Metformin hydrochloride enteric-coated tablet

Abstract

The invention provides a metformin hydrochloride enteric-coated tablet, which is composed of a tablet core containing a therapeutically effective amount of metformin hydrochloride and an enteric coating layer wrapping the tablet core, and the dissolution rate of the metformin hydrochloride of the enteric-coated tablet in a medium with a pH value of 4.5 within 2 hours is not higher than 15%, and the dissolution rate of the metformin hydrochloride of the enteric-coated tablet in a medium with a pH value of 6.8 within 20 minutes is not lower than 85%. The metformin hydrochloride enteric-coated tablet with specific drug release technical requirements is obtained by selecting the tablet core disintegration time limit, the enteric coating material starting point and the coating weight increment, and compared with a metformin hydrochloride common preparation (such as Glycidan) and enteric-coated tablets with other release characteristics, the metformin hydrochloride enteric-coated tablet has the advantages that the effect of reducing blood glucose is greatly improved under the condition that the blood glucose reducing effect is not reduced; the tolerance and the compliance of the metformin hydrochloride are improved.

Description

Technical Field

[0001] The invention provides a metformin hydrochloride enteric-coated tablet, which is a delayed-release preparation and belongs to the field of pharmaceutical preparations. Background Art

[0002] Metformin is an oral biguanide hypoglycemic drug, and its hydrochloride, namely metformin hydrochloride, is commonly used clinically. In the early days, it was believed that the main mechanism of metformin's hypoglycemic effect was the systemic effect produced after the drug was absorbed, such as inhibiting gluconeogenesis, reducing liver glucose output, acting on peripheral tissues (muscle, fat), promoting glucose utilization, and improving insulin sensitivity; recent studies have found that the intestinal mediated mechanism produced by unabsorbed drugs (such as increasing GLP-1 and PYY levels, affecting intestinal flora, and inhibiting intestinal wall cells from taking up glucose) may be more important.

[0003] In the diabetes diagnosis and treatment guidelines formulated by many countries and international organizations, metformin hydrochloride is recommended as the first-line drug for controlling hyperglycemia in patients with type 2 diabetes and as the basic drug in combination therapy. Glucophage (metformin hydrochloride tablets) is the original product of metformin, with many years of clinical application experience and sufficient evidence-based medicine. It is the standard treatment drug for type 2 diabetes at home and abroad and the most commonly used control drug in clinical trials.

[0004] However, some adverse reactions of metformin restrict its use. Some patients cannot tolerate these adverse reactions and have to stop taking the drug. The main adverse reactions of metformin include gastrointestinal reactions, such as diarrhea, nausea, vomiting, abdominal distension, abdominal pain, indigestion, abdominal discomfort, etc.; nervous system adverse reactions, such as dizziness and headache; in addition, it can also cause flu-like symptoms and vitamin B12 absorption disorders, and may also cause some rare but more serious adverse reactions, such as lactic acidosis. Gastrointestinal adverse reactions (such as nausea, abdominal pain, abdominal discomfort, etc.) are the most common adverse reactions of metformin, with an incidence of 20-30%, and are also the most common cause of patient intolerance.

[0005] In order to reduce the adverse reactions caused by the use of metformin, there are many studies and reports on its enteric-coated preparations in the prior art. Enteric-coated preparations refer to preparations that do not release or almost do not release the drug in the stomach within a specified time, but can release most or all of the drug in a certain part of the intestine after entering the intestine.

[0006] Early studies and reports on enteric-coated metformin hydrochloride preparations, such as CN101190179B, only focused on whether the drug was not released or almost not released in 0.1 mol / L hydrochloric acid, and whether it was completely released in pH 6.8 phosphate buffer. Later related studies and reports, such as CN101785763B, disclosed enteric-coated sustained-release tablets of metformin hydrochloride, which released about 30% of the drug in 1 hour, about 50% in 3 hours, and more than 85% in 10 hours in pH 6.8 phosphate buffer, claiming that the sustained release of the drug improved the bioavailability and avoided the toxic side effects that may be caused by excessive blood drug concentration in a short period of time; CN102357088A disclosed an enteric-coated metformin hydrochloride preparation that was rapidly released in pH 5.5-6.8 buffers, and the release was maintained above 80% even in a pH 5.5 phosphate buffer for 45 minutes, claiming that it could avoid drug-induced adverse reactions, and the rapid release characteristics made it The product can ensure effective release in intestinal fluid with a pH value of 5.5-6.8 and can more effectively ensure the clinical efficacy of the product; CN106420653A discloses metformin hydrochloride enteric-coated tablets with a dissolution amount of 20-30% in pH 6.8 phosphate buffer in 1 hour, 45-55% in 2 hours, and more than 85% in 4 hours, claiming to have low adverse reactions and be suitable for patients with contraindications to metformin; CN111888339A discloses metformin hydrochloride enteric-coated tablets which release more than 85% in pH 4.5-5.0 buffer in only 15-30 minutes, have rapid release and high release rate, claiming to have improved bioavailability and be bioequivalent to the original drug. The enteric-coated metformin hydrochloride preparations disclosed and reported in these prior arts, in addition to meeting the common requirements that enteric-coated preparations do not release or almost release no drugs in acidic media of pH 1.0-3.0, and release most or all of the drugs in buffered salt media of pH 6.8, have further release requirements (such as the speed or degree of release in the medium, etc.) and the therapeutic effects achieved by the claimed enteric-coated preparations. The prior arts report that some of them are rapid release to ensure efficacy and / or safety, and some are sustained release to ensure efficacy and / or safety, which are obviously contradictory to each other and lack further verification of efficacy and / or safety.

[0007] In addition, ELCELYX THERAPEUTICS, INC. disclosed in WO2013103384A, WO2013103919A, and WO2014107617A an enteric-coated preparation of metformin hydrochloride, which is a delayed release preparation (DR) intended to push the drug to the distal small intestine to release the active drug, thereby improving the gastrointestinal tolerance of the biguanide compound and reducing the adverse events caused by the biguanide compound. WO2013103384A and WO2013103919A disclose an enteric-coated preparation of metformin hydrochloride that is similar to a conventional preparation having an equal amount of the biguanide compound, namely an immediate-release preparation (DR). WO2014107617A discloses an enteric-coated oral dosage form containing a biguanide compound, which lasts for at least about 5 or 10 minutes after contacting a pH of 6.0, 6.5, 6.8 or 7.0, preferably for at least about 15 or 20 minutes after contacting a desired pH, and more preferably for at least about 25 or 30 minutes after contacting a pH of 6.0, 6.5, 6.8 or 7.0. 0 minute lag period; in a preferred embodiment, the enteric coated oral dosage form containing a biguanide compound releases less than 15% of the biguanide compound at acidic pH for two hours and at least ten minutes or fifteen minutes lag period at pH 6.8, releases at least 60% of the biguanide compound after the lag period and within 60 minutes at pH 6.8, and releases at least 90% of the biguanide compound within 90 to 120 minutes at pH 6.8; in another preferred embodiment, the enteric coated oral dosage form containing a biguanide compound releases less than 15%, 10% or 5% of the biguanide compound at acidic pH for two hours, at pH 5.5 for 30 minutes, and at least ten minutes or fifteen minutes lag period at pH 6.8, releases at least 60% of the biguanide compound after the lag period and within 60 minutes at pH 6.8, and releases at least 90% of the biguanide compound within 90 to 120 minutes at pH 6.8.

[0008] The enteric-coated preparation of metformin hydrochloride (delayed-release preparation; DR) disclosed in prior art such as WO2014107617A claims that its hypoglycemic efficacy is no less than that of the same dose of ordinary metformin hydrochloride tablets, i.e., immediate-release preparation (IR), and even has an increased efficacy. Moreover, compared with the IR preparation, the DR preparation of metformin hydrochloride reduces the relative bioavailability and systemic exposure of the drug, improves the gastrointestinal tolerance of the drug, and reduces adverse drug events. However, in these studies, the glucose-lowering efficacy was evaluated by fasting plasma glucose (FPG) or GLP-1, PYY, etc., which have poor accuracy, especially when the number of cases is small. Therefore, the glucose-lowering efficacy of metformin hydrochloride DR preparations described is difficult to be confirmed clinically. For example, Elcelyx later conducted a 16-week clinical study on metformin hydrochloride DR preparations with an expanded number of cases (see Robert R. Henry et al., Improved glycemic control with minimal systemic metformin exposure: Effects of Metformin Delayed-Release (Metformin DR) targeting the lower bowel over 16 weeks in a randomized trial in subjects with type 2 diabetes, PLOS Pharmacol. ONE, published on September 25, 2018, https: / / doi.org / 10.1371 / journal.pone.0203946), and used the clinically recognized gold standard glycosylated hemoglobin (HbA1c) as the evaluation index. The results showed that the metformin hydrochloride DR preparation prepared by the technical solution disclosed in its patent document failed to show the expected clinical effect. In a 16-week clinical trial, the best dosing regimen, that is, giving patients metformin hydrochloride DR every morning, DR 1500mg had a much lower hypoglycemic efficacy than the control group metformin hydrochloride IR 2000mg (regular administration according to the instructions, 1000mg each morning and evening), and the reduction in efficacy was greater than the reduction in dosage. Summary of the invention

[0009] In another patent application filed by the applicant on the same day, the applicant recorded that the invention research surprisingly found that the enteric-coated preparation of metformin hydrochloride with the following specific drug release technical requirements can produce the best therapeutic effect and the lowest adverse reaction, namely: the solubility of metformin hydrochloride in a pH 4.5 medium within 2 hours is not higher than 15%, and the solubility of metformin hydrochloride in a pH 6.8 medium within 20 minutes is not less than 85%, more preferably, the solubility of metformin hydrochloride in a pH 4.5 medium within 2 hours is not higher than 7.5%, and the solubility in a pH 6.8 medium within 15 minutes is more than 85%. According to clinical trials, The results show that the enteric-coated preparation of metformin hydrochloride with the drug release technical requirements improves the gastrointestinal tolerance of metformin hydrochloride without reducing or even improving the hypoglycemic efficacy, reduces the adverse reactions caused by the drug, and the enteric-coated preparation can be taken before meals, after meals or during meals, improving the compliance of patients with medication. Further pharmacokinetic and in vitro and in vivo correlation studies show that different enteric-coated preparations of metformin hydrochloride with the above-mentioned drug release technical requirements are bioequivalent to the preparation of the preferred embodiment (E1), that is, they have the same efficacy and safety. The content of this patent application is incorporated into this application by reference.

[0010] Enteric-coated tablets are a common enteric-coated preparation, which are usually coated with an enteric coating on the outside of ordinary tablets. The present invention has found that the core disintegration time limit of metformin hydrochloride enteric-coated tablets, the melting point of the coating material of the enteric coating (i.e., pH-dependent solubility) and the coating weight gain are closely related, especially the metformin hydrochloride enteric-coated tablets prepared by the selected melting point of the enteric coating material and the enteric coating weight gain have the above-mentioned specific drug release technical requirements, resulting in the best therapeutic effect and the lowest adverse reactions.

[0011] To this end, the technical solution of the present invention is as follows:

[0012] The invention provides a metformin hydrochloride enteric-coated tablet, which consists of a tablet core containing a therapeutically effective amount of metformin hydrochloride and an enteric coating layer wrapping the tablet core, and the dissolution rate of metformin hydrochloride in the enteric-coated tablet in a pH 4.5 medium within 2 hours is not higher than 15%, and the dissolution rate of metformin hydrochloride in a pH 6.8 medium within 20 minutes is not less than 85%; preferably, the dissolution rate of metformin hydrochloride in the enteric-coated tablet in a pH 4.5 medium within 2 hours is not higher than 7.5%, and the dissolution rate of metformin hydrochloride in a pH 6.8 medium within 15 minutes is not less than 85%.

[0013] Preferably, in the above-mentioned metformin hydrochloride enteric-coated tablets, the coating material of the enteric coating layer has a melting point of pH 5.0-6.0, and the coating weight gain of the enteric coating layer is 4.0-12.8 mg / cm 2Preferably, in the above-mentioned metformin hydrochloride enteric-coated tablets, the coating material of the enteric coating layer has a melting point of pH 5.0-6.0, and the coating weight gain of the enteric coating layer is 4.8-9.6 mg / cm 2 .

[0014] As one of the specific embodiments of the present invention, the above-mentioned metformin hydrochloride enteric-coated tablets, wherein the pH value of the coating material in the enteric coating layer is about 5.0, and the coating weight gain is 5.6-12.8 mg / cm 2 .

[0015] As one of the specific embodiments of the present invention, the above-mentioned metformin hydrochloride enteric-coated tablets, wherein the pH value of the coating material in the enteric coating layer is about 5.5, and the coating weight gain is 4.8-11.2 mg / cm 2 .

[0016] As one of the specific embodiments of the present invention, the above-mentioned metformin hydrochloride enteric-coated tablets, wherein the pH value of the coating material in the enteric coating layer is about 6.0, and the coating weight gain is 4.0-8.8 mg / cm 2 .

[0017] Preferably, in the above-mentioned metformin hydrochloride enteric-coated tablets, the coating material of the enteric coating layer is selected from one or more of the following: hydroxypropyl methylcellulose phthalate (HP-50), methacrylic acid and ethyl acrylate copolymer (L100-55), methacrylic acid and ethyl acrylate copolymer (L30D-55), hydroxypropyl methylcellulose phthalate (HP-55), hydroxypropyl methylcellulose acetate succinate (HPMCAS-L), methacrylic acid and methyl methacrylate copolymer (L100; polyacrylic resin II), hydroxypropyl methylcellulose acetate succinate (HPMCAS-M), cellulose acetate phthalate (CAP; cellulose acetate).

[0018] Preferably, in the above-mentioned metformin hydrochloride enteric-coated tablets, the disintegration time of the tablet core does not exceed 10 minutes, for example, the disintegration time of the tablet core is 2 to 8 minutes; preferably, the disintegration time of the tablet core does not exceed 5 minutes; more preferably, the disintegration time of the tablet core is 2-4 minutes.

[0019] The above-mentioned enteric-coated metformin hydrochloride tablets of the present invention can be coated with a separation layer on the tablet core before the enteric coating layer as needed. For example, when the coating weight gain of the enteric coating layer is low, adding a separation coating layer between the tablet core and the enteric coating layer can reduce the amount of enteric material and enhance the enteric effect; or for enteric materials with compatibility problems with drugs, adding a separation coating layer can increase the stability of the drug.

[0020] The above-mentioned enteric-coated metformin hydrochloride tablets of the present invention have a relative bioavailability of (60-80)% compared with ordinary preparations or rapid-release preparations (such as Glucophage) containing the same content of metformin hydrochloride.

[0021] As another object of the present invention, a method for reducing or lowering adverse reactions caused by metformin hydrochloride is provided, wherein metformin hydrochloride is prepared into the metformin hydrochloride enteric-coated tablets described above in the present invention.

[0022] Preferably, in the above method, the adverse reaction is a digestive tract adverse reaction, such as but not limited to nausea, abdominal pain, abdominal discomfort, etc.

[0023] As another object of the present invention, the use of the above-mentioned metformin hydrochloride enteric-coated tablets in the preparation of a medicament for treating a disease is also provided, wherein the disease includes but is not limited to diabetes and obesity.

[0024] Enteric-coated tablets are usually prepared by coating an enteric coating on the outside of ordinary tablets. The preparation of the enteric-coated metformin hydrochloride tablets of the present invention, such as the process of preparing the tablet core and the process of coating the tablet core with an enteric coating layer, can be prepared by those skilled in the art according to the general preparation process of enteric-coated tablets in the art, and according to the disintegration time limit of the tablet core, the melting point of the coating material of the enteric coating and the coating weight gain, especially the selected melting point of the enteric coating material and the enteric coating weight gain, to prepare the enteric-coated metformin hydrochloride tablets with the specific drug release technical requirements of the present invention. For enteric-coated tablets with low coating weight gain, although it is often not easy to meet the acid resistance requirements or the dissolution requirements in a pH 4.5 medium, by controlling appropriate process parameters, for example, checking the liquid supply speed of the peristaltic pump before coating to ensure stable liquid supply, adjusting the atomization pressure and the fan pressure so that the coating liquid has a better atomization state, increasing the liquid supply volume in the early stage of coating, controlling the tablet bed temperature at the upper limit, so that the coated tablets are quickly covered with a layer of coating material, and strictly controlling the air intake humidity during the entire coating process to ensure the density of the coating film, or adding a coating isolation coat, etc., those skilled in the art can prepare the enteric-coated tablets described in the present invention.

[0025] In the present invention, "dissolution" is also referred to as "release", and "dissolution" is also referred to as "release", which have the same meaning in terms of expression. The dissolution or release of a drug can be determined according to the commonly used determination methods in the art, for example, according to the dissolution and release determination method of the first method of General Chapter 0931 of the Chinese Pharmacopoeia (2020 Edition).

[0026] In the present invention, the melting point of the enteric coating layer coating material is a term that expresses the pH-dependent solubility of the enteric coating material, that is, the pH value when the enteric material begins to dissolve. For example, if the pH value of the melting point of the enteric material is 5.0, it means that the enteric material dissolves at pH ≥ 5.0. For understanding the melting point of coating materials, please refer to the Handbook of Pharmaceutical Excipients (Fourth Edition), Chemical Industry Press, 2005, page 534 for description of the solubility of poly(meth)acrylic acid resin: different types dissolve at different pH values, such as Eudragit L100 dissolves at pH>6, and Eudragit S100 dissolves at pH>7, which means that the melting points of Eudragit L100 and Eudragit S100 are pH6 and pH7, respectively; you can also refer to the description of solubility in the table on page 17 of Shin-Etsu Chemical's Hydroxypropyl Methylcellulose Acetate Succinate Product Manual, AS-LF and AS-LG dissolve at pH≥5.5, and AS-MF and AS-MG dissolve at pH≥6.0, which means that the melting points of AS-LF and AS-LG are pH5.5, and the melting points of AS-MF and AS-MG are pH6.0.

[0027] The disintegration time or disintegration time of the tablet core in the present invention can be determined according to the commonly used measurement methods in the art, for example, according to the disintegration time limit test method in General Chapter 0921 of the Chinese Pharmacopoeia (2020 Edition).

[0028] In the present invention, the pH 4.5 medium is preferably a pH 4.5 acetate buffer, and the pH 6.0 or pH 6.8 medium is preferably a pH 6.0 or pH 6.8 phosphate buffer.

[0029] The enteric-coated tablets of the present invention are tablets having the drug release requirements of the present invention while meeting the general requirements for drug release of enteric-coated preparations. The general requirements for drug release of enteric-coated preparations refer to preparations that do not release or almost do not release drugs in a specified acidic medium (e.g., pH 1.0-3.0), but release most or all of the drugs in a near-neutral medium (e.g., pH 6.0-6.8 phosphate buffer) within a required time.

[0030] In the present invention, the dosage or therapeutically effective amount of metformin hydrochloride in a unit preparation, the therapeutic uses of metformin hydrochloride and its adverse reactions, etc., are prior arts known in the art. For example, the prior arts mentioned in the specification, the relevant contents disclosed therein are also introduced into the present application by reference.

[0031] The present invention has obtained that the enteric-coated preparation of metformin hydrochloride with specific release technical requirements can produce the best therapeutic effect and the lowest adverse reaction. The preparation has the following release technical requirements: the dissolution rate of metformin hydrochloride in a pH 4.5 medium is not higher than 15% within 2 hours, and the dissolution rate of metformin hydrochloride in a pH 6.8 medium is not less than 85% within 20 minutes, more preferably the dissolution rate of metformin hydrochloride in a pH 4.5 medium is not higher than 7.5% within 2 hours, and the dissolution rate in a pH 6.8 medium is more than 85% within 15 minutes. For enteric-coated tablets, achieving rapid release in a pH 6.8 medium requires the selection of an enteric material with a lower melting point or a lower enteric coating weight gain, but an enteric material with a lower melting point or a lower enteric coating weight gain will easily lead to an increase in release in a pH 4.5-5.0 medium. The present invention has obtained that the selected tablet core disintegration time, the starting melting point of the enteric coating material and the coating weight gain, especially the selected starting melting point of the enteric coating material and the coating weight gain, the prepared metformin hydrochloride enteric-coated tablets can meet the above-mentioned drug release technical requirements, and improve the gastrointestinal tolerance of metformin hydrochloride without reducing or even improving the hypoglycemic efficacy, reduce the adverse reactions caused by the drug, and are significantly different from metformin hydrochloride IR or enteric-coated preparations with non-above release characteristics. Further studies such as formulation process and in vitro and in vivo correlation have shown that enteric coating materials with different starting melting points can meet the above-mentioned drug release technical requirements under the condition of controlling appropriate coating weight gain and tablet core disintegration time, and are bioequivalent to the metformin hydrochloride enteric-coated tablets of the preferred embodiment (E1). BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 : HbA1c reduction during 12-week treatment with E1, D2, D5 and Glucophage(R)

[0033] Figure 2 :E1, D2, D5 and Gehuazhi(R)FPG change trend

[0034] Figure 3 : AE status of E1, D2, D5 and Glucophage(R)

[0035] Figure 4 :Dissolution curves of E1, D2, and D5 (pH 6.8)

[0036] Figure 5 :Concentration-time curves of E1, D2, D5 and Glucophage (R) hemostatic drugs

[0037] Figure 6 :Dissolution curves of E1, E10, E13 and D4 (pH 6.8)

[0038] Figure 7 :Blood concentration-time curves of E1, E10, E13 and D4

[0039] Figure 8 :Dissolution curves of E1, E4 and D1 (pH 6.8)

[0040] Fig. 9 :Blood concentration-time curves of E1, E4 and D1 Fig.10 :Subject distribution and flow chart Among them, Fig.10 Chinese: FAS is the full analysis set, which includes all patients who have taken the trial drug, and is used for safety / adverse event analysis; PPS is the per-protocol set, which includes all patients who have taken the trial drug according to the protocol and obtained the second HbA1c, and is used for efficacy analysis. DETAILED DESCRIPTION

[0041] The following specific examples are only used to explain or illustrate the content of the present invention. Obviously, the implementation mode of the present invention is not limited to the specific examples listed, so they should not be understood as constituting any limitation on the protection scope of the claims of this patent application.

[0042] The tablet cores, coating materials, and coating weight gain of the metformin hydrochloride enteric-coated tablets of the examples of the present invention and the comparative examples are shown in the following table.

[0043]

[0044]

[0045] Description: A: The melting point is pH 5.0; B: The melting point is pH 5.5; C: The melting point is pH 6.0; D: The melting point is pH 6.5

[0046] A1, Hydroxypropyl methylcellulose phthalate (HP-50)

[0047] B1, Methacrylic acid and ethyl acrylate copolymer (L100-55)

[0048] B2, Methacrylic acid and ethyl acrylate copolymer (L30D-55)

[0049] B3, Hydroxypropyl methylcellulose phthalate (HP-55 or HP-55S)

[0050] B4, Hydroxypropyl methylcellulose acetate succinate (HPMCAS-L)

[0051] C1, methacrylic acid and methyl methacrylate copolymer (L100; polyacrylic resin II)

[0052] C2, Hydroxypropyl methylcellulose acetate succinate (HPMCAS-M)

[0053] C3, Cellulose acetate phthalate (CAP; Cellulose acetate)

[0054] D1, Eudragit FS+Eudragit L(pH6.5)

[0055] ++: Dissolution in pH 6.8 medium in 20 minutes> 85%

[0056] +++: Dissolution in pH 6.8 medium > 85% in 15 minutes

[0057] **: Clinical trial and pharmacokinetic test prescription;

[0058] VV1: in vitro and in vivo correlation test (test 1);

[0059] VV2: In vitro and in vivo correlation test (Test 2)

[0060] Coating weight gain "%" and "mg / cm 2 "Conversion method: mg / cm 2 =X*core weight / surface area ("X" is the percentage of coating weight gain, for example, "X=5%" means the coating weight gain is 5%); the surface area of ​​the preparation can refer to the "Eutrogenic Manual - Surface Area Calculation" and other literature methods.

[0061] Example 1 (E1): Metformin hydrochloride enteric-coated tablets

[0062] Core composition:

[0063]

[0064]

[0065] Preparation method: Metformin hydrochloride is crushed and passed through an 80-mesh sieve, the crushed raw materials and internal auxiliary materials are placed in a wet granulator and mixed for 5 minutes, and then purified water is added for wet granulation. After wet granulation using a vertical granulator (with a 5×5mm square hole screen installed), the granules are placed in a fluidized bed for drying, and the moisture content of the dry granules is controlled within the range of 1.0-4.0%. After the dry granules are granulated (the granulator is equipped with a 1.5mm round hole screen), magnesium stearate is added and mixed in a total mixer for 5 minutes, and tablets are pressed using a 12mm round punch, and the hardness of the plain tablets is controlled to be 8-11kg.

[0066] According to the disintegration time test method in General Chapter 0921 of Part IV of the 2020 edition of the "Chinese Pharmacopoeia", it was measured that the plain tablets disintegrated completely within 2 to 4 minutes.

[0067] Enteric coating liquid composition:

[0068] name Dosage(g) Methacrylic acid and ethyl acrylate copolymer (L100-55) 6.00 Triethyl citrate 0.60 talcum powder 1.50 90% ethanol 91.90

[0069] Enteric layer coating: Add methacrylic acid and ethyl acrylate copolymer (L100-55) to 90% ethanol and stir until completely dissolved. Then add triethyl citrate and talcum powder in turn and stir until evenly dispersed. Use a coating machine to coat the enteric layer. After coating, dry to remove residual solvent. The enteric layer coating weight gain is 4.5% (7.2mg / cm 2 ).

[0070] Example 2 (E2): Metformin Hydrochloride Enteric-coated Tablets

[0071] Tablet cores were prepared according to the tablet core composition and preparation method of Example 1, and enteric coating was performed according to the enteric layer coating liquid composition and process of Example 1. The coating weight gain was 3.5% (5.6 mg / cm 2 ).

[0072] Example 3 (E3): Metformin Hydrochloride Enteric-coated Tablets

[0073] Tablet cores were prepared according to the tablet core composition and preparation method of Example 1, and enteric coating was performed according to the enteric coating liquid composition and process of Example 1. The coating weight gain was 7.0% (11.2 mg / cm 2 ).

[0074] Example 4 (E4): Metformin Hydrochloride Enteric-coated Tablets

[0075] The total mixed granules were obtained according to the core composition and preparation method of Example 1, and the hardness of the plain tablets was controlled at 15-18 kg during tableting. Referring to the disintegration time limit test method of Part IV of the 2020 edition of the Chinese Pharmacopoeia, it was found that the plain tablets completely disintegrated within 6-8 minutes. The composition, process and weight gain of the enteric layer coating solution were the same as those in Example 1.

[0076] Example 5 (E5): Metformin Hydrochloride Enteric-coated Tablets

[0077] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0078] Enteric coating liquid composition:

[0079]

[0080] Enteric layer coating: Add polyethylene glycol 6000 and talc to purified water, use a high shear homogenizer to fully homogenize for 5 to 10 minutes, then slowly pour the above liquid into the L30D-55 aqueous dispersion, slowly stir to disperse evenly, and pass through an 80-mesh sieve before coating. Use a coating machine to coat the enteric layer, dry it after coating to age the enteric layer, and the enteric layer coating weight gain is 5.5% (8.8mg / cm 2 ).

[0081] Example 6 (E6): Metformin Hydrochloride Enteric-coated Tablets

[0082] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0083] Enteric coating liquid composition:

[0084] name Dosage(g) Hydroxypropyl methylcellulose phthalate (HP-55) 8.00 Triethyl citrate 0.40 talcum powder 2.40 80% ethanol 89.20

[0085] Enteric layer coating: Use 95% ethanol and purified water to make 80% ethanol, add hydroxypropyl methylcellulose phthalate to 80% ethanol, stir to completely dissolve, then add triethyl citrate and talcum powder in turn and stir to disperse evenly. Use a coating machine to coat the enteric layer, dry after coating to remove residual solvent, and the enteric layer coating weight gain is 4.5% (7.2mg / cm 2 ).

[0086] Example 7 (E7): Metformin Hydrochloride Enteric-coated Tablets

[0087] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0088] Enteric coating liquid composition:

[0089] name Dosage(g) Hydroxypropyl methylcellulose acetate succinate (HPMCAS-L) 7.00 Triethyl citrate 1.40 talcum powder 2.10 Sodium Lauryl Sulfate 0.21 Purified water 89.29

[0090] Enteric layer coating: Cool the purified water to below 25°C, add triethyl citrate and sodium lauryl sulfate while stirring, and stir until completely dissolved. Then gradually add hydroxypropyl methylcellulose acetate succinate (micro powder) and talcum powder, stir until evenly dispersed, sieve through 100 mesh before coating, and use a coating machine to coat the enteric layer. The coating liquid needs to be cooled during the coating process, preferably kept below 15°C. After coating, dry the enteric layer for aging treatment. The enteric layer coating weight gain is 5.8% (9.3mg / cm 2 ).

[0091] Example 8 (E8): Metformin Hydrochloride Enteric-coated Tablets

[0092] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0093] Enteric coating liquid composition:

[0094]

[0095] Enteric layer coating: Add methacrylic acid and methyl methacrylate copolymer and hydroxypropyl methylcellulose phthalate into 90% ethanol and stir until completely dissolved. Then add triethyl citrate and talcum powder in turn and stir until evenly dispersed. Use a coating machine to coat the enteric layer. After coating, dry to remove residual solvent. The enteric layer coating weight gain is 5.0% (8.0 mg / cm 2 ).

[0096] Example 9 (E9): Metformin Hydrochloride Enteric-coated Tablets

[0097] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0098] Enteric coating liquid composition:

[0099]

[0100] Enteric layer coating: Add methacrylic acid and ethyl acrylate copolymer to 90% ethanol and stir until completely dissolved. Then add polyethylene glycol 6000 and talcum powder in turn and stir until evenly dispersed. Use a coating machine to coat the enteric layer. After coating, dry to remove residual solvent. The enteric layer coating weight gain is 5.5% (8.8 mg / cm 2 ).

[0101] Example 10 (E10): Metformin hydrochloride enteric-coated tablets

[0102] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0103] Enteric coating liquid composition:

[0104] name Dosage(g) Hydroxypropyl methylcellulose phthalate (HP-50) 8.00 Triethyl citrate 0.40 talcum powder 2.40 80% ethanol 89.20

[0105] Enteric layer coating: Add hydroxypropyl methylcellulose phthalate to 80% ethanol, stir until completely dissolved, then add triethyl citrate and talcum powder in turn and stir until evenly dispersed. Use a coating machine to coat the enteric layer, dry after coating to remove residual solvent, and the enteric layer coating weight gain is 8.0% (12.8mg / cm 2 ).

[0106] Example 11 (E11): Metformin hydrochloride enteric-coated tablets

[0107] Tablet cores were prepared according to the tablet core composition and preparation method of Example 1, and enteric coating was performed according to the enteric coating liquid composition and process of Example 10. The coating weight gain was 6.0% (9.6 mg / cm 2 ).

[0108] Example 12 (E12): Metformin hydrochloride enteric-coated tablets

[0109] Tablet cores were prepared according to the composition and preparation method of the tablet core of Example 1, and enteric coating was performed according to the composition and process of the enteric coating solution of Example 10. The coating weight gain was 4.0% (6.4 mg / cm 2 ).

[0110] Example 13 (E13): Metformin Hydrochloride Enteric-coated Tablets

[0111] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0112] Enteric coating liquid composition:

[0113]

[0114]

[0115] Enteric layer coating: Add methacrylic acid and methyl methacrylate copolymer to 90% ethanol and stir until completely dissolved. Then add triethyl citrate and talcum powder in turn and stir until evenly dispersed. Use a coating machine to coat the enteric layer. After coating, dry to remove residual solvent. The enteric layer coating weight gain is 3.5% (5.6mg / cm 2 ).

[0116] Example 14 (E14): Metformin Hydrochloride Enteric-coated Tablets

[0117] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0118] Enteric coating liquid composition:

[0119]

[0120] Enteric layer coating: Add methacrylic acid and methyl methacrylate copolymer to 90% ethanol and stir until completely dissolved. Then add triethyl citrate and talcum powder in turn and stir until evenly dispersed. Use a coating machine to coat the enteric layer. After coating, dry to remove residual solvent. The enteric layer coating weight gain is 3.0% (4.8mg / cm 2 ).

[0121] Example 15 (E15): Metformin Hydrochloride Enteric-coated Tablets Prescription

[0122] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0123] Composition of isolation layer coating liquid:

[0124] name Dosage(g) Gastric soluble film coating premix (Opadry 85F) 15.0 Purified water 85.0

[0125] Separation layer coating: Add the gastric soluble film coating premix into purified water, stir to disperse evenly, and sieve through 80 mesh before coating. Use a coating machine to coat the isolation coating, dry it after coating to remove the residual moisture, and the coating weight gain is 2.0%.

[0126] Enteric coating liquid composition:

[0127]

[0128] Enteric layer coating: Add methacrylic acid and methyl methacrylate copolymer to 90% ethanol and stir until completely dissolved. Then add triethyl citrate and talcum powder in turn and stir until evenly dispersed. Use a coating machine to coat the enteric layer. After coating, dry to remove residual solvent. The enteric layer coating weight gain is 2.5% (4.0 mg / cm 2 ).

[0129] Example 16 (E16): Metformin hydrochloride enteric-coated tablets

[0130] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0131] Enteric coating liquid composition:

[0132]

[0133] Enteric layer coating: Add methacrylic acid and methyl methacrylate copolymer to 90% ethanol and stir until completely dissolved. Then add triethyl citrate and talcum powder in turn and stir until evenly dispersed. Use a coating machine to coat the enteric layer. After coating, dry to remove residual solvent. The enteric layer coating weight gain is 4.5% (7.2mg / cm 2 ).

[0134] Example 17 (E17): Metformin hydrochloride enteric-coated tablets

[0135] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0136] The enteric coating liquid formulation and process were the same as in Example 16, and the enteric coating weight gain was 5.5% (8.8 mg / cm 2 ).

[0137] Example 18 (E18): Metformin hydrochloride enteric-coated tablets

[0138] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0139] Enteric coating liquid composition:

[0140]

[0141] Enteric layer coating: Use 95% ethanol and purified water to make 80% ethanol, add hydroxypropyl methylcellulose acetate succinate to 80% ethanol, stir to dissolve completely. Use a coating machine to coat the enteric layer, dry after coating to remove residual solvent, and the enteric layer coating weight gain is 3.5% (5.6mg / cm 2 ).

[0142] Example 19 (E19): Metformin Hydrochloride Enteric-coated Tablets

[0143] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0144] Enteric coating liquid composition:

[0145] name Dosage(g) Cellulose acetate (CAP) 7.50 Triacetin 2.50 acetone 90.00

[0146] Enteric layer coating: Add cellulose acetate and triacetin to acetone, stir until completely dissolved, and sieve through a 100-mesh sieve before use. Use a coating machine to coat the enteric layer. After coating, dry to remove residual solvent. The enteric layer coating weight gain is 3.5% (5.6 mg / cm 2 ).

[0147] Example 20 (E20): Metformin Hydrochloride Enteric-coated Tablets

[0148] Tablet cores were prepared according to the composition and preparation method of Example 1; isolation coating was applied according to the composition and process of the coating solution of Example 15, and the isolation coating was increased by 2.0%; enteric coating was applied according to the composition and process of the enteric layer coating solution of Example 1, and the enteric layer coating was increased by 3.0% (4.8 mg / cm 2 ).

[0149] Example 21 (E21): Metformin hydrochloride enteric-coated tablets

[0150] Tablet cores were prepared according to the composition and preparation method of Example 1; isolation coating was applied according to the composition and process of the coating solution of Example 15, and the isolation coating weight was increased by 2.0%; enteric coating was applied according to the composition and process of the enteric layer coating solution of Example 10, and the enteric layer coating weight was increased by 3.5% (5.6 mg / cm 2 ).

[0151] Comparative Example 1 (D1): Metformin Hydrochloride Enteric-coated Tablets

[0152] The composition of the tablet core refers to Glucophage (metformin hydrochloride tablets), specifically:

[0153] Name of raw materials Dosage (mg) Metformin Hydrochloride 500.00 Povidone K30 20.00 Magnesium Stearate (Added) 4.00 Purified water Moderate Tablet weight 524

[0154] Preparation method: dissolve povidone K30 in purified water to prepare an adhesive for use, grind metformin hydrochloride and pass it through a 100-mesh sieve, place the ground raw materials in a fluidized bed granulator, and then spray the adhesive for one-step granulation, control the moisture content of the dry particles within the range of 1.0-4.0%, granulate the dry particles (the granulator is equipped with a 1.5 mm round hole screen), add magnesium stearate, and mix in a total mixer for 5 minutes, and then use a 12 mm round punch to press the tablets, and the hardness of the plain tablets is controlled within the range of 11-15 kg.

[0155] According to the disintegration time test method in General Chapter 0921 of Part IV of the 2020 edition of the "Chinese Pharmacopoeia", it was measured that the plain tablets disintegrated completely within 12 to 15 minutes.

[0156] The composition, process and weight gain of the enteric layer coating solution are the same as those in Example 1.

[0157] Comparative Example 2 (D2): Metformin Hydrochloride Enteric-coated Tablets

[0158] Tablet cores were prepared according to the tablet core composition and preparation method of Example 1, and enteric coating was performed according to the enteric coating solution composition and process of Example 10. The coating weight gain was 2.5% (4.0 mg / cm 2 ).

[0159] Comparative Example 3 (D3): Metformin Hydrochloride Enteric-coated Tablets

[0160] Tablet cores were prepared according to the composition and preparation method of the tablet core of Example 1, and enteric coating was performed according to the composition and process of the enteric layer coating solution of Example 13. The coating weight gain was 2.0% (3.2 mg / cm 2 ).

[0161] Comparative Example 4 (D4): Metformin Hydrochloride Enteric-coated Tablets

[0162] Tablet cores were prepared according to the composition and preparation method of the tablet core of Example 1, and enteric coating was performed according to the composition and process of the enteric coating solution of Example 16. The coating weight gain was 6.5% (10.4 mg / cm 2 ).

[0163] Comparative Example 5 (D5): Metformin Hydrochloride Enteric-coated Tablets Prescription

[0164] The tablet core is based on Glucophage, and the enteric-coated material is Eudragit FS30D + Eudragit L30D-55 = 4:6, and its initial melting point pH value is close to 6.5, as follows:

[0165] The tablet core was prepared according to the tablet core composition and preparation method of Comparative Example 1.

[0166] Composition of isolation layer coating liquid:

[0167] name Dosage(g) Gastric soluble film coating premix (Opadry 85F) 15.0 Purified water 85.0

[0168] Separation layer coating: Add the gastric soluble film coating premix into purified water, stir to disperse evenly, and sieve through 80 mesh before coating. Use a coating machine to coat the isolation layer, dry it after coating to remove the residual moisture, and the coating weight gain is 1.1%.

[0169] Enteric coating liquid composition:

[0170]

[0171]

[0172] Enteric layer coating: Add triethyl citrate and talc to purified water, use a high shear homogenizer to fully homogenize for 5 to 10 minutes, then slowly pour the above liquid into the Eudragit FS30D and L30D-55 aqueous dispersion, slowly stir to disperse evenly, and pass through an 80-mesh sieve before coating. Use a coating machine to coat the enteric layer, dry it after coating to age the enteric layer, and the enteric layer coating weight gain is 3.8% (6.1mg / cm 2 ).

[0173] Comparative Example 6 (D6): Metformin Hydrochloride Enteric-coated Tablets

[0174] Tablet cores were prepared according to the tablet core composition and preparation method of Example 1, and enteric coating was performed according to the enteric layer coating liquid composition and process of Example 1. The coating weight gain was 2.5% (4.0 mg / cm 2 ).

[0175] Comparative Example 7 (D7): Metformin Hydrochloride Enteric-coated Tablets

[0176] Tablet cores were prepared according to the tablet core composition and preparation method of Example 1, and enteric coating was performed according to the enteric layer coating liquid composition and process of Example 1. The coating weight gain was 9.0% (14.4 mg / cm 2 ).

[0177] Comparative Example 8 (D8): Metformin Hydrochloride Enteric-coated Tablets

[0178] The tablet core was prepared according to the tablet core composition and preparation method of Example 1. Enteric coating was applied according to the enteric coating solution composition and process of Example 10, and the coating weight gain was 10.0% (16.0 mg / cm 2 ).

[0179] Dissolution test methods and results

[0180] Referring to the dissolution test conditions of metformin hydrochloride enteric-coated tablets in the 2020 edition of the "Chinese Pharmacopoeia", the dissolution and release determination method (General Chapter 0931 Method 1) was used for determination.

[0181] Acid dissolution

[0182] Dissolution conditions: Use 900 ml of 0.1 mol / L hydrochloric acid solution as the dissolution medium, rotate at 100 revolutions per minute, operate according to the law, and take samples after 2 hours.

[0183] Test solution: Take 20 ml of the eluate, filter, discard 10 ml of the initial filtrate, and take the subsequent filtrate.

[0184] Reference solution: Take an appropriate amount of metformin hydrochloride reference substance, weigh it accurately, add 0.1 mol / L hydrochloric acid solution to dissolve it and quantitatively dilute it to make a solution containing about 28 μg per 1 ml.

[0185] Determination method: Take the test solution and the reference solution, measure the absorbance at a wavelength of 233nm respectively, and calculate the dissolution amount.

[0186] Limit: Not more than 10% of the labeled amount.

[0187] Dissolution in pH 4.5 buffer: Use 900 ml of pH 4.5 acetate buffer as the dissolution medium, blue method, rotation speed of 100 revolutions per minute, operate according to the law, and take samples after 2 hours. The test solution and reference solution are determined in the same way as the pH 6.0 and pH 6.8 medium determination methods.

[0188] Dissolution amount in pH 6.0 and pH 6.8 buffer: Take the rotating basket after 2 hours under the acid-resistant item, and immediately immerse it in 900ml of buffer preheated to 37℃±0.5℃. Keep the speed unchanged and continue to operate according to the method. Take samples after 5, 10, 15, 20, 30, 45, and 60 minutes.

[0189] Test solution: Take 20 ml of the eluate, filter, discard 10 ml of the initial filtrate, accurately measure an appropriate amount of the subsequent filtrate, and quantitatively dilute with water to make a solution containing approximately 5 μg of metformin hydrochloride per 1 ml.

[0190] Reference solution: Take an appropriate amount of metformin hydrochloride reference substance, weigh it accurately, dissolve it in water and quantitatively dilute it to make a solution containing about 5 μg per 1 ml.

[0191] Determination method: Take the test solution and the reference solution, measure the absorbance at a wavelength of 233nm respectively, and calculate the dissolution amount.

[0192] Preparation of dissolution medium:

[0193] Preparation method of pH 4.5 medium (acetate buffer): weigh 1.80g of anhydrous sodium acetate (or 2.99g of sodium acetate trihydrate), add 1.596ml of glacial acetic acid to 1L of degassed purified water, stir until completely dissolved, and adjust the pH value to 4.50 with glacial acetic acid.

[0194] Preparation method of pH 6.0 medium (phosphate buffer): Take 6.80g of potassium dihydrogen phosphate and 0.224g of sodium hydroxide and dissolve them in 1000ml of purified water. If necessary, adjust the pH value to 6.0±0.05 with 2mol / L hydrochloric acid solution or 2mol / L sodium hydroxide solution.

[0195] Preparation method of pH 6.8 medium (phosphate buffer): Take 0.1 mol / L hydrochloric acid solution and 0.2 mol / L sodium phosphate solution, mix them evenly at a ratio of 3:1, and adjust the pH value to 6.8±0.05 with 2 mol / L hydrochloric acid solution or 2 mol / L sodium hydroxide solution when necessary.

[0196] The dissolution test results of the metformin hydrochloride enteric-coated tablets of the embodiment and the comparative example: the acid resistance test was suitable; the dissolution results in acid-resistant and pH 4.5 media are shown in Table 1 (the pH 1.0 value is the average value of the acid-resistant data in the pH 6.0 and pH 6.8 media); the dissolution results in the pH 6.0 and pH 6.8 media are shown in Tables 2 and 3 (the dissolution at 0 in the chart is the acid-resistant 2h test value; 6 formulation units are used for each dissolution curve measurement).

[0197] Table 1 Dissolution of Examples and Comparative Examples in pH 1.0 and pH 4.5 Media for 2 Hours (%)

[0198] Example pH 1.0 pH4.5 Example pH 1.0 pH4.5 Example 1 0.3 3.9 Example 12 2.3 11.9 Example 2 3.2 12.6 Embodiment 13 2.7 6.9 Example 3 0.0 0.0 Embodiment 14 4.5 14.6 Example 4 0.2 2.9 Embodiment 15 2.9 11.2 Example 5 0.3 4.2 Example 16 0.1 1.7 Example 6 0.3 2.3 Embodiment 17 0.3 0.0 Example 7 0.2 1.8 Embodiment 18 3.1 8.7 Example 8 0.7 4.2 Embodiment 19 1.8 5.2 Example 9 0.4 2.7 Embodiment 20 2.3 6.7 Example 10 0 0.8 Embodiment 21 2.6 11.1 Embodiment 11 0.6 3.0 Comparative Example 1 0.5 1.8 Comparative Example 5 0 1.5 Comparative Example 2 6.3 21.6 Comparative Example 6 5.7 21.9 Comparative Example 3 9.6 27.8 Comparative Example 7 0.0 0.0 Comparative Example 4 0 0 Comparative Example 8 0.0 0.0

[0199] Table 2 Dissolution of Examples and Comparative Examples in pH 6.0 Medium

[0200]

[0201]

[0202] Table 3 Dissolution of Examples and Comparative Examples in pH 6.8 Medium

[0203]

[0204]

[0205] The enteric-coated metformin hydrochloride preparation disclosed in WO2014107617A requires that less than 15%, 10% or 5% of the biguanide compound be released in a hysteresis period of at least ten minutes or fifteen minutes at an acidic pH of two hours and at pH 6.8, at least 60% of the biguanide compound be released within 60 minutes after the hysteresis period and at pH 6.8, and at least 90% of the biguanide compound be released within 90 to 120 minutes at pH 6.8. It can be seen that the dissolution of Comparative Example 5 meets the requirements of the enteric-coated metformin hydrochloride preparation described in the patent document.

[0206] Clinical trials and results

[0207] Patients who were intolerant to ordinary immediate-release metformin hydrochloride tablets (IR preparation) were randomly given metformin hydrochloride enteric-coated tablets of comparative example 2 (D2), example 1 (E1) and comparative example 5 (D5) and ordinary immediate-release metformin hydrochloride tablets (reference preparation R, commercial product Commercially available), to evaluate the effects of metformin hydrochloride enteric-coated tablets with different release characteristics on controlling blood sugar and improving patient tolerance.

[0208] Inclusion criteria: Subjects who meet all of the following criteria can be included in this trial:

[0209] (1) Aged 28 to 78 years old, regardless of gender;

[0210] (2) diagnosed with type 2 diabetes according to the WHO (1999) diabetes diagnostic criteria;

[0211] (3) Patients who have not taken other hypoglycemic drugs but are intolerant to regular immediate-release metformin hydrochloride tablets, including gastrointestinal reactions such as diarrhea, nausea, vomiting, bloating, indigestion, and abdominal discomfort; adverse reactions of the nervous system such as dizziness and headache; and various adverse reactions that may be related to the drug, and have been taking the drug for less than 2 weeks and are willing to change the drug.

[0212] (4) Glycated hemoglobin (HbA 1c )≥7.0% and ≤11.0%;

[0213] (5) fasting blood glucose (FPG) ≤15 mmol / L (270 mg / dL) at the screening visit;

[0214] (6) Body mass index (BMI) ≥19 kg / m 2 And ≤35kg / m 2 ;

[0215] Dosage method: Replace the original regular rapid-release metformin hydrochloride tablets with the same dose of E1, D2, D5 or Glucophage. After replacement, increase the dose by 500 mg per week (take once in the morning and evening) until it reaches 2000 mg / day. For those who have already reached 2000 mg / day, do not increase the dose and continue to take the replacement drug according to the original dose and method. For those who are still intolerant after changing the drug, the dose can be reduced to 1500 mg / day or 1000 mg / day.

[0216] During the treatment period, assessors who have other diseases that affect the efficacy and adverse events may withdraw from the trial. For subjects who withdraw due to adverse events, the adverse events will be recorded and included in the statistical analysis.

[0217] Main efficacy index: HbA after 12 weeks of treatment 1c Change from baseline.

[0218] Secondary efficacy indicators:

[0219] (1) Changes in fasting blood glucose (FPG) compared with baseline at 4, 8, and 12 weeks of medication;

[0220] (2) changes in body weight compared with baseline at 4, 8, and 12 weeks of medication;

[0221] (3) changes in blood lipids (TC, TG, LDL-C, HDL-C) compared with baseline at 4, 8, and 12 weeks of medication;

[0222] Safety evaluation: adverse events were recorded at any time during the study: special attention was paid to the common gastrointestinal adverse reactions of metformin (including abdominal pain, diarrhea, constipation, abdominal distension, indigestion, etc.);

[0223] All medications (including combined medications) and adverse events of the patients were recorded in diary cards. The diary cards were collected at the next visit and medication compliance was calculated (by calculating the number of tablets used, generally requiring the actual number of tablets used to be > 80% of the theoretical amount). Patients with poor compliance were supervised. Subjects who took other hypoglycemic drugs were excluded.

[0224] The experimental process and subject distribution are shown in Table 4 and Fig.10

[0225] Table 4 Test process

[0226]

[0227]

[0228] *: No need to do this if done within 2 weeks; efficacy statistics are based on the value of the last examination before taking the medicine.

[0233] Test results and discussion

[0234] E1 had the best efficacy in terms of HbAlc, and fasting blood glucose showed a similar trend. In addition, the decrease in fasting blood glucose showed an increasing trend as the duration of E1 medication increased, indicating that E1 may have a better long-term efficacy (see Figure 1-2 and Table 6; FPG at week 16 was not a planned test, the number of patients was small, and the time span was long, so no statistical analysis was performed); E1 was also superior to other preparations in terms of blood lipids, liver and kidney function. There was no significant difference between D2 and the control drug Glucophage in hypoglycemic effect, and D5 was significantly different from Glucophage (P < 0.05, and the difference exceeded the clinical non-inferiority margin of 0.3-0.4).

[0235] Table 6: Efficacy indicators

[0236]

[0237]

[0238] *: P < 0.05 compared with baseline; **: P < 0.01 compared with baseline

[0239] Table 7: Adverse events

[0240]

[0241] AE: adverse event

[0242] Upper gastrointestinal AEs include: nausea, vomiting, abdominal pain, abdominal discomfort, bloating, acid reflux

[0243] Lower gastrointestinal AEs include: diarrhea, constipation

[0244] Ratio = adverse events during the trial period / adverse events during the screening period*100%;

[0245] *: P<0.05 compared with R

[0246] E1, D2, and D5 were significantly superior to Glucophage in terms of upper gastrointestinal adverse events (AEs) such as nausea, vomiting, abdominal pain, abdominal discomfort, abdominal distension, and acid reflux, especially E1 and D5. The probability of upper gastrointestinal AEs in patients taking metformin hydrochloride tablets was only 33% of that before the change of medication after switching to E1 and D5, while that of Glucophage was 93%. The improvement of D2 was not very obvious, and the probability of upper gastrointestinal AEs after the change of medication was 59% of that before the change of medication. E1 also had certain advantages in other AEs (see Table 7).

[0247] The inventors further analyzed the patients in group D2 and found that the occurrence of upper gastrointestinal reactions in this group of patients was significantly related to the time of taking the medicine: the proportion of patients who took the medicine before meals (30 minutes before meals) who had upper gastrointestinal reactions was much lower than those who took the medicine after meals or during meals (E1 and D5 did not have such a correlation). This is obviously inconsistent with the adverse reaction characteristics of metformin reported in the literature. The literature shows that the adverse reactions of taking the medicine before meals are higher than those of taking it during meals and after meals. Therefore, the instructions of various countries require that metformin (ordinary preparations) be taken during meals (or immediately after meals) to reduce adverse gastrointestinal reactions.

[0248] After noticing the above phenomenon, the researchers compared the relationship between adverse events and meal times and observed that the adverse events of patients taking the drug before and after meals are as shown in Table 8:

[0249] Table 8: Comparison of adverse events between pre-meal and post-meal administration in patients in group D2

[0250]

[0251] The definition of upper gastrointestinal AE is the same as in the above table.

[0252] Data that could not distinguish the correlation between medication / meal / AE were excluded because the diary card did not clearly record the time of medication and meal. Therefore, the number of people counted before meals + meals and after meals was less than the total number of D2 groups.

[0253] The inventor analyzed the reasons by comparing the prescription process and dissolution of D2, and believed that it might be because D2 has a low initial dissolution point, a small coating weight gain (thinner casing), a higher pH in the stomach and upper small intestine during and after meals (up to 5 or higher), and faster gastric motility and delayed emptying after meals, coupled with food squeezing, which may cause the enteric coating to dissolve and rupture faster, thereby releasing the drug in advance. Before meals, the pH value in the stomach is lower, gastric motility is slow and gentle, and emptying is faster, so the enteric coating truly achieves the enteric effect, and the drug is released only after passing through the stomach, avoiding drug irritation to the upper digestive tract.

[0254] The inventors designed a dissolution test: simulated postprandial gastric juice (acetate buffer and milk were mixed in a ratio of 1:1, pH value was adjusted to 5.0 using sodium hydroxide or hydrochloric acid, acetate buffer contained 13.85 g / L sodium chloride, 1.03 g / L acetic acid, and 2.44 g / L sodium acetate), paddle method, 75 rpm for D2 dissolution test, tablets began to break at 30 minutes, dissolution reached more than 75% at 60 minutes, and metformin was completely dissolved at 90 minutes. The test results show that it is difficult to achieve the "enteric" effect of taking D2 after a meal.

[0255] The inventors re-performed the dissolution test of postprandial gastric juice with Example 12 (E12) and Example 15 (E15), and the test method was the same as above. The tablets of Example 12 (E12) began to break at about 60 minutes, with a dissolution rate of about 20%, and the dissolution rate reached more than 30% at 90 minutes; the tablets of Example 15 (E15) began to swell and deform at about 60 minutes, with a dissolution rate of about 10%, and the dissolution rate was about 25% at 90 minutes. Considering that the drug dissolved in the human stomach will be continuously diluted and discharged into the intestine, the concentration of metformin in the stomach should be much lower than that of the immediate-release tablets.

[0256] When taking medicine during or after a meal, the drug often stays in the stomach longer than when taking medicine on an empty stomach, and the pH value is also higher, which can reach 4.5-5.0. According to the analysis of the pharmacokinetic and BA test results, metformin enteric-coated tablets taken during meals can stay in the stomach for several hours, so the dissolution in pH4.5 medium is of great value to this product. The results of clinical and simulated postprandial gastric juice tests showed that when the dissolution in pH4.5 medium exceeded 20% (D2), the intragastric release increased significantly, and the adverse reactions also increased significantly, while when it was less than 15% (E12, E15), limited intragastric release could be achieved, and when it was less than 7.5% (E4, E13, E22), it could achieve bioequivalence with the best target product (E1).

[0257] At present, the requirements of drug regulatory authorities in most countries for enteric-coated tablets are that the dissolution in a medium of pH 1.0 is less than 5% to 10% in 2 hours. D2 meets this requirement, which shows that this requirement may be difficult to ensure that the enteric effect is still achieved when taking the medicine after meals. Since ordinary preparations of metformin hydrochloride (i.e., immediate release preparations) are all taken after meals or during meals, many patients still habitually take metformin hydrochloride enteric-coated tablets after meals or during meals, so ensuring "enteric coating" after meals is more important for metformin hydrochloride. At the same time, it can be taken before meals, after meals or during meals, which can significantly improve the compliance of patients with medication.

[0258] The upper gastrointestinal adverse reactions of D5 were significantly improved compared with those of Glucophage, but the lower gastrointestinal reactions were higher than those of Glucophage, D2, and E1. The incidence of lower gastrointestinal adverse events (mainly diarrhea) was 130% of that of ordinary tablets, and if the duration of diarrhea was calculated, it was 156% of that of ordinary tablets. In addition, 5 patients of D5 had severe watery stools, 2 of which occurred after taking ordinary metformin tablets and worsened after switching to D5, and 3 were normal after taking ordinary metformin tablets and appeared after switching to D5. The researchers judged that this symptom was an adverse reaction caused by the drug.

[0259] Since metformin has strong irritation to gastrointestinal mucosa, the inventor considers that watery stool is caused by the stimulation of the drug to the colorectal mucosa. According to the drug prescription and dissolution, D2 should be released in the stomach, duodenum and upper small intestine (different according to the time of taking the medicine), and E1 should be released in the small intestine. The small intestine moves faster and has a large amount of intestinal fluid, so the drug is diluted quickly and has a weaker irritation to the colon. D5 dissolves more slowly and is likely to be released in the colon. The colon moves slowly, the intestinal fluid is less, and the drug absorption is less, and a larger concentration may be formed locally, which stimulates the colon mucosa.

[0260] Pharmacokinetic studies and their results

[0261] In order to study the absorption of metformin enteric-coated preparations with different release characteristics, as well as their relationship with hypoglycemic effects and adverse reactions, the inventors conducted a pharmacokinetic study of the preparations.

[0262] Four products with different release characteristics in the above clinical trials were selected, namely, three metformin hydrochloride enteric-coated tablets E1, D2, and D5 (the dissolution curves of which are shown in Figure 2). Figure 4 ; Considering that the drug dissolved in acid will also be absorbed, where D2 is the cumulative dissolution, cumulative dissolution = dissolution + dissolution at 0 / dissolution in acid) and the reference preparation (metformin hydrochloride tablets, trade name: ), a pharmacokinetic study was conducted in healthy subjects, and the bioavailability of E1, D2, and D5 relative to Glucophage (R) was calculated.

[0263] Test method:

[0264] Inclusion Criteria. Subjects must meet all of the following criteria to be included:

[0265] 1) Healthy subjects: medical history, vital signs, physical examination, laboratory tests, electrocardiogram, chest X-ray and other related examinations are within the normal range, or the researchers judge that the abnormalities have no clinical significance;

[0266] 2) Men and women between 18 and 65 years old (including borderline values);

[0267] 3) Male weight ≥ 50 kg, female weight ≥ 45 kg, body mass index between 19 and 28 (including the critical value) [body mass index (BMI) = weight (kg) / height 2 (m 2 )];

[0268] Before statistical analysis, if any of the following situations occurs, a comprehensive judgment will be made on whether to exclude the subject based on factors such as the degree of completion of the trial and the reason for withdrawal:

[0269] 1) The first sample is C max If the subject is not given an early sample (within 30 minutes after administration), the pharmacokinetic data of the corresponding period will not be included in the evaluation;

[0270] 2) After the drug administration, the subjects max If vomiting occurs within twice the median time, the pharmacokinetic data of the corresponding period of the subject will not be included in the evaluation;

[0271] 3) The blood drug concentration before administration (0-hour concentration) is greater than the corresponding C after administration. max 5%, the pharmacokinetic data of the corresponding period of the subject will not be included in the evaluation;

[0272] 4) During the trial, the trial data may have large deviations or the PK parameters cannot be calculated due to reasons such as violation of the dosing regimen, incorrect blood collection time, improper sample handling or storage, and poor subject compliance.

[0273] Dosage regimen. A four-cycle crossover design was used, with medication administered once on the first day of each cycle, and a three-day washout period during the two-week period. Twenty subjects were randomly divided into four groups at a ratio of 1:1:1:1. Subjects were fasting but not drinking water for 10 hours before medication. On the day of medication, the reference preparation (R / Glucophage, 1 tablet, 500 mg) or the test preparation (E1, D2, D5; all 500 mg) was taken on an empty stomach with 240 ml of warm water. A standard lunch was eaten 4 hours after medication.

[0274] The experimental design is shown in Table 9.

[0275] Table 9: Experimental design

[0276]

[0277] During the entire trial period, the subjects consumed the standard meals provided by the research center. During the trial, the subjects avoided strenuous exercise and prolonged bed rest, and were prohibited from taking caffeine- or ethanol-containing beverages such as fruit juice, tea, coffee, and wine, and smoking was also prohibited. If an adverse event occurred during the trial, the researcher needed to follow up the subject until the adverse event was alleviated or the symptoms disappeared.

[0278] Blood samples were collected at 0 h (within 60 min before the subject took the drug), 0.5 h, 1.0 h, 1.5 h, 2.0 h, 2.5 h, 3.0 h, 3.5 h, 4.0 h, 4.5 h, 5.0 h, 6.0 h, 7.0 h, 8.0 h, 10.0 h, 12.0 h, 15 h, and 24.0 h in each cycle (a total of 18 blood collection points, and 72 blood collection points in 4 cycles). 3 ml of peripheral venous blood was collected at each blood collection point and placed in a K2EDTA blood collection tube, centrifuged (1700 g, 2 °C - 8 °C, with the set temperature at 4 °C) for 10 min to separate the plasma, and the plasma samples were stored in a cryogenic refrigerator until detection. The drug concentration of metformin hydrochloride in plasma was determined by liquid chromatography-tandem mass spectrometry (HPLC-MS / MS) (Reference: Zhang D, Wang GC, Huang JQ, et al., LC-MS / MS determination of metformin in human plasma[J]. Chin J Pharm Anal (Journal of Pharmaceutical Analysis), 2011, 31(2): 317 - 321; Zhang Dan, Post-marketing human bioequivalence re-evaluation of metformin hydrochloride enteric-coated tablets, Chinese Pharmaceutical Journal, Vol. 47, No. 18, October 2012).

[0279] The test results are as follows (Table 10 - 11 and Figure 5 ).

[0280] Table 10: Pharmacokinetic parameters (PKPS)

[0281] Parameters (Mean±SD) D2(n=20) E1(n=18) D5(n=20) R(n=19) <![CDATA[C max (ng / ml)]]> 982.99±254.50 710.51±299.89 567.26±399.85 1115.05±216.59 <![CDATA[AUC 0-t (h*ng / ml)]]> 5701.69±1235.03 4836.79±1636.07 3110.98±1614.21 6323.58±1333.26 <![CDATA[AUC 0-∞ (h*ng / ml)]]> 5978.04±1217.67 5108.78±1716.44 3432.56±1614.64 6436.91±1375.07 <![CDATA[T max (h)]]> 4.50(2.5-5.0) 5.00(3.0-12.0) 7.00(1.5-15.0) 1.00(0.5-2.0) <![CDATA[T 1 / 2 (h)]]> 5.50±2.06 4.75±1.50 5.26±1.42 4.00±0.82

[0282] Note: Mean±SD represents the arithmetic mean ± standard deviation; T max is expressed as the median (minimum - maximum).

[0283] Table 11: Relative bioavailability

[0284]

[0285]

[0286] The test results showed that the dissolution behavior of metformin enteric-coated tablets was clearly correlated with absorption. The relative bioavailability of metformin hydrochloride enteric-coated tablets with the fastest (D2), medium (E1) and slowest (D5) release was 91%, 72% and 48% relative to that of glucophage, respectively. Dissolution was highly correlated with absorption (see Figure 4 , 5 ), combined with clinical trials, it can be seen that dissolution is also significantly correlated with clinical efficacy and adverse reactions.

[0287] There was one case of nausea in the reference preparation group and one case of diarrhea on D5, both of which recovered spontaneously the next day. No adverse reactions were found in the other groups.

[0288] The enteric-coated preparations disclosed in WO2013103384A and WO2013103919A have a relative bioavailability reduction of 20% to 60%, preferably 40% to 60%, compared to the common preparations, i.e., immediate-release preparations, having the same amount of the biguanide compound. It can be seen that D5 meets the enteric-coated preparations of metformin hydrochloride described in the patent document. Consistent with the results of a 16-week clinical study conducted by Elcelyx (Robert R. Henry et al.), D5 (bioavailability reduced by 52%) did not achieve the desired clinical efficacy. On the contrary, a relative bioavailability of 60% to 80% (E1) produced the best efficacy and the lowest adverse reactions.

[0289] In vivo and in vitro correlation studies and results

[0290] The clinical trials and pharmacokinetic studies of E1, D2 and D5 above show that the efficacy, safety and absorption of metformin enteric-coated preparations are significantly correlated with drug dissolution. To further study the relationship between release characteristics and drug absorption, efficacy and safety, the inventors conducted the following in vitro and in vivo correlation studies.

[0291] Test 1:

[0292] Study the effects of enteric coating materials, weight gain and related release profiles on drug absorption; select the following representative formulations:

[0293] Example 1 (E1): used as a reference preparation (93.8% dissolution in pH 6.8 medium in 15 minutes and 101.1% dissolution in 20 minutes).

[0294] Example 10 (E10): The tablet core is the same as E1, and hydroxypropyl methylcellulose phthalate (HP-50) with a melting point of pH 5.0 is used as the enteric coating material. The coating weight gain is 8%, and the dissolution in pH 6.8 medium is 71.1% in 15 minutes and 93.3% in 20 minutes.

[0295] Example 13 (E13): The tablet core is the same as E1, and the enteric coating material is methacrylic acid and methyl methacrylate copolymer (Eutrac L100) with a melting point of pH 6.0. The coating weight gain is 3.5%, and the dissolution in pH 6.8 medium is 95.6% in 15 minutes and 98.1% in 20 minutes.

[0296] Comparative Example 4 (D4): The tablet core is the same as E1, and the copolymer of methacrylic acid and methyl methacrylate (Eutrac L100) with a melting point of pH 6.0 is used as the enteric coating material. The coating weight gain is 6.5%, and the dissolution rate in pH 6.8 medium is 25.0% in 15 minutes and 73.0% in 20 minutes.

[0297] The dissolution curves of E1, E10, E13 and D4 in pH 6.8 medium are shown in Figure 6 (Where D2 is the cumulative dissolution).

[0298] The experimental design is shown in Table 12.

[0299] Table 12: Experimental design

[0300]

[0301]

[0302] Because the previous pharmacokinetic test showed that the blood drug concentration was still high at 24 hours, this test extended the blood collection time to 48 hours (adding two blood collection points at 36 hours and 48 hours), and other test methods (inclusion criteria, dosing regimen, blood drug concentration detection method, etc.) were the same as the pharmacokinetic test.

[0303] Test results: See Tables 13, 14 and Figure 7

[0304] Table 13: Pharmacokinetic parameters (PKPS)

[0305] Parameters (Mean±SD) E10(n=20) E13 (n=20) D4 (n=19) E1(n=20) <![CDATA[C max (ng / ml)]]> 864.46±191.19 898.64±213.11 724.08±230.87 910.68±203.74 <![CDATA[AUC 0-t (h*ng / ml)]]> 5705.69±1459.71 6329.51±1271.74 4959.86±1256.55 6382.01±1233.42 <![CDATA[AUC 0-∞ (h*ng / ml)]]> 5765.44±1458.68 6399.42±1288.50 5008.66±1259.49 6463.54±1259.21 <![CDATA[T max (h)]]> 5.00(2.50-10.00) 4.50(2.50-12.00) 6.00(1.50-10.00) 5.00(1.50-8.00) <![CDATA[T 1 / 2 (h)]]> 7.53±3.44 7.57±2.38 7.42±1.95 7.85±3.90

[0306] Note: Mean±SD means arithmetic mean±standard deviation; T max Expressed as median (minimum value - maximum value).

[0307] Table 14: Relative bioavailability

[0308]

[0309] E13 is bioequivalent to E1, with a BA (relative bioavailability) of about 99%; although E10 is bioequivalent to E1, its BA is only 88% of that of E1; and D4 has significantly reduced absorption, with a BA of only 77%, which is not bioequivalent to E1. The test results further show that the in vitro dissolution (especially the dissolution in a pH 6.8 medium) of the metformin hydrochloride enteric-coated tablets of the present invention is well consistent with its in vivo absorption.

[0310] One adverse reaction (diarrhea) occurred on D4, and no adverse reactions were found in other groups.

[0311] Test 2:

[0312] To study the effects of tablet core disintegration rate and related release on drug absorption, the following representative formulations were selected:

[0313] Example 1 (E1): used as a reference preparation (R; tablet core disintegration time 2-4 minutes, dissolution 93.8% in pH 6.8 medium within 15 minutes).

[0314] Example 4 (E4): Enteric coating is the same as E1, the tablet core disintegration time is 6 to 8 minutes, and the dissolution in pH 6.8 medium is 81.3% in 15 minutes and 93.6% in 20 minutes.

[0315] Comparative Example 1 (D1): Enteric coating was the same as that of E1, the tablet core disintegrated in 12-15 minutes, and dissolved in a pH 6.8 medium at 54.3% in 15 minutes and 77.7% in 20 minutes.

[0316] The dissolution curve in pH 6.8 medium is as follows Figure 8 .

[0317] The experimental design is shown in Table 15.

[0318] Table 15: Experimental design

[0319]

[0320] The test methods (inclusion and exclusion criteria, dosing regimen, blood drug concentration detection method, etc.) are the same as those in Test 1.

[0321] Test results: See Tables 16, 17 and Fig. 9

[0322] Table 16: Pharmacokinetic parameters (PKPS)

[0323] Parameters (Mean±SD) D1(n=18) E4 (n=18) E1(n=18) <![CDATA[C max (ng / ml)]]> 718.52±145.13 850.39±248.99 882.52±231.72 <![CDATA[AUC 0-t (h*ng / ml)]]> 4703.92±1076.55 5617.34±1590.36 5990.16±1652.69 <![CDATA[AUC 0-∞ (h*ng / ml)]]> 4752.18±1083.80 5674.26±1606.71 6054.96±1667.50 <![CDATA[T max (h)]]> 6.00(3.00-12.00) 5.00(2.00-12.00) 4.50(2.50-7.00) <![CDATA[T 1 / 2 (h)]]> 8.17±2.47 9.06±2.39 8.25±2.53

[0324] Note: Mean±SD means arithmetic mean±standard deviation; T max Expressed as median (minimum value - maximum value).

[0325] Table 17: Relative bioavailability

[0326]

[0327] E4 is bioequivalent to E1, but its BA is only 94% of that of E1. D1 cannot be bioequivalent to E1, and its BA is only about 80% of that of E1. The test results show that the disintegration time of the tablet core has a significant effect on the dissolution and absorption of the drug.

[0328] No adverse reactions were observed in any group.

[0329] The absorption site of metformin hydrochloride is the upper part of the small intestine. It is generally believed that the dissolution of the pH 6.0 medium better reflects the dissolution of the upper part of the small intestine, and its dissolution rate is an important factor affecting the absorption of such drugs and the performance of drug efficacy, but the present invention surprisingly found that the absorption of this product is mainly associated with the dissolution of the pH 6.8 medium. The pharmaceutical industry often distinguishes the difference in prescription process (effect) by dissolution characteristics, and expects to predict in vivo absorption or bioavailability (BA) by dissolution behavior. Relative to BA, the study of dissolution is much simpler and faster. If the correlation between dissolution and BA can be established, it is of great value to select suitable product prescriptions and processes and predict drugability.

[0330] The results of the above clinical trials, pharmacokinetic studies (E1, D2, D5) and in vitro and in vivo correlation studies (E1, E10, E13, D4; E1, D1, E4) all show that the in vivo absorption of metformin hydrochloride enteric-coated preparations has a good correlation with the in vitro dissolution (especially the dissolution in pH 6.8 buffer), and the rapid dissolution in pH 6.8 buffer (more than 85% dissolution in 20 minutes, especially more than 85% dissolution in 15 minutes) and the limited release in pH 4.5 medium (less than 7.5-15% release in 2 hours) can achieve the best therapeutic effect and the lowest adverse reactions. The bioavailability of metformin hydrochloride enteric preparations (such as Glucophage) is about 60-80%.

[0331] The research of the present invention shows that there is a close correlation between the tablet core disintegration time of metformin hydrochloride enteric-coated tablets, the melting point of the coating material of the enteric coating, and the coating weight gain. The selected tablet core disintegration time, the melting point of the enteric coating material, and the enteric coating weight gain can obtain metformin hydrochloride enteric-coated tablets with the above-mentioned specific drug release characteristics, resulting in better therapeutic effects and lower adverse reactions.

Claims

1. A metformin hydrochloride enteric-coated tablet, comprising a tablet core containing a therapeutically effective amount of metformin hydrochloride and an enteric coating layer wrapping the tablet core, wherein the dissolution rate of metformin hydrochloride in a pH 4.5 medium within 2 hours is not higher than 15%, and the dissolution rate of metformin hydrochloride in a pH 6.8 medium within 20 minutes is not less than 85%; preferably, the dissolution rate of metformin hydrochloride in a pH 4.5 medium within 2 hours is not higher than 7.5%, and the dissolution rate of metformin hydrochloride in a pH 6.8 medium within 15 minutes is not less than 85%.

2. The metformin hydrochloride enteric-coated tablets according to claim 1, wherein The coating material of the enteric coating layer has a melting point pH value of 5.0 to 6.0, and a coating weight gain of 4.0 to 12.8 mg / cm 2 Preferably, the coating material of the enteric coating layer has a melting point pH of 5.0 to 6.0, and a coating weight gain of 4.8 to 9.6 mg / cm 2 .

3. The metformin hydrochloride enteric-coated tablets according to claim 2, wherein: The coating material of the enteric coating layer has a melting point pH value of about 5.0, and the coating weight gain is 5.6-12.8 mg / cm 2 .

4. The metformin hydrochloride enteric-coated tablets according to claim 2, wherein The coating material of the enteric coating layer has a melting point pH value of about 5.5, and the coating weight gain is 4.8-11.2 mg / cm 2 .

5. The metformin hydrochloride enteric-coated tablets according to claim 2, wherein: The coating material of the enteric coating layer has a melting point pH value of about 6.0, and the coating weight gain is 4.0-8.8 mg / cm 2 .

6. The metformin hydrochloride enteric-coated tablets according to claims 1-5, wherein The coating material of the enteric coating layer is selected from one or more of the following: hydroxypropyl methylcellulose phthalate (HP-50), methacrylic acid and ethyl acrylate copolymer (L100-55), methacrylic acid and ethyl acrylate copolymer (L30D-55), hydroxypropyl methylcellulose phthalate (HP-55), hydroxypropyl methylcellulose acetate succinate (HPMCAS-L), methacrylic acid and methyl methacrylate copolymer (L100; polyacrylic resin II), hydroxypropyl methylcellulose acetate succinate (HPMCAS-M), cellulose acetate phthalate (CAP; cellulose acetate).

7. The metformin hydrochloride enteric-coated tablets according to claims 1-6, wherein The disintegration time limit of the tablet core is no more than 10 minutes; preferably, the disintegration time limit of the tablet core is no more than 5 minutes; more preferably, the disintegration time limit of the tablet core is 2-4 minutes.

8. The metformin hydrochloride enteric-coated tablets according to claims 1-7, wherein: If necessary, the tablet cores may be coated with a barrier layer before the enteric coating layer.

9. The metformin hydrochloride enteric-coated tablets according to claims 1-8, characterized in that Compared with common preparations or rapid-release preparations (such as Glucophage) containing the same amount of metformin hydrochloride, it has a relative bioavailability of (60-80)%.

10. Use of the metformin hydrochloride enteric-coated tablets according to claims 1-9 in the preparation of a medicament for treating a disease; preferably, the disease includes but is not limited to diabetes and obesity.

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