CN110840856A - Composition containing linagliptin and application thereof - Google Patents
Composition containing linagliptin and application thereof Download PDFInfo
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- CN110840856A CN110840856A CN201911325540.6A CN201911325540A CN110840856A CN 110840856 A CN110840856 A CN 110840856A CN 201911325540 A CN201911325540 A CN 201911325540A CN 110840856 A CN110840856 A CN 110840856A
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- linagliptin
- mannitol
- pregelatinized starch
- magnesium stearate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- Diabetes (AREA)
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Abstract
The invention relates to the technical field of medicines, and particularly relates to a composition containing linagliptin and application thereof. The composition consists of an active ingredient and pharmaceutic adjuvants, wherein the active ingredient is linagliptin, and the pharmaceutic adjuvants are mannitol, pregelatinized starch and magnesium stearate; the components by weight are as follows: 2-5% of linagliptin, 72-90% of mannitol, 5-20% of pregelatinized starch and 0.5-1.5% of magnesium stearate. The composition is coated to obtain gastric-soluble film coated tablet, wherein the weight of the film coating material is 2-3% of the composition. According to the invention, by reducing the use of copovidone and corn starch, the linagliptin tablet which has few auxiliary materials and simple process, and can be dissolved out similar to or even better than that in the original research can be obtained.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a composition containing linagliptin and application thereof.
Background
Linagliptin is a dipeptidylpeptidase-4 (DPP-4) inhibitor, is mainly used for adjuvant therapy of diet and exercise in the treatment of type 2 diabetes in adults to improve blood sugar control, and can be used singly or in combination with metformin hydrochloride and sulfonylureas drugs. Linagliptin has a structural formula shown in formula 1:
linagliptin structural formula 1
Linagliptin is extremely stable under high temperature, high humidity and illumination conditions, but the linagliptin has a structural formula containing primary amino groups, and the amino groups react with reducing sugar, other reactive carbonyl groups and carboxylic acid functional groups (formed by oxidation on the surface of microcrystalline cellulose, for example), so that the linagliptin reacts with various excipients used in solid dosage forms and impurities of the excipients, such as various pharmaceutic adjuvants of microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, tartaric acid, citric acid, glucose, fructose, sucrose, lactose, maltodextrin and the like, and incompatibility, degradation problems or extraction problems exist. In order to prepare the linagliptin tablet with high dissolution rate and stable performance, the formula and process research is carried out on the linagliptin tablet according to the properties of the linagliptin tablet, so that the related quality problems of the linagliptin tablet are solved.
Chinese patent CN101437493B mentions a linagliptin-containing pharmaceutical composition comprising, as an active ingredient, a DPPIV inhibitor compound having an amino group, a first diluent, a second diluent, a binder, a disintegrant, and a lubricant, wherein the first diluent is mannitol, the second diluent is pregelatinized starch, the binder is copovidone, the disintegrant is corn starch, and the lubricant is magnesium stearate. The dissolution rate and stability of the prepared sample are not further described in the patent. Copovidone (copovidone), commonly used as a binder in tablets; the auxiliary material is a high molecular polymer, and the impurities contain aldehyde group, peroxide and the like, so that linagliptin is easy to generate degradation impurities, and the stability of a preparation product is influenced. And the prior art of granulating copovidone dissolved in purified water may result in an uncertain amount of binder addition.
Starch is the most commonly used disintegrant, usually at a concentration of 3% to 15% (W/W). However, ordinary starch has poor compressibility, and the chips are brittle and prone to bursting at high concentrations.
Therefore, the selection of the pharmaceutical excipients is a key controlling factor for the drug effect.
Disclosure of Invention
The invention aims to provide a composition containing linagliptin and application thereof.
In order to achieve the purpose, the invention adopts the technical scheme that:
a composition containing linagliptin comprises an active ingredient and pharmaceutic adjuvants, wherein the active ingredient is linagliptin, and the pharmaceutic adjuvants are mannitol, pregelatinized starch and magnesium stearate;
the components by weight are as follows: 2-5% of linagliptin, 72-90% of mannitol, 5-20% of pregelatinized starch and 0.5-1.5% of magnesium stearate.
Further components by weight: 2.78% of linagliptin, 75.72-86.72% of mannitol, 10-20% of pregelatinized starch and 0.5-1.5% of magnesium stearate.
Further components by weight: 2.78% of linagliptin, 81.22% of mannitol, 15% of pregelatinized starch and 1% of magnesium stearate.
The mannitol is 200SD, 100SD or 160C.
The preferred mannitol is type 160C.
The composition is coated to obtain gastric-soluble film coated tablet, wherein the weight of the film coating material is 2-3% of the composition.
The preparation method comprises the following steps:
1) weighing linagliptin, mannitol and pregelatinized starch, adding into a wet granulator, mixing for 5min, adding purified water, wet mixing for 2min, and wet granulating with 1.5mm screen mesh;
2) drying the wet granules obtained in the step 1) at 50-60 ℃ until the moisture content is 1.0-3.0%, and finishing the dry granules by a 1.5mm screen;
3) adding magnesium stearate into the dry granules obtained in the step 2), and uniformly mixing;
4) carrying out phi 8mm shallow concave die tabletting on the mixture obtained in the step 3), wherein the tabletting force is 3.0-6.0KN, and the rotating speed is 20-45rpm, so as to obtain a plain tablet with the hardness of 20-70N;
5) preparing a film coating premix with solid content of 10% by using purified water, and coating the plain tablets obtained in the step 4) to obtain the gastric-soluble film coated tablets.
The film coating material is hydroxypropyl methylcellulose, polyethylene glycol, talcum powder, titanium dioxide and yellow ferric oxide, or the film coating material is hydroxypropyl methylcellulose, talcum powder, titanium dioxide and yellow ferric oxide.
The invention has the beneficial effects that:
the technical scheme of the invention has the following advantages:
(1) the pregelatinized starch has the function of an adhesive, and is promoted to play the adhesive characteristic by adopting purified water granulation, compared with the starch, the pregelatinized starch can increase the fluidity and the compressibility, wherein the pregelatinized starch plays the role of a self-lubricating agent, and in addition, the pregelatinized starch has the disintegration function.
(2) While ensuring the dissolution consistent with the original dissolution, the method effectively reduces the growth of related substances in the storage process of the tablet and improves the stability of the preparation.
(3) According to the invention, proper mannitol types, dosage and pregelatinized starch dosage are screened out through prescription process optimization, so that the problems of poor tablet compressibility and unqualified hardness are well solved.
Detailed Description
The present invention will be further described with reference to the following examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Mannitol is available in the form of 200SD, 100SD or 160C.
Example 1:
the prescription composition is as follows: (g/1000 tablets)
| Composition (I) | Dosage per gram | Percent/%) |
| Linagliptin | 5 | 2.78 |
| Mannitol 160C | 146.2 | 81.22 |
| Pregelatinized starch | 27 | 15 |
| Magnesium stearate | 1.8 | 1 |
| Total amount of | 180 | 100 |
Preparation method
1) Weighing linagliptin, mannitol and pregelatinized starch in a formula amount, adding into a wet granulator, mixing for 5min, adding purified water, wet mixing for 2min, granulating, and wet granulating with a 1.5mm screen;
2) drying the wet granules obtained in step 1) at 55 deg.C until the water content is about 2.0%, and grading the dry granules with 1.5mm screen
3) Adding magnesium stearate into the dry granules obtained in the step 2), and uniformly mixing;
4) carrying out phi 8mm shallow concave die tabletting on the mixture obtained in the step 3), wherein the tabletting force is about 4.0KN, the rotating speed is about 35rpm, and the hardness is 30-40N;
5) preparing a film coating premix with solid content of 10% by using purified water, and coating the compressed tablets obtained in the step 4) to obtain the medicine containing linagliptin.
The film coating material is hydroxypropyl methylcellulose, talcum powder, titanium dioxide and yellow ferric oxide, and the film coating material accounts for 2-3% of the total weight of the prescription.
The usage and dosage are as follows: once a day, one tablet at a time.
Example 2:
the prescription composition is as follows: (g/1000 tablets)
| Composition (I) | Dosage per gram | Percent/%) |
| Linagliptin | 5 | 2.78 |
| Mannitol 200SD | 146.2 | 81.22 |
| Pregelatinized starch | 27 | 15 |
| Magnesium stearate | 1.8 | 1 |
| Total amount of | 180 | 100 |
The preparation method is the same as example 1.
Comparative example 1:
referring to CN101437493B, a linagliptin tablet was prepared.
The prescription composition is as follows: (g/1000 tablets)
| Composition (I) | Dosage per gram | Percent/%) |
| Linagliptin | 5 | 2.78 |
| Mannitol 160C | 130.9 | 72.72 |
| Pregelatinized starch | 18 | 10 |
| Corn starch | 18 | 10 |
| Co-polyvidone | 5.4 | 3 |
| Magnesium stearate | 2.7 | 1.5 |
| Total amount of | 180 | 100 |
The preparation method comprises the following steps:
1) dissolving copovidone in purified water, and standing until the solution is clear for later use; 2) putting linagliptin, mannitol, pregelatinized starch and corn starch in a wet granulator, stirring and mixing uniformly, adding copovidone aqueous solution for granulation, and wet granulating with a 1.5mm screen; 3) drying the wet granules until the moisture content is 1.0-3.0%, and grading the dry granules by a 1.5mm screen; 4) adding magnesium stearate, mixing, and tabletting.
Comparative example 2
The preparation method is the same as that of example 2, different types of mannitol are used, and the result is shown in table 1.
TABLE 1 investigation results of different types of mannitol
As can be seen from Table 1, the mannitol 200SD, 100SD and 160C prepared into granules has better material compressibility and meets the requirement of tablets. When mannitol 50C is used, the material compressibility is poor.
Test example 1:
comparative example 1, and original preparation (commercial Linagliptin tablet, trade name)
) The dissolution rate of (D) is shown in Table 2. The dissolution and release rate of the drug are measured according to the measurement method of 0931 dissolution rate and release rate in the four parts of the 2015 Chinese pharmacopoeia, the basket method is 50rpm and 900ml 37 ℃, and the detection method comprises the following steps: high performance liquid chromatography.
Table 2: example 1, comparative example 1, dissolution of original developer sample in various solutions
The test data in table 2 show that the dissolution rate of linagliptin in example 1 is consistent with the dissolution behavior of the original preparation at ph1.0, ph4.5 and ph6.8, and is greater than 85% in 15 min. Therefore, the dissolution behavior of the invention is consistent with that of the original preparation after reducing the types of the two auxiliary materials.
Test example 2:
the samples (bare chips) of comparative example 1, example 1 and example 2 were placed under accelerated conditions (temperature 40. + -. 2 ℃ C., relative humidity 75. + -. 5%) and the samples were sampled for detection of the relevant substances at 15 days and 30 days, respectively, and the results are shown in Table 3.
Table 3: detection of related substances
Table 3 the test results show that: after the types of auxiliary materials are reduced, the total impurities of related substances are reduced under an acceleration condition, and the stability of a product can be improved; in addition, under the condition of meeting the product quality requirement, the quality of the medicament containing mannitol 160C is better than that of the medicament containing mannitol 200 SD.
In conclusion, by reducing the usage of the copovidone and the corn starch, the linagliptin tablet which has few auxiliary materials and simple process, and can be dissolved out similar to or even better than the original research can be obtained.
Claims (7)
1. A composition comprising linagliptin, characterized in that: the composition consists of an active ingredient and pharmaceutic adjuvants, wherein the active ingredient is linagliptin, and the pharmaceutic adjuvants are mannitol, pregelatinized starch and magnesium stearate;
the components by weight are as follows: 2-5% of linagliptin, 72-90% of mannitol, 5-20% of pregelatinized starch and 0.5-1.5% of magnesium stearate.
2. The linagliptin-containing composition according to claim 1, characterized in that:
the components by weight are as follows: 2.78% of linagliptin, 75.72-86.72% of mannitol, 10-20% of pregelatinized starch and 0.5-1.5% of magnesium stearate.
3. The linagliptin-containing composition according to claim 2, characterized in that:
the components by weight are as follows: 2.78% of linagliptin, 81.22% of mannitol, 15% of pregelatinized starch and 1% of magnesium stearate.
4. Linagliptin-containing composition according to any one of claims 1 to 3, characterized in that: the mannitol is 200SD, 100SD or 160C.
5. The linagliptin-containing composition according to claim 4, characterized in that: mannitol was type 160C.
6. The linagliptin-containing composition according to claim 1, wherein the composition is coated to prepare gastric-soluble film-coated tablets, and the film-coating material is 2-3% by weight of the composition.
7. A process for the preparation of linagliptin-containing composition according to claim 6, characterized in that:
1) weighing linagliptin, mannitol and pregelatinized starch, adding into a wet granulator, mixing for 5min, adding purified water, wet mixing for 2min, and wet granulating with 1.5mm screen mesh;
2) drying the wet granules obtained in the step 1) at 50-60 ℃ until the moisture content is 1.0-3.0%, and finishing the dry granules by a 1.5mm screen;
3) adding magnesium stearate into the dry granules obtained in the step 2), and uniformly mixing;
4) carrying out phi 8mm shallow concave die tabletting on the mixture obtained in the step 3), wherein the tabletting force is 3.0-6.0KN, and the rotating speed is 20-45rpm, so as to obtain a plain tablet with the hardness of 20-70N;
5) preparing a film coating premix with solid content of 10% by using purified water, and coating the plain tablets obtained in the step 4) to obtain the gastric-soluble film coated tablets.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911325540.6A CN110840856A (en) | 2019-12-20 | 2019-12-20 | Composition containing linagliptin and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911325540.6A CN110840856A (en) | 2019-12-20 | 2019-12-20 | Composition containing linagliptin and application thereof |
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| Publication Number | Publication Date |
|---|---|
| CN110840856A true CN110840856A (en) | 2020-02-28 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911325540.6A Withdrawn CN110840856A (en) | 2019-12-20 | 2019-12-20 | Composition containing linagliptin and application thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115227661A (en) * | 2022-09-22 | 2022-10-25 | 北京惠之衡生物科技有限公司 | Linagliptin tablet and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150283248A1 (en) * | 2014-04-02 | 2015-10-08 | Aurobindo Pharma Ltd. | Pharmaceutical compositions of Linagliptin and process for preparation thereof |
| CN105456270A (en) * | 2014-08-27 | 2016-04-06 | 石药集团中奇制药技术（石家庄）有限公司 | Dipeptidyl peptidase IV inhibitor pharmaceutical composition, use and preparation method thereof |
| CN107174571A (en) * | 2016-03-09 | 2017-09-19 | 四川科伦药物研究院有限公司 | A kind of Li Gelieting and its salt, ester, the pharmaceutical composition of derivative and preparation method thereof |
-
2019
- 2019-12-20 CN CN201911325540.6A patent/CN110840856A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150283248A1 (en) * | 2014-04-02 | 2015-10-08 | Aurobindo Pharma Ltd. | Pharmaceutical compositions of Linagliptin and process for preparation thereof |
| CN105456270A (en) * | 2014-08-27 | 2016-04-06 | 石药集团中奇制药技术（石家庄）有限公司 | Dipeptidyl peptidase IV inhibitor pharmaceutical composition, use and preparation method thereof |
| CN107174571A (en) * | 2016-03-09 | 2017-09-19 | 四川科伦药物研究院有限公司 | A kind of Li Gelieting and its salt, ester, the pharmaceutical composition of derivative and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115227661A (en) * | 2022-09-22 | 2022-10-25 | 北京惠之衡生物科技有限公司 | Linagliptin tablet and preparation method thereof |
| CN115227661B (en) * | 2022-09-22 | 2022-12-13 | 北京惠之衡生物科技有限公司 | Linagliptin tablet and preparation method thereof |
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