Metformin hydrochloride enteric-coated formulation

Abstract

This invention provides a novel enteric-coated metformin hydrochloride formulation, an oral dosage form made from a therapeutically effective amount of biguanide compound and pharmaceutically acceptable excipients. The enteric-coated metformin hydrochloride formulation exhibits a dissolution rate of no more than 15% within 120 minutes in a pH 4.5 medium and no less than 85% within 20 minutes in a pH 6.8 medium. Preferably, the dissolution rate is no more than 7.5% within 120 minutes in a pH 4.5 medium and no less than 85% within 15 minutes in a pH 6.8 medium. The enteric-coated metformin hydrochloride formulation meeting the drug dissolution technology requirements of this invention improves gastrointestinal tolerance of metformin hydrochloride without reducing, and may even improve, its hypoglycemic efficacy, reducing adverse drug reactions. Furthermore, it can be taken before, after, or with meals, improving patient compliance.

Description

Technical Field

[0001] This invention provides an enteric-coated formulation of a biguanide compound, and more particularly, an enteric-coated formulation of metformin hydrochloride. It belongs to the field of pharmaceutical preparations. Background Technology

[0002] Metformin is a biguanide oral hypoglycemic agent, and its hydrochloride salt, metformin hydrochloride, is commonly used clinically. Early studies suggested that the main mechanism of metformin's hypoglycemic effect was its systemic effects after absorption, such as inhibiting gluconeogenesis, reducing hepatic glucose output, acting on peripheral tissues (muscle, fat), promoting glucose utilization, and improving insulin sensitivity. Recent studies have found that the intestinal-mediated mechanisms of unabsorbed drugs (such as increasing GLP-1 and PYY levels, affecting gut microbiota, and inhibiting glucose uptake by intestinal parietal cells) may be more important.

[0003] In many national and international guidelines for the diagnosis and treatment of diabetes, metformin hydrochloride is recommended as a first-line drug for controlling hyperglycemia in patients with type 2 diabetes and as a fundamental drug in combination therapy. Glucophage (metformin hydrochloride tablets) is the original metformin product, with many years of clinical application experience and ample evidence-based medicine support. It is a standard treatment drug for type 2 diabetes both domestically and internationally, and the most commonly used control drug in clinical trials.

[0004] However, metformin's adverse reactions limit its use, and some patients cannot tolerate these side effects and have to discontinue the medication. The main adverse reactions of metformin include gastrointestinal reactions such as diarrhea, nausea, vomiting, bloating, abdominal pain, indigestion, and abdominal discomfort; neurological adverse reactions such as dizziness and headache; in addition, it can cause flu-like symptoms and vitamin B12 malabsorption, and may also cause some rare but more serious adverse reactions such as lactic acidosis. Gastrointestinal adverse reactions (such as nausea, abdominal pain, and abdominal discomfort) are the most common adverse reactions of metformin, with an incidence of 20-30%, and are also the most common reason for patient intolerance.

[0005] To reduce adverse reactions caused by metformin, there are already numerous studies and reports on its enteric-coated formulations. Enteric-coated formulations are those that release little to no drug in the stomach within a specified time, but enter the intestines and release most or all of the drug at a specific site within the intestines.

[0006] Early research and reports on enteric-coated metformin hydrochloride formulations, such as CN101190179B, focused only on whether the drug was not released or released almost nothing in 0.1 mol / L hydrochloric acid, and whether it was completely released in pH 6.8 phosphate buffer. Later related studies and reports, such as CN101785763B, disclosed enteric-coated sustained-release metformin hydrochloride tablets, showing approximately 30% drug release in pH 6.8 phosphate buffer after 1 hour, approximately 50% after 3 hours, and over 85% after 10 hours, claiming sustained-release, improved bioavailability, and avoidance of potential toxic side effects from excessively high short-term blood drug concentrations; CN102357088A disclosed a metformin hydrochloride enteric-coated formulation with rapid release in buffers ranging from pH 5.5 to 6.8, maintaining a release rate of over 80% even in pH 5.5 phosphate buffer after 45 minutes, claiming to avoid adverse drug reactions, and that the rapid release characteristic... The product can be effectively released in intestinal fluid with a pH of 5.5-6.8, thus ensuring the clinical efficacy of the product. CN106420653A discloses metformin hydrochloride enteric-coated tablets with a dissolution rate of 20-30% in 1 hour, 45-55% in 2 hours, and greater than 85% in 4 hours in phosphate buffer at pH 6.8, claiming low adverse reactions and suitability for patients with contraindications to metformin. CN111888339A discloses metformin hydrochloride enteric-coated tablets that release more than 85% in just 15-30 minutes in buffer at pH 4.5-5.0, with rapid and high release rate, claiming improved bioavailability and bioequivalence to the original drug. The existing technologies that disclose and report on enteric-coated metformin hydrochloride formulations, besides meeting the common requirement that enteric-coated formulations release little or no drug in acidic media with pH 1.0–3.0 and release most or all of the drug in buffered salt media with pH 6.8, lack further verification of release requirements (such as the rate or extent of release in the medium) and the claimed therapeutic effects. Some reports claim rapid release to ensure efficacy and / or safety, while others claim sustained release, which is clearly contradictory and lacks further validation of efficacy and / or safety. In fact, around 2000, several enteric-coated metformin hydrochloride formulations were launched in the Chinese market. These products, due to insufficient verification of efficacy and safety, did not meet the requirements of drug regulatory authorities, and were largely withdrawn from the market after the Chinese government strengthened drug regulation between 2016 and 2021.

[0007] Furthermore, Elcelyx Therapeutics, Inc. disclosed enteric-coated metformin hydrochloride formulations in WO2013103384A, WO2013103919A, and WO2014107617A. These are delayed-release (DR) formulations designed to deliver the drug to the distal small intestine to release the active drug, thereby improving the gastrointestinal tolerability of the biguanide compound and reducing adverse events caused by the biguanide compound. WO2013103384A and WO2013103919A also disclose immediate-release formulations containing an equivalent amount of the biguanide compound. Compared to delayed-release formulations with a 20% to 60% reduction in relative bioavailability (IR), preferably 40% to 60%, delayed-release formulations are disclosed in WO2014107617A. These formulations exhibit 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 at least about 15 or 20 minutes after contact with the desired pH, and more preferably 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 the biguanide compound exhibits a lag period of at least two hours at acidic pH and at pH 6.8. The biguanide compound is released in a 10- or 15-minute lag period, releasing less than 15% of the biguanide compound, releasing at least 60% of the biguanide compound after the lag period and within 60 minutes at pH 6.8, and releasing 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 the biguanide compound releases less than 15%, 10%, or 5% of the biguanide compound in a lag period of at least 10 or 15 minutes at pH 6.8, at least 60% of the biguanide compound after the lag period and within 60 minutes at pH 6.8, and at least 90% of the biguanide compound within 90 to 120 minutes at pH 6.8.

[0008] The prior art, including WO2014107617A, discloses enteric-coated metformin hydrochloride formulations that claim to have hypoglycemic efficacy no less than that of the same dose of metformin hydrochloride immediate-release tablets (IR), or even increased efficacy. Furthermore, compared with IR formulations, metformin hydrochloride DR formulations reduce the relative bioavailability and systemic exposure of the drug, improve gastrointestinal tolerability, and reduce adverse drug events. However, these studies used fasting plasma glucose (FPG) or GLP-1, PYY, etc., as evaluation indicators for the glycemic efficacy, which had poor accuracy, especially with a small number of cases. Therefore, the described glycemic efficacy of metformin hydrochloride DR preparations is difficult to confirm clinically. For example, Elcelyx later conducted a 16-week clinical study with an expanded number of cases on metformin hydrochloride DR preparations (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). ONE (published on September 25, 2018, https: / / doi.org / 10.1371 / journal.pone.0203946), using the clinically recognized gold standard glycated hemoglobin (HbA1c) as the evaluation index, the results showed that the metformin hydrochloride DR preparation prepared by the technical solution disclosed in the patent literature failed to show the expected clinical effect. In a 16-week clinical trial, with the optimal dosing regimen of giving patients metformin hydrochloride DR 1500mg every morning, the hypoglycemic effect of DR 1500mg was much lower than that of the control group metformin hydrochloride IR 2000mg (administered according to the instructions, 1000mg twice a day, morning and evening), and the reduction in efficacy was greater than the reduction in dosage. Summary of the Invention

[0009] The present invention aims to provide a novel enteric-coated formulation of biguanide compounds, particularly a metformin hydrochloride enteric-coated formulation that, compared with enteric-coated formulations of metformin hydrochloride with IR or other release rates, improves the gastrointestinal tolerance of metformin hydrochloride without reducing or even improving its hypoglycemic efficacy, and reduces adverse drug reactions, which is significantly different from enteric-coated formulations without the above-mentioned release characteristics.

[0010] The technical solution of this invention is as follows:

[0011] The invention provides an enteric-coated formulation of a biguanide compound, an oral dosage form made from a therapeutically effective amount of the biguanide compound and pharmaceutically acceptable excipients, characterized in that the dissolution rate of the biguanide compound is not higher than 15% within 120 minutes in a pH 4.5 medium, and not lower than 85% within 20 minutes in a pH 6.8 medium; more preferably, the dissolution rate of the biguanide compound in the enteric-coated formulation is not higher than 7.5% within 120 minutes in a pH 4.5 medium, and not lower 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.

[0012] In this invention, "dissolution rate" is also called "release rate," and "dissolution" is also called "release," and they have the same meaning in terms of expression. The dissolution rate of a drug can be determined according to the commonly used determination methods in the field, such as the dissolution and release rate determination method of General Chapter 0931, Method I of the Chinese Pharmacopoeia (2020 Edition).

[0013] In this 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 phosphate buffer or a pH 6.8 phosphate buffer.

[0014] The enteric-coated formulation of the present invention is a formulation that meets the drug release requirements described in this invention while conforming to the general requirements for drug release in enteric-coated formulations. The general requirements for drug release in enteric-coated formulations refer to formulations that release little or no drug in a specified acidic medium (e.g., pH 1.0–3.0), but release most or all of the drug in a near-neutral medium (e.g., pH 6.0–6.8 phosphate buffer) within a specified time.

[0015] The enteric-coated formulations described above in this invention can be tablets, capsules (including enteric-coated capsules or microcapsules) or granules.

[0016] Preferably, the enteric-coated formulation of the present invention has a relative bioavailability of 60% to 80% compared with an immediate-release formulation (or a conventional formulation, such as glucophage) having an equal amount of the biguanide compound.

[0017] As another object of the present invention, the use of biguanide compounds or salts thereof in the preparation of medicaments for reducing the risk of adverse events caused by administration of biguanide compounds to individuals in need thereof is also provided, wherein the medicament is an enteric-coated formulation as described above in the present invention.

[0018] As another object of the present invention, the use of biguanide compounds or salts thereof in the preparation of medicaments for metabolic disorders is also provided, wherein the medicament is an enteric-coated formulation as described above in the present invention.

[0019] As another object of the present invention, the use of biguanide compounds or salts thereof in the preparation of medicaments for diabetes is also provided, wherein the medicament is an enteric-coated formulation as described above in the present invention.

[0020] As another object of the present invention, the use of biguanide compounds or salts thereof in the preparation of medicaments for weight reduction is also provided, wherein the medicament is an enteric-coated formulation as described above in the present invention.

[0021] As another object of the present invention, the use of biguanide compounds or salts thereof in the preparation of medicaments which can be taken before, after, or with meals to improve patient compliance is provided, wherein the medicament is an enteric-coated formulation as described above.

[0022] The enteric-coated formulation described above is an oral dosage form made from a therapeutically effective amount of a biguanide compound and pharmaceutically acceptable excipients. The dosage or therapeutically effective amount of the biguanide compound (e.g., metformin hydrochloride) in a unit dosage form, its therapeutic use, and its adverse reactions are prior art known to those skilled in the art, such as prior art mentioned in the specification, the relevant disclosure of which is incorporated herein by reference. Excipients used in the enteric-coated formulation of this invention, such as fillers and disintegrants for tablets, gelatin for capsules, flavoring agents for granules, and related enteric materials, are either commercially available or prepared or formulated according to prior art. Those skilled in the art can obtain them according to general enteric solvent preparation processes in the field. For enteric-coated tablets with low coating weight gain, since they are often not acid-resistant or do not meet the pH 4.5 dissolution requirement, 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 stable liquid supply, and the atomization pressure and fan pressure should be adjusted to ensure that the coating liquid has a good atomization state. In the early stage of coating, the liquid supply can be increased, and the tablet bed temperature should be controlled at the upper limit so that the coated tablets can be 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 tightness of the coating film, or an isolation coat can be added, etc., to obtain a metformin hydrochloride enteric-coated formulation that meets the requirements of this invention.

[0023] The present invention has unexpectedly revealed that a metformin hydrochloride enteric-coated formulation having the specific drug release technology requirements described herein can produce optimal efficacy and minimal adverse reactions. These specific drug release technology requirements are: a metformin hydrochloride dissolution rate of no more than 15% within 120 minutes in a pH 4.5 medium, and a metformin hydrochloride dissolution rate of no less than 85% within 20 minutes in a pH 6.8 medium; more preferably, a biguanide compound dissolution rate of no more than 7.5% within 120 minutes in a pH 4.5 medium, and a metformin hydrochloride dissolution rate of more than 85% within 15 minutes in a pH 6.8 medium. Clinical trials, pharmacokinetic studies, and in vitro-in vivo correlation studies have shown that the enteric-coated metformin hydrochloride formulation with the drug release technology requirements described above in this invention, compared with metformin hydrochloride IR formulations (e.g., glucophage) or other enteric-coated formulations with different release rates, reduces or even improves the hypoglycemic efficacy without reducing or even improving the hypoglycemic effect. Furthermore, the enteric-coated formulation can be taken before, after, or during meals, improving patient compliance and is significantly different from enteric-coated formulations without the above-mentioned release characteristics.

[0024] In particular, in vitro and in vivo correlation studies of this invention have shown a high correlation between dissolution and drug absorption in a pH 6.8 medium. Bioavailability (BA) studies show that metformin hydrochloride enteric-coated formulations with different formulations meeting the drug release technology requirements described above are all bioequivalent to the formulation of the preferred embodiment (E1). In the pharmaceutical field, drug dissolution or release behavior is often used to differentiate products, as well as to distinguish differences in formulation composition and / or manufacturing processes, and is expected to predict drug absorption or bioavailability (BA) based on drug dissolution or release behavior. Compared to BA, drug dissolution or release studies are much simpler and faster. Establishing a correlation between drug dissolution and BA is of great value for determining suitable product formulations and processes, predicting drug-likeness, etc. This invention, through extensive research, demonstrates the correlation between in vitro dissolution and in vivo absorption of the metformin hydrochloride enteric-coated formulation, providing a method for predicting the human absorption, clinical efficacy, and safety of metformin hydrochloride enteric-coated formulations through in vitro dissolution, demonstrating the clinical advantages of metformin hydrochloride enteric-coated formulations meeting the drug release technology requirements described above. Attached Figure Description

[0025] Figure 1 HbA1c reduction during 12 weeks of treatment with E1, D2, D5, and Glucophage (R)

[0026] Figure 2 FPG variation trends of E1, D2, D5, and Glucose (R)

[0027] Figure 3AE status of E1, D2, D5, and Glucose (R)

[0028] Figure 4 Dissolution curves of E1, D2, and D5 (pH 6.8)

[0029] Figure 5 Blood concentration-time curves of E1, D2, D5, and Glucophage (R)

[0030] Figure 6 Dissolution profiles of E1, E10, E13, and D4 (pH 6.8)

[0031] Figure 7 Blood drug concentration-time curves for E1, E10, E13, and D4

[0032] Figure 8 Dissolution curves of E1, E4, and D1 (pH 6.8)

[0033] Figure 9 Blood concentration-time curves of E1, E4, and D1

[0034] Figure 10 Dissolution curves of E1 and E22 (pH 6.8)

[0035] Figure 11 Blood concentration-time curves of E1 and E22 Detailed Implementation

[0036] The following specific embodiments are only used to explain or illustrate the content of the present invention. Obviously, the implementation of the present invention is not limited to the specific embodiments listed, and therefore should not be construed as constituting any limitation on the scope of protection of the claims of this patent application.

[0037] Example 1 (E1): Metformin Hydrochloride Enteric-coated Tablets

[0038] Chip core composition:

[0039] Raw material names Dosage (mg) Metformin Hydrochloride 500.00 corn starch 16.54 Mannitol 20.00 Sodium carboxymethyl starch 16.68 Magnesium stearate (added) 2.78 Purified water Appropriate amount Piece weight 556

[0040] Preparation method: Metformin hydrochloride was pulverized and passed through an 80-mesh sieve. The pulverized raw material and added excipients were mixed in a wet granulator for 5 minutes, and then purified water was added for wet granulation. After wet granulation using a vertical granulator (equipped with a 5×5mm square hole screen), the granules were put into a fluidized bed for drying, and the moisture content of the dry granules was controlled within the range of 1.0-4.0%. After granulation of the dry granules (the granulator is equipped with a 1.5mm round hole screen), magnesium stearate was added and mixed in a mixer for 5 minutes. The tablets were compressed using a 12mm round punch, and the hardness of the tablets was controlled within the range of 8-11kg.

[0041] According to the disintegration time test method in General Chapter 0921 of Part IV of the 2020 edition of the Chinese Pharmacopoeia, the tablets were found to disintegrate completely within 2 to 4 minutes.

[0042] Composition of the enteric coating solution:

[0043] name Dosage (g) Copolymer of methacrylic acid and ethyl acrylate (L100-55) 6.00 Triethyl citrate 0.60 talcum powder 1.50 90% ethanol 91.90

[0044] Enteric coating: Methacrylic acid and ethyl acrylate copolymer (L100-55) were added to 90% ethanol and stirred until completely dissolved. Then, triethyl citrate and talc were added sequentially and stirred until evenly dispersed. Enteric coating was performed using a coating machine. After coating, the mixture was dried to remove residual solvent. The enteric coating showed a weight gain of 4.5% (7.2 mg / cm³). 2 ).

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

[0046] The total mixed granules were obtained according to the tablet core composition and preparation method of Example 1. During tableting, the hardness of the unprocessed tablets was controlled within the range of 15-18 kg. Referring to the disintegration time test method in General Chapter 0921 of Part IV of the 2020 Chinese Pharmacopoeia, the unprocessed tablets were found to disintegrate completely within 6-8 minutes. The composition, process, and weight gain of the enteric coating solution were the same as in Example 1.

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

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

[0049] Composition of the enteric coating solution:

[0050] name Dosage (g) Hydroxypropyl methylcellulose phthalate HP-50 8.00 Triethyl citrate 0.40 talcum powder 2.40 80% ethanol 89.20

[0051] Enteric coating: Hydroxypropyl methylcellulose phthalate was added to 80% ethanol and stirred until completely dissolved. Then, triethyl citrate and talc were added sequentially and stirred until evenly dispersed. Enteric coating was performed using a coating machine. After coating, the product was dried to remove residual solvent. The enteric coating showed a weight gain of 8.0% (12.8 mg / cm³). 2 ).

[0052] Example 4 (E12): Metformin Hydrochloride Enteric-coated Tablets

[0053] The tablet cores were prepared according to the composition and preparation method of Example 1. Enteric coating was performed according to the composition and process of the enteric coating solution in Example 3, resulting in a coating weight gain of 4.0% (6.4 mg / cm³). 2 ).

[0054] Example 5 (E13): Metformin Hydrochloride Enteric-coated Tablets

[0055] The tablet cores were prepared according to the tablet core composition and preparation method of Example 1. The enteric coating solution composition is as follows:

[0056] name Dosage (g) Copolymer of methacrylic acid and methyl methacrylate (L100) 6.00 Triethyl citrate 0.90 talcum powder 1.50 90% ethanol 91.60

[0057] Enteric coating: The copolymer of methacrylic acid and methyl methacrylate was added to 90% ethanol and stirred until completely dissolved. Then, triethyl citrate and talc were added sequentially and stirred until evenly dispersed. Enteric coating was performed using a coating machine. After coating, the mixture was dried to remove residual solvent. The enteric coating showed a weight gain of 3.5% (5.6 mg / cm³). 2 ).

[0058] Example 6 (E15): Metformin Hydrochloride Enteric-coated Tablets Formula

[0059] The core was prepared according to the core composition and preparation method of Example 1.

[0060] Composition of the isolation layer coating solution:

[0061] name Dosage (g) Gastric-soluble film-coating premix (Opadry 85F) 15.0 Purified water 85.0

[0062] Separator coating: Add the gastrointestinal 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 coat the separator, and dry after coating to remove residual moisture. The coating weight gain is 2.0%.

[0063] Composition of the enteric coating solution:

[0064]

[0065] Enteric coating: The copolymer of methacrylic acid and methyl methacrylate was added to 90% ethanol and stirred until completely dissolved. Then, triethyl citrate and talc were added sequentially and stirred until evenly dispersed. Enteric coating was performed using a coating machine. After coating, the mixture was dried to remove residual solvent. The enteric coating showed a weight gain of 2.5% (4.0 mg / cm³). 2 ).

[0066] Example 7 (E22): Metformin Hydrochloride Enteric-coated (Microcapsule) Capsules

[0067] Prescription composition:

[0068]

[0069] Preparation method:

[0070] 1. Drug-loaded coating

[0071] (1) Preparation of coating solution: Dissolve hydroxypropyl methylcellulose and metformin hydrochloride in purified water, add cross-linked polyvinyl ketone and stir to disperse evenly, and pass the coating solution through an 80-mesh sieve for later use.

[0072] (2) Coating: Place the sucrose pellet core in a fluidized bed coating machine, adjust the air volume and atomization pressure to make the pellets in a good fluidized state; set the air temperature and peristaltic pump speed to coat the pellets. The weight gain after coating is about 458.3%. After coating, stop spraying and dry the pellets. The qualified pellets are then screened out.

[0073] 2. Enteric coating

[0074] (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.

[0075] (2) Coating: Place the qualified drug-loaded pellets in a fluidized bed coating machine, adjust the air volume and atomization pressure to make the pellets in a good fluidized state; set the air temperature and peristaltic pump speed, and carry out coating. The weight gain of the coating is about 25.0%. After the coating is completed, stop spraying and dry the pellets. The qualified pellets are then screened out.

[0076] 3. Capsule filling: Use No. 0 gelatin capsules for filling.

[0077] Comparative Example 1 (D1): Metformin Hydrochloride Enteric-coated Tablets

[0078] The chip core composition is based on that of Givaudan, specifically as follows:

[0079] Raw material names Dosage (mg) Metformin Hydrochloride 500.00 Povidone K30 20.00 Magnesium stearate (added) 4.00 Purified water Appropriate amount Piece weight 524

[0080] Preparation method: Dissolve povidone K30 in purified water to prepare a binder for later use. Crush metformin hydrochloride and pass it through a 100-mesh sieve. Place the crushed raw material in a fluidized bed granulator, then spray in the binder for one-step granulation. Control the moisture content of the dry granules within the range of 1.0-4.0%. After granulating the dry granules (the granulator is equipped with a 1.5mm round hole sieve), add magnesium stearate and mix in a mixer for 5 minutes. Then, use a 12mm round punch to compress the tablets. The hardness of the unprocessed tablets is controlled within the range of 11-15kg.

[0081] According to the disintegration time test method in General Chapter 0921 of Part IV of the 2020 edition of the Chinese Pharmacopoeia, the tablets were found to disintegrate completely within 12 to 15 minutes.

[0082] The composition, process, and weight gain of the enteric coating solution are the same as in Example 1.

[0083] Comparative Example 2 (D2): Metformin Hydrochloride Enteric-coated Tablets

[0084] The tablet cores were prepared according to the composition and preparation method of Example 1. Enteric coating was performed according to the composition and process of the enteric coating solution in Example 3, resulting in a 2.5% (4.0 mg / cm³) weight gain. 2 ).

[0085] Comparative Example 3 (D4): Metformin Hydrochloride Enteric-coated Tablets

[0086] The core was prepared according to the core composition and preparation method of Example 1.

[0087] Composition of the enteric coating solution:

[0088] name Dosage (g) Copolymer of methacrylic acid and methyl methacrylate (L100) 6.00 Triethyl citrate 0.6 talcum powder 1.50 90% ethanol 91.90

[0089] Enteric coating: The copolymer of methacrylic acid and methyl methacrylate was added to 90% ethanol and stirred until completely dissolved. Then, triethyl citrate and talc were added sequentially and stirred until evenly dispersed. Enteric coating was performed using a coating machine. After coating, the mixture was dried to remove residual solvent. The enteric coating showed a weight gain of 6.5% (10.4 mg / cm³). 2 ).

[0090] Comparative Example 4 (D5): Metformin Hydrochloride Enteric-coated Tablets

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

[0092] Composition of the isolation layer coating solution:

[0093] name Dosage (g) Gastric-soluble film-coating premix (Opadry 85F) 15.0 Purified water 85.0

[0094] Separator coating: Add the gastrointestinal 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 coat the separator, and dry after coating to remove residual moisture. The coating weight gain is 1.1%.

[0095] Composition of the enteric coating solution:

[0096]

[0097] Enteric coating: Triethyl citrate and talc were added to purified water and homogenized thoroughly for 5-10 minutes using a high-shear homogenizer. The liquid was then slowly poured into the aqueous dispersions of Eutech FS30D and L30D-55, and stirred slowly to ensure uniform dispersion. The mixture was passed through an 80-mesh sieve before coating. Enteric coating was performed using a coating machine. After coating, the enteric layer was dried and aged. The weight gain of the enteric coating was 3.8% (6.1 mg / cm³). 2 ).

[0098] Dissolution detection methods and results

[0099] The dissolution test conditions for metformin hydrochloride enteric-coated tablets in the 2020 edition of the Chinese Pharmacopoeia were determined according to the method for determination of dissolution and release (General Rule 0931, Method 1).

[0100] Acid dissolution amount

[0101] Dissolution conditions: Use 900 ml of 0.1 mol / L hydrochloric acid solution as the dissolution medium, rotate at 100 rpm, operate according to the procedure, and take samples after 2 hours.

[0102] Test solution: Take 20 ml of the dissolution solution, filter it, discard 10 ml of the initial filtrate, and take the subsequent filtrate.

[0103] Reference solution: Weigh an appropriate amount of metformin hydrochloride reference standard accurately, dissolve it in 0.1 mol / L hydrochloric acid solution and dilute quantitatively to prepare a solution containing approximately 28 μg per ml.

[0104] Assay: Take the test solution and the reference solution, measure the absorbance at a wavelength of 233 nm, and calculate the dissolution amount.

[0105] Limit: Not exceeding 10% of the labeled amount.

[0106] Dissolution in pH 4.5 buffer: Using 900 ml of pH 4.5 acetate buffer as the dissolution medium, the blue method was used at a rotation speed of 100 rpm. The procedure was followed, and samples were taken after 2 hours. The test solution, reference solution, and assay method were the same as those used for pH 6.0 and pH 6.8 media.

[0107] Dissolution in pH 6.0 and pH 6.8 buffer solutions: Take the rotating basket after 2 hours of acid resistance test, and immediately immerse it in 900 ml of buffer solution preheated to 37℃±0.5℃. Keep the rotation speed unchanged and continue to operate according to the method. Take samples at 5, 10, 15, 20, 30, 45 and 60 minutes.

[0108] Test solution: Take 20 ml of the dissolution solution, filter it, discard 10 ml of the initial filtrate, accurately measure an appropriate amount of the subsequent filtrate, and dilute it quantitatively with water to prepare a solution containing approximately 5 μg of metformin hydrochloride per 1 ml.

[0109] Reference solution: Weigh an appropriate amount of metformin hydrochloride reference standard accurately, dissolve it in water and dilute it quantitatively to prepare a solution containing approximately 5 μg per ml.

[0110] Assay: Take the test solution and the reference solution, measure the absorbance at a wavelength of 233 nm, and calculate the dissolution amount.

[0111] Preparation of dissolution medium:

[0112] Preparation method of pH 4.5 medium (acetate buffer): Weigh 1.80g of anhydrous sodium acetate (or 2.99g of sodium acetate trihydrate), measure 1.596ml of glacial acetic acid and add it to 1L of degassed purified water. Stir until completely dissolved, and adjust the pH value to 4.50 with glacial acetic acid.

[0113] Preparation method of pH 6.0 medium (phosphate buffer): Dissolve 6.80g of potassium dihydrogen phosphate and 0.224g of sodium hydroxide in 1000ml of purified water. If necessary, adjust the pH value to 6.0±0.05 with 2mol / L hydrochloric acid solution or 2mol / L sodium hydroxide solution.

[0114] Preparation method of pH 6.8 medium (phosphate buffer): Take 0.1 mol / L hydrochloric acid solution and 0.2 mol / L sodium phosphate solution, mix them evenly at a ratio of 3:1, and adjust the pH value to 6.8±0.05 if necessary with 2 mol / L hydrochloric acid solution or 2 mol / L sodium hydroxide solution.

[0115] The dissolution results of metformin hydrochloride enteric solvent in the examples and comparative examples are as follows: All acid resistance tests were passed. The acid resistance and dissolution results in pH 4.5 medium are shown in Table 1 (the acid resistance values ​​are the average values ​​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 Tables 2 and 3, respectively (the dissolution rate at 0 in the tables represents the acid resistance value after 2 hours; 6 formulation units were used for each dissolution curve determination).

[0116] Table 1. Dissolution rates (%) of the examples and comparative examples in media at pH 1.0 and pH 4.5 for 2 hours.

[0117]

[0118] Table 2. Dissolution rate (%) of the examples and comparative examples in pH 6.0 medium.

[0119] Time (min) 0 5 10 15 20 30 45 60 Example 1 (E1) 0.5 0.5 1.2 9.3 35.0 93.5 97.1 98.6 Example 2 (E4) 0.3 0.6 1.1 8.3 22.2 65.8 95.9 99.5 Example 3 (E10) 0.0 0.1 2.5 38.1 85.5 96.0 100.2 101.2 Example 4 (E12) 2.2 8.7 72.8 91.1 96.2 98.2 98.1 97.4 Example 5 (E13) 2.5 0.1 0.6 1.0 2.3 5.0 13.5 32.7 Example 6 (E15) 4.7 0.1 0.1 0.2 0.3 3.6 13.8 41.7 Example 7 (E22) 2.3 1.5 3.7 12.7 28.9 86.8 95.8 98.7 Comparative Example 1 (D1) 0.4 0.5 0.9 2.6 11.3 38.5 79.3 95.8 Comparative Example 2 (D2) 7.2 16.2 79.3 93.1 94.3 93.9 94.0 94.1 Comparative Example 3 (D4) 0.0 0.1 0.0 0.0 0.1 0.2 1.8 3.1 Comparative Example 4 (D5) 0.0 0.0 0.1 0.2 0.2 0.3 0.4 0.5

[0120] Table 3. Dissolution rates of the examples and comparative examples in pH 6.8 medium.

[0121]

[0122]

[0123] WO2014107617A discloses an enteric-coated metformin hydrochloride formulation that requires the release of less than 15%, 10%, or 5% of the biguanide compound within a lag period of at least 10 or 15 minutes at pH 6.8 after two hours at an acidic pH, and at least 60% of the biguanide compound within 60 minutes at pH 6.8 after the lag period, and at least 90% of the biguanide compound within 90 to 120 minutes at pH 6.8. Therefore, the dissolution of D5's enteric-coated metformin hydrochloride tablets conforms to the enteric-coated metformin hydrochloride formulation described in this patent document.

[0124] Clinical trials and results

[0125] Treatment-naïve patients who were intolerant to immediate-release metformin hydrochloride tablets (IR formulation) were randomly assigned to receive either enteric-coated metformin hydrochloride tablets or immediate-release metformin hydrochloride tablets (i.e., reference formulation R, brand name) on E1, D2, and D5. (Commercially available) To evaluate the effects of metformin hydrochloride enteric-coated tablets with different release characteristics on blood glucose control and patient tolerability.

[0126] Inclusion criteria: Subjects who meet all of the following criteria are eligible for this trial:

[0127] (1) Age 28-78 years old, gender not limited;

[0128] (2) Diagnosed with type 2 diabetes according to the WHO (1999) diagnostic criteria for diabetes;

[0129] (3) Those who have not taken other hypoglycemic drugs, are intolerant to ordinary immediate-release metformin hydrochloride tablets, including gastrointestinal reactions such as diarrhea, nausea, vomiting, bloating, indigestion, and abdominal discomfort; neurological adverse reactions such as dizziness and headache; and various adverse reactions that are judged to be related to the drug, have been taking the drug for less than 2 weeks, and have the intention to change the drug.

[0130] (4) Screening for glycated hemoglobin (HbA1c) at the time of the visit 1c ≥7.0% and ≤11.0%;

[0131] (5) Fasting plasma glucose (FPG) ≤15mmol / L (270mg / dL) at the time of screening visit;

[0132] (6) Body Mass Index (BMI) ≥ 19 kg / m² 2 And ≤35kg / m 2 ;

[0133] Administration: Replace the original immediate-release metformin hydrochloride tablets with the same dose of E1, D2, D5, or glucophage. After replacement, increase the dose by 500 mg per week (twice daily, morning and evening) until reaching 2000 mg / day. If the original dose has already reached 2000 mg / day, do not increase the dose further; continue taking the alternative medication at the original dose and method. For patients who still do not tolerate the changed medication, the dose may be reduced to 1500 mg / day or 1000 mg / day.

[0134] Subjects who develop other illnesses that affect treatment efficacy or adverse events during treatment 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.

[0135] Primary efficacy endpoint: HbA1c after 12 weeks of medication 1c Changes from the baseline.

[0136] Secondary efficacy endpoints:

[0137] (1) Changes in fasting plasma glucose (FPG) from baseline at 4, 8, and 12 weeks of medication;

[0138] (2) Changes in body weight from baseline at 4, 8, and 12 weeks of medication;

[0139] (3) Changes in blood lipids (TC, TG, LDL-C, HDL-C) from baseline at 4, 8, and 12 weeks of medication;

[0140] Safety assessment: Adverse events should be recorded throughout the study: special attention should be paid to common gastrointestinal adverse reactions of metformin (including abdominal pain, diarrhea, constipation, bloating, indigestion, etc.);

[0141] All medications used by patients (including concomitant medications) and adverse events were recorded in a diary card. The diary cards were collected at the next visit, and medication adherence was calculated (by calculating the number of tablets used; generally, the actual number used should be greater than 80% of the theoretical dosage). Supervision was provided to patients with poor adherence. Subjects taking other hypoglycemic drugs were excluded.

[0142] Subject distribution and trial procedure are shown in Table 4-5 below.

[0143] Table 4 Test Procedure

[0144]

[0145] *: If the test has been done within 2 weeks, it is not necessary to do it again; the efficacy statistics are based on the values ​​of the last test before taking the medication.

[0146] Table 5: Subject Distribution and Procedure

[0147]

[0148] FAS: Full Analysis Set, encompassing all individuals who have taken the investigational drug, used for safety / adverse event analysis.

[0149] PPS: Compliant protocol set, all participants who followed the protocol and achieved a second HbA1c result, used for efficacy analysis.

[0150] Experimental Results and Discussion

[0151] Based on HbA1c, E1 showed the best efficacy, and fasting blood glucose levels also showed a similar trend. Furthermore, the reduction in fasting blood glucose with E1 showed an increasing trend with increasing medication duration, suggesting that E1 may have better long-term efficacy (see...). Figure 1-2(See Table 6; FPG in week 16 was an unplanned test, with a small number of patients and a long time span, therefore no statistical analysis was performed); E1 also showed better effects than other preparations on blood lipids, liver and kidney function. The hypoglycemic effect on D2 was not significantly different from the control drug Glucophage, but the difference on D5 was significant (P<0.05, and the difference exceeded the clinical non-inferiority margin of 0.3-0.4).

[0152] Table 6: Therapeutic Indicators

[0153]

[0154] *: P < 0.05 compared to baseline; **: P < 0.01 compared to baseline.

[0155] Table 7: Adverse Events

[0156]

[0157]

[0158] AE: Adverse Events

[0159] Upper gastrointestinal adverse events (AEs) include: nausea, vomiting, abdominal pain, abdominal discomfort, bloating, and acid reflux.

[0160] Lower gastrointestinal adverse events (AEs) include: diarrhea and constipation.

[0161] Ratio = Adverse events during the trial period / Adverse events during the screening period * 100%;

[0162] *: P < 0.05 compared to R

[0163] E1, D2, and D5 were significantly superior to Glucophage in terms of upper gastrointestinal adverse events (AEs) such as nausea, vomiting, abdominal pain, abdominal discomfort, bloating, and acid reflux, especially E1 and D5. Patients who experienced upper gastrointestinal adverse events while taking regular metformin hydrochloride tablets had a 33% lower chance of experiencing AEs after switching to E1 and D5, compared to 93% with Glucophage. The improvement with D2 was not significant; the probability of experiencing upper gastrointestinal AEs after switching was 59% of the previous rate. E1 also showed some advantages in other AEs (see Table 7). Figure 3 ).

[0164] Further analysis of patients in group D2 revealed a significant correlation between the timing of upper gastrointestinal reactions and the frequency of medication administration: patients who took the medication before meals (30 minutes before eating) experienced a significantly lower rate of upper gastrointestinal reactions compared to those who took it after or with meals. This association was not observed in groups E1 and D5. Existing reports on metformin adverse reactions suggest that pre-meal administration is more likely to cause adverse reactions than administration with or after meals. Therefore, metformin (conventional formulation) instructions in various countries recommend administration with meals (or immediately after meals) to reduce gastrointestinal adverse reactions.

[0165] After noticing the above phenomenon, the researchers compared the relationship between adverse events and mealtime, and observed the adverse events when patients took medication before and after meals, as shown in Table 8 below:

[0166] Table 8: Comparison of adverse events following pre- and post-meal medication administration in Group D2

[0167]

[0168] The definition of upper gastrointestinal AE is the same as in the table above.

[0169] Because the diary cards did not clearly record the medication time and meal time, the data that could not distinguish the correlation between medication / meal / AE were excluded. Therefore, the number of people counted before meals and after meals was less than the total number of people counted in group D2.

[0170] The inventors designed a separate dissolution test: Using simulated postprandial gastric juice (acetate buffer and milk mixed in a 1:1 ratio, pH adjusted to 5.0 with sodium hydroxide or hydrochloric acid; the acetate buffer contained 13.85 g / L sodium chloride, 1.03 g / L acetic acid, and 2.44 g / L sodium acetate), a slurry method was employed, and the D2 dissolution test was conducted at 75 rpm. The tablets began to break after 30 minutes, the dissolution rate reached over 75% after 60 minutes, and metformin was completely dissolved after 90 minutes. The test results indicate that postprandial administration of D2 is unlikely to achieve an "enteric-coated" effect.

[0171] The inventors re-conducted the dissolution test in postprandial gastric juice using Examples 4 (E12) and 6 (E15), following the same testing method. The tablet in Example 12 (E12) began to break at approximately 60 minutes, with a dissolution rate of about 20%, and reached over 30% at 90 minutes. The tablet in Example 6 (E15) began to swell and deform at approximately 60 minutes, with a dissolution rate of about 10%, and reached approximately 25% at 90 minutes. Considering that the drug dissolved in the human stomach will be continuously diluted and excreted into the intestines, the concentration of metformin in the stomach should be significantly lower than that of the immediate-release tablet.

[0172] When medication is taken with or after meals, the retention time in the stomach is often longer than on an empty stomach, and the pH value is also higher, reaching 4.5-5.0. Based on pharmacokinetic and biochemical analysis (BA) results, metformin enteric-coated tablets taken with meals can remain in the stomach for several hours. Therefore, dissolution in a pH 4.5 medium is of great value for this product. Clinical and simulated postprandial gastric fluid tests show that when dissolution in a pH 4.5 medium exceeds 20% (D2), gastric release is significantly increased, and adverse reactions are also significantly increased. Dissolution below 15% (E12, E15) achieves limited gastric release, and dissolution below 7.5% (E4, E13, E22) achieves bioequivalence with the optimal product (E1).

[0173] Currently, most national drug regulatory authorities require enteric-coated formulations to dissolve at a rate of less than 5-10% within 2 hours in a pH 1.0 medium. D2 meets this requirement, indicating that ensuring enteric coating when taken after meals may be difficult. Since metformin immediate-release formulations are typically taken after or with meals, many patients still habitually take enteric-coated metformin after or with meals. Therefore, ensuring postprandial enteric coating is of greater importance for metformin. Furthermore, allowing for administration before, after, or with meals significantly improves patient compliance.

[0174] Upper gastrointestinal adverse reactions of D5 were significantly improved compared to Glucophage, but lower gastrointestinal adverse reactions were higher than those of Glucophage, D2, and E1. The incidence of lower gastrointestinal adverse events (mainly diarrhea) was 130% of that of the regular tablets, and the duration of diarrhea was 156% of that of the regular tablets. Furthermore, five patients experienced severe watery stools with D5; two of these cases occurred after taking regular metformin and worsened after switching to D5, while three cases were normal after taking regular metformin and developed the symptoms after switching to D5. Researchers determined this symptom to be a drug-induced adverse reaction.

[0175] Because metformin has a strong irritant effect on the gastrointestinal mucosa, the inventors considered that the watery condition was caused by the drug's irritation of the colonic mucosa. Based on the drug dissolution and adverse reactions, they speculated that D2 should be released in the stomach, duodenum, and upper small intestine (depending on the time of administration), and E1 should be released in the small intestine. The small intestine has rapid peristalsis and a large amount of intestinal fluid, thus the drug is quickly diluted, resulting in a weaker irritant effect on the colon. D5 is likely released in the colon, where peristalsis is slow, intestinal fluid is scarce, and drug absorption is low, potentially leading to a higher local concentration and irritation of the colonic mucosa.

[0176] Pharmacokinetic studies and results

[0177] To investigate the absorption of metformin enteric-coated formulations with different release characteristics, and their relationship with hypoglycemic effects and adverse reactions, the inventors conducted pharmacokinetic studies.

[0178] 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 1). Figure 4 Considering that drugs dissolved in acid will also be absorbed, where D2 is the cumulative dissolution rate (cumulative dissolution rate = dissolution rate + dissolution rate at 0 / dissolution rate in acid), and comparing it with the reference formulation (metformin hydrochloride tablets, trade name: ), to conduct pharmacokinetic studies in healthy subjects, and to calculate the bioavailability of E1, D2, and D5 relative to Glucophage (R).

[0179] Test method:

[0180] Inclusion criteria. Participants must meet all of the following criteria to be included:

[0181] 1) Healthy subjects: Medical history, vital signs, physical examination, laboratory tests, electrocardiogram, chest X-ray and other relevant examinations are all within the normal range, or the researchers judge that the abnormalities are not clinically significant;

[0182] 2) Men and women aged 18 to 65 (including boundary values);

[0183] 3) Men weighing ≥ 50 kg and women weighing ≥ 45 kg, with a body mass index (BMI) between 19 and 28 (inclusive) [BMI = weight (kg) / height] 2 (m 2 )];

[0184] Before statistical analysis, a comprehensive judgment should be made on whether to exclude a subject based on factors such as the subject's completion of the trial and the reason for withdrawal, if any of the following situations occur:

[0185] 1) The first sample was C max If no early (within 30 minutes after administration) samples are collected, the corresponding periodic pharmacokinetic data of the subject will not be included in the evaluation.

[0186] 2) After administration, the subject's condition at T... max If vomiting occurs within twice the median time frame, the corresponding period's pharmacokinetic data for that subject will not be included in the evaluation.

[0187] 3) The blood drug concentration before administration (concentration at 0) is greater than the corresponding concentration after administration (C). max If 5% of the subjects are included, then the corresponding period's pharmacokinetic data for those subjects will not be included in the evaluation;

[0188] 4) During the trial, if the data may be significantly biased or the PK parameters cannot be calculated due to reasons such as violation of the dosing protocol, incorrect blood collection time, improper sample processing or storage, or poor subject compliance.

[0189] Dosing regimen. A four-period crossover trial design was used, with one dose administered on day 1 of each period, followed by a 3-day washout period between the two weeks. Twenty subjects were randomly assigned to four groups in a 1:1:1:1 ratio. Subjects were fasting for 10 hours prior to administration, but could drink water freely. On the day of administration, the reference formulation (R / Glucophage, 1 tablet, 500 mg) or the test formulation (E1, D2, D5; all 500 mg) was taken on an empty stomach with 240 ml of warm water. A standard lunch was eaten 4 hours after administration.

[0190] The experimental design is shown in Table 9.

[0191] Table 9: Experimental Design

[0192]

[0193] Throughout the trial, participants consumed standard meals provided by the research center. Participants were advised to avoid strenuous exercise and prolonged bed rest, and to abstain from caffeinated or alcoholic beverages such as fruit juice, tea, coffee, and alcohol, as well as smoking. If any adverse events occurred during the trial, participants were required to be followed up by researchers until the adverse events subsided or the symptoms disappeared.

[0194] Blood samples were collected at 0h (within 60 minutes before drug administration) and at 0.5h, 1.0h, 1.5h, 2.0h, 2.5h, 3.0h, 3.5h, 4.0h, 4.5h, 5.0h, 6.0h, 7.0h, 8.0h, 10.0h, 12.0h, 15h, and 24.0h after drug administration (a total of 18 blood collection points, 72 blood collection points for 4 cycles). 3ml of peripheral venous blood was collected from each collection point and placed in a K2EDTA blood collection tube. The tube was centrifuged (1700g, 2℃~8℃, set temperature 4℃) for 10min to separate the plasma. The plasma samples were stored in a low-temperature freezer until testing. The concentration of metformin hydrochloride in plasma was determined by liquid chromatography-tandem mass spectrometry (HPLC-MS / MS) (References: Zhang D, Wang GC, Huang JQ, et al., LC-MS / MS determination of metformin in human plasma[J]. Chin JPharm Anal, 2011, 31(2):317-321; Zhang Dan, Post-marketing bioequivalence re-evaluation of metformin hydrochloride enteric-coated tablets in humans, Chinese Pharmaceutical Journal, October 2012, Vol. 47, No. 18).

[0195] The experimental results are as follows (Tables 10-11 and 10-12). Figure 5 ).

[0196] Table 10: Pharmacokinetic Parameters (PKPS)

[0197] Parameters (Mean±SD) D2(n=20) E1(n=18) D5(n=20) R(n=19) <![CDATA[C max (ng / ml)]]> 982.99±254.50 710.51±299.89 567.26±399.85 1115.05±216.59 <![CDATA[AUC 0-t (h*ng / ml)]]> 5701.69±1235.03 4836.79±1636.07 3110.98±1614.21 6323.58±1333.26 <![CDATA[AUC 0-∞ (h*ng / ml)]]> 5978.04±1217.67 5108.78±1716.44 3432.56±1614.64 6436.91±1375.07 <![CDATA[T max (h)]]> 4.50(2.5-5.0) 5.00(3.0-12.0) 7.00(1.5-15.0) 1.00(0.5-2.0) <![CDATA[T 1 / 2 (h)]]> 5.50±2.06 4.75±1.50 5.26±1.42 4.00±0.82

[0198] Note: Mean±SD represents the arithmetic mean ± standard deviation; T max Represented by the median (minimum value - maximum value).

[0199] Table 11: Relative Bioavailability

[0200]

[0201] The experimental results showed that the dissolution behavior of metformin enteric-coated tablets was clearly correlated with absorption. The relative bioavailability of D2, E1, and D5 (enteric-coated tablets) relative to Glucophage was 91%, 72%, and 48%, respectively, indicating a high correlation between dissolution and absorption (see [link to study]. Figure 4 , 5 Clinical trials have shown that dissolution is significantly associated with clinical efficacy and adverse reactions.

[0202] One case of nausea occurred in the reference preparation group, and one case of diarrhea occurred on day 5. Both cases resolved spontaneously the following day. No adverse reactions were observed in the other groups.

[0203] The enteric-coated formulations disclosed in WO2013103384A and WO2013103919A have a 20% to 60% reduction in relative bioavailability, preferably 40% to 60%, compared to conventional formulations (i.e., immediate-release formulations) containing an equal amount of the biguanide compound. Therefore, D5 conforms to the metformin hydrochloride enteric-coated formulation described in these patent documents. Consistent with the results of a 16-week clinical study conducted by Elcelyx (Robert R. Henry et al.), D5 (52% reduction in bioavailability) did not achieve the expected clinical efficacy; instead, a relative bioavailability of 60% to 80% (E1) produced the best efficacy and the lowest adverse reactions.

[0204] In vivo and in vitro correlation studies and results

[0205] The results of the aforementioned clinical trials and pharmacokinetic studies at E1, D2, and D5 indicate that the efficacy, safety, and absorption of metformin enteric-coated formulations are significantly correlated with drug dissolution. To further investigate the relationship between release characteristics and drug absorption, efficacy, and safety, the inventors conducted the following in vitro-in vivo correlation studies.

[0206] Experiment 1:

[0207] This study investigates the effect of enteric-coated formulation release on drug absorption.

[0208] E1: As a reference preparation (93.8% dissolved in pH 6.8 medium at 15 minutes and 101.1% dissolved at 20 minutes).

[0209] E10: The core is the same as E1. In a medium of pH 6.8, 71.1% dissolves after 15 minutes and 93.3% dissolves after 20 minutes.

[0210] E13: The core material is the same as E1. In pH 6.8 medium, 95.6% dissolves after 15 minutes and 98.1% dissolves after 20 minutes.

[0211] D4: The core material is the same as E1. In pH 6.8 medium, 25.0% dissolves in 15 minutes and 73.0% dissolves in 20 minutes.

[0212] The dissolution curves of E1, E10, E13, and D4 in a medium at pH 6.8 are shown below. Figure 6 (E13 is shown as cumulative dissolution).

[0213] The experimental design is shown in Table 12.

[0214] Table 12: Experimental Design

[0215]

[0216]

[0217] Since the pharmacokinetic studies showed that the blood drug concentration was still high at 24 hours, the blood collection time was extended to 48 hours in this study (adding two blood collection points at 36 hours and 48 hours). Other experimental methods (inclusion and exclusion criteria, dosing regimen, blood drug concentration detection methods, etc.) were the same as those in the pharmacokinetic studies.

[0218] Experimental results: see Tables 13 and 14. Figure 7

[0219] Table 13: Pharmacokinetic Parameters (PKPS)

[0220] Parameters (Mean±SD) E10(n=20) E13(n=20) D4(n=19) E1(n=20) <![CDATA[C max (ng / ml)]]> 864.46±191.19 898.64±213.11 724.08±230.87 910.68±203.74 <![CDATA[AUC 0-t (h*ng / ml)]]> 5705.69±1459.71 6329.51±1271.74 4959.86±1256.55 6382.01±1233.42 <![CDATA[AUC 0-∞ (h*ng / ml)]]> 5765.44±1458.68 6399.42±1288.50 5008.66±1259.49 6463.54±1259.21 <![CDATA[T max (h)]]> 5.00(2.50-10.00) 4.50(2.50-12.00) 6.00(1.50-10.00) 5.00(1.50-8.00) <![CDATA[T 1 / 2 (h)]]> 7.53±3.44 7.57±2.38 7.42±1.95 7.85±3.90

[0221] Note: Mean±SD represents the arithmetic mean ± standard deviation; T max Represented by the median (minimum value - maximum value).

[0222] Table 14: Relative Bioavailability

[0223]

[0224] E13 is bioequivalent to E1, with a relative bioavailability (BA) of approximately 99%; E10, while bioequivalent to E1, has only 88% of the BA of E1; D4 shows significantly reduced absorption, with a BA of only 77%, and is not bioequivalent to E1. The experimental results further demonstrate that the in vitro dissolution (especially in pH 6.8 medium) and in vivo absorption of the metformin hydrochloride enteric-coated tablets described in this invention are highly consistent.

[0225] One adverse reaction (diarrhea) occurred in D4, but no adverse reactions were found in the other groups.

[0226] Experiment 2:

[0227] The study investigated the effect of drug release on drug absorption.

[0228] E1: As a reference preparation (R), 93.8% dissolves in 15 minutes in a medium at pH 6.8.

[0229] E4: 81.3% dissolved in pH 6.8 medium after 15 minutes and 93.6% dissolved after 20 minutes.

[0230] D1: 54.3% dissolved in pH 6.8 medium after 15 minutes and 77.7% dissolved after 20 minutes.

[0231] The dissolution curves of E1, E4, and D1 in pH 6.8 medium are as follows: Figure 8 .

[0232] The experimental design is shown in Table 15.

[0233] Table 15: Experimental Design

[0234]

[0235] The experimental methods (inclusion and exclusion criteria, dosing regimen, blood drug concentration detection methods, etc.) are the same as those in Experiment 1.

[0236] Experimental results: see Tables 16 and 17. Figure 9

[0237] Table 16: Pharmacokinetic Parameters (PKPS)

[0238] Parameters (Mean±SD) D1(n=18) E4(n=18) E1(n=18) <![CDATA[C max (ng / mL)]]> 718.52±145.13 850.39±248.99 882.52±231.72 <![CDATA[AUC 0-t (mg / mL)]]> 4703.92±1076.55 5617.34±1590.36 5990.16±1652.69 <![CDATA[AUC 0-∞ (mg / mL)]]> 4752.18±1083.80 5674.26±1606.71 6054.96±1667.50 <![CDATA[T max (h)]]> 6.00(3.00-12.00) 5.00(2.00-12.00) 4.50(2.50-7.00) <![CDATA[T 1 / 2 (h)]]> 8.17±2.47 9.06±2.39 8.25±2.53

[0239] Note: Mean±SD represents the arithmetic mean ± standard deviation; T max Represented by the median (minimum value - maximum value).

[0240] Table 17: Relative Bioavailability

[0241]

[0242] E4 is bioequivalent to E1, but BA is only 94% of that of E1. D1 is not bioequivalent to E1, and BA is only about 80% of that of E1. The experimental results show that the tablet core disintegration time and the in vitro dissolution and in vivo absorption of the drug are very consistent.

[0243] No adverse reactions were observed in any group.

[0244] Experiment 3:

[0245] The study investigated the equivalence of capsules with similar release profiles to E1.

[0246] E1: As a reference preparation (R), 93.8% dissolves in 15 minutes in a medium at pH 6.8.

[0247] E22: 92.6% dissolved in pH 6.8 medium after 15 minutes and 97.8% dissolved after 20 minutes.

[0248] The dissolution curves of E1 and E22 in pH 6.8 medium are as follows: Figure 10 .

[0249] The experimental design is shown in Table 18.

[0250] Table 18: Experimental Design

[0251]

[0252] The experimental methods (inclusion and exclusion criteria, dosing regimen, blood drug concentration detection methods, etc.) are the same as those in Experiment 1.

[0253] Experimental results: see Tables 19 and 20. Figure 11

[0254] Table 19: Pharmacokinetic Parameters (PKPS)

[0255] Parameters (Mean±SD) E22(n=20) E1(n=20) <![CDATA[C max (ng / mL)]]> 865.04±215.99 890.04±319.58 <![CDATA[AUC 0-t (mg / mL)]]> 6374.63±1745.38 6089.29±2337.33 <![CDATA[AUC 0-∞ (mg / mL)]]> 6416.88±1758.57 6143.82±2357.05 <![CDATA[T max (h)]]> 3.5(2.5-4.5) 4.5(2.5-8) <![CDATA[T 1 / 2 (h)]]> 6.60±1.26 6.94±2.84

[0256] Note: Mean±SD represents the arithmetic mean ± standard deviation; T max Represented by the median (minimum value - maximum value).

[0257] Table 20: Relative Bioavailability

[0258]

[0259] E22 and E1 are bioequivalent. Test results show that the absorption of capsules with similar in vitro dissolution (especially in pH 6.8 medium) is very consistent with that of tablets. No adverse reactions were observed with either E22 or E1.

[0260] Metformin hydrochloride is absorbed in the upper small intestine. It is generally believed that a pH 6.0 medium best reflects dissolution in the upper small intestine, and dissolution rate is a crucial factor affecting the absorption and efficacy of this type of drug. However, this invention unexpectedly reveals that the absorption of this product is primarily correlated with dissolution in a pH 6.8 medium. The pharmaceutical industry often uses dissolution characteristics to differentiate between formulations and processes, hoping to predict drug absorption or bioavailability (BA) based on dissolution behavior. Compared to BA, dissolution studies are much simpler and faster. Establishing the correlation between dissolution and BA is of great value for selecting appropriate product formulations and processes, and predicting drug properties. The results of the aforementioned clinical trials, pharmacokinetic studies (E1, D2, D5), and in vitro-in vivo correlation studies (E1, E10, E13, D4; E1, E4, D1; E1, E22) indicate that the enteric-coated formulation of metformin hydrochloride, which features limited release in pH 4.5 (less than 7.5-15% release at 120 minutes) and rapid dissolution in pH 6.8 (more than 85% dissolution at 20 minutes, especially more than 85% dissolution at 15 minutes), achieves the best efficacy and the lowest adverse reactions. Its bioavailability compared to conventional metformin hydrochloride formulations (such as Glucophage) is approximately 60-80%.

Claims

1. An enteric-coated formulation of a biguanide compound, an oral dosage form comprising a therapeutically effective amount of a biguanide compound and pharmaceutically acceptable excipients, characterized in that, The enteric-coated formulation exhibits a biguanide compound dissolution rate of no more than 15% within 120 minutes in a pH 4.5 medium and a biguanide compound dissolution rate of no less than 85% within 20 minutes in a pH 6.8 medium. The biguanide compound is metformin hydrochloride, and the enteric-coated formulation is an enteric-coated tablet consisting of a tablet core and an enteric coating. The tablet core comprises 500.00g of metformin hydrochloride, 16.54g of corn starch, 20.00g of mannitol, 16.68g of sodium carboxymethyl starch, and 2.78g of magnesium stearate. The enteric coating comprises 6.00g of a copolymer of methacrylic acid and ethyl acrylate L100-55, 0.60g of triethyl citrate, and 1.50g of talc.

2. An enteric-coated formulation of a biguanide compound, comprising an oral dosage form of a therapeutically effective amount of a biguanide compound and pharmaceutically acceptable excipients, characterized in that, The enteric-coated formulation exhibits a biguanide compound dissolution rate of no more than 15% within 120 minutes in a pH 4.5 medium and a biguanide compound dissolution rate of no less than 85% within 20 minutes in a pH 6.8 medium. The biguanide compound is metformin hydrochloride, and the enteric-coated formulation is an enteric-coated tablet consisting of a tablet core and an enteric coating. The tablet core comprises 500.00g of metformin hydrochloride, 16.54g of corn starch, 20.00g of mannitol, 16.68g of sodium carboxymethyl starch, and 2.78g of magnesium stearate. The enteric coating comprises 8.00g of hydroxypropyl methylcellulose phthalate HP-50, 0.40g of triethyl citrate, and 2.40g of talc.

3. An enteric-coated formulation of a biguanide compound, an oral dosage form made from a therapeutically effective amount of a biguanide compound and pharmaceutically acceptable excipients, characterized in that... The enteric-coated formulation exhibits a biguanide compound dissolution rate of no more than 15% within 120 minutes in a pH 4.5 medium and a biguanide compound dissolution rate of no less than 85% within 20 minutes in a pH 6.8 medium. The biguanide compound is metformin hydrochloride, and the enteric-coated formulation is an enteric-coated tablet consisting of a tablet core and an enteric coating. The tablet core comprises 500.00g of metformin hydrochloride, 16.54g of corn starch, 20.00g of mannitol, 16.68g of sodium carboxymethyl starch, and 2.78g of magnesium stearate. The enteric coating comprises 6.00g of L100 copolymer of methacrylic acid and methyl methacrylate, 0.90g of triethyl citrate, and 1.50g of talc.

4. An enteric-coated formulation of a biguanide compound, an oral dosage form made from a therapeutically effective amount of a biguanide compound and pharmaceutically acceptable excipients, characterized in that, The enteric-coated formulation exhibits a biguanide compound dissolution rate of no more than 15% within 120 minutes in a pH 4.5 medium and a biguanide compound dissolution rate of no less than 85% within 20 minutes in a pH 6.8 medium. The biguanide compound is metformin hydrochloride, and the enteric-coated formulation is an enteric capsule composed of a base capsule, a drug-loaded layer, and an enteric coating layer. The base capsule contains a 60.00 mg sucrose core (600-710 μm). The drug-loaded layer consists of 250.00 mg metformin hydrochloride, 12.50 mg hydroxypropyl methylcellulose E5, and 12.50 mg crospovidone XL-10. The enteric coating layer consists of 62.04 mg hydroxypropyl methylcellulose phthalate HP-55, 3.10 mg triethyl citrate, and 18.61 mg talc.

5. The enteric-coated formulation according to any one of claims 1-4, characterized in that, The enteric-coated formulation exhibits a biguanide compound dissolution rate of no more than 7.5% within 120 minutes in a pH 4.5 medium, and a biguanide compound dissolution rate of no less than 85% within 15 minutes in a pH 6.8 medium.

6. The enteric-coated formulation according to any one of claims 1-4, characterized in that, Compared to an immediate-release formulation containing an equal amount of the biguanide compound, the enteric-coated formulation has a relative bioavailability of 60% to 80%.

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