Pharmaceutical compositions of DP-IV inhibitors

Abstract

This invention provides a pharmaceutical composition for a DP-IV inhibitor, comprising octagliptin and a reducing sugar. This invention overcomes prejudice by providing a domestically produced octagliptin formulation that is low in cost, has the same dissolution rate as the original drug, and exhibits higher stability than the original drug.

Description

Technical Field

[0001] This invention relates to a pharmaceutical composition of a DP-IV inhibitor. Background Technology

[0002] Ogliptin is a novel dipeptidyl peptidase-IV (DP-IV) inhibitor that can be used to treat type 2 diabetes and even obesity and hypertension.

[0003] Studies have found that octagliptin is sensitive to acids and bases and is prone to Maillard reactions. WO2015031228 explicitly states in its specification and claim 1 that non-reducing sugars should be used as excipients for octagliptin. WO2015031228 also points out that CC-Na (cross-linked methylcarboxycellulose sodium salt) is a high-degradation-risk excipient. Through research, the original formulation ultimately used neutral, non-reducing D-mannitol and other excipients, and also employed a special formulation process.

[0004] Ogliptin is a long-acting formulation, making domestic production difficult. It is prone to problems such as large fluctuations in sustained-release properties, inequivalence, and formulation instability. The price of excipients is also an issue. Summary of the Invention

[0005] This invention overcomes the shortcomings of existing technologies by screening maltodextrin from numerous reducing sugars as an excipient. It was found that maltodextrin meets the stability requirements of octagliptin without causing degradation or Maillard reactions, thus providing a domestically produced octagliptin formulation. Specifically, the technical solution adopted in this invention is as follows:

[0006] A pharmaceutical composition of a DP-IV inhibitor comprising ogliptin and maltodextrin.

[0007] Optionally, the pharmaceutical composition may further comprise corn starch and / or microcrystalline cellulose.

[0008] Optionally, the pharmaceutical composition further comprises a lubricant, such as magnesium stearate.

[0009] Optionally, the percentage of corn starch in the pharmaceutical composition is 4-12 wt%, such as 8-12%, preferably 8%.

[0010] Optionally, the content of microcrystalline cellulose in the pharmaceutical composition is 2-4%, such as 3%.

[0011] Optionally, the lubricant content in the pharmaceutical composition is 1-3%, such as containing 2% magnesium stearate.

[0012] Optionally, the content of ozogliptin in the pharmaceutical composition is 20-30%, such as 25%.

[0013] Optionally, the maltodextrin content in the pharmaceutical composition is 31-39%, such as 35%; and its DE value (glucose equivalent value) is optionally 5-20, such as 11-15.

[0014] Optionally, the pharmaceutical composition, consisting of the components in the aforementioned percentages, may be a solid dosage form, such as tablets, and its specific composition may be as follows:

[0015]

[0016] The inventors have discovered that the above-mentioned tablets not only have dissolution comparable to the original formulation, but also exhibit superior stability. The formulation of this invention does not require special formulation processes or equipment, has a higher API content than the original formulation, easily ensures uniformity of formulation content, and exhibits lower friability and cost. Detailed Implementation

[0017] Example 1: Compatibility of raw materials and auxiliary materials

[0018] Ogliptin was mixed with corn starch and maltodextrin respectively to test its compatibility. After 2 weeks of accelerated treatment at 50℃ / 75%RH, the results showed that the content of total degradation impurities did not exceed 0.5%, which met the pharmaceutical requirements.

[0019] Example 2: Prescription Screening

[0020] Compress 100 tablets using the material quantities shown in the table below (each tablet contains 25mg of API):

[0021] Table 1 Prescription Screening

[0022]

[0023]

[0024] Preparation process:

[0025] (1) Pass the above excipients and API through 80 and 100 mesh sieves respectively, and set aside.

[0026] (2) Mix API with all excipients except magnesium stearate by adding them in equal amounts until homogeneous.

[0027] (3) Continue to add magnesium stearate and mix thoroughly.

[0028] (4) The samples were pressed into tablets and the disintegration time of the prepared samples was investigated. The results are shown in Table 2.

[0029] Table 2

[0030] Formulation 1 Formulation 2 Formulation 3 Disintegration timeout / min 6.0 3.5 3.0

[0031] Clearly, formulation 1 disintegrates too slowly, which is not conducive to dissolution.

[0032] Example 3: Prescription Magnification

[0033] Scale-up studies were conducted according to formulations 2 and 3, with 1000 tablets pressed per batch for each formulation. The process was as described in Example 2. The results showed that:

[0034] Formulation 3 has poor flowability and more pronounced compressibility issues, with a friability of up to 5%, while formulation 2 has a friability of only 8‰.

[0035] Example 4: Long-term validation of prescriptions

[0036] According to the formulation shown in Formulation 2, the DE value ranges of the excipient maltodextrin were set to 5-10, 11-15, and 16-20, respectively. The tableting process was as described in Example 2. After sampling, the resulting tablets were placed at a temperature of 50±2℃ and a humidity of 75±5% to examine the long-term stability of the formulation. The results are shown in Table 3.

[0037] Table 3

[0038]

[0039]

Claims

1. A pharmaceutical composition of a DP-IV inhibitor, comprising ogagliptin and a reducing sugar, wherein the reducing sugar is maltodextrin, characterized in that, The pharmaceutical composition comprises octagliptin, maltodextrin, corn starch, microcrystalline cellulose and a lubricant. The corn starch content in the pharmaceutical composition is 8 wt%, the microcrystalline cellulose content is 30 wt%, the lubricant content is 2 wt%, the octagliptin content is 25 wt%, the maltodextrin content is 35 wt%, and the lubricant is magnesium stearate.

2. The pharmaceutical composition according to claim 1, characterized in that, The DE value of maltodextrin in the pharmaceutical composition is 5-20.

3. The pharmaceutical composition according to claim 2, characterized in that, The DE value of maltodextrin in the pharmaceutical composition is 11-15.

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