Metformin hydrochloride enteric-coated tablet

Abstract

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 has a metformin hydrochloride dissolution of not higher than 15% within 2 hours in a pH 4.5 medium and a metformin hydrochloride dissolution of not less than 85% within 20 minutes in a pH 6.8 medium. The metformin hydrochloride enteric-coated tablet, which meets specific drug release technical requirements, is obtained by means of selecting the disintegration time limit of the tablet core, the dissolution point of the enteric coating material and the weight gain of the coating. Compared with common preparations of metformin hydrochloride (such as glucophage) and enteric-coated tablets having other release characteristics, the metformin hydrochloride enteric-coated tablet improves the tolerance and compliance of metformin hydrochloride without reducing the hypoglycemic efficacy.

Description

Metformin hydrochloride enteric-coated tablets 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 agent, and its hydrochloride, metformin hydrochloride, is commonly used clinically. Early studies believed that the primary mechanism of metformin's hypoglycemic effects was systemic effects after absorption, such as inhibiting gluconeogenesis, reducing hepatic glucose output, and acting on peripheral tissues (muscle and fat) to promote glucose utilization and improve insulin sensitivity. Recent studies have revealed that intestinal-mediated mechanisms (such as increasing GLP-1 and PYY levels, affecting intestinal flora, and inhibiting glucose uptake by intestinal wall cells) may be more important.

[0003] In diabetes diagnosis and treatment guidelines developed by many countries and international organizations, metformin hydrochloride is recommended as a first-line medication for controlling hyperglycemia in patients with type 2 diabetes and as a basic medication in combination therapy. Glucophage (metformin hydrochloride tablets), an original metformin product, has many years of clinical experience and extensive evidence-based medical support. It is the standard treatment for type 2 diabetes both domestically and internationally and the most commonly used control drug in clinical trials.

[0004] However, some adverse reactions of metformin restrict its use, and 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 rate of 20-30%, and are also the most common reason for patients to be intolerant.

[0005] To reduce the adverse reactions associated with metformin, numerous studies and reports have been conducted on its enteric-coated formulations. Enteric-coated formulations, which release little or no drug in the stomach within a specified timeframe, release most or all of the drug in a specific area of ​​the intestine upon entry.

[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, for example, 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 bioavailability and avoided the toxic side effects that may be caused by excessive blood drug concentrations 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 even in a pH 5.5 phosphate buffer, the release remained above 80% after 45 minutes, claiming that it could avoid adverse reactions caused by the drug, and that the rapid release feature made it possible to 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 within 1 hour, 45-55% within 2 hours, and greater than 85% within 4 hours, claiming to have low adverse reactions and be suitable for patients with contraindications to metformin; CN111888339A discloses metformin hydrochloride enteric-coated tablets that release more than 85% in pH 4.5-5.0 buffer within only 15-30 minutes, with rapid release and high release rate, claiming to have improved bioavailability and bioequivalence to the original drug. The enteric-coated metformin hydrochloride preparations disclosed and reported in these existing technologies, in addition to meeting the common requirements of enteric-coated preparations that no or almost no drug is released in acidic media of pH 1.0 to 3.0, and most or all of the drug is released in buffered salt media of pH 6.8, 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 are reported in the existing technologies. Some of them claim that rapid release guarantees efficacy and / or safety, while others claim that sustained release guarantees efficacy and / or safety. These are obviously contradictory and lack further verification of efficacy and / or safety.

[0007] In addition, ELCELYX THERAPEUTICS, INC. disclosed an enteric-coated formulation of metformin hydrochloride in WO2013103384A, WO2013103919A, and WO2014107617A. The enteric-coated formulation is a delayed-release (DR) formulation designed to deliver the active drug to the distal small intestine to improve the gastrointestinal tolerance of biguanide compounds and reduce adverse events caused by biguanide compounds. WO2013103384A and WO2013103919A disclose delayed-release formulations having a relative bioavailability reduced by 20% to 60%, preferably 40% to 60%, compared to conventional formulations, i.e., immediate-release formulations (IR), containing an equal amount of the biguanide compound; WO2014107617A discloses an enteric-coated oral dosage form containing a biguanide compound, wherein the dosage form continues for a lag period of at least about 5 or 10 minutes after contact with a pH of 6.0, 6.5, 6.8 or 7.0, preferably continues for a lag period of at least about 15 or 20 minutes after contact with the desired pH, and more preferably continues for a lag period of at least about 25 or 30 minutes after contact with a pH of 6.0, 6.5, 6.8 or 7.0; in a preferred embodiment, the enteric-coated oral dosage form containing a biguanide compound is resistant to septic shock for two hours at an acidic pH and for a period of at least 15 minutes at a pH of 6.0, 6.5, 6.8 or 7.0. The enteric-coated oral dosage form containing a biguanide compound releases less than 15% of the biguanide compound within a lag period of at least ten minutes or fifteen minutes 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 within two hours at acidic pH, 30 minutes at pH 5.5 and a lag period of at least ten minutes or fifteen minutes 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 may even have 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, the glucose-lowering efficacy of these studies was evaluated using fasting plasma glucose (FPG) or GLP-1, PYY, and other indicators, which have poor accuracy, especially when the number of patients is small. Therefore, the glucose-lowering efficacy of metformin hydrochloride DR preparations described is difficult to confirm clinically. For example, Elcelyx later conducted a 16-week clinical study of metformin hydrochloride DR preparations with an expanded number of patients (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 Pharma. ONE, published September 25, 2018, https: / / doi.org / 10.1371 / joumal.pone.0203946), using the clinically recognized gold standard, glycated hemoglobin (HbA1c), as an evaluation indicator. The results showed that the metformin hydrochloride DR preparation prepared using the technical solution disclosed in the patent literature failed to demonstrate the expected clinical efficacy. In a 16-week clinical trial, the optimal dosing regimen of metformin hydrochloride DR (1500mg) given to patients every morning was significantly less effective in lowering blood sugar than the control group of metformin hydrochloride IR (2000mg) (regular dosing according to the instructions, 1000mg in the morning and evening), and the magnitude of the reduction in efficacy was greater than the magnitude of the dose reduction.

[0009] Summary of the Invention

[0010] In another patent application filed on the same day, the applicant stated that the invention and research surprisingly revealed that an enteric-coated metformin hydrochloride preparation with the following specific drug release technical requirements can produce the best therapeutic effect and the lowest adverse reactions, namely: the dissolution rate of metformin hydrochloride in a pH 4.5 medium is no more than 15% within 2 hours, and the dissolution rate of metformin hydrochloride in a pH 6.8 medium is no less than 85% within 20 minutes. More preferably, the dissolution rate of metformin hydrochloride in a pH 4.5 medium is no more than 7.5% within 2 hours, and the dissolution rate in a pH 6.8 medium is more than 85% within 15 minutes. Clinical trials have shown that The results show that the enteric-coated metformin hydrochloride preparation with the drug release technical requirements improves the gastrointestinal tolerance of metformin hydrochloride without reducing or even improving the hypoglycemic efficacy, reduces adverse reactions caused by the drug, and can be taken before, after, or during meals, improving patient compliance with medication. Further pharmacokinetic and in vitro and in vivo correlation studies show that different enteric-coated metformin hydrochloride preparations with the above-mentioned drug release technical requirements are bioequivalent to the preparation of preferred embodiment (E1), that is, have the same efficacy and safety. The content of this patent application is incorporated into this application by reference.

[0011] Enteric-coated tablets are a common enteric-coated preparation, typically coated with an enteric coating. The present invention has demonstrated a close correlation between the core disintegration time of metformin hydrochloride enteric-coated tablets, the onset melting point of the enteric coating material (i.e., pH-dependent solubility), and the coating weight gain. Specifically, the selected onset melting point and enteric coating weight gain of the enteric-coated metformin hydrochloride tablets achieve the aforementioned specific drug release technical requirements, resulting in optimal therapeutic efficacy and minimal adverse reactions.

[0012] To this end, the technical solution of the present invention is as follows:

[0013] The invention provides a metformin hydrochloride enteric-coated tablet, which comprises a tablet core containing a therapeutically effective amount of metformin hydrochloride and an enteric coating layer wrapping the tablet core. The enteric-coated tablet has a metformin hydrochloride dissolution rate of no more than 15% in a pH 4.5 medium within 2 hours, and a metformin hydrochloride dissolution rate of no less than 85% in a pH 6.8 medium within 20 minutes. Preferably, the metformin hydrochloride enteric-coated tablet has a metformin hydrochloride dissolution rate of no more than 7.5% in a pH 4.5 medium within 2 hours, and a metformin hydrochloride dissolution rate of no less than 85% in a pH 6.8 medium within 15 minutes.

[0014] 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, the above-mentioned metformin hydrochloride enteric-coated tablets have a melting point of the coating material of the enteric coating layer of pH 5.0 to 6.0, and a coating weight gain of the enteric coating layer of 4.8 to 9.6 mg / cm 2 .

[0015] As one of the specific embodiments of the present invention, the above-mentioned metformin hydrochloride enteric-coated tablets, wherein the coating material in 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 .

[0016] As one of the specific embodiments of the present invention, the above-mentioned metformin hydrochloride enteric-coated tablets, wherein the coating material in 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 .

[0017] As one of the specific embodiments of the present invention, the above-mentioned metformin hydrochloride enteric-coated tablets, wherein the coating material in 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 .

[0018] 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: hydropropyl methylcellulose phthalate (HP-50), methacrylic acid and ethyl acrylate copolymer (L100-55), methacrylic acid and ethyl acrylate copolymer (L30D-55), hydropropyl methylcellulose phthalate (HP-55), hydropropyl methylcellulose acetate succinate (HPMCAS-L), methacrylic acid and methyl methacrylate copolymer (L100; polyacrylic resin II), hydropropyl methylcellulose acetate succinate (HPMCAS-M), and cellulose acetate phthalate (CAP; cellulose acetate).

[0019] 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.

[0020] The metformin hydrochloride enteric-coated tablets described above can, if desired, be coated with a separator layer before the enteric coating layer. For example, when the enteric coating weight gain is low, adding a separator layer between the tablet core and the enteric coating layer can reduce the amount of enteric material used and enhance the enteric effect. Alternatively, for enteric materials with compatibility issues with drugs, adding a separator layer can increase drug stability.

[0021] The above-mentioned enteric-coated metformin hydrochloride tablets of the present invention have a relative bioavailability of (60-80)% compared with conventional preparations or rapid-release preparations (such as Glucophage) containing the same amount of metformin hydrochloride.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] Enteric-coated tablets are typically prepared by coating ordinary tablets with an enteric coating. The preparation of the metformin hydrochloride enteric-coated tablets of the present invention, such as the process of preparing the tablet core and coating the tablet core with an enteric coating layer, can be performed by those skilled in the art according to the general preparation process for enteric-coated tablets in the art. Metformin hydrochloride enteric-coated tablets meeting the specific drug release technical requirements of the present invention can be prepared by taking into account the core disintegration time, the onset melting point of the enteric coating material, and the coating weight gain, particularly the selected onset melting point and enteric coating weight gain, of the tablet core described in 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 smooth liquid supply, adjusting the atomization pressure and fan pressure to ensure 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, strictly controlling the intake air 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.

[0026] In the present invention, "dissolution" is also referred to as "release rate" and "dissolution" is also referred to as "release", which have the same meaning. The dissolution or release rate of a drug can be determined according to methods commonly used in the art, such as the dissolution and release rate determination method according to Method 1 of General Chapter 0931 of the Chinese Pharmacopoeia (2020 Edition).

[0027] In the present invention, the onset 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 onset melting point of the enteric material is 5.0, it means that the enteric material dissolves at pH ≥ 5.0. For understanding the onset melting point of coating materials, please refer to the description of the solubility of poly(meth)acrylic acid resin on page 534 of the Handbook of Pharmaceutical Excipients (Fourth Edition), Chemical Industry Press, 2005: Different types dissolve at different pH values, such as Eudragit L100 dissolves at pH>6, and Eudragit S100 dissolves at pH>7. This means that the onset melting points of Eudragit L100 and Eudragit S100 are pH 6 and pH 7, 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 ≥ 55, and AS-MF and AS-MG dissolve at pH ≥ 6.0. This means that the onset melting points of AS-LF and AS-LG are pH 5.5, and those of AS-MF and AS-MG are pH 6.0.

[0028] The disintegration time limit 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 of General Chapter 0921 of the Chinese Pharmacopoeia (2020 edition).

[0029] 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.

[0030] The enteric-coated tablets of the present invention are tablets that meet the drug release requirements of the present invention while complying with the general drug release requirements of enteric-coated preparations. The general drug release requirements of enteric-coated preparations are defined as a preparation that releases no or almost no drug in a specified acidic medium (e.g., pH 1.0-3.0), but releases most or all of the drug within a specified time in a near-neutral medium (e.g., pH 6.0-6.8 phosphate buffer).

[0031] In the present invention, the dosage or therapeutically effective amount of metformin hydrochloride in a unit dosage form, the therapeutic uses of metformin hydrochloride, and its adverse reactions, etc., are known in the art. For example, the relevant disclosures of the prior art mentioned in the specification are also incorporated into this application by reference.

[0032] The present invention has discovered that an enteric-coated metformin hydrochloride formulation with specific release technology requirements can produce the best therapeutic effect and minimize adverse reactions. The formulation has the following release technology requirements: the dissolution rate of metformin hydrochloride in a pH 4.5 medium is no more than 15% within 2 hours, and the dissolution rate of metformin hydrochloride in a pH 6.8 medium is no less than 85% within 20 minutes. More preferably, the dissolution rate of metformin hydrochloride in a pH 4.5 medium is no more than 7.5% within 2 hours, and the dissolution rate in a pH 6.8 medium is greater 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 onset point or a lower enteric coating weight gain. However, enteric materials with a lower onset point or a lower enteric coating weight gain can easily lead to increased release in a pH 4.5-5.0 medium. The present invention has obtained that the selected tablet core disintegration time, enteric coating material melting point and coating weight gain, especially the selected enteric coating material melting point and coating weight gain, 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 adverse reactions caused by the drug, and are significantly different from metformin hydrochloride IR or enteric-coated preparations with non-above-mentioned release characteristics. Further studies such as formulation process and in vitro and in vivo correlation have shown that enteric coating materials with different melting points can meet the above-mentioned drug release technical requirements while controlling appropriate coating weight gain and tablet core disintegration time, and are bioequivalent to the metformin hydrochloride enteric-coated tablets of preferred embodiment (E1). BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1: HbA1c reduction during 12-week treatment with E1, D2, DS, and Glucophage(R)

[0034] Figure 2: E1, D2, DS and Glucophage(R) FPG Trends

[0035] Figure 3: AEs of E1, D2, D5, and Glucophage(R)

[0036] Figure 4: Dissolution curves of E1, D2, and D5 (pH 6.8)

[0037] Figure 5: Concentration-time curves of E1, D2, D5 and Glucophage(R)

[0038] Figure 6: Dissolution curves of E1, E10, E13, and D4 (pH 6.8)

[0039] Figure 7: Plasma concentration-time curves of E1, E10, E13, and D4

[0040] Figure 8: Dissolution curves of E1, E4, and D1 (pH 6.8)

[0041] Figure 9: Plasma concentration-time curves of E1, E4, and D1

[0042] Figure 10: Subject distribution and flow chart DETAILED DESCRIPTION

[0043] The following specific examples are only used to explain or illustrate the content of the present invention. Obviously, the embodiments of the present invention are not limited to the specific examples listed, and therefore they should not be understood as constituting any limitation on the scope of protection of the claims of this patent application.

[0044] 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 Table 1 below.

[0045] Table 1 Overview of core tablets and coatings of Examples and Comparative Examples

[0046] Note: A: Melting point is pH 5.0; B: Melting point is pH 5.5; C: Melting point is pH 6.0; D: Melting point is pH 6.5

[0047] A1, Hydroxypropyl methylcellulose phthalate (HP-50)

[0048] B1, methacrylic acid and ethyl acrylate copolymer (L100-55)

[0049] B2, methacrylic acid and ethyl acrylate copolymer (L30D-55)

[0050] B3, Hydroxypropyl methylcellulose phthalate (HP-55 or HP-55S)

[0051] B4, Hydroxypropyl methylcellulose acetate succinate (HPMCAS-L)

[0052] C1, methacrylic acid and methyl methacrylate copolymer (L100; polyacrylic resin II)

[0053] C2, Hydroxypropyl methylcellulose acetate succinate (HPMCAS-M)

[0054] C3, Cellulose acetate phthalate (CAP; Cellulose acetate)

[0055] D1, Eudragit FS+Eudragit L(pH6.5)

[0056] ++: Dissolution in pH 6.8 medium > 85% in 20 minutes

[0057] +++: Dissolution rate in pH 6.8 medium > 85% within 15 minutes

[0058] **: Clinical trial and pharmacokinetic test prescription;

[0059] VV1: in vitro and in vivo correlation test (test 1);

[0060] VV2: In vitro and in vivo correlation test (Test 2)

[0061] 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%). For the surface area of ​​the preparation, please refer to the "Eudra Manual - Surface Area Calculation" and other literature methods.

[0062] Example 1 (E1): Metformin Hydrochloride Enteric-Coated Tablets

[0063] Core composition:

[0064] 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. The granules are wet-granulated using a vertical granulator (installed with a 5×5mm square hole screen) and then placed in a fluidized bed for drying. 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. The hardness of the plain tablets is controlled to be 8-11kg.

[0065] Referring 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.

[0066] Enteric coating liquid composition:

[0067] 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 talc powder 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% (7.2 mg / cm 2 ).

[0068] Example 2 (E2): Metformin Hydrochloride Enteric-Coated Tablets

[0069] 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 1. The coating weight gain was 3.5% (5.6 mg / cm 2 ).

[0070] Example 3 (E3): Metformin Hydrochloride Enteric-Coated Tablets

[0071] 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 1. The coating weight gain was 7.0% (11.2 mg / cm 2 ).

[0072] Example 4 (E4): Metformin Hydrochloride Enteric-Coated Tablets

[0073] The tablet core composition and preparation method of Example 1 were used to obtain the total mixed granules. During tableting, the tablet hardness was controlled at 15-18 kg (a small amount of binder was added if necessary). According to the disintegration time limit test method in Part IV of the 2020 edition of the Chinese Pharmacopoeia, the tablets completely disintegrated within 6-8 minutes. The composition, process, and weight gain of the enteric layer coating solution were the same as in Example 1.

[0074] Example 5 (E5): Metformin Hydrochloride Enteric-Coated Tablets

[0075] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0076] Enteric coating liquid composition:

[0077] Enteric layer coating: Add polyethylene glycol 6000 and talc to purified water and 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 and stir slowly to disperse evenly. Pass through an 80 mesh sieve before coating. Use a coating machine to coat the enteric layer. After coating, dry the enteric layer for aging treatment. The enteric layer coating weight gain is 5.5% (8.8 mg / cm 2 ).

[0078] Example 6 (E6): Metformin Hydrochloride Enteric-Coated Tablets

[0079] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0080] Enteric coating liquid composition:

[0081] Enteric layer coating: Use 95% ethanol and purified water to make 80% ethanol, add hydroxypropyl methylcellulose phthalate to 80% ethanol, stir until completely dissolved, then add triethyl citrate and talc powder in sequence 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 4.5% (7.2mg / cm 2 ).

[0082] Example 7 (E7): Metformin Hydrochloride Enteric-Coated Tablets

[0083] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0084] Enteric coating liquid composition:

[0085] Enteric layer coating: Cool 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 (micronized powder) and talcum powder, stir until evenly dispersed, pass through a 100-mesh sieve before coating, and use a coating machine to coat the enteric layer. The coating solution 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% (9.3 mg / cm 2 ).

[0086] Example 8 (E8): 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] Enteric layer coating: Add methacrylic acid and methyl methacrylate copolymer and hydroxypropyl methylcellulose phthalate to 90% ethanol and stir until completely dissolved. Then add triethyl citrate and talc powder 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 ).

[0090] Example 9 (E9): Metformin Hydrochloride Enteric-Coated Tablets

[0091] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0092] Enteric coating liquid composition:

[0093] Enteric layer coating: Add methacrylic acid and ethyl acrylate copolymer to 90% ethanol and stir until completely dissolved. Then add polyethylene glycol 6000 and talc powder 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 ).

[0094] Example 10 (E10): Metformin Hydrochloride Enteric-Coated Tablets

[0095] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0096] Enteric coating liquid composition:

[0097] Enteric layer coating: Add Hydroxypropyl Methylcellulose Phthalate to 80% ethanol and stir until completely dissolved. Then add triethyl citrate and talc powder 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 8.0% (12.8 mg / cm 2 ).

[0098] Example 11 (E11): Metformin Hydrochloride Enteric-Coated Tablets

[0099] 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 6.0% (9.6 mg / cm 2 ).

[0100] Example 12 (E12): Metformin Hydrochloride Enteric-Coated Tablets

[0101] 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 ).

[0102] Example 13 (E13): Metformin Hydrochloride Enteric-Coated Tablets

[0103] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0104] Enteric coating liquid composition:

[0105] Enteric layer coating: Add methacrylic acid and methyl methacrylate copolymer to 90% ethanol and stir until completely dissolved. Then add triethyl citrate and talc powder 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% (5.6 mg / cm 2 ).

[0106] Example 14 (E14): Metformin Hydrochloride Enteric-Coated Tablets

[0107] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0108] Enteric coating liquid composition:

[0109] Enteric layer coating: Add methacrylic acid and methyl methacrylate copolymer to 90% ethanol and stir until completely dissolved. Then add triethyl citrate and talc powder 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% (4.8 mg / cm 2 ).

[0110] Example 15 (E15): Metformin Hydrochloride Enteric-coated Tablets Prescription

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

[0112] Isolation layer coating liquid composition:

[0113] Seal coat: Add the gastric-soluble film coating premix to purified water, stir to disperse evenly, and sieve through an 80-mesh sieve before coating. Use a coater to coat the seal coat. After coating, dry to remove residual moisture. The coating weight gain is 2.0%.

[0114] Enteric coating liquid composition:

[0115] Enteric layer coating: Add methacrylic acid and methyl methacrylate copolymer to 90% ethanol and stir until completely dissolved. Then add triethyl citrate and talc powder 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 ).

[0116] Example 16 (E16): 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] Enteric layer coating: Add methacrylic acid and methyl methacrylate copolymer to 90% ethanol and stir until completely dissolved. Then add triethyl citrate and talc powder 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% (7.2 mg / cm 2 ).

[0120] Example 17 (E17): Metformin Hydrochloride Enteric-Coated Tablets

[0121] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0122] The enteric layer coating solution formulation and process were the same as in Example 16, and the enteric layer coating weight gain was 5.5% (8.8 mg / cm 2 ).

[0123] Example 18 (E18): Metformin Hydrochloride Enteric-Coated Tablets

[0124] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0125] Enteric coating liquid composition:

[0126] 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 ).

[0127] Example 19 (E19): Metformin Hydrochloride Enteric-Coated Tablets

[0128] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0129] Enteric coating liquid composition:

[0130] Enteric layer coating: Add cellulose acetate and triacetin to acetone, stir until completely dissolved, and pass 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 ).

[0131] Example 20 (E20): Metformin Hydrochloride Enteric-Coated Tablets

[0132] 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 1, and the enteric layer coating weight was increased by 3.0% (4.8 mg / cm 2 ).

[0133] Example 21 (E21): Metformin Hydrochloride Enteric-Coated Tablets

[0134] Tablet cores were prepared according to the composition and preparation method of Example 1; isolation coating was prepared 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 prepared 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 ).

[0135] Comparative Example 1 (D1): Metformin Hydrochloride Enteric-Coated Tablets

[0136] The core composition of the tablets refers to Glucophage (metformin hydrochloride tablets), specifically:

[0137] Preparation method: Povidone K30 is dissolved in purified water to prepare an adhesive for use, metformin hydrochloride is crushed and passed through a 100-mesh sieve, the crushed raw materials are placed in a fluidized bed granulator, and then the adhesive is sprayed into the granulator for one-step granulation, the moisture content of the dry granules is controlled within the range of 1.0-4.0%, the dry granules are granulated (the granulator is equipped with a 1.5 mm round hole screen), magnesium stearate is added, and the mixture is placed in a mixer for 5 minutes, and then a 12 mm round punch is used for tableting, and the hardness of the plain tablets is controlled within the range of 11-15 kg.

[0138] Referring to the disintegration time limit test method in General Chapter 0921 of Part IV of the 2020 edition of the "Chinese Pharmacopoeia", it was measured that the plain tablets completely disintegrated within 12 to 15 minutes.

[0139] The composition, process and weight gain of the enteric layer coating solution are the same as those in Example 1.

[0140] Comparative Example 2 (D2): Metformin Hydrochloride Enteric-Coated Tablets

[0141] 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 10. The coating weight gain was 2.5% (4.0 mg / cm 2 ).

[0142] Comparative Example 3 (D3): Metformin Hydrochloride Enteric-Coated Tablets

[0143] Tablet cores were prepared according to the composition and preparation method of Example 1, and enteric coating was performed according to the composition and process of enteric coating solution of Example 13. The coating weight gain was 2.0% (3.2 mg / cm 2 ).

[0144] Comparative Example 4 (D4): Metformin Hydrochloride Enteric-Coated Tablets

[0145] Tablet cores were prepared according to the composition and preparation method 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 ).

[0146] Comparative Example 5 (D5): Metformin Hydrochloride Enteric-Coated Tablets Prescription

[0147] The tablet core is based on Glucophage, and the enteric-coated material is Eudragit FS30D + Eudragit L30D-55 = 4:6. Its melting point pH value is close to 6.5. The details are as follows:

[0148] The tablet core was prepared according to the tablet core composition and preparation method of Comparative Example 1.

[0149] Isolation layer coating liquid composition:

[0150] Seal coating: Add the gastric-soluble film coating premix to purified water, stir to disperse evenly, and pass through an 80-mesh sieve before coating. Use a coating machine to apply the seal coat. After coating, dry to remove residual moisture. The coating weight gain is 1.1%.

[0151] Enteric coating liquid composition:

[0152] Enteric layer coating: Add triethyl citrate and talc to purified water and use a high shear homogenizer to fully homogenize for 5 to 10 minutes. Then slowly pour the above liquid into the aqueous dispersion of Eudragit FS30D and L30D-55, slowly stir to disperse evenly, and pass through an 80 mesh sieve before coating. Use a coating machine to coat the enteric layer. After coating, dry the enteric layer for aging treatment. The enteric layer coating weight gain is 3.8% (6.1 mg / cm 2 ).

[0153] Comparative Example 6 (D6): Metformin Hydrochloride Enteric-Coated Tablets

[0154] 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 1. The coating weight gain was 2.5% (4.0 mg / cm 2 ).

[0155] Comparative Example 7 (D7): Metformin Hydrochloride Enteric-Coated Tablets

[0156] 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 1. The coating weight gain was 9.0% (14.4 mg / cm 2 ).

[0157] Comparative Example 8 (D8): Metformin Hydrochloride Enteric-Coated Tablets

[0158] The tablet core was prepared according to the composition and preparation method of Example 1. Enteric coating was applied according to the composition and process of the enteric layer coating solution of Example 10, and the coating weight gain was 10.0% (16.0 mg / cm 2 ).

[0159] Dissolution test method and results

[0160] Referring to the dissolution test conditions of metformin hydrochloride enteric-coated tablets in the 2020 edition of the "Chinese Pharmacopoeia", the dissolution and release rate determination method (General Chapter 0931 Method 1) was used for determination.

[0161] Acid dissolution

[0162] 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 method, and take samples after 2 hours.

[0163] Test solution: Take 20 ml of the eluate, filter, discard 10 ml of the initial filtrate, and take the subsequent filtrate.

[0164] Reference solution: Take an appropriate amount of metformin hydrochloride reference substance, accurately weigh it, dissolve it in 0.1 mol / L hydrochloric acid solution and quantitatively dilute it to make a solution containing approximately 28 μg per 1 ml.

[0165] Determination method: Take the test solution and the reference solution, measure the absorbance at a wavelength of 233nm, and calculate the dissolution amount.

[0166] Limit: Not more than 10% of the labeled amount.

[0167] Dissolution in pH 4.5 Buffer: Use 900 ml of pH 4.5 acetate buffer as the dissolution medium, using the blue method at 100 rpm. Samples are collected after 2 hours. The test and reference solutions are determined using the same method as for pH 6.0 and pH 6.8 medium.

[0168] 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 900 ml 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.

[0169] 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.

[0170] Reference solution: Take an appropriate amount of metformin hydrochloride reference substance, accurately weigh it, dissolve it in water and quantitatively dilute it to make a solution containing approximately 5 μg per 1 ml.

[0171] Determination method: Take the test solution and the reference solution, measure the absorbance at a wavelength of 233nm, and calculate the dissolution amount.

[0172] Preparation of dissolution medium:

[0173] 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 to 4.50 with glacial acetic acid.

[0174] 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 to 6.0±0.05 with 2mol / L hydrochloric acid solution or 2mol / L sodium hydroxide solution.

[0175] 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 in a ratio of 3:1, and adjust the pH to 6.8 ± 0.05 with 2 mol / L hydrochloric acid solution or 2 mol / L sodium hydroxide solution if necessary.

[0176] 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 2 (the pH 1.0 value is the average of the acid-resistant data in pH 6.0 and pH 6.8 media); the dissolution results in pH 6.0 and pH 6.8 media are shown in Tables 3 and 4 (the dissolution at 0 in the chart is the acid-resistant 2h test value; 6 formulation units are used for each dissolution curve measurement).

[0177] Table 2 Dissolution of Examples and Comparative Examples in pH 1.0 and pH 4.5 Media for 2 Hours (%)

[0178] Table 3 Dissolution of Examples and Comparative Examples in pH 6.0 Medium

[0179] Table 4 Dissolution of Examples and Comparative Examples in pH 6.8 Medium

[0180] The enteric-coated metformin hydrochloride formulation disclosed in WO2014107617A requires release of less than 15%, 10%, or 5% of the biguanide compound within two hours at an acidic pH and a lag phase of at least ten or fifteen minutes at pH 6.8. Following the lag phase, at least 60% of the biguanide compound is released within 60 minutes at pH 6.8, and at least 90% of the biguanide compound is released within 90 to 120 minutes at pH 6.8. As can be seen, the dissolution rate of Comparative Example 5 meets the requirements of the enteric-coated metformin hydrochloride formulation described in this patent document.

[0181] Clinical trials and results

[0182] Patients who were intolerant to ordinary rapid-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 rapid-release metformin hydrochloride tablets (reference preparation R, trade name Commercially available), to evaluate the effects of metformin hydrochloride enteric-coated tablets with different release characteristics on controlling blood sugar and improving patient tolerance.

[0183] Inclusion criteria: Subjects who meet all of the following criteria can be included in this trial:

[0184] (1) Ages 28 to 78 years old, male or female;

[0185] (2) diagnosed with type 2 diabetes according to the WHO (1999) diabetes diagnostic criteria;

[0186] (3) Patients who have not taken other hypoglycemic drugs and are intolerant to ordinary rapid-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, have been taking the drug for less than 2 weeks, and are willing to change the drug.

[0187] (4) Glycated hemoglobin (HbA) at the screening visit 1c )≥7.0% and ≤11.0%;

[0188] (5) fasting plasma glucose (FPG) ≤15 mmol / L (270 mg / dL) at the screening visit;

[0189] (6) Body mass index (BMI) ≥ 19 kg / m 2 and ≤35kg / m 2 ;

[0190] Dosage: Replace the original regular immediate-release metformin hydrochloride tablets with the same dose of E1, D2, D5, or Glucophage. Increase the dose by 500 mg per week (take once in the morning and evening) until it reaches 2000 mg / day. For patients who have already reached 2000 mg / day, do not increase the dose; continue taking the alternative medication at the original dose and method. For patients who continue to have intolerance after the medication change, reduce the dose to 1500 mg / day or 1000 mg / day.

[0191] During treatment, assessors who develop other diseases that affect efficacy or 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.

[0192] Main efficacy index: HbA after 12 weeks of treatment 1c Change from baseline.

[0193] Secondary efficacy indicators:

[0194] (1) Changes in fasting blood glucose (FPG) compared with baseline at 4, 8, and 12 weeks of medication;

[0195] (2) changes in body weight compared with baseline at 4, 8, and 12 weeks of medication;

[0196] (3) changes in blood lipids (TC, TG, LDL-C, HDL-C) compared with baseline at 4, 8, and 12 weeks of medication;

[0197] Safety evaluation: Adverse events were recorded at any time during the study, with special attention paid to observing common gastrointestinal adverse reactions of metformin (including abdominal pain, diarrhea, constipation, abdominal distension, indigestion, etc.);

[0198] All medications (including concomitant medications) and adverse events were recorded in diary cards. Diary cards were collected at the next visit and medication compliance was calculated (by counting the number of tablets used, generally requiring the actual number used to be greater than 80% of the theoretical dosage). Patients with poor compliance were supervised. Subjects taking other hypoglycemic medications were excluded.

[0199] The trial process and subject distribution are shown in Table 5 and Figure 10. In Figure 10, the FAS represents the full analysis set, consisting of all subjects who received the trial drug and used for safety and adverse event analyses; the PPS represents the per-protocol set, consisting of all subjects who received the trial drug according to the protocol and obtained a second HbA1c value and used for efficacy analyses.

[0200] Table 5 Test process

[0201] *: 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.

[0202] Test results and discussion

[0203] E1 demonstrated the best efficacy, measured by HbA1c, with a similar trend observed for fasting blood glucose. Furthermore, the magnitude of the reduction in fasting blood glucose increased with duration of E1 use, suggesting that E1 may have superior long-term efficacy (see Figures 1-2 and Table 6; the FPG at week 16 was an unplanned measurement due to the small number of patients and the large time span, and therefore was not statistically analyzed). E1 also outperformed other formulations in terms of its effects on blood lipids and liver and kidney function. D2 showed no significant difference in glucose-lowering effect compared to the control drug, Glucophage, while D5 showed a significant difference (P < 0.05, and the difference exceeded the clinical non-inferiority margin of 0.3-0.4).

[0204] Table 6: Efficacy indicators

[0205] *: P < 0.5 compared with baseline; **: P < 0.01 compared with baseline

[0206] E1, D2, and D5 were significantly superior to Glucophage in terms of upper gastrointestinal adverse events (AEs), including nausea, vomiting, abdominal pain, discomfort, bloating, and acid reflux. E1 and D5 were particularly effective in reducing the incidence of upper gastrointestinal adverse events (AEs) in patients taking regular metformin hydrochloride tablets. The incidence of upper gastrointestinal AEs after switching to E1 and D5 was reduced to 33% of the pre-drug switching rate, compared to 93% for Glucophage. D2 showed less significant improvement, with the incidence of upper gastrointestinal AEs after the switch to 59% of the pre-drug switching rate. E1 also demonstrated some advantages in other AEs (see Table 7 and Figure 3).

[0207] Table 7: Adverse events

[0208] AE: adverse event

[0209] Upper gastrointestinal AEs include: nausea, vomiting, abdominal pain, abdominal discomfort, bloating, and acid reflux

[0210] Lower gastrointestinal AEs include: diarrhea, constipation

[0211] Ratio = adverse events during the trial period / adverse events during the screening period*100%;

[0212] *: P < 0.05 compared with R

[0213] The inventors conducted further analysis of patients in group D2 and found a clear correlation between upper gastrointestinal reactions and the timing of medication administration: patients who took the drug before meals (30 minutes before meals) experienced significantly lower rates of upper gastrointestinal reactions than those who took the drug after or during meals (no such correlation was found for E1 and D5). This is significantly inconsistent with literature reports on the adverse reaction profile of metformin, which show that adverse reactions are higher when taken before meals than when taken during or after meals. Consequently, instructions in various countries require that metformin (common formulations) be taken during (or immediately after) meals to reduce gastrointestinal adverse reactions.

[0214] After noticing the above phenomenon, the researchers compared the relationship between adverse events and meal times and observed adverse events when patients took the drug before and after meals, as shown in Table 8:

[0215] Table 8: Comparison of adverse events between pre-meal and post-meal administration in patients in group D2

[0216] The definition of upper gastrointestinal AE is the same as the above table.

[0217] The data on the correlation between medication / meal / AE could not be distinguished because the diary card did not clearly record the time of medication and meal, etc., and therefore the number of people counted before + during meals and after meals was less than the total number of the D2 group.

[0218] The inventors analyzed the reasons by comparing the D2 formulation process and dissolution conditions, and believed that it might be because D2 has a low initial melting point, a small coating weight gain (a thinner enteric coating), a higher pH in the stomach and upper small intestine during and after meals (up to 5 or higher), and accelerated gastric motility and delayed emptying after meals. In addition, the food is squeezed, which may cause the enteric coating to dissolve and rupture faster, thereby releasing the drug in advance. The pH value in the stomach is lower before meals, the gastric motility is slow and gentle, and the emptying is faster. Therefore, 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.

[0219] The inventors designed a separate dissolution test: using simulated postprandial gastric fluid (acetate buffer and milk mixed in a 1:1 ratio, adjusted to pH 5.0 using sodium hydroxide or hydrochloric acid, acetate buffer containing 13.85 g / L sodium chloride, 1.03 g / L acetic acid, and 2.44 g / L sodium acetate), the D2 dissolution test was performed using a paddle method at 75 rpm. The tablet began to break after 30 minutes, the dissolution rate reached over 75% after 60 minutes, and all metformin was dissolved after 90 minutes (detection method: high-performance liquid chromatography, after sample filtration and dilution (pre-column added if necessary), sulfonic acid cation exchange bonded silica gel was used as the filler, 1.7% ammonium dihydrogen phosphate solution (pH adjusted to 4.0 with phosphoric acid) was used as the mobile phase, the detection wavelength was 233 nm, the column temperature was 30°C, and the flow rate was 1.3 ml / min). The test results showed that it was difficult to achieve the "enteric dissolution" effect of D2 when taken after a meal.

[0220] The inventors repeated postprandial gastric dissolution testing using Examples 12 (E12) and 15 (E15), using the same testing methods as above. The tablets in Example 12 (E12) began to break at approximately 60 minutes, with a dissolution rate of approximately 20%, and reached over 30% by 90 minutes. The tablets in Example 15 (E15) began to swell and deform at approximately 60 minutes, with a dissolution rate of approximately 10%, and reached approximately 25% by 90 minutes. Considering that the drug dissolved in the human stomach is continuously diluted and excreted into the intestines, the intragastric metformin concentration should be significantly lower than that of the immediate-release tablets.

[0221] In order to better understand the dissolution of the product in the human body, especially considering that the influence of the mechanical force of gastrointestinal motility is more obvious when taking the medicine after a meal, the inventors conducted a reciprocating barrel dissolution test, using simulated postprandial gastric juice (the composition of postprandial gastric juice and the detection method of metformin are the same as above) as the medium, and set the reciprocating barrel reciprocating speed to 30dpm. As a result, D2 began to rupture at 25 minutes, and the dissolution rate reached more than 85% after 60 minutes. E12 began to rupture at about 50 minutes, the dissolution rate was about 25% at 60 minutes, and the dissolution rate was about 40% at 90 minutes; the dissolution rate of E15 was about 15% at 60 minutes, and about 35% at 90 minutes. The experiment further shows that it is difficult to achieve the "enteric dissolution" effect of D2 after a meal.

[0222] When taken with or after a meal, the drug often remains in the stomach longer than when taken on an empty stomach, and the pH is also higher, reaching 4.5-5.0. Pharmacokinetic and bioequivalence (BA) testing indicates that metformin enteric-coated tablets can remain in the stomach for several hours when taken with a meal, making dissolution in a pH 4.5 medium of great value for this product. Clinical and simulated postprandial gastric fluid testing showed that when dissolution in a pH 4.5 medium exceeded 20% (D2), gastric release significantly increased, as did adverse reactions. However, when dissolution was below 15% (E12 and E15), limited gastric release was achieved, and when it was below 7.5% (E4, E13, and E22), bioequivalence to the optimal target product (E1) was achieved.

[0223] Currently, most national drug regulatory authorities require enteric-coated tablets to dissolve less than 5% to 10% in a pH 1.0 medium within 2 hours. D2 meets this requirement, but this requirement makes it difficult to ensure enteric coating when taken after meals. Since ordinary metformin hydrochloride preparations (i.e., immediate-release preparations) are taken after or during meals, many patients still habitually take metformin hydrochloride enteric-coated tablets after or during meals. Therefore, ensuring enteric coating after meals is even more important for metformin hydrochloride. At the same time, the ability to take the tablets before, after, or during meals can significantly improve patient compliance with medication.

[0224] D5 significantly improved upper gastrointestinal adverse reactions compared to Glucophage, but lower gastrointestinal reactions were higher than those of Glucophage, D2, and E1. The incidence of lower gastrointestinal adverse events (primarily diarrhea) was 130% of that of the standard tablets, and the duration of diarrhea was 156% of that of the standard tablets. Furthermore, five patients on D5 experienced severe watery stools. Two of these experienced this after taking standard metformin tablets and worsened after switching to D5, and three experienced normal symptoms after taking standard metformin tablets and developed them after switching to D5. The researchers determined these symptoms to be drug-induced adverse reactions.

[0225] Because metformin has strong irritation to gastrointestinal mucosa, the inventor considers that watery stool is caused by the stimulation of drug to colorectal mucosa. According to drug prescription and dissolution situation, D2 should be discharged in stomach, duodenum and upper small intestine (different according to different medication time), and E1 should be discharged in small intestine. Small intestine peristalsis is faster, and there is a large amount of intestinal fluid, so the drug is diluted very soon, and is less than colon irritation. D5 dissolves slower, is likely to be discharged in colon, and colon peristalsis is slow, intestinal fluid is few, and drug absorption is few, may form larger concentration locally, irritation to colon mucosa.

[0226] Pharmacokinetic studies and their results

[0227] 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.

[0228] Four products with different release characteristics from the above clinical trials were selected, namely, three metformin hydrochloride enteric-coated tablets, E1, D2, and D5 (their dissolution curves are shown in Figure 4; considering that the drug dissolved in acid will also be absorbed, D2 is the cumulative dissolution, cumulative dissolution = dissolution + dissolution at 0 / dissolution in acid) and compared with 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.

[0229] Test method:

[0230] Inclusion Criteria. Subjects must meet all of the following criteria to be included:

[0231] 1) Healthy subjects: medical history, vital signs, physical examination, laboratory tests, electrocardiogram, chest X-ray and other related examinations are within normal range, or the researchers judge that the abnormalities are of no clinical significance;

[0232] 2) Men and women aged 18 to 65 years (including borderline values);

[0233] 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 )];

[0234] 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:

[0235] 1) The first sample is C max If the subject does not have an early sample (within 30 minutes after administration), the pharmacokinetic data of the corresponding period will not be included in the evaluation;

[0236] 2) After the drug administration, the subjects max If vomiting occurs within twice the median time, the pharmacokinetic data of the corresponding cycle of the subject will not be included in the evaluation;

[0237] 3) The blood drug concentration before administration (0 time concentration) is greater than the corresponding C after administration max If the pharmacokinetic data of the subject in the corresponding period is less than 5%, the pharmacokinetic data of the subject in the corresponding period will not be included in the evaluation;

[0238] 4) During the trial, the trial data may have significant deviations or the PK parameters may be unable to 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.

[0239] Dosing regimen. A four - cycle crossover trial design was adopted, with dosing once on the first day of each cycle and a 3 - day washout period during the two - week period. 20 subjects were randomly divided into 4 groups at a ratio of 1:1:1:1. Subjects fasted for 10 h before dosing, but were allowed to drink water. On the day of dosing, the reference preparation (R / Glucophage, 1 tablet, 500 mg) or the test preparations (E1, D2, D5; all 500 mg) were taken orally with 240 ml of warm water on an empty stomach. Standard lunch was eaten 4 h after taking the medicine.

[0240] The trial design is shown in Table 9.

[0241] Table 9: Trial design

[0242] Throughout the trial period, subjects ate standard meals provided by the research center. During the trial, subjects avoided strenuous exercise and prolonged bed rest, and were prohibited from taking beverages containing caffeine or ethanol such as juice, tea, coffee, and wine, and smoking was also prohibited. If adverse events occurred during the trial, the researcher needed to follow up the subjects until the adverse events were alleviated or the symptoms disappeared.

[0243] Blood samples were collected at 0 h (within 60 min before the subjects took the medicine), 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 sampling points, and 72 blood sampling points in 4 cycles). 3 ml of peripheral venous blood was collected at each blood sampling point and placed in a K2EDTA blood collection tube, centrifuged (1700 g, 2℃ - 8℃, with the set temperature at 4℃) for 10 min to separate the plasma, and the plasma samples were stored in a low - temperature 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 G C, Huang J Q, etc., 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, October 2012, Vol. 47, No. 18).

[0244] The trial results are as follows (Tables 10 - 11 and Figure 5).

[0245] Table 10: Pharmacokinetic parameters (PKPS) Note: Mean±SD represents the arithmetic mean±standard deviation; T max is expressed as the median (minimum - maximum).

[0246] Table 11: Relative bioavailability

[0247] The test results showed that the dissolution behavior of metformin enteric-coated tablets had a clear correlation with absorption. The relative bioavailability of the fastest (D2), medium (E1) and slowest (D5) releasing metformin hydrochloride enteric-coated tablets relative to Glucophage were 91%, 72% and 48%, respectively. Dissolution was highly correlated with absorption (see Figures 4 and 5). Combined with clinical trials, it can be seen that dissolution is also significantly correlated with clinical efficacy and adverse reactions.

[0248] There was one case of nausea in the reference preparation group and one case of diarrhea on D5, both of which recovered on their own the next day. No adverse reactions were found in the other groups.

[0249] The enteric-coated preparations disclosed in WO2013103384A and WO2013103919A have a relative bioavailability reduction of 20% to 60%, preferably 40% to 60%, compared to conventional preparations, i.e., immediate-release preparations, containing an equal amount of the biguanide compound. It can be seen that D5 meets the requirements of the enteric-coated metformin hydrochloride preparations described in the patent documents. 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.

[0250] In vivo and in vitro correlation studies and results

[0251] The clinical trials and pharmacokinetic studies of E1, D2, and D5 demonstrated a clear correlation between the efficacy, safety, and absorption of metformin enteric-coated formulations and drug dissolution. To further investigate the relationship between release characteristics and drug absorption, efficacy, and safety, the inventors conducted the following in vitro and in vivo correlation studies.

[0252] Test 1:

[0253] To study the effects of enteric coating materials, weight gain, and related release profiles on drug absorption, the following representative formulations were selected:

[0254] Example 1 (E1): used as a reference preparation (93.8% dissolution in pH 6.8 medium within 15 minutes and 101.1% dissolution within 20 minutes).

[0255] Example 10 (E10): The tablet core is the same as E1, and the enteric coating material is hydroxypropyl methylcellulose phthalate (HP-50) with a melting point of pH 5.0. The coating weight gain is 8%. The dissolution rate in pH 6.8 medium is 71.1% in 15 minutes and 93.3% in 20 minutes.

[0256] 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.

[0257] Comparative Example 4 (D4): The tablet core was the same as E1, and the enteric coating material was a copolymer of methacrylic acid and methyl methacrylate (Eutrac L100) with a melting point of pH 6.0. The coating weight gain was 6.5%, and the dissolution rate in a pH 6.8 medium was 25.0% in 15 minutes and 73.0% in 20 minutes.

[0258] 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).

[0259] The experimental design is shown in Table 12.

[0260] Table 12: Experimental Design

[0261] Because the previous pharmacokinetic test showed that the blood drug concentration was still high at 24 hours, this trial extended the blood collection time to 48 hours (adding two blood collection points at 36 hours and 48 hours). Other test methods (inclusion and exclusion criteria, dosing regimen, blood drug concentration detection method, etc.) were the same as the pharmacokinetic test.

[0262] Test results: See Tables 13, 14 and Figure 7

[0263] Table 13: Pharmacokinetic parameters (PKPS) Note: Mean±SD means arithmetic mean±standard deviation; T max Expressed as median (minimum value - maximum value).

[0264] Table 14: Relative bioavailability

[0265] E13 was bioequivalent to E1, with a BA (relative bioavailability) of approximately 99%. While E10 was bioequivalent to E1, its BA was only 88% of that of E1. D4 significantly reduced absorption, with a BA of only 77%, was not bioequivalent to E1. The test results further demonstrated that the in vitro dissolution (particularly dissolution in a pH 6.8 medium) of the metformin hydrochloride enteric-coated tablets described herein was well consistent with in vivo absorption.

[0266] One adverse reaction (diarrhea) occurred on D4, and no adverse reactions were found in other groups.

[0267] Test 2:

[0268] To study the effects of tablet core disintegration rate and related release profile on drug absorption, the following representative formulations were selected:

[0269] 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).

[0270] Example 4 (E4): Enteric coating was the same as that of E1. The tablet core disintegrated in 6 to 8 minutes. In a pH 6.8 medium, 81.3% of the tablet was dissolved in 15 minutes and 93.6% in 20 minutes.

[0271] Comparative Example 1 (D1): Enteric coating was the same as that of E1. The tablet core disintegrated in 12-15 minutes. In a pH 6.8 medium, 54.3% of the tablet was dissolved in 15 minutes and 77.7% was dissolved in 20 minutes.

[0272] The dissolution curve in pH 6.8 medium is shown in Figure 8.

[0273] The experimental design is shown in Table 15.

[0274] Table 15: Experimental Design

[0275] The experimental methods (including inclusion and exclusion criteria, dosing regimen, blood drug concentration detection method, etc.) are the same as those of Experiment 1.

[0276] Test results: See Tables 16, 17 and Figure 9

[0277] Table 16: Pharmacokinetic parameters (PKPS) Note: Mean±SD means arithmetic mean±standard deviation; T max Expressed as median (minimum value - maximum value).

[0278] Table 17: Relative bioavailability

[0279] E4 was bioequivalent to E1, but its BA was only 94% of that of E1. D1 was not bioequivalent to E1, with its BA being only about 80% of that of E1. The results showed that the disintegration time of the tablet core had a significant impact on drug dissolution and absorption.

[0280] No adverse reactions were observed in any group.

[0281] The absorption site of metformin hydrochloride is the upper small intestine. It is generally believed that the dissolution in a pH 6.0 medium better reflects the dissolution situation in the upper small intestine, and its dissolution rate is an important factor affecting the absorption and drug efficacy of this type of drug. However, the present invention surprisingly found that the absorption of this product is mainly associated with the dissolution in a pH 6.8 medium. The pharmaceutical industry often uses dissolution characteristics to distinguish the differences in prescription processes (in terms of effect) and expects to predict in vivo absorption or bioavailability (BA) with 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 will be of great value for selecting suitable product prescriptions and processes and predicting drugability.

[0282] 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 indicate that the in vivo absorption of enteric-coated metformin hydrochloride preparations has a good correlation with their in vitro dissolution (especially dissolution in pH 6.8 buffer). Rapid dissolution in pH 6.8 buffer (more than 85% dissolution in 20 minutes, especially more than 85% dissolution in 15 minutes) and 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-coated preparations (such as Glucophage) is approximately 60-80%.

[0283] The research of the present invention shows that there is a close correlation between the tablet core disintegration time, the onset melting point of the enteric coating material and the coating weight gain of metformin hydrochloride enteric-coated tablets. The selected tablet core disintegration time, onset 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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