CN115813874B - Preparation method of oral three-way combined hypoglycemic double-release tablet and preparation thereof - Google Patents
Preparation method of oral three-way combined hypoglycemic double-release tablet and preparation thereof Download PDFInfo
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- 229960004329 metformin hydrochloride Drugs 0.000 claims abstract description 34
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to the technical field of pharmaceutical preparations, in particular to a preparation method of an oral three-way combined hypoglycemic double-release tablet and a preparation thereof. The preparation method of the invention comprises the following steps: s1, adopting wet granulation to treat an SGLT-2 inhibitor to prepare SGLT-2 inhibitor particles; s2, mixing the DPP-4 inhibitor with the SGLT-2 inhibitor particles prepared in the step S1 in a mode of adding outside to prepare a quick-release part; s3, adopting wet granulation to treat metformin hydrochloride to prepare a slow-release part; s4, pressing the quick release part and the slow release part into a plain tablet; s5, coating the tablet prepared in the step S4, and obtaining the tablet. The preparation method disclosed by the invention is simple in process, suitable for large-scale production, capable of reducing impurity content and improving the stability of the preparation. In addition, the double-release tablet prepared by the preparation method improves the proportion of active substances in the tablet layer, optimizes the tablet, ensures that patients can easily swallow the tablet, and improves the medication compliance.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a preparation method of an oral three-way combined hypoglycemic double-release tablet and a preparation thereof.
Background
Metformin (metformin, MET) is a first-line therapeutic recommended in a number of guidelines for diabetes treatment, improving glucose tolerance in type 2 diabetics and lowering basal and postprandial blood glucose. Metformin reduces hepatic glucose production, reduces glucose absorption from the intestinal tract by increasing peripheral glucose uptake and utilization, and increases insulin sensitivity. Metformin does not produce hypoglycemia, nor hyperinsulinemia, in type 2 diabetics or healthy subjects, except for special cases. Insulin secretion remained unchanged after metformin treatment, whereas fasting insulin levels and the whole day plasma insulin response could be reduced.
DPP 4 inhibitors are a class of oral hypoglycemic agents that block dipeptidyl peptidase 4 (DPP 4) and act by slowing the inactivation of incretins such as GLP 1 and GIP to increase their levels, thereby inhibiting glucagon secretion, increasing insulin secretion, and thus lowering blood glucose levels. Sitagliptin is the first DPP 4 inhibitor to be FDA approved in 2006. Other drugs in this class that are also FDA approved include saxagliptin, linagliptin, and alogliptin.
SGLT2 inhibitors are a class of drugs that inhibit glucose reabsorption by the kidneys, thereby lowering blood glucose. SGLT2 inhibitors act primarily by inhibiting sodium glucose transporter 2 (SGLT 2). The pharmaceutical agents of the drug class include canagliflozin, anggliflozin, enggliflozin, ergliflozin, isgliflozin, tolgliflozin, dapgliflozin, lu Gelie. Flozin, reggliflozin, sertgliflozin, and the like, and pharmaceutically acceptable salts thereof.
Studies have shown that for many type 2 diabetics, if an oral hypoglycemic agent of the type described above is used alone as an antidiabetic treatment, blood glucose cannot be adequately controlled during prolonged treatment. Therefore, a combination therapy of two or more oral hypoglycemic agents is generally employed to exert a synergistic hypoglycemic effect to better control blood glucose in type 2 diabetics. However, the combination of two or more oral hypoglycemic agents may lead to a complex treatment regimen that is difficult for many patients to follow. Therefore, the existing preferred dosage regimen is to combine two or more oral hypoglycemic agents into a single tablet without increasing the complexity of the patient's daily regimen, wherein the dual release tablet comprising the immediate release part and the sustained release part is the hot spot of the current study.
However, the existing three-party combined hypoglycemic oral double-release agent mostly adopts a coating and drug-loading 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 be effective in a quick-release mode, how to mix or combine the two medicaments in the quick-release part and in what form, so as to achieve good efficacy, good stability and the like have many points to be researched and improved. In addition, the existing three-party combined hypoglycemic oral medicine has the problem that the compliance of the patient taking the medicine is poor after meals in the morning when the taking time is fixed every day.
Disclosure of Invention
Aiming at the defects existing in the prior art, one of the purposes of the invention is to provide a preparation method of an oral three-part combined hypoglycemic double-release tablet, wherein the preparation comprises a drug-containing quick-release part and a drug-containing slow-release part, the active ingredients of the drug-containing quick-release part comprise SGLT-2 inhibitor and DPP-4 inhibitor, the active ingredients of the drug-containing slow-release part comprise metformin hydrochloride, and the preparation method comprises the following steps:
s1, adopting wet granulation to treat an SGLT-2 inhibitor to prepare SGLT-2 inhibitor particles;
S2, mixing the DPP-4 inhibitor with the SGLT-2 inhibitor particles obtained in the step S1 in a mode of adding outside to obtain drug particles containing a drug quick-release part;
s3, adopting wet granulation to treat metformin hydrochloride to prepare drug particles containing a drug sustained-release part;
S4, pre-pressing the drug particles of the drug-containing slow-release part obtained in the step S3, and then pressing the pre-pressed drug particles and the drug particles of the drug-containing quick-release part obtained in the step S2 together into 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 tablets obtained in the step S4.
Through the preparation process, the medicine-containing quick-release part and the medicine-containing slow-release part are in a double-layer tabletting structure in an up-down lamination mode.
Further, the drug-containing quick-release part comprises a first filler, a first adhesive, a first lubricant, a first glidant and a disintegrating agent, the drug-containing slow-release part also comprises a second filler, a second adhesive, a second lubricant, a second glidant and a slow-release material,
The step S1 is specifically that SGLT-2 inhibitor, a first filler and a first adhesive with the prescription amount required by the preparation of a quick-release part containing medicines are weighed, wet granulation, drying and sieving are carried out, and then the medicine granules of the SGLT-2 inhibitor are prepared;
Weighing DPP-4 inhibitor, disintegrating agent and first glidant with the prescription amount required by the preparation of the quick-release part containing medicine, mixing, adding the mixture into SGLT-2 inhibitor particles obtained in the step S1, adding first lubricant, and mixing again to obtain medicine particles of the quick-release part containing medicine;
the step S3 is specifically to weigh the metformin hydrochloride with the prescription amount required by the preparation of the drug-containing slow-release part, add a second filler and a second adhesive, carry out wet granulation, screen, dry, screen again, add a slow-release material and a second glidant, mix, add a second lubricant, mix again, and prepare the drug particles of the drug-containing slow-release part.
The invention also aims to provide the oral three-way combined hypoglycemic double-release tablet prepared by the method.
In the preparation method or the preparation prepared according to the preparation method, the ratio of the SGLT-2 inhibitor in the drug-containing quick-release part to the drug-containing quick-release part is 1:50-1:10 by weight; and/or, the ratio of the DPP-4 inhibitor in the drug-containing quick-release part to the drug-containing quick-release part is 1:10-1:3 by weight; and/or the ratio of the guanidine hydrochloride in the drug-containing slow-release part to the drug-containing slow-release part is 1:5-1:1.3 by weight.
Further, in the preparation method or the preparation prepared according to the preparation method, the ratio of the SGLT-2 inhibitor to the DPP-4 inhibitor is 1:20-1:1.2 by weight; and/or, the ratio of the SGLT-2 inhibitor to the metformin hydrochloride is 1:300-1:10 by weight; and/or, the ratio of the DPP-4 inhibitor to the metformin hydrochloride is 1:50-1:2 by weight.
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, ai Tuoge gliflozin 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 one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, croscarmellose sodium, calcium carboxymethylcellulose, 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 above preparation method or the preparation prepared according to the above preparation method, the content of the disintegrant in the preparation is 0.5 to 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 to 5% by weight; and/or the sum of the first filler and the second filler is 15-35% by weight of 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 0.1-3% by weight of the formulation.
Compared with the prior art, the invention has the beneficial effects that (1) a novel double-release tablet preparation method is provided, a double-layer tablet structure is adopted, the process is simple and convenient, and the method is suitable for commercial expansion production; (2) The oral three-way combined hypoglycemic double-release tablet is prepared by adopting an SGLT-2 inhibitor wet granulation method at a quick release part and then mixing the SGLT-2 inhibitor wet granulation method with a DPP-4 inhibitor dry method in an external addition mode, so that the impurity content of the oral three-way combined hypoglycemic double-release tablet is reduced, and the stability is improved. (3) The proportion of active ingredients in the tablet layer is adjusted, so that the tablet is optimized, the tablet is easy to swallow by a patient, and the compliance of the patient is improved; (4) Combines the advantages of quick release and sustained release dosage forms, can quickly take effect, can continuously and stably release after taking medicine, and reduces adverse reaction; (5) The prepared oral three-way solid preparation can be taken at any time, and has stronger maneuverability and higher patient compliance.
Drawings
FIG. 1 is a flow chart of a process for preparing a drug-containing immediate release layer according to an embodiment of the invention.
Fig. 2 is a flowchart of a preparation process of a drug-containing sustained-release layer according to an embodiment of the present invention.
Fig. 3 is a process flow chart of the preparation of the drug-containing immediate release layer of comparative example 4 of the present invention.
Fig. 4 is a sitagliptin dissolution profile of example 1 and comparative example 4 of the present invention.
Fig. 5 is a sitagliptin dissolution profile of example 3 and comparative example 3 of the present invention.
Fig. 6 is a graph of the dissolution profiles of englitazone of example 1 and comparative example 4 of the present invention.
Fig. 7 is a graph of the dissolution profiles of englitazone of example 2 and comparative example 2 of the present invention.
Fig. 8 is a graph showing the dissolution profiles of metformin hydrochloride in example 1 and comparative example 1 of the present invention.
Fig. 9 is a graph showing the dissolution profiles of metformin hydrochloride in example 1 and comparative example 5 of the present invention.
Fig. 10 is a graph showing the dissolution profiles of metformin hydrochloride in example 6 and comparative example 7 of the present invention.
FIG. 11 is a graph showing the dissolution profiles of metformin hydrochloride in example 7 and comparative example 8 of the present invention.
Detailed Description
The invention firstly provides a preparation method of an oral three-part combined hypoglycemic double-release tablet, the preparation is a double-layer tablet, the preparation comprises a drug-containing quick-release layer and a drug-containing slow-release layer which are stacked up and down, the active ingredients of the drug-containing quick-release layer comprise SGLT-2 inhibitor and DPP-4 inhibitor, the active ingredients of the drug-containing slow-release layer comprise metformin hydrochloride, the drug-containing quick-release layer comprises a first filler, a first adhesive, a first lubricant, a first glidant and a disintegrating agent, 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, the first filler and the first adhesive with the prescription amounts required by the preparation of the drug-containing quick release layer, performing wet granulation, drying and sieving to obtain the drug granules of the SGLT-2 inhibitor.
In some specific 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 sieving, and in preferred embodiments, the mesh size of the sieve is 0.18-0.38 mm.
In some specific embodiments, in the step S1, drying is carried out by adopting an oven after wet granulation, wherein the drying temperature is 45-55 ℃, and the water content of the final product is less than or equal to 3.0%; the dry granule is sieved, and the preferable mesh diameter is 0.5 mm-0.7 mm.
S2, weighing the DPP-4 inhibitor, the disintegrating agent and the first glidant with the required prescription amount for preparing the drug-containing quick-release layer, mixing, adding the mixture into the drug particles of the SGLT-2 inhibitor obtained in the step S1, adding the first lubricant, and mixing again to prepare the drug particles of the drug-containing quick-release layer.
In the invention, DPP-4 is directly mixed with granulated SGLT-2 particles 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, so that the impurity content can be reduced, and the stability of the preparation is improved.
In some embodiments, in step S2, the DPP-4 inhibitor, the disintegrating agent and the first glidant are mixed and then screened, wherein the pore diameter of the screen is 0.15-0.38 mm, and preferably, the particle diameter of the DPP-4 inhibitor after screening is less than or equal to 0.25mm.
S3, weighing the metformin hydrochloride with the prescription amount required by the preparation of the drug-containing slow-release layer, adding a second filler and a second adhesive, performing wet granulation by using purified water, performing wet granulation, sieving, drying, sieving again, adding a slow-release material and a second glidant in an external adding mode, mixing, adding a second lubricant, and mixing again to obtain the drug particles of the drug-containing slow-release layer.
In some specific embodiments, in the step S3, the metformin hydrochloride is subjected to crushing pretreatment, the mesh diameter of the screen during the crushing and sieving treatment is 0.3-0.8 mm, and preferably, the particle diameter D90 of the metformin hydrochloride is less than or equal to 130 μm after the sieving treatment;
in some specific embodiments, in the step S3, the aperture of the screen is 2.0-4.0 mm when wet-finishing particles pass through 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%;
Preferably, in the step S3, before the slow release material and the second glidant are added, the two materials are screened, the aperture of a screen is 0.38-0.83 mm, and the screened materials are uniformly mixed with the dry granules of the metformin hydrochloride.
S4, placing the drug particles of the drug-containing slow release layer obtained in the step S3 in a die of a tablet press in a prescription amount, and prepressing; then placing the drug particles of the drug-containing quick-release layer obtained in the step S2 in a prescribed amount into a die of a tablet press, and pressing into a plain tablet;
In a preferred embodiment, the tablet pressed in step S4 is a special-shaped tablet, in particular an oval tablet, and the ratio of the major to the minor diameters of the oval tablet is 1.8:1-2.2:1. After the treatment of the step S4, the drug-containing quick-release layer and the drug-containing slow-release layer are double-layer tabletting with an upper-lower laminated structure.
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 mono-diglyceride, sodium dodecyl sulfate, talcum powder and ferric oxide, and is prepared by dissolving the coating components into coating liquid when the specific coating treatment is carried out, and then the coating liquid is used for carrying out the coating treatment on the plain tablet obtained in the step S4.
In some embodiments, the plain tablet obtained in step S4 is directly packaged in a sealed manner without a coating process.
The invention also provides the oral three-part combined hypoglycemic double-release tablet prepared by the method, wherein the ratio of the SGLT-2 inhibitor in the drug-containing quick-release layer to the drug-containing quick-release layer is 1:50-1:10 by weight; and/or, the ratio of the DPP-4 inhibitor in the drug-containing quick-release layer to the drug-containing quick-release layer is 1:10-1:3 by weight; and/or the ratio of the guanidine hydrochloride in the drug-containing slow-release layer to the drug-containing slow-release layer is 1:5-1:1.3 by weight.
The ratio of the SGLT-2 inhibitor to the DPP-4 inhibitor is 1:20-1:1.2 by weight, preferably, the ratio of the SGLT-2 inhibitor to the DPP-4 inhibitor is 1:20-1:2 or 1:20-1:3 or 1:20-1:8 or 1:20-1:15 or 1:15-1:1.2 or 1:15-1:2 or 1:15-1:3 or 1:15-1:8 or 1:10-1:1.2 or 1:10-2 or 1:10-3 or 1:8-1:1.2 or 1:8-1:2 or 1:8-1:3 by weight.
The oral three-part combined hypoglycemic double-release tablet of some specific embodiments has a ratio of SGLT-2 inhibitor to metformin hydrochloride of 1:300-1:10 by weight; preferably, the ratio of the oral pharmaceutical composition SGLT-2 inhibitor to metformin hydrochloride is 1:300-1:20 or 1:300-1:60 or 1:300-1:150 or 1:300-1:230 or 1:230-1:20 or 1:230-1:60 or 1:230-1:150 or 1:150-1:20 or 1:150-1:60 or 1:60-1:20 by weight.
The oral three-part combined hypoglycemic double-release tablet of some specific embodiments has a ratio of DPP-4 inhibitor to metformin hydrochloride of 1:50-1:2 by weight; preferably, the ratio of the DPP-4 inhibitor to the metformin hydrochloride of the oral pharmaceutical composition is 1:50-1:6 or 1:50-1:15 or 1:50-1:35 or 1:35-1:2 or 1:35-1:6 or 1:35-1:15 or 1:15-1:2 or 1:15-1:6 by weight.
In some preparation method embodiments or embodiments of the oral three-way combined hypoglycemic dual-release tablet, the SGLT-2 inhibitor is one or more of dapagliflozin, engagliflozin, canagliflozin, ai Tuoge gliflozin, 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 disintegrating agent is one or more selected from low-substituted hydroxypropyl cellulose, croscarmellose sodium, calcium carboxymethyl cellulose, 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 disintegrating agent in the double-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 content of the sum of the first lubricant and the second lubricant in the double release tablet is 0.5-5% 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 content of the sum of the first binder and the second binder in the dual release tablet is 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 exemplary embodiments according to the present application. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.
The invention will now be further illustrated with reference to specific examples, which are given solely for the purpose of illustration and are not to be construed as limiting the invention. The test specimens and test procedures used in the following examples include those (if the specific conditions of the experiment are not specified in the examples, generally according to conventional conditions or according to the recommended conditions of the reagent company; the reagents, consumables, etc. used in the examples described below are commercially available unless otherwise specified).
Example 1
TABLE 1 example prescription one
In example 1, the ratio of metformin hydrochloride to slow release layer by weight was 1:1.87; the ratio of Enagliflozin (SGLT-2) to the immediate release layer was 1:21.81, and the ratio of sitagliptin phosphate monohydrate (DPP-4) to the immediate release layer was 1:3.86.
The preparation process of example 1 specifically comprises the following steps:
A. weighing 11g of enggliflozin, 137.75g of microcrystalline cellulose PH101 and 8g of hydroxypropyl cellulose HPC-L required for preparing a drug-containing quick release layer, uniformly mixing for later use, granulating by using purified water in a wet method, drying, granulating, and sieving;
B. 62.25g of sitagliptin phosphate monohydrate, 15g of crospovidone and 1.2g of colloidal silicon dioxide are added in an external adding mode to be mixed, and then 4.8g of magnesium stearate is added to be mixed to prepare quick-release layer particles for later use;
C. weighing 530g of metformin hydrochloride required for preparing a drug-containing slow-release layer, crushing, adding 87g of microcrystalline cellulose PH102 and 35g of povidone K30, performing wet granulation by using purified water, wet finishing, sieving, drying, sieving again, adding 320g of hydroxypropyl methylcellulose K100M and 5g of talcum powder, mixing, and adding 13g of sodium stearyl fumarate, mixing to prepare slow-release layer particles for later use;
D. Placing the prescription amount of drug-containing slow-release layer particles into a die of a tablet press, and prepressing; and then the prescription amount of the drug-containing quick-release layer particles are placed in a die of a tablet press to be pressed into a plain tablet.
E. and D, weighing a prescribed amount of gastric-soluble film coating to prepare coating liquid, and coating the plain tablets obtained in the step D.
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 recipe one
The comparative example formula one adjusts the ratio of metformin hydrochloride in the slow release layer compared to the example formula one, the ratio of metformin hydrochloride to slow release layer is 1:9.9, the ratio of enggliflozin (SGLT-2) to metformin hydrochloride is 1:9.09, and the ratio of sitagliptin phosphate monohydrate (DPP-4) to metformin hydrochloride is 1:1.61 by weight.
The preparation procedure of comparative example 1 was identical to that of example 1.
Example 2
TABLE 3 example prescriptions two
Example 2 was identical to the preparation process of example 1, with the main difference that in example two, the ratio of metformin hydrochloride to slow release layer by weight was 1:1.94; the ratio of Enagliflozin (SGLT-2) to the immediate release layer was 1:20.83, and the ratio of sitagliptin phosphate monohydrate (DPP-4) to the immediate release layer was 1:3.91.
Comparative example 2
TABLE 4 comparative example recipe two
Compared with the second prescription of the example 2, the second prescription of the comparative example 2 mainly adjusts the ratio of the enggliflozin (SGLT-2) in the quick release layer, wherein the ratio of the enggliflozin to the quick release layer is 1:83.3 by weight, and the ratio of the enggliflozin to the metformin hydrochloride is 1:171.67 the ratio of engagliflozin to sitagliptin phosphate monohydrate is 1:21.33.
Comparative example 2 was identical to the preparation process flow of example 1.
Example 3
TABLE 5 example prescription III
Example 3 was consistent with the preparation process flow of example 1. The main difference is that in the third formulation of example 3, the ratio of metformin hydrochloride to slow release layer is 1:2.07 by weight; the ratio of the Enagliflozin (SGLT-2) to the immediate release layer was 1:20, and the ratio of the sitagliptin phosphate monohydrate (DPP-4) to the immediate release layer was 1:3.33.
Comparative example 3
TABLE 6 comparative recipe III
Comparative example 3 formulation three essentially adjusts the ratio of sitagliptin phosphate monohydrate (DPP-4) to the immediate release layer compared to example 3 formulation three, the ratio of sitagliptin phosphate monohydrate (DPP-4) to the immediate release layer being 1:2.12 by weight.
Comparative example 3 was identical to the preparation process flow of example 1.
Example 4
TABLE 7 example prescriptions four
In example 4, formulation IV, the ratio of sitagliptin phosphate monohydrate (DPP-4) to immediate release layer is 1:6.47 by weight.
Example 4 corresponds to the preparation process of example 1.
Example 5
TABLE 8 example prescription five
In example prescription five, the ratio of sitagliptin phosphate monohydrate (DPP-4) to immediate release layer was 1:9.33 by weight.
Example 5 was consistent with the preparation process flow of example 1.
Comparative example 4
The material composition and the material consumption of the prescription (the fourth prescription of the comparative example) of the comparative example are completely identical with those of the example 1, and the preparation method is different from the preparation method of the example 1 in that the preparation process of the engagliflozin and the sitagliptin phosphate monohydrate of the comparative example 4 adopts a wet granulation method.
The preparation process flow of the quick release layer of comparative example 4 is shown in fig. 3, and the preparation process flow of the slow release layer of comparative example 4 is shown in fig. 2.
Comparative example 5
The recipe of comparative example 5 (comparative example recipe five) is different from example 1 in that the slow-release material "hydroxypropyl methylcellulose K100M" in the slow-release layer is replaced by "hydroxypropyl methylcellulose K15M", and the other components, the dosage and the preparation process are completely identical, so as to examine the influence of different slow-release materials on the dissolution rate of metformin hydrochloride in the slow-release agent.
Comparative example 5 was identical to the preparation process flow of example 1.
Comparative example 6
The formulation of comparative example 6 (comparative example formulation six) 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", the remaining components, amounts and preparation process being completely identical in order to investigate the effect of different fillers on parameters such as stability of the formulation, impurities etc.
Comparative example 6 was identical to the preparation process flow of example 1.
Example 6
TABLE 9 example prescription six
In the sixth embodiment, the sustained release material, hydroxypropyl methylcellulose K100M, comprises 17.86% by weight of the formulation.
The tablet obtained in example 6 was not subjected to film coating, and the rest was the same as the preparation process flow in example 1.
Comparative example 7
TABLE 10 comparative example recipe seven
The formulation of comparative example 7 (comparative example formulation seven) differs from example 6 mainly in that the weight ratio of the slow-release material is adjusted, and the slow-release material, hydroxypropyl methylcellulose K100M, accounts for 5.95% of the formulation by weight.
Comparative example 7 was identical to the preparation process flow of example 6.
Example 7
TABLE 11 example prescription seven
In the seventh embodiment, the second lubricant sodium stearyl fumarate in the sustained-release layer accounts for 1.57% of the total weight of the oral three-way hypoglycemic double-release tablet according to the invention.
Example 7 was consistent with the preparation process flow of example 1.
Comparative example 8
TABLE 12 comparative example recipe eight
The formulation of comparative example 8 (comparative example eight) differs from example 7 mainly in that the ratio of the second lubricant in the sustained-release layer was adjusted, and the second lubricant sodium stearyl fumarate in the sustained-release layer accounted for 0.16% by weight of the total weight of the oral three-way hypoglycemic double-release tablet.
Comparative example 8 was identical to the preparation process flow of example 1.
Example 8
Dissolution rate test
Dissolution conditions were 37 ℃ + -0.5 ℃, slurry method (sedimentation basket), 75rpm, pH phosphate buffer, 900ml.
The dissolution requirement of sitagliptin (sitagliptin phosphate monohydrate) is 0.25h, and the dissolution rate is 60% -80%; 0.75h, and the dissolution rate is more than 80%.
Engliflozin dissolution requirement: 0.25h, the dissolution rate is 80-90%; 0.75h, and the dissolution rate is more than 90 percent.
Guanidine hydrochloride diformate dissolution requirement: 4h, the dissolution rate is 60% -70%; and the dissolution rate is more than 90% after 10 hours.
TABLE 13 dissolution test of sitagliptin (sitagliptin phosphate monohydrate)
The dissolution rate curves of different prescriptions of sitagliptin (sitagliptin phosphate monohydrate) are shown in fig. 4 and 5.
TABLE 13 Engliflozin dissolution test
The dissolution rate curves of different prescriptions of englitz are shown in fig. 6 and 7.
TABLE 13 dissolution test of guanidine hydrochloride
The dissolution rate curves of guanidine hydrochloride for different formulations are shown in FIGS. 8-11.
Example 9
Stability test
The method comprises determining impurity content of different formulations
TABLE 14 stability test case
The difference between comparative example 4 and examples 1, 4 and 5 is that in the preparation process of the drug-containing quick-release layer of comparative example 4, the effective components of sitagliptin and engagliptin are all prepared by adopting a wet granulation mode; the preparation process of the quick-release layer of the embodiment is that the alogliptin is subjected to wet granulation, then dried, granulated and sieved, and the sitagliptin phosphate monohydrate is added in a mode of adding the sitagliptin phosphate monohydrate outside, and the medicament-containing quick-release layer of the oral three-way combined hypoglycemic double-release tablet is prepared after mixing, wherein the process of granulating the sitagliptin phosphate monohydrate is not needed, and the preparation process flow is simplified.
As can be seen from the test results in Table 14, examples 1,4 and 5 each reduced the impurity content of the final product formulation and improved the stability of the formulation as compared with comparative example 4.
In addition, in the process of the pharmaceutical preparation, coating and drug application are complex and difficult processes, the requirements on parameters are strict, and more experience is required to accumulate.
It should be understood that the foregoing examples of the present invention are merely illustrative of the present invention and are not intended to limit the present invention to the specific embodiments thereof. Any modification, equivalent replacement, improvement, etc. that comes 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 (6)
1. The oral three-way combined hypoglycemic double-release tablet is characterized by comprising a drug-containing quick-release part and a drug-containing slow-release part, wherein the drug-containing quick-release part comprises engagliflozin, sitagliptin phosphate monohydrate, a first filler, a first adhesive, a first lubricant, a first glidant and a disintegrating agent, and the drug-containing slow-release part comprises metformin hydrochloride, a second filler, a second adhesive, a second lubricant, a second glidant and a slow-release material;
The method comprises the steps that the ratio of the engagliflozin in a drug-containing quick-release part to the drug-containing quick-release part is 1:50-1:10, the ratio of the sitagliptin phosphate monohydrate in the drug-containing quick-release part to the drug-containing quick-release part is 1:10-1:3, the ratio of the guanidine hydrochloride in the drug-containing slow-release part to the drug-containing slow-release part is 1:5-1:1.3, the ratio of the engagliflozin to the sitagliptin phosphate monohydrate is 1:20-1:1.2, the ratio of the engagliflozin to the metformin hydrochloride is 1:300-1:10, and the ratio of the sitagliptin phosphate monohydrate to the metformin hydrochloride is 1:50-1:2;
the preparation method of the oral three-part combined hypoglycemic double-release tablet comprises the following steps:
s1, weighing the required prescription amount of the englitz powder, the first filler and the first adhesive for preparing the quick-release part containing the medicine, performing wet granulation, drying and sieving to obtain the englitz powder;
S2, weighing the sitagliptin phosphate monohydrate, the disintegrating agent and the first glidant with the amounts of the prescription required for preparing the quick-release part containing the medicine, mixing, adding the mixture into the englitjing particles obtained in the step S1, adding the first lubricant, and mixing again to prepare the medicine particles of the quick-release part containing the medicine;
S3, weighing the metformin hydrochloride with the prescription amount required by the preparation of the drug-containing slow-release part, adding a second filler and a second adhesive, performing wet granulation, sieving, drying, sieving again, adding a slow-release material and a second glidant, mixing, adding a second lubricant, and mixing again to obtain drug particles of the drug-containing slow-release part;
S4, pre-pressing the drug particles of the drug-containing slow-release part obtained in the step S3, and then pressing the pre-pressed drug particles and the drug particles of the drug-containing quick-release part obtained in the step S2 together into a plain tablet;
S5, coating the plain tablets obtained in the step S4, and then sealing and packaging; or directly sealing and packaging the plain tablets obtained in the step S4.
2. The oral three-part combined hypoglycemic double-release tablet according to claim 1, wherein in the step S1, the mesh diameter is 0.4-0.8 mm when sieving, and in the step S2, the particle diameter of the sitagliptin phosphate monohydrate 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.
3. The oral three-part combined hypoglycemic dual-release tablet according to claim 1, wherein in step S5, the coating is a film coating.
4. The oral three-part combined hypoglycemic double-release tablet according to any one of claims 1-3, wherein the oral three-part 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 three-part combined hypoglycemic double-release tablet is an elliptic tablet with the ratio of the length to the diameter of 1.8:1-2.2:1.
5. The oral three-way combined hypoglycemic dual-release tablet according to any one of claims 1-3, wherein the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, croscarmellose sodium, calcium carboxymethylcellulose, 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.
6. The oral three-way combined hypoglycemic double-release tablet according to any one of claims 1-3, wherein the content of the disintegrating agent in the oral three-way combined hypoglycemic double-release tablet is 0.5-5% by weight; and/or, the content of the slow-release material in the oral three-way combined hypoglycemic double-release tablet is 15-35% by weight; and/or, the content of the sum of the first lubricant and the second lubricant in the oral three-way combined hypoglycemic double-release tablet is 0.5-5% by weight; and/or, the content of the sum of the first filler and the second filler in the oral three-way combined hypoglycemic double-release tablet is 15-35% by weight; and/or, the content of the sum of the first adhesive and the second adhesive in the oral three-way combined hypoglycemic double-release tablet is 1-5% by weight; and/or the content of the sum of the first glidant and the second glidant in the oral three-way combined hypoglycemic double-release tablet is 0.1-3% by weight.
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| WO2024263130A1 (en) * | 2023-06-19 | 2024-12-26 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A pharmaceutical formulation comprising linagliptin, metformin and a sglt-2 inhibitor |
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| CN114010612A (en) * | 2021-11-24 | 2022-02-08 | 上海普康药业有限公司 | Sitagliptin and metformin double-layer sustained release tablet and preparation method thereof |
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| CN115297847A (en) * | 2020-03-30 | 2022-11-04 | 韩美药品株式会社 | Compound tablet for oral administration comprising sitagliptin, dapagliflozin and metformin |
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