Metformin Mini Tablets

Abstract

The present invention relates to a method for obtaining sustained release metformin mini-tablets, to the mini-tablets obtainable by this method, and to the use of these mini-tablets as monotherapy or in combination with other active pharmaceutical agents.

Description

[Technical Field]

[0001] The present invention relates to a method for obtaining sustained release metformin mini-tablets, to the mini-tablets obtainable by this method, and to the use of these mini-tablets as monotherapy or in combination with other active pharmaceutical agents. [Background technology]

[0002] Aging is the gradual loss and deterioration of function at the cellular, tissue, and organ levels, leading to a progressive loss of physiological integrity, increased susceptibility to disease and external stressors, and ultimately death. As the global population ages, the incidence of age-related diseases increases annually. Consequently, numerous attempts have been made to treat age-related diseases and delay the onset of the complex process of aging. As a result, many age-related pathways that can be targeted to extend lifespan and healthspan have been identified. For example, there is overwhelming evidence that single-gene mutations in nutrient-sensing pathways, such as insulin / insulin-like growth factor (IGF) signaling or the mechanistic target of rapamycin (mTOR) signaling pathway, extend lifespan and healthspan in invertebrates. These pathways have also been evaluated in mammalian models where healthspan and lifespan have been extended by genetic manipulation or drugs. This raises hopes for new approaches, including drugs that can slow the aging process and delay the appearance of age-related diseases by regulating conserved pathways of aging, except for some symptomatic treatments. Unfortunately, no known approaches have been shown to effectively slow the aging process in humans. Consequently, in addition to treating existing diseases and disorders through medical means, there is an increasing need and demand for measures to delay healthy aging.

[0003] Metformin is widely used and approved as an antidiabetic drug for the treatment of type 2 diabetes. It increases insulin sensitivity, thereby improving insulin action at the cellular level without affecting insulin secretion. Metformin has also been shown to exert positive effects on several cardiovascular risk factors. Furthermore, metformin has been shown to target many aging mechanisms. Specifically, metformin reduces insulin levels, IGF-1 signaling, mTOR, mitochondrial complex I in the electron transport chain, and reduces the endogenous production of reactive oxygen species, AMP-activated kinase (AMPK), and DNA damage. Metformin has also been shown to favorably affect metabolic and cellular processes closely related to the development of age-related conditions, such as inflammation, autophagy, and cellular senescence (Barzilai et al., Cell Metab. 2016). Using a C. elegans model system, we have also confirmed the health-promoting and life-extending effects of metformin in type 2 diabetes. Human studies have further shown that metformin significantly reduces the risk of cancer in diabetic patients (Fuming et al. Oncol Lett. 2018) and coronary artery disease (Hong et al. Diabetes Care. 2014). However, all of these effects have been observed when metformin is administered at fairly high therapeutic doses of at least 850 mg / day. Furthermore, to date, no synergistic effects of metformin in combination with another compound against age-related diseases have been confirmed.

[0004] Galantamine, an acetylcholinesterase inhibitor that allosterically modulates nicotinic receptors, is widely known as a drug administered to patients with Alzheimer's disease. In C. elegans, galantamine has been shown to promote cholinergic neurotransmission in a manner similar to that seen in humans and rescue the paralysis phenotype in a transgenic C. elegans Alzheimer's disease model (Xin et al., Plos One, 2013). However, no effects of galantamine on locomotion, mobility, or other forms of age-related decline have been reported in C. elegans. In humans, galantamine has been shown to significantly reduce death from myocardial infarction (Nordstrom et al., 2013). Furthermore, galantamine attenuates inflammation and insulin resistance in subjects with metabolic syndrome (Consolim-Colombo et al.; JCI Insight. 2017). However, all of these effects were observed at fairly high therapeutic doses of at least 24 mg / day. Furthermore, when galantamine was combined with another compound, no synergistic effects against age-related diseases were identified.

[0005] Previous work by the applicant (EP 3813882 A1) showed a potentiating and even synergistic effect against age-related diseases using the biguanide metformin in combination with the acetylcholinesterase inhibitor galantamine, notably, this effect was observed even when at least one or both compounds were administered at their sub-therapeutic doses.

[0006] Minitablets are a promising patient-friendly drug delivery system to overcome therapeutic barriers such as dysphagia and polypharmacy, and also offer several therapeutic benefits such as dose flexibility and combined release patterns (Aleksovski et al. Expert Opinion on Drug Delivery 2014 12, 65). Minitablets are typically tablets with a diameter of 3 mm or less that are produced on conventional tablet presses with multiple tooling. The production of minitablets is similar to the production of standard tablets, but requires excellent powder flow due to small dies, precise control of process parameters, and special care during tablet press assembly to avoid tool damage.

[0007] US2009142378 discloses sustained release tablets of metformin, in which blending with PVA solution is carried out in a fluidized bed to produce granules, and in US2006222709 sustained release metformin tablets were prepared by fluidized bed granulation of the active ingredient with a filler and a binder. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] EP3813882A1 [Patent Document 2] US2009142378 [Patent Document 3] US2006222709 Summary of the Invention [Problem to be solved by the invention]

[0009] In the present invention, no fluidized bed blending of the ingredients is used, but instead a dry powder blend is used, followed by direct compression of the blend. This method has surprisingly been found to provide particular advantages, particularly in terms of powder flowability and low friability of the compressed cores. It is therefore an object of the present invention to address the problems associated with the production of mini-tablets, by providing a novel method for the production of metformin mini-tablets, mini-tablets obtained by this method, and the use of metformin mini-tablets as monotherapy or in combination with other therapeutic agents in the treatment of age-related diseases. [Means for solving the problem]

[0010] According to a first aspect, the present invention provides a method for preparing sustained release mini-tablets for oral administration comprising metformin or a pharmaceutical salt thereof as an active pharmaceutical ingredient, the method comprising the steps of: (1) blending an active pharmaceutical ingredient with a first glidant and a first binder, thereby forming a first blend; (2) blending the first blend obtained in step (1) with a filler, a second glidant, and a lubricant, thereby obtaining a second blend; (3) tableting the second blend obtained in step (2), thereby forming mini-tablets; (4) preparing a coating suspension; and (5) Coating the mini-tablets obtained in step (3) with the coating suspension of step (4).

[0011] In particular, the present invention provides a method for preparing sustained release mini-tablets for oral administration containing metformin or a pharmaceutical salt thereof as a pharmaceutically active ingredient, the method comprising the steps of: (1) blending an active pharmaceutical ingredient with a first glidant and a first binder, thereby forming a first dry powder blend; (2) blending the first dry powder blend obtained in step (1) with a filler, a second glidant, and a lubricant, thereby obtaining a second dry powder blend; (3) compressing (tableting) the second dry powder blend obtained in step (2) by direct compression, thereby forming mini-tablets; (4) preparing a coating suspension; and (5) Coating the mini-tablets obtained in step (3) with the coating suspension of step (4).

[0012] According to one embodiment of the present invention, the process for preparing the coating suspension comprises the following steps: (4a) preparing a first dispersion including a second binder; (4b) blending the first suspension obtained in step (4a) with a surfactant, an anti-adherent agent, and a sustained-release polymer, thereby forming the coating suspension; and (4c) Optionally, filtering the coating suspension obtained in step (4b).

[0013] According to a particular embodiment of the invention, the coating suspension is filtered through a 500 μm mesh screen.

[0014] According to one embodiment of the present invention, the coating of the mini-tablets is carried out via fluidized bed coating or perforated pan coating. According to a particular embodiment of the present invention, the coating of the mini-tablets is carried out via fluidized bed coating by bottom spraying of the coating suspension.

[0015] According to a different embodiment of the present invention, the mini-tablets obtained in step (5) have a coating mass in the range of 5-40 wt%, preferably in the range of 10-35 wt%, more preferably in the range of 15-30 wt%, based on the total mass of the coated mini-tablets.

[0016] According to a different embodiment of the present invention, the uncoated mini-tablets obtained in step (3) have an average diameter in the range of 1 to 3 mm, preferably in the range of 1.5 to 2.5 mm, more preferably in the range of 1.8 to 2.2 mm.

[0017] According to a different embodiment of the present invention, the mini-tablets comprise 15-35% w / w of a pharmaceutical active ingredient, 0.1-1% w / w of a first glidant; 0.1-1% w / w of a second glidant; 1-5% w / w of a first binder; 1-5% w / w of a second binder; 35-60% w / w of a filler; 0.5-5% w / w of a lubricant; 0.5-5% w / w of a surfactant; 5-20% w / w of a sustained release polymer and 5-20% w / w of an anti-tacking agent.

[0018] According to different embodiments of the invention, the first binder is selected from the list comprising hydroxypropyl methylcellulose, gum arabic, alginic acid, carbomer, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), magnesium aluminum silicate, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, copovidone, sodium alginate, starch paste, pregelatinized starch, sucrose (syrup), and mixtures thereof. According to a particular embodiment, the first binder is hydroxypropyl cellulose.

[0019] According to different embodiments of the invention, the second binder is selected from the list comprising hydroxypropyl methylcellulose, gum arabic, alginic acid, carbomer, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), magnesium aluminum silicate, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, copovidone, sodium alginate, starch paste, pregelatinized starch, sucrose (syrup), and mixtures thereof. According to a particular embodiment, the second binder is hydroxypropyl cellulose.

[0020] According to different embodiments of the invention, the filler is selected from the list comprising microcrystalline cellulose, calcium carbonate, calcium phosphate (dibasic), calcium phosphate (tribasic), calcium sulfate, cellulose, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose monohydrate, magnesium carbonate, maltitol, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, xylitol. According to a particular embodiment, the first filler is microcrystalline cellulose.

[0021] According to a different embodiment of the invention, said first glidant is selected from the list comprising colloidal hydrated silica, colloidal silica, corn starch, talc. According to certain embodiments, the first glidant is colloidal hydrated silica.

[0022] According to different embodiments of the invention, the second glidant is selected from the list comprising colloidal hydrated silica, colloidal silica, cornstarch, talc, According to a particular embodiment, the second glidant is colloidal hydrated silica.

[0023] According to different embodiments of the invention, the lubricant is selected from the list comprising magnesium stearate, sodium stearyl fumarate, calcium stearate, fumaric acid, glyceryl behenate, glyceryl palmitostearate, hydrogenated vegetable oils, magnesium lauryl sulfate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, starch, stearic acid, talc, zinc stearate, and mixtures thereof. According to a particular embodiment, the lubricant is sodium stearyl fumarate.

[0024] According to different embodiments of the invention, the surfactant is selected from polysorbate, sodium dodecyl sulfate, sodium lauryl sulfate, and, according to a particular embodiment, the surfactant is polysorbate.

[0025] According to different embodiments of the invention, the sustained release polymer is selected from polymers of methacrylic acid or methacrylic acid and ethyl acrylate, and cellulose polymers such as cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), and carboxymethylethylcellulose (CMEC). According to a particular embodiment of the invention, the sustained release polymer is a polymer obtained from a mixture of methacrylic acid and ethyl acrylate monomers.

[0026] According to different embodiments of the invention, the anti-adherent agent is selected from talc, magnesium stearate, and according to a particular embodiment, the anti-adherent agent is talc.

[0027] According to a further aspect, the present invention provides mini-tablets obtainable by said process.

[0028] According to a still further aspect, the present invention provides sustained release mini-tablets for oral administration obtainable by the process disclosed herein and comprising metformin or a pharmaceutical salt thereof as a pharmaceutically active ingredient; The uncoated mini-tablets have an average diameter in the range of 1 to 3 mm, preferably in the range of 1.5 to 2.5 mm, more preferably in the range of 1.8 to 2.2 mm; Here, the mini-tablets are coated with a sustained-release polymer, and the coating mass is in the range of 5 to 40% by mass, preferably 10 to 35% by mass, and more preferably 15 to 30% by mass, relative to the total mass of the coated mini-tablets.

[0029] According to a still further aspect, the present invention provides a pharmaceutical composition comprising a mini-tablet according to an embodiment of the present invention. [Brief explanation of the drawings]

[0030] [Figure 1A] FIG. 1A shows the dissolution profiles of Examples 1a, 1b, 1c, and 1d shown in Table 6 in phosphate buffer at pH 6.8. [Figure 1B] FIG. 1B shows the dissolution profiles of Examples 1a, 1b, 1c, and 1d as shown in Table 6 in 0.1 M HCl solution at pH 1. [Figure 2] FIG. 2 shows the dissolution profile of Example 1d, as shown in Table 6, Comparative Examples 2 and 4, in phosphate buffer at pH 6.8. DETAILED DESCRIPTION OF THE INVENTION

[0031] The present invention will now be further described. In the following paragraphs, different aspects of the present invention are defined in more detail. Each aspect so defined can be combined with any other aspect, unless expressly indicated otherwise. In particular, any feature indicated as being preferred or advantageous can be combined with any other feature indicated as being preferred or advantageous.

[0032] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, "a compound" means one compound or more than one compound. These and other terms used herein are well understood by those of ordinary skill in the art. The compounds of the present invention can be prepared according to the reaction schemes provided in the examples below, but those of ordinary skill in the art will understand that these are merely illustrative of the invention and that the compounds of the present invention can be prepared by any of several standard synthetic processes commonly used by those of ordinary skill in the art of organic chemistry.

[0033] According to a first aspect, the present invention provides a method for preparing sustained release mini-tablets for oral administration comprising metformin or a pharmaceutical salt thereof as an active pharmaceutical ingredient, the method comprising the steps of: (1) blending an active pharmaceutical ingredient with a first glidant and a first binder, thereby forming a first blend; (2) blending the first blend obtained in step (1) with a filler, a second glidant, and a lubricant, thereby obtaining a second blend; (3) tableting the second blend obtained in step (2), thereby forming mini-tablets; (4) preparing a coating suspension; and (5) Coating the mini-tablets obtained in step (3) with the coating suspension of step (4).

[0034] In particular, the present invention provides a method for preparing sustained release mini-tablets for oral administration containing metformin or a pharmaceutical salt thereof as a pharmaceutically active ingredient, the method comprising the steps of: (1) blending an active pharmaceutical ingredient with a first glidant and a first binder, thereby forming a first dry powder blend; (2) blending the first dry powder blend obtained in step (1) with a filler, a second glidant, and a lubricant, thereby obtaining a second dry powder blend; (3) compressing the second dry powder blend obtained in step (2) by direct compression, thereby forming mini-tablets; (4) preparing a coating suspension; and (5) Coating the mini-tablets obtained in step (3) with the coating suspension of step (4).

[0035] The terms "prolonged release" and "sustained release" are used interchangeably for drug release that continues over an extended period of time, as opposed to "immediate release," in which the drug is released immediately after administration. According to Ph. Eur 2.9.3, sustained or extended release refers to drug release of 1) not more than 50% of the unit after 90 minutes, and 2) not more than 80% of the unit after 180 minutes.

[0036] The term "dry powder" as used herein refers to a formulation of ingredients that is in powder form and does not contain a liquid component such as water. In the present invention, the first and second blends as used herein are obtained by blending or mixing a series of dry powder ingredients to obtain a dry powder blend. The blends of the present invention are not obtained using liquid-based techniques such as fluid bed granulation or wet bed granulation, and do not require the use of a fluid to obtain such a blend. Therefore, the method of the present invention is characterized by not including a step of fluid or wet bed granulation.

[0037] In the context of the present invention, the term "direct compression" means compressing a dry blend directly into mini-tablet form without the need for wet granulation or other intermediate steps. In particular, a dry powder blend is fed directly into a tablet press where it is compressed into mini-tablets of the desired size and shape.

[0038] According to one embodiment of the present invention, the process for preparing the coating suspension comprises the following steps: (4a) preparing a first dispersion including a second binder; (4b) blending the first suspension obtained in step (4a) with a surfactant, an anti-adherent agent, and a sustained-release polymer, thereby forming the coating suspension; and (4c) Optionally, filtering the coating suspension obtained in step (4b).

[0039] According to further particular embodiments, the coating suspension may contain additional ingredients, for example to improve the visual appearance and / or taste of the coated mini-tablets. Examples of such additional ingredients may be colorants, flavors, sweeteners, glazing agents, anti-adherents, etc.

[0040] According to a particular embodiment of the invention, the coating suspension is filtered through a 500 μm mesh screen.

[0041] According to one embodiment of the present invention, the coating of the mini-tablets is carried out via fluidized air bed coating or perforated pan coating. According to a particular embodiment of the present invention, the coating of the mini-tablets is carried out via fluidized air bed coating by bottom spraying of the coating suspension.

[0042] According to a different embodiment of the present invention, the mini-tablets obtained in step (5) have a coating concentration (by mass) in the range of 5 to 40 wt%, preferably in the range of 10 to 35 wt%, more preferably in the range of 15 to 30 wt%, based on the total mass of the coated mini-tablets.

[0043] It should be understood that the mini-tablets obtained in step (5) refer to coated mini-tablets according to different embodiments of the present invention.

[0044] According to a different embodiment of the present invention, the mini-tablets obtained in step (3) have an average diameter in the range of 1 to 3 mm, preferably in the range of 1.5 to 2.5 mm, more preferably in the range of 1.8 to 2.2 mm.

[0045] It should be understood that the mini-tablets obtained in step (3) refer to uncoated mini-tablets according to different embodiments of the present invention.

[0046] According to a different embodiment of the present invention, the mini-tablets comprise 15-35% w / w of a pharmaceutical active ingredient, 0.1-1% w / w of a first glidant; 0.1-1% w / w of a second glidant; 1-5% w / w of a first binder; 1-5% w / w of a second binder; 35-60% w / w of a filler; 0.5-5% w / w of a lubricant; 0.5-5% w / w of a surfactant; 5-20% w / w of a sustained release polymer and 5-20% w / w of an anti-tacking agent.

[0047] According to a different embodiment of the present invention, no more than 50% of the metformin or pharmaceutical salt thereof in the mini-tablets is released within the first 90 minutes.

[0048] According to a different embodiment of the present invention, 80% or less of the metformin or pharmaceutical salt thereof in said mini-tablets is released within the first 90 minutes.

[0049] According to different embodiments of the invention, the first binder is selected from the list comprising hydroxypropyl methylcellulose, gum arabic, alginic acid, carbomer, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), magnesium aluminum silicate, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, copovidone, sodium alginate, starch paste, pregelatinized starch, sucrose (syrup), and mixtures thereof. According to a particular embodiment, the first binder is hydroxypropyl cellulose.

[0050] According to different embodiments of the invention, the second binder is selected from the list comprising hydroxypropyl methylcellulose, gum arabic, alginic acid, carbomer, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), magnesium aluminum silicate, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, copovidone, sodium alginate, starch paste, pregelatinized starch, sucrose (syrup), and mixtures thereof. According to a particular embodiment, the second binder is hydroxypropyl cellulose.

[0051] According to different embodiments of the invention, the filler is selected from the list comprising microcrystalline cellulose, calcium carbonate, calcium phosphate (dibasic), calcium phosphate (tribasic), calcium sulfate, cellulose, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose monohydrate, magnesium carbonate, maltitol, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, xylitol. According to a particular embodiment, the first filler is microcrystalline cellulose.

[0052] According to a different embodiment of the invention, said first glidant is selected from the list comprising colloidal hydrated silica, colloidal silica, corn starch, talc. According to certain embodiments, the first glidant is colloidal hydrated silica.

[0053] According to different embodiments of the invention, the second glidant is selected from the list comprising colloidal hydrated silica, colloidal silica, cornstarch, talc, According to a particular embodiment, the second glidant is colloidal hydrated silica.

[0054] According to different embodiments of the invention, the lubricant is selected from the list comprising magnesium stearate, sodium stearyl fumarate, calcium stearate, fumaric acid, glyceryl behenate, glyceryl palmitostearate, hydrogenated vegetable oils, magnesium lauryl sulfate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, starch, stearic acid, talc, zinc stearate, and mixtures thereof. According to a particular embodiment, the lubricant is sodium stearyl fumarate.

[0055] According to different embodiments of the invention, the surfactant is selected from polysorbate, sodium dodecyl sulfate, sodium lauryl sulfate, and, according to a particular embodiment, the surfactant is polysorbate.

[0056] According to different embodiments of the invention, the sustained release polymer is selected from polymers of methacrylic acid or methacrylic acid and ethyl acrylate, and cellulose polymers such as cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), and carboxymethylethylcellulose (CMEC). According to a particular embodiment of the invention, the sustained release polymer is a polymer obtained from a mixture of methacrylic acid and ethyl acrylate monomers.

[0057] According to different embodiments of the invention, the anti-adherent agent is selected from talc and magnesium stearate. According to a particular embodiment of the invention, the anti-adherent agent is talc.

[0058] According to certain embodiments of the present invention, the mini-tablets comprise metformin or a pharmaceutical salt thereof, hydroxypropyl cellulose, microcrystalline cellulose, colloidal hydrated silica, sodium stearyl fumarate, polysorbate, polymethacrylate, and talc.

[0059] According to a particular embodiment of the invention, the mini-tablets comprise 15-35% w / w metformin, 0.2-2% w / w colloidal hydrated silica; 2-10% w / w hydroxypropyl cellulose; 35-60% w / w microcrystalline cellulose; 0.5-5% w / w sodium stearyl fumarate; 0.5-5% w / w polysorbate; 5-20% w / w polymethacrylate and 5-20% w / w talc.

[0060] According to a further aspect, the present invention provides mini-tablets obtainable by said process.

[0061] According to a still further aspect, the present invention provides sustained release mini-tablets for oral administration comprising metformin or a pharmaceutical salt thereof as the pharmaceutically active ingredient; wherein the uncoated mini-tablets have an average diameter in the range of 1 to 3 mm, preferably in the range of 1.5 to 2.5 mm, more preferably in the range of 1.8 to 2.2 mm; Here, the mini-tablets are coated with a sustained-release polymer, and the coating mass is in the range of 5 to 40% by mass, preferably 10 to 35% by mass, and more preferably 15 to 30% by mass, relative to the total mass of the coated mini-tablets.

[0062] According to yet a further aspect, the present invention provides pharmaceutical compositions comprising mini-tablets according to embodiments of the present invention. Such pharmaceutical compositions can be prepared and formulated by methods known in the art and can take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form, preferably suitable for systemic administration, such as oral, transdermal, or by injection.

[0063] For example, mini-tablets can be formulated with common excipients, diluents, or carriers and formed into oral tablets, capsules, sprays, mouthwashes, oral liquids (e.g., suspensions, solutions, emulsions), powders, or any other suitable dosage form.

[0064] According to one embodiment of the present invention, the pharmaceutical composition can be used alone or in pharmaceutical combination with another agent used for the prevention, stabilization, and / or reduction of age-related disorders, degenerative dysfunction, and / or degenerative disorders. According to one embodiment of the present invention, the pharmaceutical composition can be used alone or in pharmaceutical combination with another agent to improve measures of lifespan and / or healthspan. According to a specific embodiment, the pharmaceutical composition comprises an acetylcholinesterase inhibitor, and / or a hydrate, pharmaceutically acceptable salt, or solvate thereof, as another agent. According to a more specific embodiment, the pharmaceutical composition comprises galantamine as another agent. [Example]

[0065] material Metformin HCl (Met.HCl) was purchased from Fagron. Microcrystalline cellulose (Avicel (登録商標) PH102) was purchased from FMC Health and Nutrition. Magnesium stearate (coordinated MF-2-V) and talcum (talc) were purchased from IMCD Benelux. Sodium stearyl fumarate (Pruv) was purchased from JRS Pharma. Colloidal hydrated silica (Syloid 244FP) was purchased from Grace Davison. Hydroxypropyl methylcellulose (HPMC E5) was purchased from Colorcon. Ethyl cellulose (Aqualon EC-N10) and hydroxypropyl cellulose (Klucel EXF ULTRA Pharm) were purchased from Ashland. Poly(ethyl acrylate-co-methyl methacrylate) 2:1 (Eudragit NM30D) was purchased from Evonik. Polysorbate 80 (Tween 80) was purchased from VWR.

[0066] method Bulk density and tapped density The bulk and tapped densities of the powders were measured using a Tap Density Tester TD1 (Sotax, Allschwil, Switzerland) equipped with a 25 mL graduated cylinder (readable to 0.5 mL). The tap height and tapping speed were set at 3 mm and 250 taps / min. Approximately 25 mL of material was poured into the 25 mL graduated cylinder. The powder weight and exact volume were used to calculate the bulk density (ρB). The samples were then subjected to 10, 500, and 1250 taps, and the corresponding volumes V10, V500, and V1250 were determined to the nearest graduated unit. If the difference between V500 and V1250 was 2 mL or less, V1250 was retained as the tapped volume. If the difference in volume after 500 taps differed by more than 2 mL from the volume obtained after 1250 taps, an additional 1250 taps were performed. The volume measurements were then used to determine the tapped density (ρT). Finally, the Hausner Ratio (HR) and Compressibility Index (CI) were calculated and used as a measure of powder flowability: Equation 1 Hausner ratio (HR) = ρT / ρB Equation 2 Compressibility Index (CI) = 100 x (ρT-ρB) / ρT

[0067] size Immediately after tabletting, the diameter and height of the minitablets (n = 20 per batch) were recorded using a digital caliper (Mahr, Göttingen, Germany).

[0068] weight The individual weights of 30 mini-tablets (of each batch) were recorded using an analytical 5d balance (Sartorius ME235P, Gottingen, Germany).

[0069] Hardness Testing The diametral breaking force of the mini-tablets (n = 6 per batch) was measured using a pharmaceutical tablet hardness tester (Sotax HT10, Basel, Switzerland).

[0070] Disintegration test The disintegration time of the mini-tablets was determined (n = 3 per batch) using a Ph. Eur. disintegration apparatus (Sotax DT2, Basel, Switzerland). Given the small diameter of the mini-tablets, the screen opening dimensions were reduced to 1.4 x 1.4 mm. All tests were performed in Elix™ water using discs at a temperature of 37 ± 0.5°C.

[0071] Friability measurement The friability of the mini-tablets was determined by subjecting approximately 6.5 g of mini-tablets (according to Ph. Eur. Standards) to a crushing machine (Sotax FT2, Basel, Switzerland) set at a speed of 25 rpm for 4 minutes. The weight loss rate was expressed as the tablet friability.

[0072] Quantitative testing Metformin was quantified by Ultra High-Performance Liquid Chromatography (Ph Eur 2.2.29) using UV absorbance measurement at 230 nm. Evaluation was based on peak area measurement and external standardization by relative response.

[0073] Example 1 - Sustained Release (Reservoir System) Stage 1 Pre-blend A preblend was prepared by weighing (and sieving / calibrating at 600 μm) Syloid 244FP (approximately 11 g), HPC Klucel (approximately 119 g), and Met HCl (approximately 1210 g), followed by blending for approximately 30 minutes using a Turbula T2A blender.

[0074] Stage 2 Blend A blend was prepared (and 600 μm) by weighing / calibrating Avicel PH102 (approximately 2568 g), pre-blend (approximately 1341 g), Syloid 244FP (approximately 11 g) and Pruv (approximately 80 g) and then introducing them into a suitable container in the following order: 1 / 2 Avicel PH102, Syloid 244FP, Preblend, Pruv, 1 / 2 Avicel PH102, and Blending was carried out using a Turbula T2A blender for approximately 20 minutes to obtain a white homogeneous blend.

[0075] The compositional data of the resulting blends are shown in Table 1. Table 1: Composition data of preblends & blends according to Example 1 [Table 1-1] Pre-Blend: Pre-Blend Mass total batch(g):Total amount of compound batch(g) Mass (mean) per minitablet (mg): Mass (mean) per minitablet (mg) Relative(%): Relative(%) Colloidal silica (Syloid 244FP): Colloidal silica (Syloid 244FP) HPC (Klucel EXF ULTRA Pharm) Met.HCl Subtotal: Subtotal [Table 1-2] Blend Compound: Compound Mass total batch(g): Mass total batch(g) Mass (mean) per minitablet (mg): Mass (mean) per minitablet (mg) Relative(%): Relative(%) MCC (Avicel PH 102) Colloidal silica (Syloid 244FP): Colloidal silica (Syloid 244FP) Sodium Stearyl Fumarate (Pruv): Sodium Stearyl Fumarate (Pruv) Subtotal: Subtotal Total Blend: Total Blend

[0076] The analytical data of the resulting blends are shown in Table 2. Table 2: Analytical data of the blends according to Example 1 [Table 2] Bulk density (g / ml): Bulk density (g / ml) Tapped density (g / ml): Tapped density (g / ml) Compressibility index(%): Compressibility index(%) Hausner ratio: Aptitude to flowability: Aptitude to flowability Passable: Yes Aptitude to compressibility: Compressibility Intermediate compressibility: LOD (%)

[0077] Stage 3 Tabletization The tableting process was carried out on an eccentric tablet press (Korsch XP1, Korsch AG, Berlin, Germany) equipped with eight D2 mm punches. Tableting parameters: average compression force: 5.5–6.5 kN.

[0078] The analytical data of the obtained mini-tablets are shown in Table 3. Table 3: Analytical data of mini-tablets according to Example 1 [Table 3] Appearance: Nature (appearance) White round brightening tablets: White round brightening tablets Friability: Friability (n=20) 0.325% Hardness: (N=6, mean ± standard deviation) 12 ± 1 N Height: (n=20, mean ± standard deviation) 1.98±0.03 mm Mass: Mass (n=20, mean value ± standard deviation) 7.14 ± 0.12 mg

[0079] observation: The resulting mini-tablets have high abrasion resistance. Thus, the friability of the mini-tablets is well below 1.0 (Ph. Eur. standard for tablets) and 0.5% (guideline for mini-tablets intended for coating). In addition to the low friability value, the height of the mini-tablets is similar to the diameter of the tablets (i.e., 2.0 mm), which results in an aspect ratio of about 1 (beneficial for coating).

[0080] Stage 4 Coating Suspension The coating suspension was prepared as follows: 1) Add HMPC E5 (approximately 28 g) to purified water and stir using an overhead stirrer for approximately 30 minutes; 2) Add polysorbate 80 (approximately 28 g) to purified water and stir for approximately 75 minutes at an increased stirring speed; 3) adding the polysorbate solution to the HMPC solution under overhead stirring for about 10 minutes; 4) Add talc (approximately 273 g) gradually while stirring vigorously, and then stir for approximately 10 minutes (after incorporation). 5) Add the solution to Eudragit NM30D (approximately 244 g) and stir for a further 5 minutes.

[0081] Optionally, the coating suspension can be filtered through a 500 μm screen. The composition data of the resulting coating suspension is shown in Table 4. Table 4: Coating composition (dry weight) according to Example 1 [Table 4] Coating: Compound: Compound Mass: Mass (g) Relative: Relative (%) Methacrylic Copolymer(Eudragit NM30D):Methacrylic Acid Copolymer(Eudragit NM30D) HPMC (Methocel E5 Premium LV) Polysorbate 80: Polysorbate 80 (Montanox 80 PHA Premium) Talc: Talc subtotal

[0082] Stage 5 Coating The mini-tablets (immediate release) described in Stage 3 were introduced into the appropriate product container of fluid bed equipment (Oystar Huttlin Mycrolab). Coating was carried out with the suspension prepared in the previous stage according to the parameters listed in Table 5 and further cured at about 40°C for about 24 hours to obtain dull white coated mini-tablets. Table 5: Coating parameters [Table 5] Granulation parameters Inlet flow rate: Inlet flow rate (m 3 / h) Inlet temperature: Inlet temperature (℃) Product temperature: Product temperature (℃) Outlet temperature: Outlet temperature (℃) Duration: Duration (minutes) Pre-heating: Coating: Drying

[0083] During the coating process, coated mini-tablet samples were collected and additional coating liquid was sprayed onto the mini-tablets during the coating process, resulting in different mini-tablet samples [Examples 1a (control), 1b, 1c, and 1d] with different weights and coating thickness / weights, as shown in Table 6.

[0084] Table 6. Coating weight of mini-tablets according to Example 1 [Table 6] Example: Mass: Mass (average) (mg) Coating mass: Coating mass (average) (mg) Weight increase: Mass increase (w / w) (%) Relative coating amount: Relative coating amount (wt%) Control:

[0085] Stage 6 Dissolution Test The (coated) mini-tablets were filled into capsules (dose strength 100 mg) and subjected to in vitro dissolution tests using two different media (pH 1.0 and pH 6.8).

[0086] observation: As shown in Figures 1A and 1B, slower release kinetics were observed with increasing coating weight. Furthermore, intermediate pH was found to have no effect on metformin release from coated minitablets.

[0087] Comparative Example 2 - Sustained Release (Matrix System)

[0088] Stage 1 Pre-Blend A preblend was prepared by weighing (and sieving / calibrating at 600 μm) Syloid 244FP (approximately 3 g) and Met.HCl (approximately 605 g), followed by blending for approximately 30 minutes using a Turbula T2A blender.

[0089] Stage 2 Blend The blend was prepared by weighing (and sieving / calibrating at 600 μm) Avicel PH102 (approximately 15 g), Stage 1 pre-blend (approximately 12 g), HPMC (Metolose 90 SH 100,000 SR) (approximately 12 g) and Ligamed MF-2V (approximately 0.8 g), which were then introduced into a suitable container and blended using a Turbula T2A blender for approximately 20 minutes to obtain a white, homogeneous blend.

[0090] The compositional data for the resulting blends are shown in Table 7. Table 7. Composition data of preblends and blends according to Comparative Example 2 [Table 7] Pre-blend: Pre-blend Compound: Compound Mass total batch: Mass total batch (g) Mass (means) per minitablet: Mass (mean) per minitablet (mg) Relatives: Relative (%) Colloidal silica: Colloidal silica (Syloid 244FP) Met.HCl Subtotal: Subtotal Blen: Blend Compound: Compound Mass total batch: Mass total batch (g) Mass (mean) per minitablet: Mass (mean) per minitablet (mg) Relative: Relative (%) Pre-blend: Pre-blend Colloidal silica: Colloidal silica (Syloid 244FP) Met.HCl MCC (Avicel PH 102) HPMC (Metolose 90 SH 100.000 SR) Magnesium stearate: Magnesium stearate (Ligamed MF-2V) Total blend: Total blend

[0091] The analytical data for the resulting blends are shown in Table 8. Table 8. Analytical data for blends of Comparative Example 2 [Table 8] Hausner ratio:

[0092] Stage 3 Tabletization The tableting process was carried out on an eccentric tablet press (Korsch XP1, Korsch AG, Berlin, Germany) equipped with eight D2 mm punches. Tableting parameters: average compression force: 5.5–6.5 kN.

[0093] observation: In contrast to the blend used to prepare immediate release metformin HCl minitablets, poor flowability and capping were observed at a tableting speed of 15 strokes / min.

[0094] Stage 4 Dissolution Test HPMC 90 SH 100.000 SR minitablets were filled into capsules (dose strength 100 mg) and tested during in vitro dissolution experiments.

[0095] observation: As shown in FIG. 2, the use of 30% (w / w) HPMC 90 SH 100.000 SR did not result in sustained release kinetics compared to Example 1d, as shown in Table 6.

[0096] Comparative Example 3 - Sustained Release (Matrix System)

[0097] Stage 2 Blend The blend was prepared by weighing (and sieving / calibrating at 600 μm) Avicel PH102 (approximately 18 g), the preblend of Comparative Example 1 (approximately 30 g), HPMC (Metolose 90 SH 100,000 SR) (approximately 50 g) and Ligamed MF-2V (approximately 2 g), which were then introduced into a suitable container and blended using a Turbula T2A blender for approximately 20 minutes to obtain a white, homogeneous blend.

[0098] The compositional data for the resulting blends are shown in Table 9. Table 9. Composition data of preblends and blends according to Comparative Example 2 [Table 9] Pre-bled: Pre-blend Compound: Compound Mass total batch(g) Mass (mean) per minitablet (mg): Mass (mean) per minitablet (mg) Relative: Relative (%) Colloidal silica (Syloid 244FP): Colloidal silica (Syloid 244FP) Met.HCl Subtotal: Subtotal Blend Mass total batch(g) :Compound substance amount total batch(g) Mass (mean) per minitablet (mg): Mass (mean) per minitablet (mg) Relative: Relative (%) Pre-bled: Pre-blend Colloidal silica (Syloid 244FP): Colloidal silica (Syloid 244FP) Met.HCl MCC (Avicel PH 102) HPMC (Metolose 90 SH 100.000 SR) Magnesium stearate: Magnesium stearate (Ligamed MF-2V) Total Blend: Total Blend

[0099] The analytical data for the resulting blends are shown in Table 10. Table 10. Analytical data for blends of Comparative Example 3 [Table 10] Hausner ratio:

[0100] Stage 3 Tabletization The tableting process was carried out on an eccentric tablet press (Korsch XP1, Korsch AG, Berlin, Germany) equipped with eight D2 mm punches. Tableting parameters: average compression force: 5.5–6.5 kN.

[0101] Observation: Poor powder flow properties of the blend were observed during tableting, resulting in uneven filling of the die. It was therefore concluded that increasing the HPMC 90SH-100,000 SR concentration was not a viable option.

[0102] Comparative Example 4 - Sustained release (matrix system)

[0103] Stage 2 Blend The blend was prepared by weighing (and sieving / calibrating at 600 μm) Avicel PH102 (approximately 30 g), the preblend of Comparative Example 2 (approximately 30 g), ethyl cellulose (Ethocel) (approximately 30 g) and Ligamed MF-2V (approximately 2 g) into a suitable container and blending them for approximately 20 minutes using a Turbula T2A blender to obtain a white homogeneous blend.

[0104] The compositional data for the resulting blends are shown in Table 11. Table 11. Composition data of preblends and blends according to Comparative Example 4 [Table 11] Pre-bled: Pre-blend Compound: Compound Mass total batch(g) Mass (mean) per minitablet (mg): Mass (mean) per minitablet (mg) Relative: Relative (%) Colloidal silica (Syloid 244FP): Colloidal silica (Syloid 244FP) Met.HCl Subtotal: Subtotal Blend Compound: Compound Mass total batch(g) Mass (mean) per minitablet (mg): Mass (mean) per minitablet (mg) Relative: Relative (%) Pre-bled: Pre-blend Colloidal silica (Syloid 244FP): Colloidal silica (Syloid 244FP) Met.HCl MCC (Avicel PH 102) Ethyl-cellulose: Ethyl cellulose (Ethocel) Magnesium stearate: Magnesium stearate (Ligamed MF-2V) Total Blend: Total Blend

[0105] The analytical data for the resulting blends are shown in Table 12. Table 12. Analytical data for blends of Comparative Example 4 [Table 12] Hausner ratio: 1.20

[0106] Stage 3 Tabletization The tableting process was carried out on an eccentric tablet press (Korsch XP1, Korsch AG, Berlin, Germany) equipped with eight D2 mm punches. Tableting parameters: average compression force: 5.5–6.5 kN.

[0107] observation: Compared to HPMC as a matrix former, better flow properties and more uniform die filling during tableting tests were observed. The friability values ​​of the resulting mini-tablets were higher than those of HPMC-based mini-tablets.

[0108] Stage 4 Dissolution Test The ethylcellulose mini-tablets were filled into capsules (100 mg dose strength) and tested during in vitro dissolution experiments.

[0109] observation: As shown in Figure 2, the use of 30% (w / w) ethylcellulose did not result in sustained release release kinetics compared to Example 1d, as shown in Table 6. A similar release pattern was observed when 50% (w / w) ethylcellulose was used.

Claims

1. A method for preparing sustained-release mini-tablets for oral administration containing metformin or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient, the method comprising the steps of: (1) blending an active pharmaceutical ingredient with a first glidant and a first binder, thereby forming a first dry powder blend; (2) blending the first blend obtained in step (1) with a filler, a second glidant, and a lubricant, thereby obtaining a second dry powder blend; (3) tableting the second blend obtained in step (2) by direct compression, thereby forming mini-tablets; (4) preparing a coating suspension; (5) Coating the mini-tablets obtained in step (3) with the coating suspension of step (4).

2. 10. The method of claim 1, wherein the step (4) of preparing the coating suspension comprises the steps of: (4a) preparing a first dispersion comprising a second binder; (4b) blending the first suspension obtained in step (4a) with a surfactant, an anti-blocking agent, and a sustained release polymer, thereby forming the coating suspension; (4c) Optionally, filtering the coating suspension obtained in step (4b).

3. 3. The method according to any one of claims 1 to 2, wherein the coating of the mini-tablets in step (5) is carried out using a fluidized bed system or a perforated pan coating system, in particular the coating is carried out using a fluidized bed system with bottom spraying of the coating suspension.

4. 4. The method according to any one of claims 1 to 3, wherein the coated mini-tablets have a coating mass in the range of 5 to 40 wt.%, preferably in the range of 10 to 35 wt.%, more preferably in the range of 15 to 30 wt.%, relative to the total mass of the coated mini-tablets.

5. 5. The method according to any one of claims 1 to 4, wherein the uncoated mini-tablets have an average diameter in the range of 1 to 3 mm, preferably in the range of 1.5 to 2.5 mm, more preferably in the range of 1.8 to 2.2 mm.

6. Mini tablets, 15 to 35% w / w of metformin or a pharmaceutical salt thereof is used as the pharmaceutically active ingredient, 0.1-1% w / w of a first glidant; 0.1-1% w / w of a second glidant; 1-5% w / w of a first binder; 1-5% w / w of a second binder; 35-60% w / w filler; 0.5-5% w / w of a lubricant; 0.5-5% w / w of a surfactant; 5-20% w / w of sustained release polymer and containing 5-20% w / w of an anti-tacking agent, The method according to any one of claims 1 to 5.

7. 7. The method according to any one of claims 1 to 6, wherein the glidant is selected from colloidal hydrated silica, colloidal silica, corn starch, talc, preferably the glidant is colloidal hydrated silica.

8. the lubricant is selected from magnesium stearate, sodium stearyl fumarate, calcium stearate, fumaric acid, glyceryl behenate, glyceryl palmitostearate, hydrogenated vegetable oil, magnesium lauryl sulfate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, starch, stearic acid, talc, zinc stearate, and mixtures thereof; The use according to any one of claims 1 to 7, wherein preferably the lubricant is sodium stearyl fumarate.

9. The method according to any one of claims 1 to 8, wherein the surfactant is selected from polysorbate, sodium dodecyl sulfate, sodium lauryl sulfate, preferably the surfactant is polysorbate.

10. 10. The method according to any one of claims 1 to 9, wherein the sustained release polymer is selected from polymers of methacrylic acid or methacrylic acid and ethyl acrylate, and cellulose polymers such as cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), and carboxymethylethylcellulose (CMEC), preferably the sustained release polymer is a polymer obtained from a mixture of methacrylic acid and ethyl acrylate monomers.

11. The method according to any one of claims 1 to 10, wherein the anti-adherent agent is selected from talc, magnesium stearate, preferably the anti-adherent agent is talc.

12. Mini-tablets obtainable by the method according to any one of claims 1 to 11.

13. 13. The mini-tablet of claim 12, wherein the uncoated mini-tablets have an average diameter in the range of 1 to 3 mm, preferably in the range of 1.5 to 2.5 mm, more preferably in the range of 1.8 to 2.2 mm; the mini-tablets are coated with a sustained-release polymer; and the coating mass is in the range of 5 to 40% by weight, preferably in the range of 10 to 35% by weight, more preferably in the range of 15 to 30% by weight, relative to the total mass of the coated mini-tablets.

14. 14. The mini-tablets according to claim 13, wherein the sustained release polymer is selected from polymers of methacrylic acid or methacrylic acid and ethyl acrylate, and cellulose polymers such as cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS) and carboxymethylethylcellulose (CMEC), preferably the sustained release polymer is a polymer obtained from a mixture of methacrylic acid and ethyl acrylate monomers.

15. A pharmaceutical composition comprising the mini-tablets of any one of claims 12 to 14.

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