CN111759838B - Pharmaceutical composition of pharmaceutically acceptable salt of sitagliptin and application thereof - Google Patents
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Abstract
The invention relates to a pharmaceutical composition of a pharmaceutically acceptable salt of sitagliptin and application thereof, belonging to the technical field of medicines. The invention discloses a pharmaceutical composition containing a pharmaceutically acceptable salt of sitagliptin and a surfactant and application thereof, wherein the surfactant in the pharmaceutical composition can improve the bioavailability of the pharmaceutically acceptable salt of sitagliptin. The invention also discloses a pharmaceutical preparation containing the composition. The pharmaceutical composition and the pharmaceutical preparation of the pharmaceutically acceptable salt of sitagliptin disclosed by the invention can improve the bioavailability of the pharmaceutically acceptable salt of sitagliptin, and are beneficial to clinical application of the composition and the pharmaceutical preparation.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a pharmaceutical composition of a pharmaceutically acceptable salt of sitagliptin and application thereof.
Background
The metabolic syndrome is a group of clinical syndromes which are determined by genes and environmental factors and are characterized by the combined occurrence of various metabolic diseases such as obesity, diabetes, hypertension, dyslipidemia and the like. With the development of socio-economic, people's lifestyle changes (energy intake increases and exercise decreases, etc.), the incidence of metabolic syndrome has a tendency to increase year by year around the world, and has become a public health challenge facing the world.
The Xigelatan is a new molecular entity drug discovered by Shenzhen micro-core biotechnology limited company, has the capability of selectively activating PPAR-alpha, PPAR-gamma and PPAR-sigma, and can be used for treating diseases related to metabolic syndrome, such as diabetes, hypertension, obesity, insulin resistance, hypertriglyceridemia, hyperglycemia, hypercholesterolemia, atherosclerosis, coronary heart disease and the like.
The solubility of the sitagliptin in water is low, the bioavailability is low, and the disadvantages of poor medicament absorption, high dosage, high toxicity of the digestive tract and the like in clinic are brought. Therefore, the improvement of the bioavailability of the sitagliptin can reduce the dosage of the medicine, and has important significance in reducing the use burden of the medicine and the toxicity of the digestive tract.
CN109276543A discloses a sitaglipta solid dispersion, a preparation method and an application thereof, which contains active ingredients and a carrier matrix, wherein the carrier matrix is copovidone or povidone, and the mass ratio of the copovidone to the povidone is as follows: support matrix 1: 2-10, preferably in a ratio of 1: 3-10, wherein the active ingredient is sitagliptin or 2- (2- (4-fluorobenzoyl) phenylamino) -3- (4- (2- (9H-carbazole-9-yl) ethoxy) phenyl) propionic acid. The solid dispersion preparation contains the solid dispersion and one or more auxiliary materials of diluent, disintegrant and glidant. The solid dispersion can be highly dispersed in a water-soluble carrier material in a molecular form or an amorphous state, so that the water solubility of the sitagliptin is greatly improved, and the dissolution rate and the bioavailability of the sitagliptin are improved.
The prior art also prepares the sitagliptin into an alkali metal salt such as sitagliptin sodium, and compared with the sitagliptin, the solubility of the sitagliptin sodium is obviously improved, but the technical problem of low bioavailability still exists.
Disclosure of Invention
According to the invention, the combination of the pharmaceutically acceptable salt of sitagliptin and the surfactant is found through research, so that the water solubility of the pharmaceutically acceptable salt of sitagliptin can be greatly improved, and the dissolution rate and the bioavailability of the pharmaceutically acceptable salt of sitagliptin are improved.
In view of the above, the present invention aims to provide a pharmaceutical composition for improving the bioavailability of a pharmaceutically acceptable salt of sitagliptin. The pharmaceutical composition comprises a pharmaceutically acceptable salt of sitagliptin and a surfactant.
The surfactant according to the present invention is preferably a nonionic surfactant.
The nonionic surfactant of the present invention is not particularly limited, and any nonionic surfactant that does not dissociate in water is included in the present invention. Specific examples of the nonionic surfactant of the present invention include polyoxyethylenes, polyols, alkanolamides, polyethers, amine oxides, and the like.
Among them, preferred nonionic surfactants are selected from polyoxyethylenes, polyols and polyethers; more preferably one or more kinds of polyoxyethylenes and polyhydric alcohols; most preferably one or both of tween and poloxamer.
The Tween is preferably one or more of Tween 80, Tween 60, Tween 40, Tween 20, etc.
The poloxamer is preferably one or more of poloxamer 188, poloxamer 124, poloxamer 237, poloxamer 338 and poloxamer 407.
The mass ratio of the pharmaceutically acceptable salt of the sitagliptin to the surfactant in the pharmaceutical composition is 1: 0.1-1: 10, and more preferably 1: 0.5-1: 5; most preferably 1:0.8 to 1: 3.
The pharmaceutically acceptable salt of sitagliptin according to the present invention includes alkali metal salts, alkaline earth metal salts, ammonium salts or quaternary ammonium salts thereof, and preferably includes sitagliptin potassium and sitagliptin sodium.
The sitagliptin sodium has a structure shown in a formula (I), and the chemical name of the sitagliptin sodium is 2- (2- (4-fluorobenzoyl) phenylamino) -3- (4- (2- (9H-carbazole-9-yl) ethoxy) phenyl) sodium propionate:
the invention also provides a preparation method of the pharmaceutical composition of the pharmaceutically acceptable salt of sitagliptin, which comprises the step of uniformly mixing the pharmaceutically acceptable salt of sitagliptin and a surfactant.
Preferably, the preparation method further comprises the step of pulverizing and sieving the mixed composition.
The invention also provides a pharmaceutical preparation of the pharmaceutically acceptable salt of the sitagliptin, which contains the pharmaceutical composition, and the pharmaceutical preparation comprises the pharmaceutical composition of the pharmaceutically acceptable salt of the sitagliptin and pharmaceutically acceptable auxiliary materials.
Preferably, the pharmaceutically acceptable excipients comprise a filler, a disintegrant, a binder, a glidant and a lubricant.
Preferably, the filler is one or more selected from lactose, corn starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, cetyl alcohol, stearyl alcohol, ethyl cellulose, pregelatinized starch, sucrose, microcrystalline cellulose, mannitol, calcium hydrogen phosphate, and calcium phosphate.
Preferably, the disintegrant is one or more selected from starch, microcrystalline cellulose, croscarmellose sodium, carboxymethylcellulose sodium, sodium carboxymethyl starch, crospovidone, and low-substituted hydroxypropyl cellulose.
Preferably, the binder is one or more selected from water, ethanol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, and copovidone.
Preferably, the glidant is one or more selected from colloidal silicon dioxide and talcum powder.
Preferably, the lubricant is one or more selected from stearic acid, magnesium stearate, sodium stearyl fumarate, polyethylene glycol 4000-.
Preferably, the pharmaceutical formulation of a pharmaceutically acceptable salt of sitagliptin according to the present invention is in the form of an immediate release formulation.
Preferably, the pharmaceutical preparation of the pharmaceutically acceptable salt of sitagliptin according to the invention is one of tablets, capsules, pills, oral liquid preparations, granules, powder, paste and dropping pills. Wherein the capsule comprises a soft capsule.
The pharmaceutical preparation of the pharmaceutically acceptable salt of sitagliptin according to the invention is preferably tablet, soft capsule.
According to another aspect of the present invention, there is also provided a process for the preparation of a pharmaceutical formulation of a pharmaceutically acceptable salt of sitagliptin, comprising: comprises the pharmaceutical composition of the pharmaceutically acceptable salt of the sitagliptin and pharmaceutically acceptable auxiliary materials.
Preferably, the process for the preparation of a tablet in a pharmaceutical formulation of a pharmaceutically acceptable salt of sitagliptat comprises the following steps:
mixing the pharmaceutically acceptable salt of sitagliptin and surfactant uniformly, pulverizing, sieving, mixing with filler, disintegrant and adhesive, wet granulating, and tabletting.
The invention has the beneficial effects that:
(1) the surfactant can change the state of the system interface, thereby producing a series of effects of wetting or anti-wetting, emulsifying or demulsifying, foaming or defoaming, solubilizing and the like. Surfactants are commonly used as solubilizers in oral solid formulations, and nonionic surfactants are added to the aqueous solutions of poorly soluble drugs to solubilize the drugs. However, the active ingredient of the pharmaceutical composition claimed in the present invention is a pharmaceutically acceptable salt of sitaglipta, which has a low solubility in water and a significantly improved solubility already after preparation into an alkali metal salt such as sodium sitaglipta, in which case the use of a surfactant to improve the solubility is generally not considered any longer by the skilled person. The technical means of combining the pharmaceutically acceptable salt of sitagliptin and the surfactant is unconventional, and the technical effect of unexpectedly and remarkably improving the bioavailability is achieved.
(2) The action of surfactants in pharmaceutical preparations in the body is quite complex and is related to various factors such as the structure of the surfactant, the association of micelles, the structure of the drug and the degradation route. The surfactant can reduce interfacial tension, reduce contact angle between solid medicine and gastrointestinal tract body fluid, increase medicine wettability and speed medicine dissolution, so that the surfactant can promote medicine absorption. However, the drug is wrapped or embedded in the micelle and may not be easily released, and meanwhile, the surfactant has the function of dissolving biomembrane lipid and increasing the permeability of epithelial cells, thereby delaying the absorption of the drug. Therefore, it is completely unexpected that the use of surfactants of different structures can increase the bioavailability of drugs with different structures. The combination is based on the combination of the unconventional pharmaceutically acceptable salt of the sitagliptin and the surfactant, and is discovered through rat pharmacological experiments to unexpectedly improve the bioavailability of the pharmaceutically acceptable salt of the sitagliptin.
Drawings
FIG. 1 shows the results of a rat-substituted experiment of the pharmaceutical composition of sitagliptin sodium.
Detailed Description
The invention discloses a pharmaceutical composition of a pharmaceutically acceptable salt of sitagliptin and application thereof, and a person skilled in the art can realize the pharmaceutical composition by appropriately improving process parameters by taking the contents into consideration. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the scope of the invention. While the pharmaceutical compositions of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the applications and pharmaceutical compositions described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention without departing from the spirit and scope of the invention.
The pharmaceutical composition of a pharmaceutically acceptable salt of sitagliptin and the preparation method thereof provided by the present invention are further described below.
The sagital sodium and sagital potassium in the examples are provided by Shenzhen micro-core Biotech GmbH, Inc., and other reagents are all commercially available products; wherein Kolliphor HS15 is recorded in the United states pharmacopoeia under the name polyethylene glycol-12-hydroxystearate.
Example 1: preparation of sodium sitagliptin-sodium carboxymethylcellulose (1:3) composition
The formula is as follows:
sitagliptin sodium 1.60g 25.00%
Sodium carboxymethylcellulose 4.80g 75.00%
The preparation method comprises the following steps:
(1) accurately weighing the sitagliptin sodium and the sodium carboxymethyl cellulose;
(2) and (2) mixing the weighed raw materials in the step (1) for 20min, and uniformly mixing to form the sitagliptin sodium-sodium carboxymethyl cellulose composition.
Example 2: preparation of sodium sitagliptat-sodium lauryl sulfate (1:3) composition
The formula is as follows:
sitagliptin sodium 1.60g 25.00%
Sodium dodecyl sulfate 4.80g 75.00%
The preparation method comprises the following steps:
(1) accurately weighing the sitagliptin sodium and the sodium dodecyl sulfate;
(2) and (2) mixing the weighed raw materials in the step (1) for 20min, and uniformly mixing to form the sitagliptin sodium-lauryl sodium sulfate composition.
Example 3: preparation of a composition of sodium sitagliptin-hydroxypropylmethylcellulose acetate succinate (1:3)
The formula is as follows:
sitagliptin sodium 1.60g 25.00%
4.80g of hydroxypropyl methyl cellulose acetate succinate 75.00%
The preparation method comprises the following steps:
(1) accurately weighing the sitagliptin sodium and the hydroxypropyl methyl cellulose acetate succinate;
(2) and (2) mixing the weighed raw materials in the step (1) for 20min, and uniformly mixing to form the sitagliptin sodium-hydroxypropyl methyl cellulose acetate succinate composition.
Example 4: preparation of sitagliptin sodium-poloxamer 188(1:3) composition
Prescription:
sitagliptin sodium 1.60g 25.00%
Poloxamer 1884.80 g 75.00%
The preparation method comprises the following steps:
(1) accurately weighing the sitagliptin sodium and poloxamer 188;
(2) and (2) mixing the weighed raw materials in the step (1) for 20min, and uniformly mixing to form the sitagliptin sodium-poloxamer 188 composition.
Example 5: preparation of sitagliptin sodium-Tween 80(1:3) composition
Prescription:
sitagliptin sodium 1.60g 25.00%
Tween 804.80 g 75.00%
The preparation method comprises the following steps:
(1) accurately weighing the sitagliptin and the tween 80;
(2) and (2) stirring the weighed raw materials in the step (1) for 20min, and uniformly mixing to form the sitagliptin sodium-tween 80 composition.
Example 6: preparation of sodium sitagliptin-Kolliphor HS15(1:3) composition
Prescription:
sitagliptin sodium 1.60g 25.00%
Kolliphor HS15 4.80g 75.00％
The preparation method comprises the following steps:
(1) accurately weighing sitagliptin sodium and Kolliphor HS 15;
(2) heating and mixing the weighed raw materials in the step (1) in a water bath at 60 ℃ for 20min, and uniformly mixing to form the sitagliptin sodium-Kolliphor HS15 composition.
Example 7: preparation of pharmaceutical formulation of sitaglipta potassium (sitaglipta potassium-tween 80(1: 1)))
Formulation (1000 tablets):
the preparation method comprises the following steps:
(1) accurately weighing the sitagliptin potassium, the polyvinylpyrrolidone VA64, the microcrystalline cellulose, the lactose and the sodium carboxymethyl starch, and uniformly mixing;
(2) dissolving tween 80 in an appropriate amount of ethanol, adding into the composition of the step (1), granulating by a wet method, drying, and grading;
(3) adding the obtained particles into colloidal silicon dioxide and mixing uniformly;
(4) the resulting mixed granules can be tableted to make tablets.
Example 8: preparation formula (1000 tablets) of a sitagliptin sodium pharmaceutical preparation (sitagliptin sodium-poloxamer 188 (weight ratio of 1: 3)):
the preparation method comprises the following steps:
(1) uniformly mixing poloxamer 188 and sitagliptin sodium, crushing and sieving;
(2) mixing the above mixture with microcrystalline cellulose, lactose, sodium carboxymethyl starch, and polyvinylpyrrolidone VA64, adding water, and wet granulating to obtain soft material;
(3) drying the soft material, and grading;
(4) the obtained granule can be made into tablet by tabletting.
Example 9: preparation of pharmaceutical preparation of sitagliptin potassium (sitagliptin potassium-tween 80-poloxamer 188 (weight ratio 1:1: 1)))
Prescription
The preparation method comprises the following steps:
(1) accurately weighing the sitagliptin potassium, the polyvinylpyrrolidone VA64, the microcrystalline cellulose, the lactose, the sodium carboxymethyl starch and the poloxamer 188, and uniformly mixing;
(2) dissolving tween 80 in an appropriate amount of ethanol, adding into the composition of the step (1), granulating by a wet method, drying, and grading;
(3) adding magnesium stearate into the mixed granules obtained in the step 2, and totally mixing;
(4) the obtained total mixed granule can be made into tablet by tabletting.
Example 10: rat drug replacement test
36 healthy rats (Sprague Dawley) were selected and randomly divided into 6 groups of 6 rats (3 females and 3 males) in example 1, sodium carboxymethylcellulose was used as a dispersant to improve the mixing uniformity of the gavage solution and was used as a control group to compare the experiments with the groups of example 2, example 3, example 4, example 5 and example 6. During the test period, rats were fasted overnight before administration, blood was collected from the eye socket before administration, and plasma was isolated as a blood concentration sample of 0 h. The gastric lavage fluid is dispersed by purified water, the concentration of the gastric lavage fluid is 2mg/mL, and each rat is respectively irrigated with 20mg/kg of sitagliptin sodium. After administration, blood samples were collected at 15min, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h, respectively, about 0.5mL of each sample was collected, heparin sodium was anticoagulated, and after collection, the blood plasma was placed on ice and centrifuged within 1 hour and stored at-80 ℃ for testing. Drug concentrations in plasma were measured by LC-MS/MS. The results are shown in Table 1 and FIG. 1.
TABLE 1 rat drug data comparison table
| Parameters (ng/ml) | Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Example 6 |
| AUC(0-t) | 13683.2 | 10353.7 | 12512.0 | 21650.3 | 22762.8 | 20082.2 |
| Cmax | 1280.8 | 848.9 | 1013.7 | 2622.5 | 3324.4 | 1701.0 |
As can be seen from the test results of table 1 and fig. 1, the citalopram sodium composition containing sodium dodecyl sulfate and hydroxypropylmethylcellulose acetate succinate did not significantly improve the bioavailability of the citalopram sodium compared to example 1. The sitagliptin sodium composition containing poloxamer, tween and Kolliphor HS15 can obviously improve the bioavailability of the sitagliptin sodium.
The foregoing detailed description of the invention has provided for the purpose of illustrating the principles and embodiments of the invention by way of specific examples, which are presented solely to assist in understanding the method and its core concepts, including the best mode, and to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any incorporated methods. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention. The scope of the invention is defined by the claims and may include other embodiments that occur to those skilled in the art. Such other embodiments are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.
Claims (10)
1. A pharmaceutical composition comprising a pharmaceutically acceptable salt of sitagliptin and a surfactant; the surfactant is a nonionic surfactant, and the nonionic surfactant is tween, poloxamer, Kolliphor HS15 or a combination thereof.
2. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of sitagliptin is selected from an alkali metal salt, an alkaline earth metal salt or an ammonium salt thereof.
3. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of sitagliptin is selected from quaternary ammonium salts or potassium sitagliptin or sodium sitagliptin.
4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the mass ratio of the pharmaceutically acceptable salt of sitagliptin to the surfactant is 1: 0.1-1: 10.
5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the mass ratio of the pharmaceutically acceptable salt of sitagliptin to the surfactant is 1:0.5 to 1: 5.
6. A pharmaceutical preparation of a pharmaceutically acceptable salt of sitagliptin, comprising the pharmaceutical composition of any one of claims 1 to 5 and a pharmaceutically acceptable excipient.
7. The pharmaceutical preparation of sitagliptin, which is a pharmaceutically acceptable salt according to claim 6, is one of tablets, capsules, pills, oral liquid preparations, granules, powders, ointments and dropping pills.
8. The pharmaceutical formulation of sitagliptin a pharmaceutically acceptable salt according to claim 6, characterized in that it is a soft capsule.
9. A pharmaceutical formulation of sitagliptin, a pharmaceutically acceptable salt thereof, according to claim 6, which is an immediate release formulation.
10. Use of a pharmaceutical composition according to any one of claims 1 to 5 for the preparation of a pharmaceutical formulation of a pharmaceutically acceptable salt of sitagliptin.
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