CN115813874A

CN115813874A - Preparation method of oral three-part combined hypoglycemic double-release tablet and preparation thereof

Info

Publication number: CN115813874A
Application number: CN202211710867.7A
Authority: CN
Inventors: 鲁华; 常利丽; 司俊仁; 赵晨旭
Original assignee: Transocean Pharmaceutical Development Guangzhou Co ltd
Current assignee: Transocean Pharmaceutical Development Guangzhou Co ltd
Priority date: 2022-12-29
Filing date: 2022-12-29
Publication date: 2023-03-21

Abstract

The invention relates to the technical field of medicinal preparations, in particular to a preparation method of an oral three-party combined hypoglycemic double-release tablet and a preparation thereof. The preparation method comprises the following steps: s1, processing an SGLT-2 inhibitor by adopting wet granulation to prepare SGLT-2 inhibitor particles; s2, mixing the DPP-4 inhibitor and the SGLT-2 inhibitor particles prepared in the step S1 in an external addition mode to prepare a quick-release part; s3, processing the metformin hydrochloride by adopting wet granulation to prepare a slow-release part; s4, pressing the quick-release part and the slow-release part into plain tablets; and S5, coating the plain tablets prepared in the step S4. The preparation method provided by the invention is simple in process, is suitable for large-scale production, reduces the impurity content, and improves the preparation stability. In addition, the double-release tablet prepared by the preparation method improves the active substance proportion in the tablet layer, optimizes the tablet type, enables a patient to swallow the tablet easily, and improves the medication compliance.

Description

Preparation method of oral three-part combined hypoglycemic double-release tablet and preparation thereof

Technical Field

The invention relates to the technical field of medicinal preparations, in particular to a preparation method of an oral three-party combined hypoglycemic double-release tablet and a preparation thereof.

Background

Metformin (MET) is a first-line therapeutic recommended by many guidelines for diabetes treatment, improving glucose tolerance, lowering basal and postprandial blood glucose in type 2 diabetic patients. Metformin reduces hepatic glucose production, reduces intestinal glucose absorption, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Except in special cases, metformin does not produce hypoglycemia in type 2 diabetic patients or healthy subjects, nor does it lead to hyperinsulinemia. Insulin secretion remains unchanged after metformin treatment, while fasting insulin levels and full-day plasma insulin response may decrease.

DPP 4 inhibitors are a class of oral hypoglycemic agents that block dipeptidyl peptidase 4 (DPP 4) and act by slowing the inactivation of incretin hormones (such as GLP 1 and GIP) to increase their levels, thereby inhibiting glucagon secretion, increasing insulin secretion, and thereby lowering blood glucose levels. Sitagliptin is the first DPP 4 inhibitor that obtained FDA approval in 2006. Other drugs in this class that have also gained FDA approval include saxagliptin, linagliptin, and alogliptin.

SGLT2 inhibitors are a class of drugs that inhibit the reabsorption of glucose by the kidney, thereby lowering blood glucose. SGLT2 inhibitors act primarily by inhibiting sodium glucose transporter 2 (SGLT 2). Agents of this pharmaceutical class include canagliflozin, eggliflozin, engagliflozin, ergagliflozin, ivagliflozin, tolagliflozin, dapagliflozin, luagliflozin, regagliflozin, sjogrezin, and the like, and pharmaceutically acceptable salts thereof.

Studies have shown that for many type 2 diabetic patients, if the above-mentioned class of oral hypoglycemic agents is used alone as antidiabetic therapy, adequate blood glucose control is not achieved during long-term treatment. Therefore, a combination therapy of two or more oral hypoglycemic agents is usually employed to exert a synergistic hypoglycemic effect, thereby better controlling the blood glucose in type 2 diabetic patients. However, the co-prescription of two or more oral hypoglycemic agents may lead to a complex treatment regimen that is difficult for many patients to follow. Therefore, the currently preferred drug regimen is to combine two or more oral hypoglycemic agents into a single tablet without increasing the complexity of the daily treatment regimen for patients, and among them, a dual-release tablet comprising a quick-release part and a slow-release part is the focus of current research.

However, the existing three-way combined hypoglycemic oral dual-release agent mostly adopts a coating medicine application mode in the preparation process, has complex process and is not beneficial to large-scale production. Meanwhile, because both the DPP-4 inhibitor and the SGLT-2 inhibitor are required to act in a quick release manner, there are many points to be researched and improved on how to match, in what form, or combine the two drugs in the quick release portion to achieve good drug effect, good stability, and the like. In addition, the existing three-party combined hypoglycemic oral medicine has the problem of poor compliance of patients taking the medicine after meals every morning.

Disclosure of Invention

Aiming at the defects in the prior art, one of the purposes of the invention is to provide a preparation method of an oral tripartite combined hypoglycemic double-release tablet, wherein the preparation comprises a quick-release part containing medicine and a slow-release part containing medicine, active ingredients of the quick-release part containing medicine comprise SGLT-2 inhibitor and DPP-4 inhibitor, and active ingredients of the slow-release part containing medicine comprise metformin hydrochloride, and the preparation method comprises the following steps:

s1, processing an SGLT-2 inhibitor by adopting wet granulation to prepare SGLT-2 inhibitor particles;

s2, mixing the DPP-4 inhibitor with the SGLT-2 inhibitor particles obtained in the step S1 in an external addition mode to obtain medicine particles containing a quick-release part;

s3, processing metformin hydrochloride by adopting wet granulation to prepare medicine granules containing a medicine slow-release part;

s4, prepressing the medicine particles of the medicine-containing slow-release part obtained in the step S3, and then pressing the medicine particles of the medicine-containing quick-release part obtained in the step S2 together to obtain a plain tablet;

s5, coating the plain tablets obtained in the step S4, and then sealing and packaging; and/or, directly sealing and packaging the plain film obtained in the step S4.

Through the preparation process, the quick release part containing the medicine and the slow release part containing the medicine are in a double-layer tabletting structure in an up-down laminating mode.

Further, the quick-release part containing the medicine comprises a first filler, a first adhesive, a first lubricant, a first glidant and a disintegrant, the slow-release part containing the medicine also comprises a second filler, a second adhesive, a second lubricant, a second glidant and a slow-release material,

s1, weighing the SGLT-2 inhibitor, a first filler and a first adhesive which are required by prescription amount for preparing the medicine-containing quick-release part, and carrying out wet granulation, drying and sieving to prepare medicine particles of the SGLT-2 inhibitor;

s2, weighing the DPP-4 inhibitor, the disintegrant and the first glidant which are required by prescription for preparing the medicine-containing quick-release part, mixing, adding the mixture into the SGLT-2 inhibitor particles obtained in the step S1, adding the first lubricant, and mixing again to prepare the medicine particles containing the medicine-containing quick-release part;

and the step S3 is specifically that metformin hydrochloride in the amount required by the prescription for preparing the drug-containing slow-release part is weighed, a second filling agent and a second adhesive are added, wet granulation is carried out, sieving is carried out, drying is carried out, sieving is carried out again, a slow-release material and a second glidant are added, mixing is carried out, a second lubricant is added, mixing is carried out again, and the drug granules of the drug-containing slow-release part are prepared.

The invention also aims to provide the oral three-party combined hypoglycemic double-release tablet prepared by the method.

In the above preparation method or the preparation prepared according to the above preparation method, the ratio of the SGLT-2 inhibitor in the drug-containing quick-release part to the drug-containing quick-release part is 1 to 1; and/or the ratio of the DPP-4 inhibitor in the quick release part containing the medicine to the quick release part containing the medicine is 1 to 10-1; and/or the ratio of the guanidine hydrochloride in the drug-containing slow-release part to the drug-containing slow-release part is 1 to 5-1.3.

Further, in the above preparation method or the preparation prepared according to the above preparation method, the ratio of the SGLT-2 inhibitor to the DPP-4 inhibitor is 1; and/or, the ratio of the SGLT-2 inhibitor to the metformin hydrochloride is 1; and/or the ratio of the DPP-4 inhibitor to metformin hydrochloride is 1.

Further, in the above preparation method or the preparation prepared according to the above preparation method, the SGLT-2 inhibitor is one or more of dapagliflozin, engagliflozin, canagliflozin, etogliflozin or a pharmaceutically acceptable salt thereof; and/or the DPP-4 inhibitor is one or more of sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin or a pharmaceutically acceptable salt thereof.

Further, in the above preparation method or the preparation prepared according to the above preparation method, the disintegrant is selected from one or more of low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethylcellulose calcium, crospovidone, and pregelatinized starch; and/or the slow release material is selected from one or more of hypromellose, xanthan gum, sodium alginate, carbomer and polyethylene oxide; and/or the first lubricant and the second lubricant are respectively selected from one or more of talcum powder, hydrogenated vegetable oil, sodium stearyl fumarate and magnesium stearate; and/or the first filler and the second filler are respectively selected from one or more of microcrystalline cellulose, mannitol, starch and pregelatinized starch; and/or the first glidant and the second glidant are respectively selected from one or more of colloidal silicon dioxide or talcum powder.

Further, in the preparation method or the preparation prepared according to the preparation method, the content of the disintegrant in the preparation is 0.5-5% by weight; and/or, the content of the slow release material in the preparation is 15-35% by weight; and/or the sum of the first and second lubricants is present in the formulation in an amount of 0.5 to 5% by weight; and/or, the sum of the first filler and the second filler is 15-35% by weight in the formulation; and/or, the sum of the first binder and the second binder is present in the formulation in an amount of 1-5% by weight; and/or the sum of the first glidant and the second glidant is present in the formulation in an amount of 0.1 to 3% by weight.

Compared with the prior art, the invention has the advantages that (1) the novel double-release tablet preparation method is provided, the double-layer tablet structure is adopted, the process is simple and convenient, and the method is suitable for commercial expanded production; (2) The quick-release part is prepared by adopting an SGLT-2 inhibitor wet granulation method and then mixing the granules with a DPP-4 inhibitor by an external addition method, so that the impurity content of the oral triple-effect hypoglycemic double-release tablet is reduced, and the stability is improved. (3) The tablet type is optimized by adjusting the proportion of active ingredients in the tablet layer, so that the tablet is easy to swallow by a patient and the compliance of the patient is improved; (4) The advantages of quick-release and slow-release dosage forms are combined, after the medicine is taken, the medicine can quickly take effect, can be continuously and stably released, and reduces adverse reactions; (5) The prepared oral three-part solid preparation can be taken at any time, has stronger maneuverability and higher patient compliance.

Drawings

FIG. 1 is a flow chart of the process for preparing a rapid-release layer containing a drug according to an embodiment of the present invention.

FIG. 2 is a flow chart of the process for preparing a sustained-release layer containing a drug according to an embodiment of the present invention.

FIG. 3 is a flow chart of the process for preparing the immediate release layer containing a drug in comparative example 4 of the present invention.

Fig. 4 is a dissolution rate profile of sitagliptin according to example 1 and comparative example 4 of the present invention.

Fig. 5 is a dissolution rate profile of sitagliptin according to example 3 and comparative example 3 of the present invention.

Fig. 6 is a dissolution profile of engagliflozin of example 1 of the invention and comparative example 4.

Fig. 7 is a graph showing dissolution profiles of engagliflozin of example 2 of the present invention and comparative example 2.

Fig. 8 is a graph showing the dissolution profiles of metformin hydrochloride according to example 1 and comparative example 1 of the present invention.

Figure 9 is a graph of the dissolution profile of metformin hydrochloride according to example 1 and comparative example 5 of the present invention.

Figure 10 is a graph of the dissolution profile of metformin hydrochloride according to example 6 and comparative example 7 of the present invention.

FIG. 11 is a graph showing the dissolution profiles of metformin hydrochloride of example 7 and comparative example 8 according to the present invention.

Detailed Description

The invention firstly provides a preparation method of an oral three-way combined hypoglycemic double-release tablet, the preparation is a double-layer tablet and comprises a drug-containing quick release layer and a drug-containing slow release layer which are stacked up and down, active ingredients of the drug-containing quick release layer comprise an SGLT-2 inhibitor and a DPP-4 inhibitor, active ingredients of the drug-containing slow release layer comprise metformin hydrochloride, wherein the drug-containing quick release layer comprises a first filler, a first adhesive, a first lubricant, a first glidant and a disintegrant, the drug-containing slow release layer further comprises a second filler, a second adhesive, a second lubricant, a second glidant and a slow release material, and the preparation method specifically comprises the following steps:

s1, weighing the SGLT-2 inhibitor, a first filling agent and a first adhesive which are required by prescription amounts for preparing a quick release layer containing the medicine, performing wet granulation, drying, and sieving to prepare the medicine particles of the SGLT-2 inhibitor.

In some embodiments, in step S1, the SGLT-2 inhibitor, the first filler, and the first binder need to be subjected to a pretreatment process, specifically including a sieving process, and in a preferred embodiment, the mesh has a pore size of 0.18 to 0.38mm.

In some embodiments, in step S1, after wet granulation, drying is performed in an oven, wherein the drying temperature is 45 ℃ to 55 ℃, and the water content of the final product is less than or equal to 3.0%; and (4) sieving the dry whole granules, wherein the preferred mesh size is 0.5 mm-0.7 mm.

S2, weighing the DPP-4 inhibitor, the disintegrant and the first glidant in the amount required by the prescription for preparing the quick release layer, mixing, adding the mixture into the SGLT-2 inhibitor medicine particles obtained in the step S1, adding the first lubricant, and mixing again to prepare the medicine particles containing the quick release layer.

In the invention, DPP-4 is directly mixed with the granulated SGLT-2 granules without complicated granulating steps, so that the preparation process is simplified, and experimental tests show that the quick-release part is prepared by adding DPP-4 externally, so that the impurity content can be reduced, and the preparation stability is improved.

In some embodiments, in step S2, the DPP-4 inhibitor, the disintegrant and the first glidant are mixed and sieved, wherein the mesh size of the mesh is 0.15 to 0.38mm, and preferably, the particle size of the DPP-4 inhibitor after sieving is less than or equal to 0.25mm.

S3, weighing metformin hydrochloride in the amount required by the prescription for preparing the drug-containing slow release layer, adding a second filler and a second adhesive, performing wet granulation by using purified water, sieving wet whole granules by using a sieve, drying, sieving dry whole granules by using the sieve again, adding a slow release material and a second glidant in an external adding mode, mixing, adding a second lubricant, and mixing again to prepare the drug granules containing the drug-containing slow release layer.

In some embodiments, in step S3, the metformin hydrochloride is subjected to a pulverization pretreatment, and the mesh size of the sieving treatment after pulverization is 0.3mm to 0.8mm, preferably, the particle size D90 of the metformin hydrochloride after sieving treatment is not more than 130 μm;

in some embodiments, in step S3, the mesh size of the wet whole granules is 2.0mm to 4.0mm when the granules are screened by the screen;

preferably, fluidized bed drying is adopted, the air inlet temperature is 55-65 ℃, and the water content of the final product is less than or equal to 2.0 percent;

preferably, in step S3, before the slow release material and the second glidant are added, the two materials are sieved to have a mesh size of 0.38-0.83 mm, and then the sieved materials are uniformly mixed with the dried granules of metformin hydrochloride.

S4, placing the medicine particles containing the medicine slow-release layer obtained in the step S3 in the prescription amount into a punch die of a tablet press, and prepressing; then, the medicine particles containing the quick release layer obtained in the step S2 are placed in a punch die of a tablet machine according to the prescription amount, and are pressed into plain tablets;

in a preferred embodiment, the tablet compressed in step S4 is a heteromorphic tablet, specifically an oval tablet, and the ratio of the length to the diameter of the oval tablet is 1.8. And (4) after the treatment of the step (S4), forming a double-layer tabletting with an upper-layer laminated structure and a lower-layer laminated structure by the medicine-containing quick-release layer and the medicine-containing slow-release layer.

And S5, coating the plain tablets obtained in the step S4.

In some embodiments, in step S5, the coating is a film coating, preferably a gastric-soluble film coating. The coating comprises polyvinyl alcohol, titanium dioxide, caprylic/capric acid monoglyceride and diglyceride, sodium dodecyl sulfate, talcum powder and iron oxide, and when the coating is specifically treated, the coating components are dissolved to prepare a coating solution, and then the coating solution is used for coating the plain tablets obtained in the step S4.

In some embodiments, the plain tablet obtained in step S4 is directly packaged in a sealed package without being coated.

The invention also provides an oral tripartite combined hypoglycemic double-release tablet prepared by the method, wherein the ratio of the SGLT-2 inhibitor in the quick release layer containing the medicine to the quick release layer containing the medicine is 1; and/or the ratio of the DPP-4 inhibitor in the quick release layer containing the medicine to the quick release layer containing the medicine is 1 to 10-1; and/or the ratio of guanidine hydrochloride in the drug-containing slow release layer to the drug-containing slow release layer is 1 to 5-1.3.

Wherein, the ratio of the SGLT-2 inhibitor to the DPP-4 inhibitor is 1.

According to the oral tri-combined hypoglycemic double-release tablets of some specific embodiments, the ratio of the SGLT-2 inhibitor to the metformin hydrochloride is 1 to 300-1; preferably, the ratio of the oral pharmaceutical composition SGLT-2 inhibitor to metformin hydrochloride is 1.

According to the oral triple-component combined hypoglycemic double-release tablets of some specific embodiments, the ratio of the DPP-4 inhibitor to metformin hydrochloride is 1; preferably, the ratio of the oral pharmaceutical composition DPP-4 inhibitor to metformin hydrochloride is 1.

In some method of preparation embodiments or oral triple combination hypoglycemic dual release tablets, the SGLT-2 inhibitor is one or more of dapagliflozin, engagliflozin, canagliflozin, etogliflozin or a pharmaceutically acceptable salt thereof; and/or the DPP-4 inhibitor is one or more of sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin or a pharmaceutically acceptable salt thereof; the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, croscarmellose sodium, carboxymethylcellulose calcium, crospovidone and pregelatinized starch; and/or the slow release material is selected from one or more of hypromellose, xanthan gum, sodium alginate, carbomer and polyethylene oxide; and/or the first lubricant and the second lubricant are respectively selected from one or more of talcum powder, hydrogenated vegetable oil, sodium stearyl fumarate and magnesium stearate; and/or the first filler and the second filler are respectively selected from one or more of microcrystalline cellulose, mannitol, starch and pregelatinized starch; and/or the first glidant and the second glidant are respectively selected from one or more of colloidal silicon dioxide or talcum powder.

Preferably, the content of the disintegrant in the dual release tablet is 0.5-5%; and/or, the content of the slow release material in the double-release tablet is 15-35% by weight; and/or, the sum of the first lubricant and the second lubricant is contained in the double release tablet in an amount of 0.5 to 5% by weight; and/or, the content of the sum of the first filler and the second filler in the dual release tablet is 15-35% by weight; and/or, the sum of the first binder and the second binder is present in the dual release tablet in an amount of 1-5% by weight; and/or the content of the sum of the first glidant and the second glidant in the double-release tablet is 0.1-3% by weight.

It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.

The present invention will now be further described with reference to specific examples, which are provided for the purpose of illustration only and are not to be construed as limiting the invention. The test samples and test procedures used in the following examples include the following (generally, according to the conventional conditions or according to the conditions recommended by the reagent company if the specific conditions of the experiment are not specified in the examples; and reagents, consumables and the like used in the following examples are commercially available unless otherwise specified).

Example 1

TABLE 1 example recipe I

In example 1, the ratio of metformin hydrochloride to the sustained-release layer was 1.87 by weight; the ratio of the engagliflozin (SGLT-2) to the quick release layer is 1.

The preparation process of example 1 specifically includes the following steps:

A. weighing 11g of empagliflozin, 137.75g of microcrystalline cellulose PH101 and 8g of hydroxypropyl cellulose HPC-L required for preparing a quick release layer containing the medicine, uniformly mixing for later use, performing wet granulation by using purified water, drying, grading and sieving;

B. adding 62.25g of sitagliptin phosphate monohydrate, 15g of crospovidone and 1.2g of colloidal silicon dioxide in an external addition mode, mixing, adding 4.8g of magnesium stearate, and mixing to prepare quick-release layer granules for later use;

C. weighing 530g of metformin hydrochloride required for preparing a drug-containing sustained release layer, crushing, adding 87g of microcrystalline cellulose PH102 and 35g of povidone K30, performing wet granulation by using purified water, performing wet granulation on the granules, sieving the granules by using a sieve, drying, performing dry granulation on the granules by using the sieve again, adding 320g of hydroxypropyl methyl cellulose K100M and 5g of talcum powder, mixing, adding 13g of sodium stearyl fumarate, and preparing sustained release layer granules for later use;

D. placing the drug-containing sustained-release layer particles in the prescription amount in a punch die of a tablet press, and prepressing; then the medicine-containing quick-release layer particles with the prescription amount are placed in a punch die of a tablet machine and pressed into plain tablets.

E. And D, weighing the stomach-soluble film coating according to the prescription amount to prepare coating liquid, and coating the plain tablets obtained in the step D.

Wherein, the preparation process flow of the quick release layer is shown in figure 1, and the preparation process flow of the slow release layer is shown in figure 2.

Comparative example 1

TABLE 2 comparative example formula I

Compared with the first formula of the embodiment, the first formula of the comparative example adjusts the ratio of the metformin hydrochloride in the sustained-release layer, the ratio of the metformin hydrochloride to the sustained-release layer is 1.

The preparation process of comparative example 1 was identical to example 1.

Example 2

TABLE 3 example prescription two

The preparation process flow of the embodiment 2 is consistent with that of the embodiment 1, and the main difference is that in the second formula of the embodiment, the ratio of the metformin hydrochloride to the sustained-release layer is 1.94 by weight; the ratio of the engeletin (SGLT-2) to the immediate release layer is 1.

Comparative example 2

TABLE 4 comparative example formula II

Compared with the second prescription in example 2, the second prescription in comparative example 2 mainly adjusts the ratio of the empagliflozin (SGLT-2) in the quick release layer, wherein the ratio of the empagliflozin to the quick release layer is 1:171.67, ratio of engeletin to sitagliptin phosphate monohydrate 1:21.33.

comparative example 2 is in accordance with the preparation process of example 1.

Example 3

TABLE 5 example prescription three

Example 3 is in accordance with the preparative flow of example 1. The main difference lies in that in the third prescription in the embodiment 3, the ratio of the metformin hydrochloride to the sustained-release layer is 1; the ratio of exenatide (SGLT-2) to the immediate release layer is 1.

Comparative example 3

TABLE 6 COMPARATIVE EXAMPLE FORMULATION III

Compared with the formulation III in the example 3, the formulation III in the comparative example 3 mainly adjusts the ratio of the sitagliptin phosphate monohydrate (DPP-4) in the quick release layer, and the ratio of the sitagliptin phosphate monohydrate (DPP-4) to the quick release layer is 1.

Comparative example 3 is in accordance with the preparation process of example 1.

Example 4

TABLE 7 example recipe four

Example 4 in formula four, the ratio of sitagliptin phosphate monohydrate (DPP-4) to immediate release layer was 1.

Example 4 is in accordance with the preparative flow of example 1.

Example 5

TABLE 8 example prescription five

In the fifth example, the ratio of sitagliptin phosphate monohydrate (DPP-4) to immediate release layer was 1.

Example 5 is in accordance with the preparative flow of example 1.

Comparative example 4

The formula (formula four) of the comparative example has the same material composition and dosage as those of the example 1, and is different from the example 1 in that the preparation method of the engagliflozin phosphate monohydrate and the preparation method of the sitagliptin phosphate monohydrate of the comparative example 4 adopt a wet granulation method.

Wherein, the process flow of the preparation of the quick release layer of the comparative example 4 is shown in fig. 3, and the process flow of the preparation of the slow release layer of the comparative example 4 is shown in fig. 2.

Comparative example 5

The formula of the comparative example 5 (formula five of the comparative example) is different from the formula of the example 1 in that the sustained-release material 'hydroxypropyl methyl cellulose K100M' in the sustained-release layer is replaced by 'hydroxypropyl methyl cellulose K15M', and the other components, the dosage and the preparation process are completely consistent, so that the influence of different sustained-release materials on the dissolution rate of the metformin hydrochloride in the sustained-release agent is examined.

Comparative example 5 is in accordance with the preparation process flow of example 1.

Comparative example 6

The formulation of comparative example 6 (sixth formulation of comparative example) differs from example 1 in that the filler "microcrystalline cellulose PH 101-amount 137.75mg" in the immediate release layer was replaced by a combination of "microcrystalline cellulose PH 102-amount 70mg" and "lactose monohydrate G200-amount 67.76mg", and the remaining components, amounts and preparation processes were completely identical, in order to examine the effect of different fillers on the stability of the formulation, impurities and other parameters.

Comparative example 6 is in accordance with the preparation process flow of example 1.

Example 6

TABLE 9 example prescription six

In the sixth formula of the embodiment, the sustained-release material hydroxypropyl methyl cellulose K100M accounts for 17.86% of the preparation by weight.

The plain tablets obtained in example 6 were not subjected to film coating, and the preparation process was otherwise identical to that of example 1.

Comparative example 7

TABLE 10 COMPARATIVE EXAMPLE seventy

The formula of comparative example 7 (formula seven) is different from that of example 6 mainly in that the weight ratio of the sustained-release material is adjusted, and the sustained-release material hydroxypropyl methylcellulose K100M accounts for 5.95% of the preparation by weight.

Comparative example 7 is in accordance with the preparation process of example 6.

Example 7

TABLE 11 example recipe seven

In the seventh formula of the embodiment, the second lubricant, namely sodium stearyl fumarate, in the sustained-release layer accounts for 1.57% of the total weight of the oral triple hypoglycemic double-release tablet.

Example 7 is in accordance with the preparative flow of example 1.

Comparative example 8

TABLE 12 comparative example recipe eight

The formulation of comparative example 8 (eighth formula of comparative example) is different from that of example 7 mainly in that the proportion of the second lubricant in the sustained-release layer is adjusted, and the second lubricant sodium stearyl fumarate in the sustained-release layer accounts for 0.16 percent of the total weight of the oral three-way hypoglycemic double-release tablet.

Comparative example 8 is in accordance with the preparation process of example 1.

Example 8

Dissolution rate test

Dissolution conditions 37 ℃. + -. 0.5 ℃ slurry method (settling basket), 75rpm, pH phosphate buffer, 900ml.

The dissolution requirement of sitagliptin (sitagliptin phosphate monohydrate) is 0.25h, and the dissolution rate is 60-80 percent; 0.75h, the dissolution rate is more than 80%.

The dissolution requirement of the empagliflozin is as follows: the dissolution rate is 80-90% within 0.25 h; the dissolution rate is more than 90 percent after 0.75 h.

The dissolution requirement of the guanidine hydrochloride is as follows: 4h, the dissolution rate is 60-70%; the dissolution rate is more than 90 percent within 10 hours.

TABLE 13 sitagliptin (sitagliptin phosphate monohydrate) dissolution test

The dissolution rate curves of different formulations of sitagliptin (sitagliptin phosphate monohydrate) are shown in fig. 4 and fig. 5.

TABLE 13 Empagliflozin dissolution test

The net dissolution rate curves for different prescriptions of engelia are shown in fig. 6 and 7.

TABLE 13 dissolution test of guanidine HCl

The dissolution rate curves of guanidine hydrochloride of different prescriptions are shown in fig. 8-11.

Example 9

Stability test

The method comprises detecting impurity content of different preparations

TABLE 14 stability test conditions

Wherein, the difference between the comparative example 4 and the examples 1, 4 and 5 is that the active ingredients of sitagliptin and engagliflozin are both prepared in a wet granulation mode in the process of preparing the quick release layer containing the medicine in the comparative example 4; the preparation process of the quick release layer in the embodiment is that the engeletin is subjected to wet granulation, then the dry granulation and the sieving are carried out, and the sitagliptin phosphate monohydrate is added in an external adding mode and mixed to prepare the drug-containing quick release layer of the oral tripartite combined hypoglycemic double release tablet, wherein the sitagliptin phosphate monohydrate does not need a granulation process, so that the preparation process flow is simplified.

As shown in Table 14, the impurity content of the final product preparation can be reduced and the stability of the preparation can be improved in examples 1, 4 and 5 compared with comparative example 4.

In addition, in the process of pharmaceutical preparation, coating and medicine application are a complex and difficult process, the requirements on parameters are strict, and more experience is needed to accumulate.

It should be understood that the above-mentioned embodiments of the present invention are only examples for clearly illustrating the technical solutions of the present invention, and are not intended to limit the specific embodiments of the present invention. Any modification, equivalent replacement, and improvement made within the spirit and principle of the claims of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. The preparation method of the oral tripartite combined hypoglycemic double-release tablet is characterized in that the preparation comprises a quick-release part containing medicine and a slow-release part containing medicine, the quick-release part containing medicine comprises SGLT-2 inhibitor and DPP-4 inhibitor, the slow-release part containing medicine comprises metformin hydrochloride, and the preparation method comprises the following steps:

s2, mixing the DPP-4 inhibitor and the SGLT-2 inhibitor particles obtained in the step S1 in an external addition mode to prepare medicine particles containing a quick-release part;

s3, processing the metformin hydrochloride by adopting wet granulation to prepare medicine granules containing a medicine slow-release part;

s5, coating the plain tablets obtained in the step S4, and then sealing and packaging; and/or directly carrying out sealing packaging on the plain sheet obtained in the step S4.

2. The preparation method according to claim 1, wherein the drug-containing immediate-release part further comprises a first filler, a first binder, a first lubricant, a first glidant and a disintegrant, and the drug-containing sustained-release part further comprises a second filler, a second binder, a second lubricant, a second glidant and a sustained-release material;

the step S1 specifically comprises the following steps: weighing the SGLT-2 inhibitor, a first filler and a first adhesive which are required by the prescription amount for preparing the medicine-containing quick-release part, and carrying out wet granulation, drying and sieving to prepare SGLT-2 inhibitor particles;

the step S2 specifically comprises the following steps: weighing the DPP-4 inhibitor, the disintegrant and the first glidant in the amount required by the prescription for preparing the quick-release part containing the medicine, mixing, adding the mixture into the SGLT-2 inhibitor particles obtained in the step S1, adding the first lubricant, and mixing again to prepare medicine particles of the quick-release part containing the medicine;

the step S3 specifically comprises the following steps: weighing metformin hydrochloride in the required prescription amount for preparing the drug-containing sustained-release part, adding a second filler and a second adhesive, performing wet granulation, sieving, drying, sieving again, adding a sustained-release material and a second glidant, mixing, adding a second lubricant, mixing again, and preparing the drug granules of the drug-containing sustained-release part.

3. The preparation method according to claim 2, wherein in step S1, the aperture of the screen during sieving is 0.4-0.8 mm, and in step S2, the particle size of the DPP-4 inhibitor is less than or equal to 0.25mm; and/or in the step S3, the particle size D90 of the metformin hydrochloride is less than or equal to 130 mu m.

4. The method of claim 2, wherein in step S5, the coating is a film coating.

5. The preparation method according to any one of claims 1 to 4, wherein the oral tripartite combined hypoglycemic double-release tablet is a double-layer tablet formed by stacking the drug-containing quick-release part and the drug-containing slow-release part up and down; and/or the oral tripartite combined hypoglycemic double-release tablet is an oval tablet with the ratio of the length to the diameter being 1.8.

6. The oral tripartite combined hypoglycemic double-release tablet prepared by the preparation method of any one of claims 2 to 5, wherein the ratio of the SGLT-2 inhibitor in the drug-containing quick-release part to the drug-containing quick-release part is 1 to 50-1; and/or the ratio of the DPP-4 inhibitor in the quick release part containing the medicine to the quick release part containing the medicine is 1 to 10-1; and/or the ratio of the guanidine hydrochloride in the drug-containing slow-release part to the drug-containing slow-release part is 1 to 5-1.3.

7. The oral triple-effect glucose-reducing double-release tablet according to claim 6, wherein the ratio of the SGLT-2 inhibitor to the DPP-4 inhibitor is 1 to 20-1.2 by weight; and/or, the ratio of the SGLT-2 inhibitor to the metformin hydrochloride is 1; and/or, the ratio of the DPP-4 inhibitor to the metformin hydrochloride is 1.

8. The oral triple combination hypoglycemic dual release tablet according to claim 6, wherein the SGLT-2 inhibitor is one or more of dapagliflozin, engagliflozin, canagliflozin, etogliflozin or a pharmaceutically acceptable salt thereof; and/or the DPP-4 inhibitor is one or more of sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin or a pharmaceutically acceptable salt thereof.

9. The oral triple combination hypoglycemic dual-release tablet according to claim 6, wherein the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, croscarmellose sodium, carboxymethylcellulose calcium, crospovidone, and pregelatinized starch; and/or the slow release material is selected from one or more of hypromellose, xanthan gum, sodium alginate, carbomer and polyethylene oxide; and/or the first lubricant and the second lubricant are respectively selected from one or more of talcum powder, hydrogenated vegetable oil, sodium stearyl fumarate and magnesium stearate; and/or the first filler and the second filler are respectively selected from one or more of microcrystalline cellulose, mannitol, starch and pregelatinized starch; and/or the first glidant and the second glidant are respectively selected from one or more of colloidal silicon dioxide or talcum powder.

10. The oral triple-effect glucose-reducing double-release tablet according to claim 6, wherein the content of the disintegrant in the preparation is 0.5-5% by weight; and/or, the content of the slow release material in the preparation is 15-35% by weight; and/or, the sum of the first lubricant and the second lubricant is present in the formulation in an amount of 0.5-5% by weight; and/or, the sum of the first filler and the second filler is 15-35% by weight in the formulation; and/or, the sum of the first binder and the second binder is present in the formulation in an amount of 1-5% by weight; and/or the sum of the first glidant and the second glidant is present in the formulation in an amount of 0.1 to 3% by weight.