Sitagliptin and metformin sustained release tablet without antioxidant as well as preparation method and application of Sitagliptin and metformin sustained release tablet

Abstract

The invention discloses a sitagliptin and metformin sustained release tablet without an antioxidant as well as a preparation method and application of the sitagliptin and metformin sustained release tablet. Relates to the field of medicine preparation. The sitagliptin and metformin pharmaceutical composition without the antioxidant comprises a tablet core and a coating, the tablet core comprises a sitagliptin layer and a metformin layer which are laminated; the sitagliptin layer and the metformin layer contain drug release pore channels; the metformin layer is prepared from the following components: metformin and an expansion material. According to the invention, through the dual design of the coating and the drug release pore channel, the drug has oxidation resistance and the characteristic of rapid release of the sitagliptin drug at the same time, the sitagliptin is ensured not to be oxidized under the condition that an antioxidant is not used, and rapid release of the sitagliptin is further realized, so that the treatment effect of taking effect rapidly is achieved. And meanwhile, the slow-release treatment effect of the metformin medicine is also considered.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparation, in particular to a sitagliptin metformin sustained-release tablet without antioxidant and a preparation method and application thereof. BACKGROUND

[0002] The sitagliptin metformin sustained-release tablet is a compound preparation composed of sitagliptin and metformin, mainly used for treating type II diabetes. Type II diabetes is a metabolic disease caused by insufficient insulin secretion or insulin insensitivity, accompanied by long-term high blood glucose levels. With the increasing number of global diabetes patients, the demand for treatment of type II diabetes is increasing. Sitagliptin and metformin are two important drugs for controlling blood glucose in clinical practice, among which sitagliptin belongs to dipeptidyl peptidase-4 (DPP-4) inhibitors, and metformin belongs to biguanide drugs. Sitagliptin improves insulin secretion and reduces liver glucose production by increasing the activity of incretin hormones, while metformin effectively controls blood glucose levels by reducing liver glucose production, inhibiting intestinal glucose absorption, and improving peripheral tissue sensitivity to glucose.

[0003] In 2012, Merck & Co. launched sitagliptin metformin sustained-release tablets (trade name: JANUMET XR) which was approved by the US FDA and began to be marketed. The drug has been widely used for its excellent therapeutic effect and convenient medication experience for patients. JANUMET XR provides multiple specifications such as 50mg / 500mg, 50mg / 1000mg, and 100mg / 1000mg (sitagliptin / metformin), which can be personalized according to the specific needs of patients and existing treatment plans, thereby helping more type II diabetes patients to receive effective treatment.

[0004] As a DPP-4 inhibitor, the mechanism of action of sitagliptin is to inhibit the activity of DPP-4 enzyme, prolong the half-life of incretin hormones (such as GLP-1 and GIP), thereby enhancing the insulin secretion effect of these hormones on pancreatic beta cells and inhibiting the glucagon secretion of pancreatic alpha cells, ultimately helping to reduce blood glucose levels. Metformin effectively controls blood glucose by reducing liver glucose production, improving peripheral tissue glucose uptake, and increasing insulin sensitivity. The combination of the two has a synergistic effect and can act on different mechanisms to provide more comprehensive blood glucose control.

[0005] However, sitagliptin faces the problem of oxidative stability during production. Sitagliptin is a highly active chemical substance that is easily oxidized in the air, which not only affects the stability of the drug, but also reduces its efficacy. In order to avoid the oxidation of sitagliptin, antioxidants such as tocopherol, ascorbic acid or other related compounds are usually added. For example, some patents mention protecting sitagliptin by adding antioxidants in the coating. However, this method also has certain defects, first of all, the use of antioxidants is often not easy to mix evenly; secondly, during the spraying process of the coating, the drug droplets may cause unstable drug efficacy due to the unevenness of the spray; finally, the use of these antioxidants may cause unnecessary side effects or health problems in some cases, especially during long-term use.

[0006] Improving the coating technology is an effective solution. By coating sitagliptin, the contact between oxygen and sitagliptin can be effectively isolated, thereby preventing the occurrence of oxidation reaction. However, in order to ensure the stability of the drug without antioxidants, prevent oxygen from penetrating into the tablet core through the coating film, the coating layer needs to be dense and thick enough. However, too strong and thick coating film hinders the dissolution of sitagliptin, which contradicts the need to ensure rapid release of the drug.

[0007] Therefore, it is urgent to develop a method and drug that balances the rapid release requirement of sitagliptin and the oxidation resistance requirement of sitagliptin to solve the above problems. SUMMARY

[0008] The purpose of the present application is to develop a method and drug that does not contain antioxidants and can balance the rapid release requirement of sitagliptin and the oxidation resistance requirement of sitagliptin.

[0009] The first aspect of the present application is: Provided is a sitagliptin metformin pharmaceutical composition.

[0010] The second aspect of the present application is: Provided is a preparation method of a sitagliptin metformin pharmaceutical composition.

[0011] The third aspect of the present application is: Application of the sitagliptin metformin pharmaceutical composition.

[0012] Specifically, the technical solution adopted according to the first aspect of the present application is: A sitagliptin metformin pharmaceutical composition comprises a tablet core and a coating; The tablet core comprises a sitagliptin layer and a metformin layer arranged in layers; The sitagliptin layer contains drug release channels; The components of the metformin layer include metformin and its pharmaceutically acceptable salts and swelling materials.

[0013] According to an embodiment of the present application, one of the technical solutions has at least one of the following advantages or beneficial effects: The present application has the advantages of both coating and drug release channels, which can ensure the stability of the drug and achieve rapid release of the drug.

[0014] The structural diagram of the metformin and sitagliptin pharmaceutical composition is shown in Figure 1 Specifically, the structural diagram is shown in The role of the coating: The coating has a dense structure, which can effectively cover the drug release channels of the double-layer tablet, avoiding the contact of sitagliptin with oxygen in the air, thereby protecting the stability of the drug.

[0015] The rapid release property of the sitagliptin layer: The sitagliptin layer in the present application contains drug release channels. During the preparation of the coating, the surface of the channels in the sitagliptin layer is bridged and covered by the coating liquid, which forms a relatively thin film on the sitagliptin layer, while a relatively thick coating film is formed on the metformin layer without channels. When the drug is taken, it contacts the body fluid. Since the coating film covering the channels in the sitagliptin layer is relatively thin, it can be easily broken, and the body fluid penetrates into the interior of the sitagliptin layer along the drug release channels. During the rapid release of the drug, the area of the drug release channels increases, and the body fluid penetrates into the drug and contacts the metformin layer.

[0016] The design of the drug release channels increases the contact area with sitagliptin, promotes the rapid release of sitagliptin, and accelerates the contact time of the body fluid with the metformin layer, thereby promoting the rapid swelling of the metformin layer to further improve the rapid release of sitagliptin. Since the components of the metformin layer include swelling materials, the swelling materials swell after absorbing water, which promotes the contact of the sitagliptin layer with the body fluid, thereby further promoting the drug release rate of sitagliptin and ensuring that sitagliptin can rapidly exert a therapeutic effect.

[0017] According to an embodiment of the present application, the metformin and sitagliptin pharmaceutical composition does not contain an antioxidant.

[0018] According to an embodiment of the present application, the metformin and its pharmaceutically acceptable salts include at least one of metformin hydrochloride and metformin extended-release hydrochloride.

[0019] According to an embodiment of the present application, the depth of the drug release channel is 1.5-3 mm, and the diameter is 0.8-1.8 mm.

[0020] According to an embodiment of the present application, the drug release channel is prepared by a drug pressing process.

[0021] According to an embodiment of the present application, the pressing process is selected from one of a tablet press pressing process and a pill making machine pressing process.

[0022] According to an embodiment of the present application, the tablet press pressing process, the upper punch of the punch die used for tablet pressing has a needle head, and the lower punch is a common punch without a needle head, and the drug release hole is pressed by the upper punch with a needle head. By changing the size of the needle head, the size of the drug release channel can be adjusted, so as to adjust the release speed of the drug.

[0023] According to an embodiment of the present application, the component of the metformin layer further comprises a sustained release material. The sustained release material endows the metformin layer with sustained release characteristics. In the drug composition of the present application, the layer of sitagliptin has a rapid release characteristic, and at the same time of the rapid release, the release of metformin is effectively blocked due to the existence of the thicker coating on the surface of the metformin layer relative to the layer of sitagliptin and the sustained release characteristics of the metformin layer itself, so as to achieve the persistent release treatment effect of metformin. The present application realizes the coexistence of rapid effect and long-acting sustained treatment of the drug through the double-layer design combining the rapid release and sustained release mechanisms, reduces the frequency of administration and the stimulation to the gastrointestinal tract, and improves the treatment effect of the drug and the comfort of the patient.

[0024] According to an embodiment of the present application, the dosage form of the sitagliptin and metformin drug composition comprises a tablet.

[0025] According to an embodiment of the present application, after the sitagliptin and metformin drug composition is prepared into a tablet finished product, the length of the drug is less than 21.00 mm, the width is less than 10.50 mm, and the thickness is less than 6.60 mm. Preferably, the length of the drug is 17.00-18.00 mm, the width is 8.00-9.00 mm, and the thickness is 6.00-6.50 mm; preferably, the length of the drug is 17.40 mm, the width is 8.50 mm, and the thickness is 6.00 mm. The compound sitagliptin and metformin tablet usually has a large specification, and the patient has a problem of unsmooth swallowing. The structure of the double-layer tablet core plus the film coating and the double sustained release mechanism of the drug release through the channel can greatly reduce the component amount of the metformin layer, reduce the thickness of the metformin layer, and reduce the size of the tablet core, so as to improve the patient's compliance. The size of the original research JANUMET XR100 / 1000 mg specification is 21.00 mm x 10.50 mm x 6.60 mm, and the size is optimized in the present application.

[0026] According to an embodiment of the present application, the swelling material comprises at least one of povidone K90, hypromellose, hydroxypropyl cellulose, polyethylene oxide, carbomer.

[0027] According to an embodiment of the present application, the sustained-release material comprises at least one of polyethylene oxide, acrylic resin, shellac, glyceryl behenate.

[0028] According to an embodiment of the present application, the metformin layer comprises the following components: metformin and pharmaceutically acceptable salts thereof; swelling material; and / or, sustained-release material, and / or, osmotic pressure active substance; and / or, binder; and / or, lubricant.

[0029] According to an embodiment of the present application, the components of the metformin layer further comprise pharmaceutically acceptable excipients.

[0030] According to an embodiment of the present application, the metformin layer comprises the following components in parts by weight: metformin and pharmaceutically acceptable salts thereof, 40-85 parts; swelling material; 5-15 parts; and / or, sustained-release material, 5-15 parts; and / or, osmotic pressure active substance, 0-5 parts; and / or, binder, 2-10 parts; and / or, lubricant, 0-3 parts.

[0031] According to an embodiment of the present application, the osmotic pressure active substance comprises at least one of sodium chloride, lactose, mannitol, sorbitol, glucose, fructose.

[0032] According to an embodiment of the present application, the sitagliptin layer comprises the following components: sitagliptin and pharmaceutically acceptable salts thereof; and / or, filler; and / or, binder; and / or, lubricant.

[0033] According to an embodiment of the present application, the components of the sitagliptin layer further comprise pharmaceutically acceptable excipients.

[0034] According to an embodiment of the present application, the sitagliptin and pharmaceutically acceptable salts thereof are selected from at least one of sitagliptin phosphate, sitagliptin citrate, and sitagliptin fumarate.

[0035] According to an embodiment of the present application, the layer of sitagliptin comprises the following components by weight: sitagliptin and pharmaceutically acceptable salts thereof, 35-70 parts; and / or, a filler, 15-30 parts; and / or, a binder, 2-10 parts; and / or, a lubricant, 0-3 parts.

[0036] According to an embodiment of the present application, the filler comprises at least one of microcrystalline cellulose, lactose, mannitol, pregelatinized starch, corn starch, and the like.

[0037] According to an embodiment of the present application, the binder comprises at least one of povidone K30, povidone K90, hydroxypropyl cellulose (HPC), and hydroxypropyl methyl cellulose (HPMC).

[0038] According to an embodiment of the present application, the lubricant comprises at least one of magnesium stearate, sodium stearyl fumarate, talc, colloidal silicon dioxide.

[0039] According to an embodiment of the present application, the coating comprises the following components: a film material; and / or, a plasticizer material; and / or, a solvent material.

[0040] According to an embodiment of the present application, the film material comprises 60-95% by weight of the coating.

[0041] According to an embodiment of the present application, the film material comprises at least one of ethyl cellulose, cellulose acetate, polypropylene Eudragit S100, polypropylene Eudragit L100, polypropylene Eudragit NM30D, cellulose acetate phthalate, polyvinyl alcohol phthalate, methacrylic acid copolymer, cellulose acetate benzoate, hydroxypropyl cellulose phthalate. Preferably, the film material is selected from cellulose acetate.

[0042] According to an embodiment of the present application, the plasticizer material comprises at least one of polyethylene glycol 4000, polyethylene glycol 400, and triethyl citrate.

[0043] According to an embodiment of the present application, the solvent material comprises at least one of ethanol, acetone, purified water, ethyl acetate.

[0044] In particular, the technical solution adopted according to the second aspect of the present application is as follows: A method for preparing the sitagliptin and metformin pharmaceutical composition, comprising the following steps: Mixing the components of the sitagliptin layer to obtain a sitagliptin mixture; Mixing the components of the metformin layer to obtain a metformin mixture; Tableting the sitagliptin mixture and the metformin mixture, and forming drug release holes on the sitagliptin layer obtained by the tableting; Coating the tablet core with the coating material to obtain the sitagliptin metformin pharmaceutical composition.

[0045] According to an embodiment of the present application, one of the technical solutions has at least one of the following advantages or beneficial effects: The existing sitagliptin metformin preparation adopts a sitagliptin coating process on a metformin hydrochloride tablet core. The present application separately prepares a sitagliptin mixture and a metformin mixture, and then performs tableting and coating, thereby avoiding problems such as content loss, uneven drug application, and coating weight fluctuation.

[0046] The present application simultaneously forms drug release holes in the tableting process, without the need for an additional hole punching action after coating, thereby simplifying the process flow and making the method of the present application more suitable for commercial production.

[0047] According to an embodiment of the present application, the upper punch of the tableting machine is provided with a needle, so that the sitagliptin layer obtained by the tableting has drug release holes.

[0048] According to an embodiment of the present application, as shown in Figure 1 The sitagliptin layer and the metformin layer are tableted by a tablet press, so that the sitagliptin layer and the metformin layer both have needle holes. Then, the sitagliptin layer and the metformin layer containing the needle holes are tableted into a sitagliptin metformin pharmaceutical composition. After the tableting, the needle holes in the metformin layer are filled with sitagliptin due to the tableting, and the needle holes in the sitagliptin layer remain to obtain drug release holes.

[0049] According to an embodiment of the present application, the tablet press is selected from a double-layer tablet press or a pelletizer.

[0050] According to an embodiment of the present application, the tablet press with a needle is selected from a double-layer tablet press with an upper punch.

[0051] According to an embodiment of the present application, the mixing of the components of the sitagliptin layer includes the following steps: premixing, granulating, first-time granulating, drying, second-time granulating, and total mixing.

[0052] According to an embodiment of the present application, the granulation in the component mixing step of the sitagliptin layer is wet granulation. The existing sitagliptin metformin preparation adopts a sitagliptin coating process on a metformin hydrochloride tablet core, and the coating process is prone to problems such as content loss, uneven coating, coating weight fluctuation, and the like. The content loss may affect the treatment effect on patients in the clinic. The sitagliptin layer of the present application adopts wet granulation, which can ensure that the sitagliptin content is not lost and the mixing uniformity is more uniform.

[0053] According to an embodiment of the present application, the component mixing of the metformin layer comprises the following steps: premixing, granulating, first granulating, drying, second granulating, and total mixing.

[0054] According to an embodiment of the present application, the granulation in the component mixing step of the metformin layer is wet granulation.

[0055] According to an embodiment of the present application, the wet granulation comprises the following steps: mixing the components of the metformin layer or the components of the sitagliptin layer, and adding them into a wet granulator for wet granulation.

[0056] According to an embodiment of the present application, the coating material is used to coat the tablet core, and the parameters in the coating process include: coating machine speed: 2-20 rpm, peristaltic pump speed: 0-30 rpm, air inlet temperature: 35-60℃, tablet bed temperature: 28-40℃, air outlet temperature: 30-40℃, air inlet volume: 120-240 m 3 / h, pot negative pressure: -20~-40Pa, and drying time: 10-60 minutes.

[0057] Another aspect of the present application also relates to the use of the sitagliptin metformin pharmaceutical composition in the preparation of a type II diabetes drug. The sitagliptin metformin pharmaceutical composition comprises the embodiments of the first aspect described above. Since the use adopts all the technical solutions of the sitagliptin metformin pharmaceutical composition described above, it at least has all the beneficial effects brought by the technical solutions of the embodiments described above.

[0058] Additional aspects and advantages of the present application will be in part apparent and in part pointed out hereinafter in the description of the application. BRIEF DESCRIPTION OF DRAWINGS

[0059] The above and / or additional aspects and advantages of the present application will become apparent and be readily appreciated from the description of the embodiments, taken in conjunction with the following drawings in which: Figure 1 FIG. 1 is a structural schematic diagram of a sitagliptin metformin pharmaceutical composition. DETAILED DESCRIPTION

[0060] The words "preferred" and "preferably" in this disclosure refer to embodiments of the application that can provide certain benefits under certain circumstances. However, other embodiments can also be preferred under the same or other circumstances. Additionally, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude those other embodiments from the scope of the application.

[0061] When a range of values is disclosed herein, the range is to be construed as having endpoints that are included in the range, and each value within the range is also included in the range. Further, when a range is disclosed, the range is inclusive of the endpoints and all integer values between the endpoints. Additionally, where a range of values is provided, it is understood that the range is inclusive of any and all sub-ranges falling within the range. Merely listing the range is understood to be a shorthand for describing each and every sub-range within the range.

[0062] The term "treatment" means therapeutic or prophylactic treatment of a particular disease, condition, or disorder; attenuation, amelioration, or elimination of one or more symptoms associated with a particular disease, condition, or disorder; or prevention or delay of the onset of one or more symptoms of a particular disease, condition, or disorder described herein. In some embodiments, "treatment" refers to improvement in at least one physical parameter, which can not be perceptible to the patient. In other embodiments, "treatment" refers to modulation of the disease or condition physically (e.g., stabilization of a perceptible symptom), physiologically (e.g., stabilization of a physical parameter), or both.

[0063] As described herein, the pharmaceutically acceptable excipients of the application include, for example, any solvent, solid diluent, binder, disintegrant, or other liquid excipient, dispersant, flavoring agent or suspending agent, surface active agent, isotonic agent, thickening agent, emulsifying agent, preservative, solid binder, glidant or lubricant, and the like, suitable for the particular dosage form intended. The use of any of these excipients is contemplated by the application, except to the extent that any conventional excipient is incompatible with the compound of the application, for example, produces any adverse biological effect or interacts in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition.

[0064] Substances which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylate, waxes, polyethylene-polyoxypropylene- block polymers, wool fat, sugars such as lactose, glucose and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, powdered tragacanth, malt, gelatin, talc, excipients such as cocoa butter and suppository waxes, oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, glycols such as propylene glycol and polyethylene glycol, esters such as ethyl oleate and ethyl laurate, agar agar, buffering agents such as magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives and antioxidants.

[0065] The technical solutions in the embodiments of the present application will be apparently and completely described below in combination with the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all the other embodiments obtained by those skilled in the art without creative work fall within the scope of the present application.

[0066] The reagents, methods and devices used in the present application are conventional reagents, methods and devices in the technical field, unless otherwise specified.

[0067] Embodiment 1 A sitagliptin metformin pharmaceutical composition without antioxidant is a tablet, the size of which is 17.40 mm x 8.50 mm x 6.00 mm, and the tablet comprises a tablet core and a coating. The tablet core comprises a sitagliptin layer and a metformin layer which are stacked, wherein the thickness of the sitagliptin layer is about 1.8 mm, and the thickness of the metformin layer is about 3.9 mm. The sitagliptin layer and the metformin layer contain drug release channels, and the depth of the drug release channels is 1.5 mm, and the diameter of the drug release channels is 1.8 mm.

[0068] The components of the sitagliptin layer are shown in Table 1. Table 1

[0069] The components of the metformin layer are shown in Table 2. Table 2

[0070] The components of the above tablet core and coating are as shown in Table 3: Table 3

[0071] The method for preparing the above pharmaceutical composition comprises the following steps: Preparation of the sitagliptin total mixture: the sitagliptin raw material and microcrystalline cellulose, lactose are added into a wet granulator and mixed for 5 minutes to obtain a premix; the binder is dissolved in purified water, and after complete dissolution, the above premix is added to the binder solution for granulation for 3 minutes; a swing granulator is used for sizing, and the sizing screen mesh size is 24 meshes to obtain wet granules; the above wet granules are placed into a fluidized bed for drying at a temperature of 50°C; after drying, a swing granulator is used for sizing, and the sizing screen mesh size is 24 meshes; the sized granules are mixed with the lubricant for 10 minutes to obtain the first layer of the sitagliptin total mixture.

[0072] Preparation of the metformin hydrochloride total mixture: the raw material metformin hydrochloride is sieved using a swing granulator, and the screen mesh size is 80 meshes; the sieved raw material metformin hydrochloride is added into a wet granulator together with polyoxyethylene, carbomer and povidone and mixed for 5 minutes to obtain a premix; an alcohol-water solution is used as a wetting agent to granulate the premix for 3 minutes; a swing granulator is used for sizing to obtain wet granules, and the sizing screen mesh size is 24 meshes; the above wet granules are placed into a fluidized bed for drying at a temperature of 50°C; after drying, a swing granulator is used for sizing, and the sizing screen mesh size is 24 meshes; the sized granules are mixed with the lubricant for 10 minutes to obtain the second layer of the metformin hydrochloride total mixture.

[0073] Tabletting: the above sitagliptin total mixture and the above metformin hydrochloride total mixture are respectively placed into different hoppers of a double-layer tablet press, and tabletting is performed using a needle head for up-punching to obtain a double-layer tablet containing a tablet core; the above double-layer tablet has a first layer (upper layer) of the sitagliptin layer and a second layer (lower layer) of the metformin hydrochloride layer; the length of the needle head is 1.5 mm, and the diameter of the needle head is 1.8 mm; Preparation of the coating solution: the weighed purified water and acetone are mixed to obtain a 95% acetone solution, the weighed polyethylene glycol 3350 is added into the 95% acetone solution under stirring, and after complete dissolution, the weighed cellulose acetate is slowly added into the solution under stirring until a visually clear solution is obtained; Coating: The above double-layer tablet core is coated with coating liquid. The coating weight gain is 8-12%, and the coating parameters need to be adjusted according to the actual operation. The coating parameters are as follows: coating machine speed: 2-20 rpm, peristaltic pump speed: 0-30 rpm, air inlet temperature: 35-60℃, tablet bed temperature: 28-40℃, air outlet temperature: 30-40℃, air inlet volume: 120-240 m 3 / h, pot negative pressure: -20--40Pa, drying time: 10-60 minutes.

[0074] Example 2 A sitagliptin metformin pharmaceutical composition without antioxidant is a tablet with a size of 17.40mmx8.50mmx6.00mm, which comprises a tablet core and a coating. The tablet core comprises a sitagliptin layer and a metformin layer arranged in layers, wherein the thickness of the sitagliptin layer is about 1.5mm, and the thickness of the metformin layer is about 4.4mm. The sitagliptin layer and the metformin layer contain drug release channels, and the depth of the drug release channels is 3mm and the diameter is 1.8mm.

[0075] The components of the sitagliptin layer are shown in Table 4: Table 4

[0076] The components of the metformin layer are shown in Table 5: Table 5

[0077] The components of the tablet core and the coating are shown in Table 6: Table 6

[0078] The method for preparing the above pharmaceutical composition is the same as that of Example 1.

[0079] Example 3 A sitagliptin metformin pharmaceutical composition without antioxidant is a tablet with a size of 17.40mmx8.50mmx6.00mm, which comprises a tablet core and a coating. The tablet core comprises a sitagliptin layer and a metformin layer arranged in layers, wherein the thickness of the sitagliptin layer is about 1.6mm, and the thickness of the metformin layer is about 4.3mm. The sitagliptin layer and the metformin layer contain drug release channels, and the depth of the drug release channels is 1.5mm and the diameter is 0.8mm.

[0080] The components of the sitagliptin layer are shown in Table 7: Table 7

[0081] The components of the above-mentioned metformin layer are as shown in Table 8: Table 8

[0082] The components of the above-mentioned tablet core and coating are as shown in Table 9: Table 9

[0083] The method for preparing the above-mentioned pharmaceutical composition is the same as that of Example 1.

[0084] Example 4 A sitagliptin metformin pharmaceutical composition without antioxidant, which is a tablet, has a size of 17.40 mm x 8.50 mm x 6.00 mm, and comprises a tablet core and a coating; The above-mentioned tablet core comprises a sitagliptin layer and a metformin layer arranged in a stack, wherein the thickness of the sitagliptin layer is about 1.6 mm and the thickness of the metformin layer is about 4.3 mm. The above-mentioned sitagliptin layer and the above-mentioned metformin layer contain a drug release channel, and the depth of the above-mentioned drug release channel is 1.5 mm and the diameter is 1.8 mm.

[0085] The components of the above-mentioned sitagliptin layer are as shown in Table 10: Table 10

[0086] The components of the above-mentioned metformin layer are as shown in Table 11: Table 11

[0087] The components of the above-mentioned tablet core and coating are as shown in Table 12: Table 12

[0088] The method for preparing the above-mentioned pharmaceutical composition is the same as that of Example 1.

[0089] Comparative Example The comparative example is a sitagliptin metformin sustained-release tablet (JANUMET XR 50 / 500 mg) commercially available from Merck Sharp & Dohme Corp., and the size of the JANUMET XR 50 / 500 mg formulation is 20.6 mm x 10.3 mm x 6.6 mm, and the batch number is T041332.

[0090] Performance test: The in-vitro dissolution of the tablet cores in the sitagliptin metformin tablets of Examples 1-4 and the comparative examples was detected by the following test, and the detection object was metformin in the sitagliptin metformin tablets (tablets, including tablet cores and coatings).

[0091] The detection method referred to the dissolution determination method in the General Rules in the Chinese Pharmacopoeia 2020 Edition, and the paddle method (with a sinker) was adopted. The experimental conditions were set as follows: temperature 37°C, rotation speed 75 rpm, and 900 mL of pH 6.8 phosphate buffer as the medium. The drug release behavior was detected by the method, and the detection results are shown in Table 13.

[0092] Table 13

[0093] It can be known from Table 13 that the sitagliptin metformin tablets of the application can realize a similar metformin release behavior as in the reference formulation JANUMET XR through technical innovation, and both exhibit sustained release, and the effects are comparable.

[0094] The metformin hydrochloride total mixture prepared in Examples 1-4 was tableted by using respective corresponding needle specifications to obtain metformin hydrochloride tablet cores, and the cumulative release behavior of the metformin hydrochloride tablet cores in the reference formulation of the comparative examples was compared in pH 6.8 phosphate buffer medium, and the similarity factor f2 is shown in Table 14 below.

[0095] Table 14

[0096] The calculation formula of the similarity factor f2 is as follows: .

[0097] R t is the average dissolution amount of the reference formulation at the t time point; T t is the average dissolution amount of the generic formulation at the t time point; T is the sampling time point; n is the number of sampling time points.

[0098] It can be known from Table 14 that by adjusting the prescription composition and the punch size of the tablet press, the dissolution speed of metformin in Examples 1, 2 and 3 can be kept consistent. In Example 4, the dissolution speed of metformin is obviously faster, and the reason is that the permeability of the ethyl cellulose coating film in the coating component is significantly higher than that of the cellulose acetate, which leads to a significant weakening of the sustained release effect under the same coating weight conditions.

[0099] The dissolution curves of sitagliptin in the sitagliptin metformin sustained-release tablets of Examples 1-4 were detected, and the detection object was sitagliptin in the sitagliptin metformin tablets (tablets including tablet cores and coatings). The detection method adopted the paddle method, the medium was a buffer solution with pH 6.8, the rotation speed was 75 rpm, and the test results were as shown in Table 15: Table 15

[0100] From Table 15, it can be known that the release behaviors of metformin in the sitagliptin metformin sustained-release tablets of Examples 1-4 were similar to the release behavior of sitagliptin in the reference preparation JANUMET XR.

[0101] The dissolution behaviors of sitagliptin in the sitagliptin metformin sustained-release tablets (tablets including tablet cores and coatings) of Examples 1-4 were compared with the cumulative release of sitagliptin in the reference preparation in a phosphate buffer medium with pH 6.8. The results of the similarity factor f2 were as shown in Table 16: Table 16

[0102] From Table 16, it can be known that the release behaviors of sitagliptin in the sitagliptin metformin sustained-release tablets of Examples 1-4 were similar to the release behavior of sitagliptin in the reference preparation JANUMET XR, and both exhibited rapid release.

[0103] The content uniformity of sitagliptin in the sitagliptin metformin drugs prepared in Examples 1-4 was detected by high performance liquid chromatography, 10 samples were detected, and the results were as shown in Table 17. In Table 17, CU stands for content uniformity.

[0104] Table 17

[0105] From Table 17, it can be known that, because wet granulation was adopted in Examples 1-4, the content uniformity of sitagliptin in the drugs of Examples 1-4 was higher.

[0106] The sitagliptin metformin drugs prepared in Examples 1-4 were packaged respectively, and the change trend of impurities was investigated, and the test results were as shown in Table 18.

[0107] Table 18

[0108] From Table 18, it is known that in Examples 1-4, the total mixed granules of sitagliptin and metformin hydrochloride were prepared by the preparation method of the present application, and were compressed into double-layer tablets with pinholes. The upper layer of the double-layer tablet was provided with pinholes, and the length and size of the pinholes were controlled within a certain range, and the outer layer was coated. The stability study data show that, from the perspective of impurities, under the conditions of 1 month, 3 months and 6 months of acceleration, the drug prepared by the present application is equivalent to the reference preparation in the growth level of sitagliptin acid impurities and total impurities without adding antioxidant, indicating that the sitagliptin metformin hydrochloride sustained-release tablet drug prepared by the present application has good stability.

[0109] The above is only an embodiment of the present application, and does not limit the patent scope of the present application, and any equivalent transformation or direct or indirect application in the related technical field using the content of the present application is also included in the patent protection scope of the present application.

Claims

1. A pharmaceutical composition of sitagliptin and metformin, characterized by: The tablet core comprises a siglitin layer and a metformin layer which are arranged in a stack. The tablet core comprises a siglitin layer and a metformin layer which are arranged in a stack. The siglitin layer contains drug release channels. The components of the metformin layer include metformin and its pharmaceutically acceptable salts and swelling material.

2. The pharmaceutical composition of claim 1, wherein: The depth of the drug release channels is 1.5-3mm and the diameter is 0.8-1.8mm.

3. The pharmaceutical composition of claim 1, wherein: The components of the metformin layer further include sustained release material.

4. The pharmaceutical composition of claim 3, wherein: The sustained release material includes at least one of polyoxyethylene, acrylic resin, shellac, glyceryl behenate.

5. The pharmaceutical composition of claim 1, wherein: The swelling material includes at least one of povidone K90, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyoxyethylene, carbomer.

6. The pharmaceutical composition of claim 1, wherein: The metformin layer comprises the following components: metformin and its pharmaceutically acceptable salts; swelling material; and / or, sustained release material, and / or, osmotic active substance; and / or, binder; and / or, lubricant.

7. The pharmaceutical composition of claim 1, wherein: The siglitin layer comprises the following components: siglitin and its pharmaceutically acceptable salts; and / or, filler; and / or, binder; and / or, lubricant.

8. A process for the preparation of a pharmaceutical composition as claimed in any one of claims 1 to 7, characterized in that: The method comprises the following steps: mixing the components of the siglitin layer to obtain a siglitin mixture; mixing the components of the metformin layer to obtain a metformin mixture; tabletting the siglitin mixture and the metformin mixture and forming drug release channels on the siglitin layer obtained by tabletting; coating the tablet core with coating material to obtain the siglitin metformin pharmaceutical composition.

9. The pharmaceutical composition according to any one of claims 1 to 7, wherein the dosage form of the pharmaceutical composition comprises a tablet.

10. Use of the pharmaceutical composition according to any one of claims 1 to 7 in the preparation of a drug for type Ⅱ diabetes.

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