Metformin hydrochloride enteric-coated preparation

Abstract

Provided in the present invention is a new metformin hydrochloride enteric-coated preparation, which is an oral dosage form prepared from a therapeutically effective amount of a biguanide compound and a pharmaceutically acceptable auxiliary material, and is characterized in that the metformin hydrochloride enteric-coated preparation has a metformin hydrochloride dissolution of not higher than 15% within 120 minutes in a pH 4.5 medium and a metformin hydrochloride dissolution of not lower than 85% within 20 minutes in a pH 6.8 medium, preferably not higher than 7.5% within 120 minutes in the pH 4.5 medium and not less than 85% within 15 minutes in the pH 6.8 medium. The metformin hydrochloride enteric-coated preparation, which meets drug dissolution technical requirements, described in the present invention improves the gastrointestinal tolerance of metformin hydrochloride and reduces adverse reactions caused by drugs in the case where the hypoglycemic efficacy is not reduced or even increased; moreover, the metformin hydrochloride enteric-coated preparation can be taken before, after or during meals, thereby improving the compliance of patients in terms of taking drugs.

Description

Metformin hydrochloride enteric-coated preparations Technical Field

[0001] The invention provides an enteric-coated preparation of a biguanide compound, in particular an enteric-coated preparation of metformin hydrochloride, belonging 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 prior arts, 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 prior arts. 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. (ELCELYX THERAPEUTICS, INC.) disclosed enteric-coated metformin hydrochloride preparations in WO2013103384A, WO2013103919A, and WO2014107617A, respectively. These are delayed-release preparations (DR) designed to push the drug to the distal small intestine to release the active drug, thereby improving the gastrointestinal tolerance of biguanide compounds and reducing adverse events caused by biguanide compounds. WO2013103384A and WO2013103919A disclose an enteric-coated metformin hydrochloride preparation that is similar to a conventional preparation containing an equal amount of the biguanide compound, namely an immediate-release preparation (DR). Release, IR) compared with a delayed-release formulation having a reduced relative bioavailability of 20% to 60%, preferably 40% to 60%; WO2014107617A discloses an enteric-coated dosage form containing a biguanide compound, wherein the dosage form continues for a hysteresis 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 hysteresis period of at least about 15 or 20 minutes after contact with the desired pH, and more preferably continues for a hysteresis 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 enteric-coated for two hours at an acidic pH and for at least 15 minutes at a pH of 6.8. The enteric-coated oral dosage form containing a biguanide compound releases less than 15% of the biguanide compound within a lag phase of ten or fifteen minutes, releases at least 60% of the biguanide compound after the lag phase 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 phase of at least ten or fifteen minutes at pH 6.8, releases at least 60% of the biguanide compound after the lag phase 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 preparations of metformin hydrochloride disclosed in the prior art, including WO2014107617A, claim that their hypoglycemic efficacy is no less than that of the same dose of ordinary metformin hydrochloride tablets, namely immediate-release preparations (IR), and even has increased efficacy. In addition, compared with IR preparations, metformin hydrochloride DR preparations reduce the relative bioavailability and systemic exposure of the drug, improve the gastrointestinal tolerance of the drug, and reduce 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 are poorly accurate, 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 / journal.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 document failed to demonstrate the expected clinical efficacy. In a 16-week clinical trial, the optimal dosing regimen of metformin hydrochloride DR (1500mg daily in the 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] The present invention aims to provide a novel enteric-coated preparation of a biguanide compound, and in particular to provide an enteric-coated preparation of metformin hydrochloride. Compared with enteric-coated preparations of metformin hydrochloride IR or other release rates, the present invention improves the gastrointestinal tolerance of metformin hydrochloride and reduces adverse reactions caused by the drug without reducing or even improving the hypoglycemic efficacy, which is significantly different from enteric-coated preparations without the above-mentioned release characteristics.

[0011] The technical solutions of the present invention are as follows:

[0012] The invention provides an enteric-coated preparation of a biguanide compound, which is an oral dosage form prepared from a therapeutically effective amount of a biguanide compound and a pharmaceutically acceptable excipient. The preparation is characterized in that the dissolution rate of the biguanide compound in a pH 4.5 medium is no more than 15% within 120 minutes, and the dissolution rate of the biguanide compound in a pH 6.8 medium is no less than 85% within 20 minutes. More preferably, the enteric-coated preparation has a dissolution rate of no more than 7.5% within 120 minutes in a pH 4.5 medium, and a dissolution rate of no less than 85% within 15 minutes in a pH 6.8 medium. Preferably, the biguanide compound is metformin or a pharmaceutically acceptable salt thereof; more preferably, the biguanide compound is metformin hydrochloride.

[0013] In the present invention, "dissolution rate" is also referred to as "release rate" and "dissolution" is also referred to as "release", which have the same meaning in terms of expression. The solubility 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).

[0014] In the present invention, the pH 4.5 medium is preferably a pH 4.5 acetate buffer, and the pH 6.0 medium or the pH 6.8 medium is preferably a pH 6.0 phosphate buffer or a pH 6.8 phosphate buffer.

[0015] The enteric-coated preparation of the present invention is a preparation that meets the drug release requirements of the present invention while complying with the general requirements for drug release of enteric-coated preparations. The general requirements for drug release 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 in a near-neutral medium (e.g., pH 6.0-6.8 phosphate buffer) within a specified time period.

[0016] The enteric-coated preparation of the present invention can be in the form of tablets, capsules (including enteric-coated capsules or micro-pellet capsules) or granules.

[0017] Preferably, the enteric-coated preparation of the present invention has a relative bioavailability of 60% to 80% compared with an immediate-release preparation (or a conventional preparation, such as Glucophage) having an equal amount of the biguanide compound.

[0018] As another object of the present invention, the use of a biguanide compound or a salt thereof in preparing a medicament for reducing the risk of adverse events caused by administering the biguanide compound to an individual in need thereof is also provided, wherein the medicament is the enteric-coated preparation of the present invention.

[0019] As another object of the present invention, there is also provided the use of a biguanide compound or a salt thereof in the preparation of a medicament for treating metabolic disorders, wherein the medicament is the enteric-coated preparation described above.

[0020] As another object of the present invention, there is also provided use of a biguanide compound or a salt thereof in the preparation of a medicament for diabetes, wherein the medicament is the enteric-coated preparation described above in the present invention.

[0021] As another object of the present invention, there is also provided use of a biguanide compound or a salt thereof in the preparation of a medicament for reducing body weight, wherein the medicament is the enteric-coated preparation described above in the present invention.

[0022] As another object of the present invention, the use of a biguanide compound or a salt thereof in preparing a drug that can be taken before, after or during meals to improve patient compliance with medication is provided, wherein the drug is the enteric-coated preparation described above.

[0023] The enteric-coated preparation of the present invention is an oral dosage form made from a therapeutically effective amount of a biguanide compound and a pharmaceutically acceptable adjuvant. The dosage or therapeutically effective amount of the biguanide compound (e.g., metformin hydrochloride) in a unit preparation, its therapeutic uses, and its adverse reactions are prior art known to those skilled in the art, such as the prior art mentioned in the specification, and its disclosed relevant contents will be incorporated into this application by reference. The adjuvants used in the enteric-coated preparation of the present invention, such as fillers and disintegrants used for tablets, gelatin used for capsules, flavorings used for granules, and related enteric materials, etc., are either commercially available on the market or prepared or formulated according to prior art. Those skilled in the art can prepare them according to the general preparation process of enteric solvents in this area. For enteric-coated tablets with low coating weight gain, since they are often not easy to meet the acid resistance requirements or the dissolution requirements of pH 4.5, it may be necessary to control appropriate process parameters. For example, before coating, the liquid supply speed of the peristaltic pump should be checked to ensure smooth liquid supply, and the atomization pressure and fan pressure should be adjusted to ensure that the coating liquid has a better atomization state. In the early stage of coating, the liquid supply volume can be increased, and the tablet bed temperature can be controlled at the upper limit so that the coated tablets are quickly covered with a layer of coating material. During the entire coating process, the humidity of the incoming air should be strictly controlled to ensure the density of the coating film, or an isolation coat can be added, etc., to obtain an enteric-coated metformin hydrochloride preparation that meets the requirements of the present invention.

[0024] The present invention has surprisingly found that an enteric-coated metformin hydrochloride preparation having the specific drug release technical requirements of the present invention can produce the best therapeutic effect and the lowest adverse reactions. The specific drug release technical requirements are: the solubility of metformin hydrochloride in a pH 4.5 medium is not higher than 15% within 120 minutes, and the solubility of metformin hydrochloride in a pH 6.8 medium is not less than 85% within 20 minutes. More preferably, the solubility of the biguanide compound in a pH 4.5 medium is not higher than 7.5% within 120 minutes, and the solubility of metformin hydrochloride in a pH 6.8 medium is greater than 85% within 15 minutes. Clinical trials, pharmacokinetic studies, and in vitro and in vivo correlation studies have shown that the enteric-coated metformin hydrochloride preparation having the above-mentioned drug release technical requirements of the present invention, compared with the metformin hydrochloride IR preparation (e.g., Glucophage) or other enteric-coated preparations with different release rates, can alleviate or reduce the adverse reactions caused by metformin hydrochloride, especially gastrointestinal adverse reactions, without reducing or even improving the hypoglycemic efficacy. Moreover, the enteric-coated preparation can be taken before, after, or during meals, thereby improving the patient's compliance with medication, which is significantly different from enteric-coated preparations without the above-mentioned release characteristics.

[0025] In particular, the present invention has shown, through in vitro and in vivo correlation studies, that dissolution in a pH 6.8 medium is highly correlated with drug absorption. BA studies have shown that enteric-coated metformin hydrochloride preparations with different formulations and compositions meeting the above-described drug release technical requirements of the present invention all achieved bioequivalence with the preparation of preferred embodiment (E1). In the pharmaceutical field, drug dissolution or release behavior is often used to distinguish between different products, as well as differences in formulation composition and / or production process. It is also hoped that drug dissolution or release behavior can be used to predict drug absorption or bioavailability (BA) in vivo. Compared to BA, the study of drug dissolution or release is much simpler and faster. If the correlation between drug dissolution and BA can be established, it will be of great value for determining appropriate product formulations and processes, predicting drugability, etc. After extensive research, the present invention has demonstrated the correlation between in vitro dissolution and in vivo absorption of the enteric-coated metformin hydrochloride preparation, provides a method for predicting human absorption, clinical efficacy, and safety of the enteric-coated metformin hydrochloride preparation by in vitro dissolution, and demonstrates the clinical advantages of the enteric-coated metformin hydrochloride preparation meeting the above-described drug release technical requirements of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1: HbA1c reduction during 12 weeks of treatment with E1, D2, D5, and Glucophage(R)

[0027] Figure 2: FPG change trends of E1, D2, D5, and Glucophage(R)

[0028] Figure 3: AEs of E1, D2, D5, and Glucophage(R)

[0029] Figure 4: Dissolution curves of E1, D2, and D5 (pH 6.8)

[0030] Figure 5: Plasma concentration-time curves of E1, D2, D5, and Glucophage(R)

[0031] Figure 6: Dissolution curves of E1, E10, E13, and D4 (pH 6.8)

[0032] Figure 7: Plasma concentration-time curves of E1, E10, E13, and D4

[0033] Figure 8: Dissolution curves of E1, E4, and D1 (pH 6.8)

[0034] Figure 9: Plasma concentration-time curves of E1, E4, and D1

[0035] Figure 10: Dissolution curves of E1 and E22 (pH 6.8)

[0036] Figure 11: Plasma concentration-time curves of E1 and E22

[0037] Figure 12: Subject distribution and flow chart DETAILED DESCRIPTION

[0038] The following specific examples are only used to explain or illustrate the contents of the present invention. Obviously, the implementation mode of the present invention is 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.

[0039] Example 1 (E1): Metformin Hydrochloride Enteric-Coated Tablets

[0040] Core composition:

[0041] 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 to 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. The tablets are pressed using a 12mm round punch, and the hardness of the plain tablets is controlled within the range of 8 to 11 kg.

[0042] 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.

[0043] Enteric coating liquid composition:

[0044] 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 ).

[0045] Example 2 (E4): Metformin Hydrochloride Enteric-Coated Tablets

[0046] 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 within the range of 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 those in Example 1.

[0047] Example 3 (E10): Metformin Hydrochloride Enteric-Coated Tablets

[0048] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0049] Enteric coating liquid composition:

[0050] 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 ).

[0051] Example 4 (E12): Metformin Hydrochloride Enteric-Coated Tablets

[0052] Tablet cores were prepared according to the composition and preparation method of Example 1. Enteric layer coating was performed according to the composition and process of the enteric layer coating solution of Example 3, and the coating weight gain was 4.0% (6.4 mg / cm 2 ).

[0053] Example 5 (E13): Metformin Hydrochloride Enteric-Coated Tablets

[0054] The tablet core was prepared according to the tablet core composition and preparation method of Example 1. The enteric layer coating solution composition:

[0055] 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 ).

[0056] Example 6 (E15): Metformin Hydrochloride Enteric-coated Tablets Prescription

[0057] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0058] Isolation layer coating liquid composition:

[0059] 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%.

[0060] Enteric coating liquid composition:

[0061] 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 ).

[0062] Example 7 (E22): Metformin Hydrochloride Enteric-coated (Pellets) Capsules

[0063] Prescription composition:

[0064] Preparation method:

[0065] 1. Drug-loaded coating

[0066] (1) Preparation of coating solution: Dissolve hydroxypropyl methylcellulose and metformin hydrochloride in purified water, add cross-linked polyvinylpyrrolidone and stir to disperse evenly, and pass the coating solution through an 80-mesh sieve for later use.

[0067] (2) Coating: Place the sucrose pellet cores in a fluidized bed coating machine, adjust the air volume and atomization pressure to keep the pellets in a good fluidized state; set the air temperature and peristaltic pump speed, and carry out coating. The coating weight gain is about 458.3%. After the coating is completed, stop spraying and dry the pellets. Screen the discharged pellets to obtain qualified pellets.

[0068] 2. Enteric coating

[0069] (1) Preparation of coating solution: Add hydroxypropyl methylcellulose phthalate to 80% ethanol and stir until completely dissolved. Then add triethyl citrate and talc powder in sequence and stir until evenly dispersed.

[0070] (2) Coating: Place qualified drug-loaded pills in a fluidized bed coating machine, adjust the air volume and atomization pressure to keep the pellets in a good fluidized state; set the air temperature and peristaltic pump speed, and carry out coating. The coating weight gain is about 25.0%. After the coating is completed, stop spraying and dry the pellets. Screen the discharged pellets to obtain qualified pellets.

[0071] 3. Capsule filling: Use No. 0 gelatin capsules for filling.

[0072] Comparative Example 1 (D1): Metformin Hydrochloride Enteric-Coated Tablets

[0073] The core composition refers to Glucophage, specifically:

[0074] 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.

[0075] 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.

[0076] The composition, process and weight gain of the enteric layer coating solution are the same as those in Example 1.

[0077] Comparative Example 2 (D2): Metformin Hydrochloride Enteric-Coated Tablets

[0078] Tablet cores were prepared according to the composition and preparation method of Example 1. Enteric layer coating was performed according to the composition and process of enteric layer coating solution of Example 3. The enteric layer coating weight was increased by 2.5% (4.0 mg / cm 2 ).

[0079] Comparative Example 3 (D4): Metformin Hydrochloride Enteric-Coated Tablets

[0080] The tablet core was prepared according to the tablet core composition and preparation method of Example 1.

[0081] Enteric coating liquid composition:

[0082] 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 6.5% (10.4 mg / cm 2 ).

[0083] Comparative Example 4 (D5): Metformin Hydrochloride Enteric-Coated Tablets

[0084] The tablet core was prepared according to the tablet core composition and preparation method of Comparative Example 1.

[0085] Isolation layer coating liquid composition:

[0086] 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%.

[0087] Enteric coating liquid composition:

[0088] 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 ).

[0089] Dissolution test method and results

[0090] 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.

[0091] Amount dissolved in acid

[0092] 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.

[0093] Test solution: Take 20 ml of the eluate, filter, discard 10 ml of the initial filtrate, and take the subsequent filtrate.

[0094] 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.

[0095] Determination method: Take the test solution and the reference solution, measure the absorbance at a wavelength of 233nm, and calculate the dissolution amount.

[0096] Limit: Not more than 10% of the labeled amount.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] Determination method: Take the test solution and the reference solution, measure the absorbance at a wavelength of 233nm, and calculate the dissolution amount.

[0102] Preparation of dissolution medium:

[0103] 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.

[0104] 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.

[0105] 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.

[0106] The dissolution test results of metformin hydrochloride in enteric solvents of the Examples and Comparative Examples were as follows: the acid resistance test was qualified. The acid resistance and dissolution results in pH 4.5 medium are shown in Table 1 (the acid resistance value is the average of the acid resistance 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 Table 2 and Table 3, respectively (the dissolution at time 0 in the chart is the acid resistance 2h test value; 6 dosage units are used for each dissolution curve measurement)

[0107] Table 1 Dissolution of Examples and Comparative Examples in pH 1.0 and pH 4.5 Media for 2 Hours (%)

[0108] Table 2 Dissolution of Examples and Comparative Examples in pH 6.0 Medium (%)

[0109] Table 3 Dissolution of Examples and Comparative Examples in pH 6.8 Medium

[0110] The enteric-coated metformin hydrochloride formulation disclosed in WO2014107617A requires the 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. Therefore, the dissolution rate of D5's enteric-coated metformin hydrochloride tablets meets the requirements of the enteric-coated metformin hydrochloride formulation described in this patent document.

[0111] Clinical trials and results

[0112] Treatment-naive patients who were intolerant to regular immediate-release metformin hydrochloride tablets (IR preparation) were randomly given E1, D2, D5 enteric-coated metformin hydrochloride tablets and regular immediate-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.

[0113] Inclusion criteria: Subjects who meet all of the following criteria can be included in this trial:

[0114] (1) Ages 28 to 78 years old, male or female;

[0115] (2) diagnosed with type 2 diabetes according to the WHO (1999) diabetes diagnostic criteria;

[0116] (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.

[0117] (4) Glycated hemoglobin (HbA) at the screening visit 1c )≥7.0% and ≤11.0%;

[0118] (5) fasting plasma glucose (FPG) ≤15 mmol / L (270 mg / dL) at the screening visit;

[0119] (6) Body mass index (BMI) ≥ 19 kg / m 2 and ≤35kg / m 2 ;

[0120] 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.

[0121] 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.

[0122] Main efficacy index: HbA after 12 weeks of treatment 1c Change from baseline.

[0123] Secondary efficacy indicators:

[0124] (1) Changes in fasting blood glucose (FPG) compared with baseline at 4, 8, and 12 weeks of medication;

[0125] (2) changes in body weight compared with baseline at 4, 8, and 12 weeks of medication;

[0126] (3) changes in blood lipids (TC, TG, LDL-C, HDL-C) compared with baseline at 4, 8, and 12 weeks of medication;

[0127] 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.);

[0128] 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.

[0129] The subject distribution and trial process are shown in Figure 12 and Table 4 below. In Figure 12, the FAS represents the full analysis set, which includes all subjects who received the trial drug and is used for safety and adverse event analyses; the PPS represents the per-protocol set, which includes all subjects who received the trial drug according to the protocol and obtained a second HbA1c value and is used for efficacy analyses.

[0130] Table 4 Test process

[0131] *: No need to do this if done within 2 weeks; efficacy statistics are based on the last examination value before taking the medicine.

[0132] Test results and discussion

[0133] 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 5; the FPG at week 16 was an unplanned measurement, given 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, 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, with the difference exceeding the clinical non-inferiority margin of 0.3-0.4).

[0134] Table 5: Efficacy indicators

[0135] * : P < 0.05 compared with baseline; ** :P<0.01 compared with baseline

[0136] Table 6: Adverse events

[0137] AE: adverse event

[0138] Upper gastrointestinal AEs include: nausea, vomiting, abdominal pain, abdominal discomfort, bloating, and acid reflux

[0139] Lower gastrointestinal AEs include: diarrhea, constipation

[0140] Ratio = adverse events during the trial period / adverse events during the screening period*100%;

[0141] * :P<0.05 compared with R

[0142] 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 6 and Figure 3).

[0143] The inventors conducted further analysis of patients in group D2 and discovered 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 compared to those who took the drug after or during meals, whereas no such correlation was observed in patients in group E1 or D5. Prior reports of adverse reactions to metformin suggest that those taking the drug before meals are more likely to experience adverse reactions than those taking the drug during or after meals. Consequently, the drug instructions for metformin (common preparations) in various countries require that it be taken during (or immediately after) meals to reduce adverse gastrointestinal reactions.

[0144] 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 7:

[0145] Table 7: Comparison of adverse events in patients in group D2 after taking medication before and after meals

[0146] The definition of upper gastrointestinal AE is the same as the above table.

[0147] 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, so the number of people counted before and after meals was less than the total number of the D2 group.

[0148] 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.

[0149] The inventors repeated postprandial gastric dissolution testing using Example 4 (E12) and Example 6 (E15), using the same testing methods as above. The tablet in Example 4 (E12) began to break at approximately 60 minutes, with a dissolution rate of approximately 20%, and reached over 30% by 90 minutes. The tablet in Example 6 (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 tablet.

[0150] 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.

[0151] When taken with or after a meal, the drug's gastric retention time is often 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.

[0152] Currently, most national drug regulatory authorities require enteric-coated preparations to dissolve less than 5-10% in a pH 1.0 medium within 2 hours. While D2 meets this requirement, it's difficult to guarantee enteric coating even after meals. Since standard metformin preparations (i.e., immediate-release preparations) are taken after or during meals, many patients still habitually take them after or during meals. Therefore, ensuring enteric coating after meals is even more crucial for metformin. Furthermore, the ability to take the drug before, after, or during meals can significantly improve patient compliance.

[0153] 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.

[0154] Because 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 situation of drug dissolution and adverse reactions, it is speculated that 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. 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 the colon irritation. D5 is likely to be released in the colon, and colon peristalsis is slow, and intestinal fluid is few, and drug absorption is few, and may form a larger concentration locally, irritating the colon mucosa.

[0155] Pharmacokinetic studies and their results

[0156] To investigate the absorption of enteric-coated metformin preparations with different release characteristics, and their relationship with hypoglycemic effects and adverse reactions, the inventors conducted a pharmacokinetic study.

[0157] 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.

[0158] Test method:

[0159] Inclusion Criteria. Subjects must meet all of the following criteria to be included:

[0160] 1) Healthy subjects: medical history, vital signs, physical examination, laboratory tests, electrocardiogram, chest X-ray and other related examinations are all within normal range, or the researchers judge that the abnormalities are of no clinical significance;

[0161] 2) Men and women aged 18 to 65 years (including borderline values);

[0162] 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 )];

[0163] 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:

[0164] 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;

[0165] 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;

[0166] 3) The blood drug concentration before administration (0 o'clock 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;

[0167] 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.

[0168] Dosing schedule: A four-period crossover design was used, with dosing occurring once on day 1 of each cycle, followed by a three-day washout period between two weeks. Twenty subjects were randomly divided into four groups at a 1:1:1:1 ratio. Subjects fasted for 10 hours before dosing. On the day of dosing, the reference preparation (R / Glucophage, one 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 consumed 4 hours after dosing.

[0169] The experimental design is shown in Table 8.

[0170] Table 8: Experimental Design

[0171] Throughout the trial period, the subjects consumed a standard meal provided by the research center. During the trial, the subjects avoided strenuous exercise and prolonged bed rest, abstained from consuming juice, tea, coffee, alcohol, and other beverages containing caffeine or ethanol, and were prohibited from smoking. If an adverse event occurred during the trial, the researcher needed to follow up on the subject until the adverse event was alleviated or the symptoms disappeared.

[0172] In each cycle, blood samples were collected at 0 h (within 60 minutes before the subject took the medication), 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 after taking the medication (a total of 18 blood collection points, and 72 blood collection points in 4 cycles). At each blood collection point, 3 ml of peripheral venous blood was collected and placed in a K2EDTA blood collection tube, centrifuged (1700 g, 2 °C - 8 °C, with the set temperature at 4 °C) for 10 minutes 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 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 enteric-coated tablets, Chinese Pharmaceutical Journal, Vol. 47, No. 18, October 2012).

[0173] The test results are as follows (Tables 9 - 10 and Figure 5).

[0174] Table 9: Pharmacokinetic parameters (PKPS) Note: Mean±SD represents the arithmetic mean ± standard deviation; T max is expressed as the median (minimum - maximum).

[0175] Table 10: Relative bioavailability

[0176] The test results showed that there was a clear correlation between the dissolution behavior and absorption of metformin enteric-coated tablets. The relative bioavailabilities of D2, E1, and D5 (enteric-coated tablets) relative to Glucophage were 91%, 72%, and 48% respectively, and the dissolution and absorption were highly correlated (see Figures 4 and 5). Combining with the clinical trials, it can be seen that there is also an obvious correlation between dissolution and clinical efficacy and adverse reactions.

[0177] 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.

[0178] The enteric-coated preparations disclosed in WO2013103384A and WO2013103919A have a relative bioavailability reduction of 20%-60%, preferably 40%-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 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.

[0179] In vivo and in vitro correlation studies and results

[0180] 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.

[0181] Test 1:

[0182] To study the effect of enteric-coated preparation release on drug absorption.

[0183] E1: Served as a reference preparation (93.8% dissolution in pH 6.8 medium within 15 minutes and 101.1% dissolution within 20 minutes).

[0184] E10: The core tablet is the same as E1. In pH 6.8 medium, 71.1% of the tablet was dissolved in 15 minutes and 93.3% was dissolved in 20 minutes.

[0185] E13: The core tablets are the same as E1. The dissolution rate in pH 6.8 medium is 95.6% in 15 minutes and 98.1% in 20 minutes.

[0186] D4: The core tablets were the same as those of E1. In pH 6.8 medium, 25.0% of the tablets were dissolved in 15 minutes and 73.0% of the tablets were dissolved in 20 minutes.

[0187] The dissolution curves of E1, E10, E13 and D4 in pH 6.8 medium are shown in Figure 6 (where E13 is shown as cumulative dissolution).

[0188] The experimental design is shown in Table 11.

[0189] Table 11: Experimental Design

[0190] 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.

[0191] Test results: See Tables 12, 13 and Figure 7

[0192] Table 12: Pharmacokinetic parameters (PKPS) Note: Mean±SD means arithmetic mean±standard deviation; T max Expressed as median (minimum value - maximum value).

[0193] Table 13: Relative bioavailability

[0194] 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.

[0195] One adverse reaction (diarrhea) occurred on D4, and no adverse reactions were found in other groups.

[0196] Test 2:

[0197] Study the effect of release profile on drug absorption.

[0198] E1: As the reference preparation (R), the dissolution rate in pH 6.8 medium was 93.8% within 15 minutes.

[0199] E4: 81.3% dissolved in pH 6.8 medium in 15 minutes and 93.6% dissolved in 20 minutes.

[0200] D1: 54.3% dissolved in pH 6.8 medium in 15 minutes and 77.7% dissolved in 20 minutes.

[0201] The dissolution curves of E1, E4, and D1 in pH 6.8 medium are shown in Figure 8.

[0202] The experimental design is shown in Table 14.

[0203] Table 14: Experimental Design

[0204] The experimental methods (including inclusion and exclusion criteria, dosing regimen, blood drug concentration detection method, etc.) are the same as those of Experiment 1.

[0205] Test results: See Tables 15, 16 and Figure 9

[0206] Table 15: Pharmacokinetic parameters (PKPS) Note: Mean±SD means arithmetic mean±standard deviation; T max Expressed as median (minimum value - maximum value).

[0207] Table 16: Relative bioavailability

[0208] E4 was bioequivalent to E1, but its BA was only 94% of E1. D1 was not bioequivalent to E1, with its BA only approximately 80% of E1. The test results showed that the tablet core disintegration time and in vitro drug dissolution were well consistent with in vivo absorption.

[0209] No adverse reactions were observed in any group.

[0210] Test 3:

[0211] The equivalence of the capsules with similar release profiles to E1 was investigated.

[0212] E1: As the reference preparation (R), the dissolution rate in pH 6.8 medium was 93.8% within 15 minutes.

[0213] E22: 92.6% dissolved in pH 6.8 medium in 15 minutes and 97.8% dissolved in 20 minutes.

[0214] The dissolution curves of E1 and E22 in pH 6.8 medium are shown in Figure 10.

[0215] The experimental design is shown in Table 17.

[0216] Table 17: Experimental Design

[0217] The experimental methods (including inclusion and exclusion criteria, dosing regimen, blood drug concentration detection method, etc.) are the same as those of Experiment 1.

[0218] Test results: See Tables 18, 19 and Figure 11

[0219] Table 18: Pharmacokinetic parameters (PKPS) Note: Mean±SD means arithmetic mean±standard deviation; T max Expressed as median (minimum value - maximum value).

[0220] Table 19: Relative bioavailability

[0221] E22 and E1 are bioequivalent, and test results show that the similar in vitro dissolution of the capsule (especially the dissolution in pH 6.8 medium) is well consistent with the absorption of the tablet. No adverse reactions were observed for either E22 or E1.

[0222] The absorption site of metformin hydrochloride is the upper small intestine. It is generally believed that a pH 6.0 medium better reflects the dissolution situation in the upper small intestine. Its dissolution rate is an important factor affecting the absorption and efficacy of this type of drug. However, the present invention surprisingly found that the absorption of this product is mainly associated with the dissolution of the pH 6.8 medium. For a specific compound, the BA of the drug basically depends on the formulation process of the product. The pharmaceutical industry often uses dissolution characteristics to distinguish the differences in formulation processes, and hopes to predict the absorption or bioavailability (BA) of the drug in the body based on dissolution behavior. Compared with BA, the study of dissolution is much simpler and faster. Establishing the correlation between dissolution and BA is of great value for selecting appropriate product formulations and processes, predicting drugability, etc. 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, E4, D1; E1, E22) indicate that enteric-coated metformin hydrochloride preparations with limited release in a pH 4.5 medium (less than 7.5-15% release in 120 minutes) and rapid dissolution in a pH 6.8 medium (more than 85% dissolution in 20 minutes, especially more than 85% dissolution in 15 minutes) can achieve the best therapeutic effect and the lowest adverse reactions, and their bioavailability is approximately 60-80% relative to ordinary metformin hydrochloride preparations (such as Glucophage).

Claims

1. An enteric-coated preparation of a biguanide compound, which is an oral dosage form prepared from a therapeutically effective amount of a biguanide compound and a pharmaceutically acceptable excipient, characterized in that: The dissolution rate of the biguanide compound in the enteric-coated preparation in a pH 4.5 medium is not higher than 15% within 120 minutes, and the dissolution rate of the biguanide compound in a pH 6.8 medium is not lower than 85% within 20 minutes.

2. The enteric-coated preparation according to claim 1, characterized in that: The dissolution rate of the biguanide compound in the enteric-coated preparation in a pH 4.5 medium within 120 minutes is not higher than 7.5%, and the dissolution rate of the biguanide compound in a pH 6.8 medium within 15 minutes is not lower than 85%.

3. The enteric-coated preparation according to claim 1-2, characterized in that: Compared with the immediate release preparation containing the same amount of the biguanide compound, the enteric-coated preparation has a relative bioavailability of 60% to 80%.

4. The enteric-coated preparation according to claims 1-3, wherein the biguanide compound is metformin or a pharmaceutically acceptable salt thereof; preferably, the biguanide compound is metformin hydrochloride.

5. The enteric-coated preparation according to claims 1-4, wherein the oral dosage form is a tablet, capsule or granule.

6. Use of a biguanide compound or a salt thereof for preparing a medicament for reducing the risk of adverse events caused by a biguanide compound, wherein the medicament is an enteric-coated preparation according to claims 1 to 5.

7. Use of a biguanide compound or a salt thereof in the preparation of a medicament for treating metabolic disorders, wherein the medicament is an enteric-coated preparation according to claims 1 to 5.

8. Use of a biguanide compound or a salt thereof in the preparation of a medicament for diabetes, wherein the medicament is an enteric-coated preparation according to claims 1-5.

9. Use of a biguanide compound or a salt thereof in the preparation of a medicament for reducing body weight, wherein the medicament is an enteric-coated preparation according to claims 1 to 5.

10. Use of a biguanide compound or a salt thereof for preparing a drug that can be taken before, after or during meals to improve patients' compliance with medication, wherein the drug is an enteric-coated preparation according to claims 1 to 5.

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