Metformin oral dosage form and preparation method thereof

Abstract

The invention provides a preparation form and a preparation method of metformin. The preparation is composed of a tablet core and a controlled release film wrapping the tablet core, and the controlled release film is provided with at least one channel which allows the metformin or the pharmaceutically acceptable salt of the metformin to be released from the tablet core in a water phase environment. The design of the dosage form can control the release of the metformin or the pharmaceutically acceptable salt of the metformin to be less than 30% in 4 hours and less than 92% in 24 hours in a medium with the temperature of 37 DEG C and the pH value of 6.8. The design of the dosage form can control the plasma concentration of the metformin to reach the peak value at about 8-24 after the metformin or the pharmaceutically acceptable salt of the metformin is taken for a single time.

Description

TECHNICAL FIELD

[0001] The present disclosure generally relates to pharmaceutical compositions for the treatment of type 2 diabetes, and more particularly to oral dosage forms of anti-diabetic drugs, such as metformin. The oral dosage forms mainly comprise a controlled release form of metformin or a pharmaceutically acceptable salt thereof, which is designed such that the amount of metformin released in the upper gastrointestinal tract is relatively low, and the amount of metformin released in the lower gastrointestinal tract is relatively high, thereby achieving a more stable dose release at different release time points. The present disclosure also relates to methods of preparing such oral dosage forms, as well as methods of using such oral dosage forms for the treatment of type 2 diabetes. BACKGROUND

[0002] Type 2 diabetes mellitus, also known as hyperglycemia, is a chronic progressive disease that has been identified as a global epidemic, affecting approximately 9% of the world’s population. Type 2 diabetes mellitus is mainly caused by endocrine defects or deficiencies, such as insulin resistance and impaired insulin secretion.

[0003] Treatment of type 2 diabetes mellitus usually starts with diet and exercise, followed by oral anti-diabetic monotherapy. There are currently multiple types / classes of anti-diabetic drugs available for oral anti-diabetic monotherapy, including biguanides, dipeptidyl peptidase 4 (DPP-4) inhibitors, sulfonylureas, glinides, thiazolidinediones, sodium-glucose co-transporter 2 (SGLT2) inhibitors, and alpha-glucosidase inhibitors, among others.

[0004] As a first-line approved anti-diabetic drug, metformin is a biguanide that improves glucose tolerance and reduces fasting and postprandial blood glucose levels in patients with type 2 diabetes mellitus. Metformin improves insulin sensitivity by reducing hepatic glucose production, decreasing intestinal glucose absorption, and increasing peripheral glucose uptake and utilization. Except in special cases, metformin does not cause hypoglycemia in patients with type 2 diabetes mellitus or healthy subjects, nor does it cause hyperinsulinemia. During metformin therapy, insulin secretion remains unchanged, while fasting insulin levels and daytime plasma insulin response can be reduced.

[0005] In one notable example, metformin salts, especially metformin hydrochloride, generally have a high water solubility. This high solubility often leads to gastrointestinal side effects, such as diarrhea, nausea, and vomiting, at a higher incidence than all other oral anti-diabetic drugs if administered in an uncontrolled manner. However, given its pharmacokinetic and pharmacodynamic characteristics, the duration of action of this drug is also limited. Although these gastrointestinal side effects diminish over time and can be minimized by taking metformin with meals or by carefully adjusting the dose, they can affect patient compliance and even lead to discontinuation of treatment in some patients. Similar gastrointestinal side effects have also been observed in other anti-diabetic drugs.

[0006] Although metformin has become the first-line drug for the treatment of type 2 diabetes, it can not be used in some patients due to the risk of lactic acidosis. Metformin, like other biguanides, primarily inhibits mitochondrial respiration in the liver, increasing plasma lactate levels in a plasma concentration-dependent manner. Elevated plasma metformin concentrations, as occurs in patients with renal insufficiency, and secondary events or conditions that further impair lactate production or clearance, such as cirrhosis, sepsis, or hypoperfusion, are usually necessary to cause metformin-associated lactic acidosis. Since these secondary events can not be predictable and the mortality rate of lactic acidosis is close to 50%, metformin has been prohibited for use in patients with moderate and severe renal insufficiency since its approval by the U.S. Food and Drug Administration, and is only suitable for patients with normal or mild renal insufficiency to minimize the risk of metformin toxicity levels and lactic acidosis. A delayed-release metformin is currently being developed, which is expected to provide a treatment option for patients with renal insufficiency after the results of future studies are available.

[0007] In view of these problems, a number of patent documents (including U.S. Patent Nos. 4,915,952, 5,328,942, 5,451,409, 5,945,125, 6,090,411, 6,210,710, 6,217,903, 6,488,962, 6,723,340, 6,866,866, and 8,323,692, and International Patent Application Nos. WO1996026718A2 and WO1997018814A1) have disclosed controlled-, sustained-, or extended-release pharmaceutical dosage forms of metformin hydrochloride. This extended release or controlled release is achieved in two ways: one is to limit the rate at which the surrounding gastric fluid diffuses through the matrix, contacts the drug, dissolves the drug, and diffuses back out with the dissolved drug; the other is to use a slowly eroding matrix, thereby continuously exposing fresh drug to the surrounding fluid. Thus, the drug achieves controlled release in at least a portion of the region defined by the stomach and upper gastrointestinal tract in vivo, thereby providing a sustained and non-pulsatile level of metformin hydrochloride for human subjects in need of such treatment for 12 to 24 hours.

[0008] In the prior art, various techniques have been employed to provide controlled- and sustained-release pharmaceutical dosage forms to maintain therapeutic serum levels of the drug and minimize the impact of missed doses due to poor patient compliance, while reducing side effects by reducing the likelihood of a bolus release of the drug in the gastrointestinal system or reducing the excessive exposure of the drug to the surface of the gastrointestinal system.

[0009] Despite the extensive research on controlled or sustained release compositions, especially osmotic dosage forms, currently available products still cause side effects in patients and the tablets of the available products show significant variation in release rate at different time points, which can lead to a burst release of the drug and thus induce severe side effects. Therefore, there is still a need for further reduction of side effects and to provide a dosage form of metformin for patients with moderate and severe renal insufficiency. SUMMARY

[0010] In a first aspect, the present disclosure provides an oral dosage form of a pharmaceutical composition for treating diabetes or prediabetes in a subject.

[0011] The oral dosage form mainly comprises a core portion (i.e. tablet core or core) and a controlled release membrane which coats the tablet core portion. The tablet core portion comprises metformin or a pharmaceutically acceptable salt thereof, which is optionally designed at a therapeutically effective amount. The controlled release membrane is provided with at least one channel which allows the release of metformin or a pharmaceutically acceptable salt thereof from the tablet core when the oral dosage form is in an aqueous environment (e.g. in water or in the gastrointestinal tract of the subject).

[0012] The oral dosage form is designed to achieve a controlled release of metformin. Specifically, the oral dosage form is designed to have a dissolution profile in which less than 30% of metformin or a pharmaceutically acceptable salt thereof is released within 4 hours and less than 92% is released within 24 hours when the dissolution profile is tested in a medium at about 37°C and at a pH of about 6.8.

[0013] The oral dosage form can be further optionally designed to have a dissolution profile in which about 30-50% of metformin or a pharmaceutically acceptable salt thereof is released within 8 hours when the dissolution profile is tested in a medium at about 37°C and at a pH of about 6.8.

[0014] Further optionally, the oral dosage form can be designed to have a dissolution profile in which about 45-70% of metformin or a pharmaceutically acceptable salt thereof is released within 12 hours when the dissolution profile is tested in a medium at about 37°C and at a pH of about 6.8.

[0015] The oral dosage form can be further optionally designed to have a dissolution profile wherein the release of metformin or a pharmaceutically acceptable salt thereof is about 18% to about 21% within 4 hours and about 82% to about 90% within 24 hours when the dissolution profile is measured in a medium having a pH of about 6.8 at about 37°C. Further optionally, the oral dosage form is designed to have a dissolution profile wherein the release of metformin or a pharmaceutically acceptable salt thereof is about 35% to about 45% within 8 hours when the dissolution profile is measured in a medium having a pH of about 6.8 at about 37°C. Further optionally, the oral dosage form is designed to have a dissolution profile wherein the release of metformin or a pharmaceutically acceptable salt thereof is about 50% to about 65% within 12 hours when the dissolution profile is measured in a medium having a pH of about 6.8 at about 37°C.

[0016] In any of the above oral dosage forms, the relative standard deviation (RSD) of the release of metformin or a pharmaceutically acceptable salt thereof from the oral dosage form is not more than 11%, preferably not more than 6%, at any time point between 4 hours and 24 hours when the dissolution profile is measured in a medium having a pH of about 6.8 at about 37°C.

[0017] In any of the above oral dosage forms, the relative standard deviation (RSD) of the release of metformin or a pharmaceutically acceptable salt thereof from the oral dosage form is not more than 7.5% when the release is measured for 8 hours in a medium having a pH of about 6.8 at about 37°C.

[0018] In any of the above oral dosage forms, the relative standard deviation (RSD) of the release of metformin or a pharmaceutically acceptable salt thereof from the oral dosage form is not more than 6.0% when the release is measured for 12 hours in a medium having a pH of about 6.8 at about 37°C.

[0019] In any of the above oral dosage forms, the oral dosage form can be designed to further achieve a controlled release of metformin or a pharmaceutically acceptable salt thereof such that the oral dosage form provides a maximum plasma concentration of metformin or a pharmaceutically acceptable salt thereof to a subject within about 8 to 24 hours after a single oral administration.

[0020] Optionally herein, the oral dosage form reaches a mean maximum plasma concentration of metformin or a pharmaceutically acceptable salt thereof in a subject at about 13.5 hours (with a standard deviation of about 4.4 hours) after a single oral administration.

[0021] In any of the oral dosage forms described above, the oral dosage form can be configured to achieve controlled release of metformin or a pharmaceutically acceptable salt thereof, such that upon single oral administration, based on administration of an oral dosage form comprising X mg metformin hydrochloride, the oral dosage form provides a mean maximum plasma concentration (Cmax) of metformin of about 0.5X ng / ml to about 0.9X ng / ml, wherein X ranges from about 100-1000.

[0022] In any of the oral dosage forms described above, the oral dosage form can be configured to provide a mean maximum AUCo-t of about 7Y hr ng / mL to about 16Y hr ng / mL, based on administration of an oral dosage form comprising Y mg metformin hydrochloride, wherein Y ranges from about 100-1000.

[0023] In any of the oral dosage forms described above, the controlled release film comprises at least one water-insoluble polymer, each polymer selected from the group consisting of cellulose ester, cellulose diester, cellulose triester, cellulose ether, cellulose ester-ether, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate, and cellulose acetate butyrate. According to some embodiments of the oral dosage form, the at least one water-insoluble polymer in the controlled release film comprises cellulose acetate, which can optionally have an acetyl content of about 39.3%-40.3%.

[0024] In the oral dosage form, the controlled release film can further comprise at least one pore former, each pore former selected from the group consisting of sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, polyvinyl alcohol, and methacrylic acid copolymer. According to some embodiments of the oral dosage form, the at least one pore former in the controlled release film comprises polyethylene glycol.

[0025] In any of the oral dosage forms described above, the controlled release film can have a weight percent of 1.8%-6.0%.

[0026] In any of the oral dosage forms described above, the number of at least one channel in the controlled release film is two.

[0027] Optionally herein, two channels are designed on two sides of the oral dosage form.

[0028] Optionally herein, each of the at least one channel has a diameter of about 0.30-2.00 mm.

[0029] Optionally herein, each of the at least one channel has a depth of about 0.10-2.00 mm.

[0030] In any of the above oral dosage forms, the metformin or pharmaceutically acceptable salt thereof includes at least one of metformin hydrochloride, metformin sulfate, metformin phosphate, metformin hydrobromide, metformin salicylate, metformin maleate, metformin benzoate, metformin succinate, metformin ethanesulfonate, metformin fumarate, or metformin glycolate.

[0031] According to some embodiments, the metformin or pharmaceutically acceptable salt thereof includes metformin hydrochloride, which can be in a dose of about 100-1200 mg.

[0032] In any of the above oral dosage forms, the core portion can further comprise at least one binder, each binder selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, polymethacrylate, and wax.

[0033] According to some embodiments, the at least one binder in the core portion comprises polyvinylpyrrolidone, hydroxypropyl cellulose, or a combination thereof.

[0034] According to some embodiments, the at least one binder in the core portion comprises hydroxypropyl cellulose.

[0035] According to some embodiments, the at least one binder in the core portion comprises polyvinylpyrrolidone having a weight average molecular weight of 25,000 to 3,000,000 g / mol.

[0036] In any of the above oral dosage forms, the core portion further comprises at least one absorption enhancer, each absorption enhancer selected from the group consisting of fatty acid, surfactant, chelating agent, and bile salt.

[0037] According to some embodiments, the at least one absorption enhancer in the core portion comprises a surfactant selected from the group consisting of sodium lauryl sulfate, sodium taurocholate, and polyoxyethylene 20 sorbitan monooleate (i.e., Tween 80). Herein, according to some embodiments, the at least one absorption enhancer in the core portion comprises sodium lauryl sulfate.

[0038] In any of the above oral dosage forms, the core portion further comprises at least one lubricant, each lubricant selected from the group consisting of magnesium stearate, stearic acid, sodium fumarate, glyceryl behenate, and glyceryl dibehenate.

[0039] Herein, according to some embodiments, the at least one lubricant in the core portion consists of magnesium stearate, glyceryl dibehenate, or a combination thereof. Herein, optionally, the at least one lubricant in the core portion consists of glyceryl dibehenate.

[0040] In any of the above oral dosage forms, the oral dosage form can further comprise at least one of an inner seal film sandwiched between the core portion and the controlled release film, which serves to provide a protective coating for the core portion encased therein; or an outer seal film encasing the outer surface of the controlled release film.

[0041] Optionally herein, at least one of the inner seal film or the outer seal film can comprise at least one film forming polymer, each film forming polymer being selected from the group consisting of hypromellose, hypromethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, and polyvinyl alcohol and polyethylene glycol.

[0042] According to some embodiments, the inner seal film or the outer seal film has a weight that is about 0.4% to 40% of the total weight of the oral dosage form.

[0043] Further details of the above oral dosage forms are provided below.

[0044] In any of the above oral dosage forms, the core portion can further comprise at least one granulation binding polymer. Each of the at least one binding polymer can be selected from the group consisting of hypromethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, polyethylene oxide, polyvinyl alcohol, povidone and copovidone. Mixtures of the above binding agents can also be used. A preferred binding agent is water-soluble, such as polyvinylpyrrolidone having a weight average molecular weight of 25,000 to 3,000,000 g / mol. The binding agent can be present in a proportion of about 0% to about 40%, preferably about 3% to about 15% of the total weight of the core. The core should contain at least one permeation / absorption enhancer. The absorption enhancer can be any type of absorption enhancer generally known in the art, such as a fatty acid, a surfactant, a chelating agent, a bile salt or a mixture thereof. Some examples of preferred absorption enhancers include fatty acids (such as capric acid, oleic acid and their monoglycerides), surfactants (such as sodium lauryl sulfate, sodium taurocholate and polysorbate 80), chelating agents (such as citric acid, phytic acid, ethylenediaminetetraacetic acid (EDTA) and ethylene glycol bis(β-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA)). The absorption enhancer can be present in a proportion of about 0% to about 20%, most preferably about 2% to about 10% of the total weight of the core. In this embodiment, the core comprising the antihyperglycemic drug, the binding agent (preferably a pharmaceutically acceptable water-soluble polymer) and the absorption enhancer is preferably formed by wet granulation of the core ingredients and compression into tablets on a rotary tablet press after addition of a lubricant. The core can also be formed by dry granulation of the core ingredients and compression into tablets after addition of a lubricant or by direct compression. Other commonly used excipients, such as lubricants, pigments or dyes, can also be included in the core.

[0045] In its core portion, metformin or a pharmaceutically acceptable salt thereof may include at least one of metformin hydrochloride, metformin sulfate, metformin phosphate, metformin hydrobromide, metformin salicylate, metformin maleate, metformin benzoate, metformin succinate, metformin ethanesulfonate, metformin fumarate, or metformin glycolate, as disclosed in U.S. Patent No. 3,174,901. A preferred example of metformin or a pharmaceutically acceptable salt thereof herein is metformin hydrochloride, in dosage forms of about 100-2000 mg. For example, oral dosage forms provided in this disclosure may contain 100 mg, 250 mg, 500 mg, 750 mg, 1000 mg, or 2000 mg of metformin hydrochloride, preferably 250 mg, 500 mg, 750 mg, and 1000 mg.

[0046] When the oral dosage form was tested in a USP Type II device at approximately 37°C and 50 rpm in 900 ml of medium with a pH of approximately 6.8, metformin hydrochloride was prepared to exhibit the following dissolution profiles: less than 30% of metformin hydrochloride was released within 4 hours after contact with the medium; 30%-50% was released within 8 hours; 40%-65% was released within 12 hours; and at least 75% was released within 24 hours.

[0047] A controlled-release oral dosage form of metformin hydrochloride is formulated to provide a mean maximum plasma concentration of metformin of about 0.5X ng / ml to about 0.9X ng / ml based on an oral dosage form containing X mg of metformin hydrochloride, wherein X ranges from about 100 to 1000. In some embodiments, the controlled-release oral dosage form contains 1000 mg of metformin hydrochloride, and based on an oral dosage form containing 1000 mg of metformin once daily, the oral dosage form is formulated to provide a mean maximum plasma concentration of the drug of about 500-900 ng / ml. In another embodiment, the controlled-release oral dosage form contains 500 mg of metformin hydrochloride, and based on an oral dosage form containing 500 mg of metformin once daily, the oral dosage form is formulated to provide a mean maximum plasma concentration of the drug of about 250-450 ng / ml.

[0048] A controlled-release oral dosage form of metformin hydrochloride is formulated to provide a mean maximum AUC0-t of about 7Y hr ng / mL to about 16Y hr ng / mL based on an oral dosage form containing Y mg of metformin hydrochloride, wherein Y ranges from about 100 to 1000. In some embodiments, the controlled-release oral dosage form contains 1000 mg of metformin hydrochloride, and based on an oral dosage of 1000 mg metformin once daily, the controlled-release dosage form provides a mean AUC0-24hr of about 7000-16000 ng·hr / mL. In another embodiment, the controlled-release oral dosage form contains 500 mg of metformin hydrochloride, and based on an oral dosage of 500 mg metformin once daily, the controlled-release dosage form provides a mean AUC0-24hr of about 3500-8000 ng·hr / mL.

[0049] In any embodiment of the oral dosage form described above, the controlled-release membrane may comprise at least one water-insoluble polymer. Each of the at least one water-insoluble polymer is selected from cellulose acetate or cellulose acetate phthalate. According to some embodiments, the at least one water-insoluble polymer in the controlled-release membrane of the oral dosage form of the pharmaceutical composition may be cellulose ester, cellulose diester, cellulose triester, cellulose ether, cellulose acetate phthalate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate, and cellulose acetate butyrate. Other suitable polymers are described in U.S. Patent Nos. 3,845,770, 3,916,899, 4,008,719, 4,036,228, and 4,11210, the entire contents of which are incorporated herein by reference. The most preferred membrane material is cellulose acetate, which may be selected from CA-320S, CA-398-3, CA-398-6, CA-398-10, CA-398-30, CA398-60S, or any combination thereof. In this article, CA-320S, CA-398-3, CA-398-6, CA-398-10, CA-398-30, and CA398-60S should be interpreted in the same sense as those skilled in the art, and can be referred to in the "Handbook of Pharmaceutical Excipients" respectively. More specifically, CA-320S may refer to cellulose acetate molecules with a weight-average molecular weight of approximately 38,000 g / mol, CA-398-3 may refer to cellulose acetate molecules with a weight-average molecular weight of approximately 30,000 g / mol, CA-398-6 may refer to cellulose acetate molecules with a weight-average molecular weight of approximately 35,000 g / mol, CA-398-10 may refer to cellulose acetate molecules with a weight-average molecular weight of approximately 40,000 g / mol, CA-398-30 may refer to cellulose acetate molecules with a weight-average molecular weight of approximately 50,000 g / mol, and CA398-60S may refer to cellulose acetate molecules with a weight-average molecular weight of approximately 60,000 g / mol. In some specific embodiments, at least one controlled-release polymer comprises CA-398-10. According to some embodiments of oral dosage forms of pharmaceutical compositions, the relative amount of at least one controlled-release polymer in the controlled-release membrane of a metformin hydrochloride controlled-release oral dosage form may be from about 1% to 100% by weight of the controlled-release membrane. Optionally, the relative amount of at least one controlled-release polymer may be from about 1.5% to 7.0% by weight of the tablet. According to some embodiments of the oral dosage form of the pharmaceutical composition, the controlled-release film may further comprise at least one plasticizer (such as polyethylene glycol), which may be from about 0.1% to 40% by weight of the controlled-release film. Optionally, the at least one polyethylene glycol may comprise polyethylene glycol (PEG) 6000 or 3350, which may be from about 0.1% to 40% by weight of the controlled-release film.

[0050] According to some embodiments of oral dosage forms of pharmaceutical compositions, at least one channel is formed in the middle of the film-coated tablet by mechanical or optical means.

[0051] In this document, the term "channel" includes a hole, opening, borehole, cavity, weakened region, or erodible element (such as a gelatin stopper) that, upon erosion, forms a permeation channel for the release of an antihyperglycemic drug from the dosage form. Detailed descriptions of channels can be found in U.S. Patent Nos. 3,845,770, 3,916,899, 4,034,758, 4,063,064, 4,077,407, 4,088,864, 4,783,337, and 5,071,607 (the disclosures of which are incorporated herein by reference). In some embodiments, the channel is formed by laser drilling. In a preferred embodiment of the invention, the dosage form includes one channel on each side of each tablet to provide desired formulation pharmacokinetic parameters.

[0052] In any embodiment of the above-described oral dosage form, two channels may be provided, which may be disposed on each side of the controlled-release membrane. Preferably, each of the two channels may be disposed within ±5 mm of the center of each side of the controlled-release membrane, more preferably within ±2 mm. The diameter of each channel is approximately 0.30-2.00 mm, preferably 0.40-0.60 mm. The depth of each channel is approximately 0.10-2.00 mm, preferably 0.30-1.40 mm.

[0053] According to certain embodiments, the oral dosage form may optionally further include an inner sealing film sandwiched between the tablet core portion and the controlled-release membrane to provide a protective coating for the tablet core portion encapsulated therein.

[0054] According to certain embodiments, the oral dosage form may optionally further include an outer sealing film, which wraps around the outer surface of the outer portion to provide a protective coating for the outer portion therein.

[0055] According to certain embodiments, the oral dosage form may optionally include an inner sealing film sandwiched between the tablet core portion and the controlled-release membrane, and an outer sealing film wrapped around the outer surface of the film-coated tablet.

[0056] In the above-described oral dosage form embodiments, at least one of the inner sealing film or the outer sealing film contains at least one film-forming polymer, each film-forming polymer being selected from hydroxypropyl methylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose, polyvinylpyrrolidone (PVP), and polyvinyl alcohol and polyethylene glycol (PEG).

[0057] In the above-mentioned oral dosage form implementation scheme, the weight of the inner or outer sealing film accounts for approximately 0.4% to 40% of the total weight of the oral dosage form, preferably 2% to 10%.

[0058] In the above-described oral dosage form embodiments, the inner sealing film, the outer sealing film, or both may further contain at least one of a plasticizer, a pigment, a dispersant, or an antioxidant.

[0059] In any embodiment of the oral dosage form of the above-described pharmaceutical composition, the subject may be a human or a mammal with diabetes.

[0060] In a second aspect, this disclosure further provides a method for preparing an oral dosage form of a pharmaceutical composition. The oral dosage form may be an oral dosage form of the composition described in any of the embodiments of the first aspect.

[0061] The method may include the following steps (AC):

[0062] (A) Preparing a tablet core portion containing metformin or a pharmaceutically acceptable salt thereof;

[0063] (B) The core portion is wrapped with a controlled-release membrane, wherein the controlled-release membrane has at least one channel for allowing at least one antidiabetic drug to be released from the core portion;

[0064] Optionally, the method includes the following steps between step (A) and step (B):

[0065] The chip core portion is wrapped with an inner sealing film, which serves to provide a protective coating for the core portion encased within it.

[0066] Optionally, the method includes the following steps after step (B):

[0067] Film-coated tablets are wrapped with an outer sealing film, which provides a protective coating for the film coating encapsulated within them.

[0068] In step (A) of this method, the core component comprising at least one antidiabetic drug can be prepared via the following sub-steps:

[0069] (1) Granulation - dry granulation, wet granulation or fluidized bed granulation;

[0070] (2) Crushing;

[0071] (3) Mixing; and

[0072] (4) Tableting.

[0073] Optionally, after obtaining the tablet core portion in sub-step (4), step (A) further includes sub-step (5): coating the tablet core portion with a sealing coating solution, wherein the sealing coating solution can be prepared by first dissolving hydroxypropyl methylcellulose or hydroxypropyl cellulose and polyethylene glycol, or other suitable water-soluble materials. The coating solution is then sprayed onto the tablet core using a pan coating machine. The sealing film accounts for about 2%-10% of the weight of the oral dosage form. In step (B) of the method, the controlled-release membrane may contain at least one controlled-release polymer, each controlled-release polymer optionally selected from cellulose acetate or cellulose acetate phthalate polymers; at least one channel may then be formed in the controlled-release membrane.

[0074] According to some implementations of this method, step (B) of wrapping the tablet core portion with a controlled-release membrane includes the following sub-steps:

[0075] (1) Preparation of a coating solution, wherein the coating solution comprises CA-398-10 and PEG 400, 3350, 6000 or 8000; and

[0076] (2) The core portion is coated with a coating solution to obtain a coated tablet; and

[0077] (3) Solidified coated tablets.

[0078] In the implementation scheme of the above method, the above sub-step (3) of curing the coated sheet includes:

[0079] The coated film should be cured at 50°C for at least one hour.

[0080] In some embodiments, each of at least one channel is formed by laser drilling. In a preferred embodiment of the invention, the oral dosage form includes one channel on each side of each tablet to provide the desired formulation pharmacokinetic parameters. The pore should be located within ±2 mm of the center of the tablet, with a diameter between 0.30 and 0.60 mm and a depth between 0.10 and 1.40 mm.

[0081] In some embodiments of the method for further coating film-coated tablets with an external sealing film, the external sealing film can be prepared by the following procedure. In short, the external sealing coating solution can be prepared by mixing all excipients in a desired amount of purified water using a suitable homogenizer until the solids dissolve. The film-coated tablets can be loaded into a suitable perforated side-ventilated coating pan equipped with baffles and a single or multiple spray guns to produce a spray covering the entire width of the tablet bed; the average weight of the warm, uncoated tablets is determined as the initial starting weight; the sealing coating solution is sprayed onto the tablet bed at a suitable spray rate and atomization pressure; spraying continues while monitoring the tablet weight until the desired weight gain is achieved.

[0082] Throughout this publication, the term "tablet" is intended to encompass all compressed pharmaceutical dosage forms of all shapes and sizes, whether coated or not.

[0083] As used herein, the term “pharmaceutically acceptable” means, to a reasonable extent of medical judgment, a compound, material, composition, and / or dosage form that is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or any other problems or complications, and that is commensurate with a reasonable benefit / risk ratio.

[0084] The terms “pharmaceutical composition” or “dosage form” as used herein are used interchangeably and are defined as a pharmaceutical composition, formulation, or system comprising a dose of a drug or an active pharmaceutical ingredient. Pharmaceutical compositions or dosage forms may be administered via any route of administration known to those skilled in the art, including but not limited to oral, parenteral, pulmonary, rectal, vaginal, nasal, and topical administration.

[0085] As used herein, the term "dosage form" refers to at least one unit dosage form of the present invention (e.g., a daily dose of an antihyperglycemic drug may be contained in two unit dosage forms of the present invention for once-daily administration).

[0086] As used herein, the term "oral dosage form" is defined as a dosage form administered orally for absorption through the oral mucosa and / or swallowed via the gastrointestinal tract. Such oral dosage forms include, but are not limited to, solutions, syrups, suspensions, emulsions, gels, powders, granules, capsules, tablets, buccal formulations, and sublingual formulations.

[0087] The term "therapeutic effective dose" as used in this article refers to the amount of an antidiabetic drug that, when administered orally once daily in a controlled-release formulation to a human patient, reduces blood glucose levels by approximately the same amount or more as an immediate-release reference standard (such as Glucophage).

[0088] For the purposes of this disclosure, the term "immediate release" (abbreviated as "IR") is defined as the release of an active pharmaceutical ingredient from an oral dosage form into the gastrointestinal tract shortly after administration, typically with peak plasma drug levels occurring shortly after administration. Therefore, the term "immediate-release dosage form" refers to a dosage form that exhibits "immediate release" of the active pharmaceutical ingredient and thus provides a substantially immediate rate of release of the active pharmaceutical ingredient.

[0089] The term “controlled release” (abbreviated as “CR”) used throughout this disclosure is considered interchangeable with the terms “extended release” (abbreviated as “ER”), “prolonged release” (abbreviated as “PR”), and “sustained release” (abbreviated as “SR”). For the purposes of this disclosure, it is defined as the release of the active drug over a prolonged period of time (e.g., from about 12 hours to about 24 hours) compared to an immediate-release formulation, such that the plasma concentration of the active drug is maintained at therapeutic levels for a longer period and the therapeutic benefit is maintained for a prolonged period. Therefore, the terms “controlled-release formulation,” “immediate-release formulation,” “prolonged-release formulation,” and / or “sustained-release formulation” refer to formulations that exhibit “controlled release,” “immediate release,” “prolonged release,” and / or “sustained release” of the active drug.

[0090] Throughout the disclosure, the formulation different from Fortamet is referred to as a sustained-release formulation of metformin hydrochloride, manufactured by AndrxLabs and other companies, as described in U.S. Patent No. 6,866,866. 1000 mg Glumetza refers to a formulation of metformin manufactured by Santarus Inc., as described in U.S. Patent No. 7,780,978.

[0091] Throughout the disclosure, terms such as "about," "approximately," and "around" following numbers indicate that the actual figure is within 5% of the indicated figure. For example, "about 1.00" can be interpreted as the actual figure being between 0.95 and 1.05. Attached Figure Description

[0092] Figure 1 This is a schematic diagram of an oral dosage form of metformin or a pharmaceutically acceptable salt thereof according to some embodiments of this disclosure. Detailed Implementation

[0093] The technical solutions of the various embodiments disclosed herein will be clearly and completely described below with reference to the accompanying drawings. It should be noted that the described embodiments represent only a portion of the embodiments of this disclosure, and not all of them. Based on the embodiments described herein, those skilled in the art can obtain other embodiments, all of which should fall within the scope of protection sought by this disclosure.

[0094] In a first aspect, this disclosure provides a pharmaceutical composition dosage form specifically for treating subjects with diabetes or prediabetes.

[0095] In this article, the preferred dosage form is an oral dosage form that can be taken orally by the subject. The subject can be, but is not limited to, humans, or other mammals that produce insulin, such as monkeys, chimpanzees, dogs, cats, etc.

[0096] Regarding the controlled-release formulation of an antidiabetic drug in an oral dosage form of a pharmaceutical composition, it can be achieved by placing the antidiabetic drug at the core of the dosage form and further encapsulating the core with a controlled-release membrane configured to achieve controlled release of the antidiabetic drug in the core.

[0097] Figure 1 A structural diagram of an oral dosage form of a pharmaceutical composition according to certain embodiments of the present disclosure is illustrated. As shown in the figure, the oral dosage form 001 of the pharmaceutical composition mainly comprises a core portion 100 containing at least one antidiabetic drug.

[0098] The tablet core portion 100 is surrounded by a controlled-release membrane 150, thereby enclosing the tablet core portion 100. The controlled-release membrane 150 is provided with one or more delivery channels (e.g., holes, openings, pores, etc.) 151, which are used to provide a delivery channel for at least one antidiabetic drug in the tablet core portion 100 to leave the controlled-release membrane 150, thereby achieving its controlled release or sustained release. Figure 1 Only two delivery channels 151 are shown in the diagram, but it should be noted that this is for illustrative purposes only, and there is no limitation on the number of delivery channels provided in the controlled-release membrane 150. Optionally, each delivery channel may be further provided with a soluble plug (not shown in the diagram), such as a water-soluble material (e.g., gelatin) or an enteric material, which is used to seal the channel but can dissolve or leach in an aqueous solution (e.g., gastrointestinal fluid), thereby opening the delivery channel and allowing the release of at least one antidiabetic drug from the tablet core portion 100. In this document, the controlled-release membrane 150 may account for about 1% to about 7% of the total oral dosage form, preferably about 2% to about 6%. In some preferred embodiments of this disclosure, the dosage form comprises two channels configured to provide the desired formulation pharmacokinetic parameters.

[0099] In this document, the controlled-release membrane 150 may be a semi-permeable membrane that allows the passage of external fluids (such as water and biofluids) but not the antidiabetic drug in the tablet core. Therefore, the controlled-release membrane 150 may comprise at least one water-insoluble polymer. Non-limiting examples of insoluble polymers that may be used to form the controlled-release membrane 150 herein include cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester-ethers, cellulose acylates, cellulose diacids, cellulose triacylates, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate, or cellulose acetate butyrate, etc. Other suitable polymers are described in U.S. Patent Nos. 3,845,770, 3,916,899, 4,008,719, 4,036,228, and 4,11210, the entire contents of which are incorporated herein by reference. For example, one such membrane material could be CA-398-10, which is cellulose acetate with an acetyl content of 39.3%-40.3%, and is available from Eastman Fine Chemicals.

[0100] Optionally, the controlled-release membrane 150 may comprise at least one insoluble polymer and at least one soluble excipient (i.e., a porogen), which are mixed together. The at least one soluble excipient may optionally include at least one porogen and / or at least one plasticizer. The main components of the controlled-release membrane 150 and their proportions are summarized in Table 1.

[0101] Table 1. Main components of controlled-release membranes in oral dosage forms

[0102] Note: The percentages in the table represent the weight percentage of each component, that is, the weight percentage of each component in the controlled-release membrane.

[0103] Optionally, the controlled-release membrane 150 may comprise one or more of the aforementioned insoluble polymers and at least one porogen. The at least one porogen increases the volume of fluid (water and biofluid) permeating into the tablet core, enabling dosage forms of metformin or its pharmaceutically acceptable salts to be dispensed through channels and / or porous membranes, distributing virtually all of the metformin or its pharmaceutically acceptable salts. The porogen may be a water-soluble or enteric-coated material. Examples of some preferred materials that can be used as porogens include sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol (PEG), propylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyvinyl alcohol, methacrylic acid copolymers, and mixtures thereof. According to some embodiments, at least one porogen may comprise polyethylene glycol (PEG), which may be PEG400, PEG 3350, PEG 6000, PEG 8000, or any combination thereof. In this document, PEG 400, PEG 3350, PEG 6000, and PEG 8000 have meanings well known to those skilled in the art, referring to polyethylene glycol with weight-average molecular weights of approximately 400 g / mol, approximately 3350 g / mol, approximately 6000 g / mol, and approximately 8000 g / mol, respectively. At least one porogen constitutes approximately 0% to approximately 40% of the total weight of the coating (i.e., the controlled-release membrane), most preferably approximately 2% to approximately 20%. When the oral dosage form comes into contact with an aqueous solution (such as gastrointestinal fluid), the porogen dissolves or leaches from the controlled-release membrane 150, thereby creating a pathway within the controlled-release membrane 150 for fluid to enter the tablet core and dissolve the active ingredient (i.e., metformin or a pharmaceutically acceptable salt thereof).

[0104] Optionally, but preferably, the controlled-release membrane 150 may also be formed from certain excipients, such as at least one plasticizer. Some commonly used plasticizers include adipate, azelaate, benzoate, citrate, stearate, isobutyrate, sebacic acid ester, triethyl citrate, tri-n-butyl citrate, acetylated tri-n-butyl citrate, citrate, and those described in Volume 10 (1969) of the Encyclopedia of Polymer Science and Technology, published by John Willie & Sons. Preferred plasticizers are polyethylene glycol (PEG), propylene glycol, triacetin, acetylated monoglycerides, grapeseed oil, olive oil, sesame oil, acetylated tributyl citrate, acetylated triethyl citrate, glyceryl sorbitol, diethyl oxalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, dibutyl sebate, triethyl citrate, tributyl citrate, glyceryl tributate, etc. Depending on the specific plasticizer, the amount of plasticizer used can be from 0% to about 25% based on the total weight of the coating (i.e., controlled-release membrane), preferably from about 2% to about 15%.

[0105] In this document, the term "channel" can refer to an opening (e.g., a hole, opening, bore, aperture, etc.) in the controlled-release membrane 150 that allows the release of at least one antidiabetic drug encapsulated in the core portion 100, or a weakened or erodible region (e.g., a stopper erodible in an aqueous environment) in the controlled-release membrane 150 that can be induced to form an opening, thereby allowing the release of metformin or a pharmaceutically acceptable salt thereof. Detailed descriptions of the term "channel" can be found in U.S. Patent Nos. 3,845,770, 3,916,899, 4,034,758, 4,063,064, 4,077,407, 4,088,864, 4,783,337, and 5,071,607, the disclosures of which are incorporated herein by reference. In some embodiments, the channel of the controlled-release membrane 150 in oral dosage form 001 is formed by mechanical or laser drilling. In other embodiments, the channel is formed by creating indentations on the core before film coating, forming a weakened region of the film at the indentation.

[0106] Optionally, the oral dosage form of the pharmaceutical composition may further include an inner sealing film ( Figure 1 (Not shown), which is sandwiched between the core portion 100 and the controlled-release membrane 150. The inner sealing membrane substantially encloses the core portion 100 and is configured to provide a sealing means for the core portion 100 before it is enclosed by the controlled-release membrane 150, so that the properties of the active pharmaceutical ingredient contained in the core portion of the oral dosage form of the pharmaceutical composition provided in this disclosure are not affected during the coating process.

[0107] In this document, the inner sealing membrane may comprise at least one film-forming polymer and one or more pharmaceutically acceptable excipients. Examples of film-forming polymers include hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sodium carboxymethyl cellulose, polyvinylpyrrolidone (PVP), polyvinyl alcohol, polyethylene glycol (PEG), hydroxypropyl methylcellulose, or other suitable water-soluble polymer materials. Excipients included in the outer sealing membrane may similarly include plasticizers, pigments (i.e., dyes or colorants), dispersants, and antioxidants. The composition of plasticizers, pigments, dispersants, and antioxidants is known to those skilled in the art. Examples of plasticizers include polyethylene glycol (PEG) grades 400, 3350, 6000, and 8000 (PEG 400, PEG 3350, PEG 6000, and PEG 8000, respectively) and triethyl citrate. Examples of dispersants may be hydrated aluminum silicate (kaolin). Examples of antioxidants include α-tocopherol, γ-tocopherol, δ-tocopherol, naturally derived extracts rich in tocopherol, L-ascorbic acid and its sodium or calcium salts, ascorbate palmitate, propyl gallate, octyl gallate, dodecyl gallate, butylated hydroxytoluene (BHT), or butylated hydroxyanisole (BHA), etc. A preferred antioxidant is propyl gallate. In this document, antioxidants are used to prevent oxidative degradation of the core portions of the oral dosage forms of the pharmaceutical compositions provided in this disclosure.

[0108] In this document, the relative amount of the inner sealing film relative to the entire tablet may vary within the scope of the invention and depend on the desired drug loading, which may account for about 0.5% to 40% of the tablet dosage form weight, for example 2% to 10%.

[0109] In the tablet core portion 100 of the oral dosage form disclosed herein, metformin or a pharmaceutically acceptable salt thereof may consist of a water-soluble metformin salt (such as metformin hydrochloride (HCl)) in a dose (i.e., the weight of metformin hydrochloride) of about 100-1500 mg, for example 100 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg or 1500 mg. Furthermore, metformin hydrochloride may comprise approximately 50% to approximately 98% of the total oral dosage form, or optionally approximately 75% to approximately 95% (e.g., 80%). Therefore, with this substantial osmotic pump formulation provided by this disclosure, metformin or a pharmaceutically acceptable salt thereof can achieve controlled or sustained release after a subject takes the oral dosage form without the use of any expanding polymer.

[0110] In some embodiments, the core portion of the metformin hydrochloride controlled-release oral dosage form of the present invention further comprises, in addition to metformin or a pharmaceutically acceptable salt thereof, at least one binder (also referred to as a “binder”), and / or optionally at least one absorption enhancer, and / or optionally at least one lubricant, as listed in Table 2.

[0111] Table 2. Main components in the core of oral dosage forms

[0112] Note: The percentages in the table represent the weight percentage of each component in the core portion, that is, the weight percentage of each component in the core portion.

[0113] In this document, the binder may be any pharmaceutically acceptable binder conventionally known in the art, such as polyvinylpyrrolidone (also known as "povidone"), hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, polymethyl methacrylate, waxes, etc. Mixtures of the above binders may also be used. Optionally, the binder for the core portion of the metformin oral dosage form may contain water-soluble molecules, such as hydroxypropyl cellulose (e.g., Klucel-EF, i.e., hydroxypropyl cellulose with a weight-average molecular weight of about 80,000 g / mol, or Klucel-HF, i.e., hydroxypropyl cellulose with a weight-average molecular weight of about 1,200,000 g / mol), or povidone (e.g., povidone-K30 and K90, i.e., polyvinylpyrrolidone with weight-average molecular weights of 50,000 g / mol and 1,000,000 g / mol, respectively). The binder constitutes about 0.5% to about 40% of the total weight of the tablet core portion of the oral dosage form, optionally about 3% to about 15%, preferably about 4% to about 8%. Further optionally, the binder accounts for about 0% to about 30% of the weight of the oral dosage form, optionally about 2% to about 10%, preferably about 5% to about 8%.

[0114] The core portion of the tablet may optionally contain one or more absorption enhancers. The absorption enhancer can be any type of absorption enhancer commonly known in the art, such as fatty acids, surfactants, chelating agents, bile salts, or mixtures thereof. Some preferred examples of absorption enhancers include fatty acids (such as decanoic acid, oleic acid, and their monoglycerides), surfactants (such as sodium lauryl sulfate, sodium taurocholate, and polysorbate 80), and chelating agents (such as calcium acetate, citric acid, cyclodextrin, pentaacetic acid, etc.). The absorption enhancer constitutes about 0% to about 20% of the total weight of the core portion, most preferably about 2% to about 10%. Optionally, the absorption enhancer used in the core portion of metformin oral dosage forms may include sodium lauryl sulfate, which may optionally constitute about 1% to about 10% of the weight of the metformin oral dosage form, optionally about 2% to about 8%, preferably about 3% to about 5%.

[0115] The tablet core portion of the oral dosage form provided herein may use one or more lubricants, which may be any type of lubricant commonly known in the art, such as magnesium stearate, stearic acid, sodium fumarate, glyceryl behenate, glyceryl dibehenate, etc. Optionally, the lubricant component accounts for about 0.1% to about 8% of the total weight of the oral dosage form tablet core portion, and optionally about 0.5% to about 6%. More optionally, the lubricant component accounts for about 1% to about 10% of the weight of the oral dosage form, and optionally about 1% to about 6%.

[0116] In addition to the binders, absorption promoters, and lubricants described above, the core portion may optionally contain other excipients. Examples may include pigments or dyes.

[0117] In some embodiments of the oral dosage form provided herein, the tablet core (i.e., the core portion) may contain metformin hydrochloride (i.e., the active pharmaceutical ingredient), United States Pharmacopeia grade povidone (polyvinylpyrrolidone or PVP) (i.e., the binder), sodium lauryl sulfate (i.e., the absorption enhancer), and magnesium stearate (i.e., the lubricant).

[0118] According to certain embodiments of the oral dosage form provided herein, metformin hydrochloride can reach peak plasma levels 8 to 20 hours after administration under various conditions. Furthermore, the controlled release of metformin effectively reduces the gastrointestinal side effects (such as diarrhea, nausea, and vomiting) that are frequently caused by this drug.

[0119] Based on the controlled-release oral formulation of metformin hydrochloride, which is administered once daily at a dose of 1000 mg, the average maximum plasma concentration of the drug provided is approximately 500-900 ng / ml.

[0120] Based on the controlled-release formulation of metformin hydrochloride with a once-daily dose of 1000 mg, the average AUC0-24hr provided is approximately 7000-16000 ng·hr / ml, preferably approximately 9000-14000 ng·hr / ml.

[0121] Due to the above configuration, for controlled-release formulations of metformin or its pharmaceutically acceptable salts suitable for once-daily administration to human subjects with non-insulin-dependent diabetes or prediabetes, this formulation can control blood glucose levels for up to approximately 24 hours and provide controlled release of the drug with an average time to peak concentration of 8 to 20 hours after administration and an average half-width at half-maximum (WHM) of plasma concentration-time of approximately 6 to 15 hours.

[0122] According to some embodiments, at least one antidiabetic drug in the core portion 100, in addition to metformin or a pharmaceutically acceptable salt thereof, may further comprise one or more other types of antidiabetic drugs, which can also be released from the oral dosage form after oral administration due to the controlled-release membrane 150 in the oral dosage form of the pharmaceutical composition.

[0123] According to some other implementation schemes, at least one antidiabetic drug in core component 100 may not contain biguanides, but may contain one or more other types of antidiabetic drugs that can be released from an oral dosage form after oral administration.

[0124] In one specific embodiment, the oral dosage form of the pharmaceutical composition comprises a controlled-release form of metformin at a dose of approximately 100-1200 mg.

[0125] According to certain embodiments of the oral dosage form of the pharmaceutical composition provided herein, such as Figure 1As shown, the outer sealing film 200 is configured to encapsulate the outer surface of the film-coated tablet. The outer sealing film 200 is configured to provide a protective coating for oral dosage forms, ensuring that the properties of the active pharmaceutical ingredient contained in the oral dosage form are not affected by the environment.

[0126] In this document, the outer sealing film 200 of the oral dosage form may have a composition similar to that of the inner sealing film described above. In short, the outer sealing film may comprise at least one pharmaceutically acceptable film-forming polymer and one or more pharmaceutically acceptable excipients.

[0127] Examples of film-forming polymers include hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, hydroxypropyl methylcellulose, or other suitable water-soluble polymer materials. A specific form of hydroxypropyl methylcellulose used as a film-forming polymer is HPMC 2910.

[0128] The excipients contained in the outer sealing film may similarly include plasticizers, pigments (i.e., dyes or colorants), dispersants, and antioxidants. Examples of plasticizers include polyethylene glycol 400, 3350, 6000, 8000 grades and triethyl citrate. Examples of dispersants may be hydrated aluminum silicate (kaolin). Examples of antioxidants include α-tocopherol, γ-tocopherol, δ-tocopherol, naturally derived extracts rich in tocopherol, L-ascorbic acid and its sodium or calcium salts, ascorbate palmitate, propyl gallate, octyl gallate, dodecyl gallate, butylated hydroxytoluene, or butylated hydroxyanisole, etc. A preferred antioxidant is propyl gallate. In this document, antioxidants are used to prevent oxidative degradation of the core portion of the oral dosage form of the pharmaceutical composition provided in this disclosure.

[0129] In this article, the relative amount of the outer sealing film relative to the whole tablet can vary within the scope of the invention and depends on the desired drug loading, which can account for about 0.5% to 40% of the tablet dosage form weight, preferably 2% to 10%.

[0130] In this invention, the relative amounts of film-forming polymer and plasticizer can vary within the scope of this invention. Plasticizers can be used alone or in various proportions. The relative amount of plasticizer relative to the entire tablet can vary within the scope of this invention and depends on the desired drug loading. In most cases, the plasticizer can account for about 0.1% to 10% of the tablet dosage form weight, preferably 1% to 8%. Furthermore, the antioxidant content can be about 0.03% to 0.05%. If hydrated aluminum silicate is used as a dispersant, it can account for about 0.2% to 5% of the tablet dosage form weight, preferably 0.5% to 2%.

[0131] The following embodiments further describe and demonstrate implementations within the scope of the present invention. These embodiments are for illustrative purposes only and should not be construed as limiting the invention, as many variations can be made without departing from the spirit and scope of the invention.

[0132] According to some preferred embodiments, the oral dosage form of the pharmaceutical composition comprises a controlled-release form of metformin or a pharmaceutically acceptable salt thereof. More specifically, in this document, metformin or a pharmaceutically acceptable salt thereof corresponds to a formulation such as... Figure 1 The oral dosage form 001 shown is an antidiabetic drug located at the core portion 100.

[0133] One particular solid dosage form relates to tablets comprising a controlled-release form of metformin hydrochloride. Optionally, the unit dose strength of metformin hydrochloride incorporated into the fixed-dose combinations of this disclosure may be 100, 250, 500, 600, 750, 850, 1000, or 1200 mg.

[0134] The following examples further describe and demonstrate embodiments within the scope of this disclosure. More specifically, six embodiments of oral metformin dosage forms are provided, which are essentially metformin hydrochloride controlled-release tablets (hereinafter referred to as "metformin hydrochloride controlled-release tablets"). It should be noted that these examples are for illustrative purposes only and should not be construed as limiting the disclosure, as many variations can be made without departing from the spirit and scope of the disclosure. Example 1 (Metformin controlled-release tablets, 1000 mg oral dosage form)

[0135] This embodiment illustrates the preparation process of an oral dosage form of a pharmaceutical composition, which essentially comprises an osmotic pump controlled-release tablet containing 1000 mg of metformin hydrochloride.

[0136] More specifically, the core portion of the metformin hydrochloride controlled-release tablet is prepared by fluidized bed granulation, in which hydroxypropyl cellulose is dissolved in water to prepare an aqueous solution of about 5% (w / w) hydroxypropyl cellulose, which is then sprayed onto depolymerized metformin hydrochloride, sorbitol and sodium lauryl sulfate.

[0137] The dry granules were dried and pulverized using a 0.8 mm conical pulverizer. The pulverized granules were then mixed with magnesium stearate in a V-type mixer at a speed of 25 rpm for approximately 5 minutes. The granulation conditions for the core portion of metformin controlled-release tablets are summarized in Table 3.

[0138] Table 3. Granulation conditions for the core portion of 1000 mg metformin controlled-release tablets (Example 1)

[0139] The total granules are compressed into tablets using an automatic tableting machine using a 10.0×20.5 mm long die.

[0140] The metformin hydrochloride controlled-release tablet cores were then coated with an acetone solution containing cellulose acetate CA-398-10 (the polymer material for the controlled-release membrane) and polyethylene glycol 6000 (the flux enhancer for the controlled-release membrane), and cured at 50°C for 60 minutes. The controlled-release membrane coating conditions are summarized in Table 4.

[0141] Table 4. Controlled-release film coating conditions for 1000 mg metformin controlled-release tablets (Example 1)

[0142] Laser drilling is performed on the coated tablets to create two holes (e.g., one hole on each side of the tablet, such as...). Figure 1 As shown), each hole should be located within ±5 mm of the center of the tablet, with a diameter between 0.40 and 0.60 mm and a depth between 0.10 and 2.00 mm.

[0143] The tablets are then coated with an outer sealing film. The sealing coating solution for the outer sealing film is prepared by first dissolving hydroxypropyl methylcellulose and polyethylene glycol or other suitable water-soluble materials (preferably Opadry Clear (YS-1-7006), which is a mixed coating material containing hydroxypropyl methylcellulose and polyethylene glycol) in purified water. The Opadry coating solution is then sprayed onto the coated tablets using a pan coating machine under the following conditions: exhaust temperature 38-42°C; atomization pressure 28-40 psi; spray rate 10-15 ml / min. The amount of Opadry Clear used for coating is approximately 20-25 mg / tablet.

[0144] In Example 1 (i.e., metformin hydrochloride controlled-release tablets, 1000 mg), the oral dosage form obtained by the above preparation method, the various components of the 1000 mg metformin hydrochloride controlled-release tablets are summarized in Table 5.

[0145] Table 5. Composition of 1000 mg metformin film-coated tablets (Example 1)

[0146] Note: "% w / w" indicates the percentage of a single ingredient by weight in the entire tablet.

[0147] Further dissolution studies were conducted on the 1000 mg metformin controlled-release tablets provided in Example 1. Specifically, the dissolution profiles of multiple tablets prepared above were detected in a buffer solution at pH 6.8, and the dissolution profiles of different tablets at different time points (i.e., 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, and 24 hours) were measured using a USP II instrument at 37°C and 50 rpm. The results are summarized in Table 6.

[0148] Table 6. Dissolution profiles of various tablets of 1000 mg metformin controlled-release tablets (Example 1)

[0149] Note: "% Diss" represents the percentage of dissolution from each tablet; "% RSD" represents the relative standard deviation (RSD) of dissolution between different tablets, expressed as a percentage, and is defined as the ratio of the standard deviation of dissolution ratio to the average dissolution ratio multiplied by 100. Example 2 (Metformin controlled-release tablets, 500 mg oral dosage form)

[0150] This embodiment illustrates the preparation process of an oral dosage form of a pharmaceutical composition, which essentially comprises a metformin hydrochloride osmotic pump controlled-release tablet containing 500 mg of metformin hydrochloride.

[0151] More specifically, the core portion of the metformin hydrochloride controlled-release coated tablet is prepared by fluidized bed granulation, in which povidone K90 is dissolved in water to prepare a povidone solution of about 7% (w / w), which is then sprayed onto depolymerized metformin hydrochloride and sodium lauryl sulfate.

[0152] The dry granules were dried and pulverized using a 0.8 mm conical pulverizer. The granulated granules were then mixed with magnesium stearate at 25 rpm for approximately 5 minutes using a V-mixer. The granulation conditions for the core portion of metformin controlled-release tablets are summarized in Table 7.

[0153] Table 7. Granulation conditions for the core portion of 500 mg metformin controlled-release tablets (Example 2)

[0154] Using a 12.0×12.0 mm circular mold, the total granules are compressed into 500 mg tablets on an automatic tableting machine.

[0155] The tablet cores were then coated with a controlled-release membrane using an acetone solution containing cellulose acetate CA-398-10 (the polymer material for the controlled-release membrane) and polyethylene glycol 3350 (the pore-forming agent / plasticizer for the controlled-release membrane). The coating was then cured at 50°C for 60 minutes. The controlled-release membrane coating conditions are summarized in Table 8.

[0156] Table 8. Controlled-release film coating conditions for 500 mg metformin controlled-release tablets (Example 2)

[0157] Laser drilling is performed on the coated tablets to create two holes (e.g., one hole on each side of the tablet, such as...). Figure 1 As shown), each hole should be located within ±5 mm of the center of the tablet, with a diameter between 0.30 and 0.80 mm and a depth between 0.10 and 2.00 mm.

[0158] The coated tablets are then wrapped with an outer sealing film. The sealing coating solution for the outer sealing film is prepared by first dissolving hydroxypropyl methylcellulose and polyethylene glycol (Opadry material or other suitable water-soluble material), preferably Opadry Clear (YS-1-7006) (which is a mixed coating material containing hydroxypropyl methylcellulose and polyethylene glycol) in purified water. The Opadry coating solution is then sprayed onto the tablets using a pan coating machine under the following conditions: exhaust temperature 38-42°C; atomization pressure 28-40 psi; spray rate 10-15 ml / min. The amount of Opadry Clear used for coating is approximately 20-25 mg / tablet.

[0159] The various components of the oral dosage form (i.e., metformin hydrochloride controlled-release tablets (500 mg)) obtained by the above preparation method (i.e., Example 2) are summarized in Table 9.

[0160] Table 9. Composition of 500 mg metformin film-coated tablets (Example 2)

[0161] Further dissolution studies were conducted on the 500 mg metformin controlled-release tablets provided in Example 2. Specifically, the dissolution profiles of multiple tablets prepared above were detected in a buffer solution at pH 6.8, and the dissolution profiles of different tablets at different time points (i.e., 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 20 hours, and 24 hours) were measured using a USP II instrument at 37°C and 50 rpm. The results are summarized in Table 10.

[0162] Table 10. Dissolution profile of 500 mg metformin controlled-release tablets (Example 2) Example 3 (Metformin controlled-release tablets, 600 mg oral dosage form)

[0163] This example illustrates the preparation of an osmotic pump controlled-release tablet core containing 600 mg metformin hydrochloride.

[0164] The process steps used are similar to those in Example 2 above, so Example 2 can be referred to, but with some variations. More specifically, the granulation conditions for the core portion of the metformin controlled-release tablets and the controlled-release film coating conditions are summarized in Tables 11 and 12, respectively.

[0165] Table 11. Granulation conditions for the core portion of 600 mg metformin controlled-release tablets (Example 3)

[0166] Table 12. Controlled-release film coating conditions for 600 mg metformin controlled-release tablets (Example 3)

[0167] The various components of the oral dosage form (i.e., metformin hydrochloride controlled-release tablets (600 mg)) obtained by the above preparation method (i.e., Example 3) are summarized in Table 13.

[0168] Table 13. Composition of 600 mg metformin film-coated tablets (Example 3)

[0169] Further dissolution studies were conducted on the 600 mg metformin CR tablets provided in Example 3. Specifically, multiple tablets prepared above were dissolved in a buffer solution at pH 6.8, and the dissolution of different tablets at different time points (i.e., 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 20 hours, and 24 hours) were measured using a USP II instrument at 37°C and 50 rpm.

[0170] Table 14. Dissolution curves of various tablets of 600mg metformin controlled-release tablets (Example 3) Example 4 (Metformin controlled-release tablets, 750 mg oral dosage form)

[0171] This embodiment illustrates the preparation process of an osmotic pump controlled-release metformin hydrochloride tablet containing 750 mg metformin hydrochloride.

[0172] The process used is similar to that in Example 2 above, so Example 2 can be referred to, but with some changes. More specifically, the granulation conditions for the metformin controlled-release tablet core and the controlled-release film coating conditions are summarized in Tables 15 and 16, respectively.

[0173] Table 15. Granulation conditions for the core portion of 750mg metformin controlled-release tablets (Example 4)

[0174] Table 16. Conditions for 750 mg metformin controlled-release tablets and controlled-release film coating (Example 4)

[0175] The various compositions of the oral dosage form (i.e., metformin hydrochloride controlled-release tablets (750 mg)) obtained by the preparation method described above (i.e., Example 4) are summarized in Table 17.

[0176] Table 17. Composition of 750mg metformin film-coated tablets (Example 4)

[0177] Further dissolution studies were conducted on the 750 mg metformin controlled-release tablets provided in Example 4. Specifically, the dissolution profiles of multiple tablets prepared above were measured in a buffer solution at pH 6.8. The dissolution profiles of different tablets at different time points (i.e., 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 20 hours, and 24 hours) were measured using a USP II device at 37 °C and 50 rpm. The results are summarized in Table 18.

[0178] Table 18. Dissolution profiles of various tablets of 750mg metformin controlled-release tablets (Example 4) Example 5 (Metformin controlled-release tablets, 1200mg oral dosage form)

[0179] This embodiment illustrates the preparation of an osmotic pump controlled-release metformin hydrochloride tablet containing 1200 mg metformin hydrochloride.

[0180] The procedure used is similar to that in Example 1 above, so Example 1 can be referred to, but with some changes. More specifically, the granulation conditions for the metformin tablet core controlled-release tablet and the controlled film coating conditions are summarized in Tables 19 and 20, respectively.

[0181] Table 19. Partial Granulation Conditions for 1200mg Metformin Controlled-Release Tablet Cores (Example 5)

[0182] Table 20. Controlled film coating conditions for 1200 mg metformin controlled-release tablets (Example 5)

[0183] The composition of the oral dosage form (i.e., metformin hydrochloride controlled-release tablets (1200mg)) obtained by the preparation method described above (i.e., Example 5) is summarized in Table 21.

[0184] Table 21. Composition of 1200mg metformin film-coated tablets (Example 5)

[0185] Further dissolution studies were conducted on the 1200mg metformin controlled-release tablets provided in Example 5. Specifically, multiple tablets prepared above were dissolved in a buffer solution at pH 6.8, and the dissolution curves of different tablets at different time points (i.e., 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 20 hours, and 24 hours) were measured at 37 °C and 50 rpm using the USP II method. The results are summarized in Table 22.

[0186] Table 22. Dissolution curves of various tablets of 1200mg metformin controlled-release tablets (Example 5) Example 6 (Metformin controlled-release tablets, 1000 mg oral dosage form)

[0187] This embodiment illustrates the preparation of an osmotic pump controlled-release tablet containing 1000 mg metformin hydrochloride.

[0188] The process flow used is similar, so you can refer to Example 1 as described above, for example, with some variations in the composition of the metformin controlled-release tablets. More specifically, the granulation conditions for the core portion of the metformin controlled-release tablets and the controlled-release film coating conditions are summarized in Tables 23 and 24, respectively.

[0189] Table 23. Granulation conditions for the core components of 1000mg metformin CR tablets (Example 6)

[0190] Table 24. Controlled-release film coating conditions for 1000mg metformin controlled-release tablets (Example 6)

[0191] In the oral dosage form (i.e., metformin hydrochloride controlled-release tablets (1000 mg)) obtained by the preparation method described above (i.e. Example 6), various compositions of metformin hydrochloride controlled-release tablets 1000 mg are summarized in Table 25.

[0192] Table 25. Composition of 1000mg metformin film-coated tablets (Example 6)

[0193] Further dissolution studies were conducted on the 1000 mg metformin controlled-release tablets provided in Example 6. Specifically, the dissolution profiles of multiple tablets prepared above were detected in a buffer solution at pH 6.8. The dissolution profiles of different tablets at different time points (i.e., 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 20 hours, and 24 hours) were measured using the USP II method at 37°C and 50 rpm. The results are summarized in Table 26.

[0194] Table 26. Dissolution profiles of various tablets of 1000mg metformin controlled-release tablets (Example 6)

[0195] In each of the above six embodiments, the in vitro dissolution profile of metformin hydrochloride was determined under the following conditions:

[0196] Dissolution medium: 900 mL, United States Pharmacopeia phosphate buffer, pH 6.8. For detailed preparation procedures, please refer to the United States Pharmacopeia.

[0197] Dissolution: United States Pharmacopeia dissolution tester type II, 50 rpm, 37 °C.

[0198] Detection methods: Ultraviolet and high-performance liquid chromatography methods were developed to measure metformin hydrochloride dissolved in samples collected at test time points.

[0199] Table 27 below compares the in vitro dissolution results of metformin hydrochloride in six formulations of the above-mentioned oral dosage forms and three known antidiabetic prescription drugs (Glumetza XR 1000mg, Fortamet 500mg and Fortamet 1000mg).

[0200] Table 27. Comparison of dissolution rates of metformin controlled-release tablets

[0201] Note: Each value at each time point in each example is the average of the dissolution curve.

[0202] As shown in Table 27, metformin dissolved more slowly in each of the six embodiments of the oral dosage forms provided herein compared to the three known prescription antidiabetic drugs. More specifically, at approximately 4 hours, approximately 17.2-25.8% of the metformin in the six embodiments of the oral dosage forms of this disclosure dissolved, compared to approximately 36-51% in the three prescription drugs; at approximately 8 hours, approximately 32.5-46.2% and 73-85% of the metformin dissolved in the six embodiments of the oral dosage forms and the three prescription drugs, respectively; and at approximately 12 hours, approximately 48.7-63.2% and 94-96% of the metformin dissolved in the six embodiments of the oral dosage forms and the three prescription drugs, respectively. It is noteworthy that almost all of the metformin in these three prescription drugs dissolves completely within approximately 16 hours, while the metformin in the six embodiments of the oral dosage form disclosed herein does not dissolve completely even after approximately 24 hours, at which point approximately 81.5-90.3% of the metformin dissolves.

[0203] Under feeding conditions, the in vivo plasma bioavailability of an antidiabetic oral pharmaceutical composition of one of the embodiments of this disclosure (i.e., the metformin hydrochloride extended-release tablet 1000 mg formulation provided in Example 1, hereinafter referred to as the "test formulation") was tested and compared with the in vivo plasma bioavailability of a known antidiabetic prescription drug (i.e., Fortamet 1000 mg, hereinafter referred to as the "reference formulation", "control formulation" or "R").

[0204] Specifically, the results for Example 1 (i.e., “Formulation T” or “T”) and the reference formulation were measured at different time points (0, 2.0, 3.0, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 14.0, 16.0, 16.0, 20.0, 24.0, 28.0, and 36.0 hours) after oral administration of the oral dosage form. The metformin plasma concentrations of the control (R) and test (T) formulations under the given conditions are summarized in Tables 28 and 29, respectively.

[0205] It is important to note that metformin plasma concentrations are expressed in ng / ml; each value highlighted in both tables represents the maximum plasma concentration (Cmax) of metformin in each subject after a single oral dose of the oral formulation T or R; time point 0 represents the pre-dose concentration of metformin. Here, "Cmax" is used to indicate the pre-dose concentration. max "T" indicates the maximum plasma concentration; max "AUC0-t" represents the time to reach maximum plasma concentration, and "AUC0-t" represents the area under the concentration-time curve from drug administration (time 0) to the final concentration measurement. -∞"" refers to the area under the concentration-time curve extrapolated from time 0 to infinity; "t1 / 2" represents the time required for the drug plasma concentration to decrease by 50%; "K" el "AUC_%" represents the elimination rate constant; "Extrap_obs(%)" refers to the value from the time of administration (time t - last measured concentration) to the time extrapolated to infinity to AUC0- ∞ The area under the concentration-time curve (%).

[0206] Table 28. Metformin plasma concentration (ng / ml) curves measured at different time points after oral administration of a single dose of the reference formulation (R) to different subjects under food conditions.

[0207] Note: "SD" represents standard deviation; "CV%" represents coefficient of variation, which is equivalent to the relative standard deviation (RSD) defined above.

[0208] Table 29. Metformin plasma concentration (ng / ml) curves measured at different time points after oral administration of a single dose of the test formulation (T) to different subjects under food conditions.

[0209] As shown in Table 29, after oral administration of a single dose of the oral formulation T, the maximum plasma concentration (Tmax) of metformin in each subject was approximately 8–20 hours after oral administration, and peaked at 13.5 hours after oral administration.

[0210] In addition, Table 30 further summarizes the key pharmacokinetic (PK) parameters after oral administration of the reference (R) formulation and the investigational (T) formulation.

[0211] Table 30. Pharmacokinetic (PK) parameters of the reference (R) and test (T) formulations.

[0212] Notice: # For T 最大 Median (Minimum – Maximum)

[0213] It should be noted that the above examples and embodiments containing metformin hydrochloride are merely illustrative examples and should not be construed as limiting the scope.

[0214] All references cited in this disclosure are incorporated herein by reference in their entirety. Although specific embodiments have been described in detail above, the description is for illustrative purposes only. Therefore, it should be understood that, unless expressly stated otherwise, many aspects of the above description are not essential or essential elements.

[0215] In addition to the foregoing, those skilled in the art, having benefited from this disclosure, may make various modifications to the aspects disclosed in the illustrated embodiments and their equivalents without departing from the spirit and scope of this disclosure as defined by the following claims, which should be interpreted in the broadest possible sense to cover such modifications and equivalent structures.

Claims

1. An oral dosage form of a pharmaceutical composition for treating or managing diabetes or prediabetes in a subject, characterized in that, include: A tablet core containing metformin or a pharmaceutically acceptable salt of metformin; A controlled-release membrane surrounding the tablet core, wherein the controlled-release membrane has at least one channel allowing the oral dosage form to release metformin or a pharmaceutically acceptable salt of metformin from the tablet core in an aqueous environment; in: The dissolution profile of the oral dosage form in a medium at pH 6.8 and 37 degrees Celsius is characterized in that the release of metformin or a pharmaceutically acceptable salt of metformin is less than 30% at 4 hours and less than 92% at 24 hours.

2. The oral dosage form according to claim 1, wherein the dissolution profile of the oral dosage form in a medium at pH 6.8 and 37 degrees Celsius is characterized in that... The release of the metformin or a pharmaceutically acceptable salt of the metformin is approximately 30%-50% at 8 hours.

3. The oral dosage form according to claim 1 or claim 2, wherein the dissolution profile of the oral dosage form in a medium at 37 degrees Celsius and pH 6.8 is characterized in that... The release of the metformin or a pharmaceutically acceptable salt of the metformin is approximately 45%-70% at 12 hours.

4. The oral dosage form according to any one of claims 1-3, wherein the dissolution profile of the oral dosage form in a medium at pH 6.8 and 37 degrees Celsius is characterized in that... The metformin or a pharmaceutically acceptable salt of the metformin has a release of approximately 18%-21% at 4 hours and approximately 82%-90% at 24 hours.

5. The oral dosage form according to claim 4, wherein the oral dosage form is at pH 37 degrees Celsius. The dissolution profile in the medium of 6.8 is characterized in that the release of metformin or a pharmaceutically acceptable salt of metformin is approximately 35%-45% at 8 hours.

6. The oral dosage form according to claim 4 or claim 5, wherein the oral dosage form is at pH 37 degrees Celsius. The dissolution curve in the medium 6.8 is characterized in that, The release of the metformin or a pharmaceutically acceptable salt of the metformin is approximately 50%-65% at 12 hours.

7. The oral dosage form according to any one of claims 1-6, characterized in that, In a medium at 37°C and pH 6.8, the release of the metformin or a pharmaceutically acceptable salt of the metformin from the oral dosage form at a time point between 4 and 24 hours has a relative standard deviation of no more than 11%.

8. The oral dosage form according to claim 7, characterized in that, In a medium at 37 degrees Celsius and pH 6.8, the release of the metformin or a pharmaceutically acceptable salt of the metformin from the oral dosage form has a relative standard deviation of no more than 6%.

9. The oral dosage form according to any one of claims 1-6, characterized in that, In a medium at 37°C and pH 6.8, the release of the metformin or a pharmaceutically acceptable salt of the metformin from the oral dosage form over 8 hours has a relative standard deviation of no more than 7.5%.

10. The oral dosage form according to any one of claims 1-6, characterized in that, In a medium at 37°C and pH 6.8, the release of the metformin or a pharmaceutically acceptable salt of the metformin from the oral dosage form over 12 hours has a relative standard deviation of no more than 6.0%.

11. The oral dosage form according to any one of claims 1-10, characterized in that, The oral dosage form enables controlled release of metformin or a pharmaceutically acceptable salt of metformin, such that, upon single-dose oral administration, the oral dosage form provides the subject with the maximum plasma concentration of metformin or a pharmaceutically acceptable salt of metformin approximately 8–24 hours after administration.

12. The oral dosage form according to claim 11, characterized in that, The oral dosage form enables controlled release of metformin or a pharmaceutically acceptable salt of metformin, such that when the oral dosage form is administered in a single oral dose, the average time for the metformin or a pharmaceutically acceptable salt of metformin to reach maximum plasma concentration in the subject is approximately 13.5 hours, with a standard deviation of 4.4 hours.

13. The oral dosage form according to any one of claims 1-12, characterized in that, The oral dosage form enables controlled release of metformin or a pharmaceutically acceptable salt of metformin, such that, when administered orally in a single dose, the mean peak plasma concentration (Cmax) of metformin or a pharmaceutically acceptable salt of metformin in the subject is between approximately 0.5*X ng / ml and approximately 0.9*X ng / ml, calculated based on the dose of metformin hydrochloride taken as X, where X is approximately 100-1000.

14. The oral dosage form according to any one of claims 1-12, characterized in that, The oral dosage form enables controlled release of metformin or a pharmaceutically acceptable salt of metformin, such that, upon single oral administration, the mean area under the plasma concentration-time curve (AUC0-t) in the subject is between approximately 7*Y hr*ng / mL and approximately 16*Y hr*ng / mL, calculated based on a dose of metformin hydrochloride of Y mg, where Y is approximately 100-1000.

15. The oral dosage form according to any one of claims 1-14, characterized in that, The controlled-release membrane comprises at least one water-insoluble polymer, each of which is selected from cellulose ester, cellulose diester, cellulose triester, cellulose ether, cellulose acetate phthalate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate, and cellulose acetate butyrate.

16. The oral dosage form according to claim 15, wherein, The controlled-release membrane contains at least one water-insoluble polymer, which includes cellulose acetate.

17. The oral dosage form according to claim 16, wherein, The acetyl content of the cellulose acetate is 39.3%-40.3%.

18. The oral dosage form according to any one of claims 15-17, wherein, The controlled-release membrane contains at least one porogen, each porogen selected from sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol (PEG), propylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyvinyl alcohol, and methacrylic acid copolymer.

19. The oral dosage form according to claim 18, wherein, At least one porogen contained in the controlled-release membrane is polyethylene glycol (PEG).

20. The oral dosage form according to any one of claims 1-19, wherein, The controlled-release membrane accounts for 1.8-6.0% of the weight of the oral dosage form.

21. The oral dosage form according to any one of claims 1-20, wherein, The controlled-release membrane has two channels.

22. The oral dosage form according to claim 21, wherein, The two channels are located on opposite sides of the oral dosage form.

23. The oral dosage form according to any one of claims 1-22, wherein, The diameter of each of the at least one channel is approximately 0.30 - 2.00 mm.

24. The oral dosage form according to any one of claims 1-23, wherein, The depth of each of the at least one channel is approximately 0.10 - 2.00 mm.

25. The oral dosage form according to any one of claims 1-24, wherein the metformin or a pharmaceutically acceptable salt thereof comprises at least one of metformin hydrochloride, metformin sulfate, metformin phosphate, metformin hydrobromide, metformin salicylate, metformin maleate, metformin benzoate, metformin succinate, metformin ethanesulfonate, metformin fumarate, or metformin glycolate.

26. The oral dosage form according to any one of claims 1-24, wherein, The metformin or its pharmaceutically acceptable salt is metformin hydrochloride.

27. The oral dosage form according to claim 26, wherein, The metformin or a pharmaceutically acceptable salt thereof comprises approximately 100-1200 mg of metformin hydrochloride.

28. The oral dosage form according to any one of claims 1-27, wherein, The core further comprises at least one adhesive, wherein each adhesive may be one of polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, polymethyl methacrylate, or wax.

29. The oral dosage form of claim 28, wherein the at least one binder in the tablet core comprises polyvinylpyrrolidone, hydroxypropyl cellulose, or a mixture of both.

30. The oral dosage form according to claim 29, wherein the at least one binder in the tablet core is hydroxypropyl cellulose.

31. The oral dosage form according to claim 29, wherein the at least one binder in the tablet core is a polyvinylpyrrolidone with an average molecular weight of 25,000 to 3,000,000 g / mol.

32. The oral dosage form according to any one of claims 1-31, wherein the tablet core further comprises an absorption enhancer, wherein each absorption enhancer is selected from fatty acids, surfactants, chelating agents and bile salts.

33. The oral dosage form according to claim 32, wherein the at least one absorption enhancer contained in the tablet core comprises a surfactant selected from sodium lauryl sulfate, sodium taurocholate, and polyoxyethylene 20 sorbitan monooleate (i.e., Tween 80).

34. The oral dosage form according to claim 33, wherein, The at least one absorption enhancer in the core portion comprises sodium lauryl sulfate.

35. The oral dosage form according to any one of claims 1-31, wherein the tablet core further comprises at least one lubricant, wherein each lubricant is selected from magnesium stearate, stearic acid, sodium fumarate, glyceryl behenate, and glyceryl dibehenate.

36. The oral dosage form according to claim 35, wherein the at least one lubricant contained in the tablet core is magnesium stearate or glyceryl behenate, or a mixture thereof.

37. The oral dosage form according to claim 36, wherein the at least one lubricant contained in the tablet core is glyceryl behenate.

38. The oral dosage form according to any one of claims 1-37, wherein, The oral dosage form may further include at least one of the following: an inner sealing film sandwiched between the tablet core and the controlled-release membrane, which provides a protective coating for the tablet core encased therein; or an outer sealing film encased on the outer surface of the controlled-release membrane.

39. The oral dosage form according to claim 38, wherein, At least one of the inner sealing membrane or the outer sealing membrane may contain at least one film-forming polymer, wherein each film-forming polymer is selected from hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and polyethylene glycol.

40. The oral dosage form according to claim 38 or claim 39, wherein the weight of the inner sealing film or the outer sealing film accounts for about 0.4% to 40% of the total weight of the oral dosage form.

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