate, crospovidone, hydroxypropyl cellulose, carboxymethylcellulose calcium, gelatinized starch, croscarmellose sodium, an ion exchange resin, com starch, microcrystalline cellulose, lactose and anhydrous lactose.

14. A process for manufacturing a modified-release formulation according to any of the preceding claims comprising: preparing an immediate-release part by blending vildagliptin or a pharmaceutically acceptable salt thereof, and a rapid-acting excipient. preparing a sustained-release part by dry granulation of a mixture comprising vildagliptin or a pharmaceutically acceptable salt thereof, and a release controlling agent; and filling capsules with the immediate-release part and the sustained-release part, or tableting the immediate-release part and the sustained-release part by using a bilayer tablet tableting machine.