Galantamine mini-tablets

Abstract

The present invention relates to a method for obtaining galantamine mini-tablets, to the mini-tablets obtained by said method, and to the use of these mini-tablets as a sole therapeutic agent or in combination with other active pharmaceutical agents.

Description

[Technical Field]

[0001] The present invention relates to a method for obtaining galantamine mini-tablets, to the mini-tablets obtained by said method, and to the use of these mini-tablets as a sole therapeutic agent 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. With the global aging population, the incidence of age-related diseases is expanding year by year. Therefore, numerous efforts have been made not only to treat age-related diseases but also to delay the onset of the complex aging process. As a result, many aging-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 the insulin / insulin-like growth factor (IGF) signaling or mechanistic target of rapamycin (mTOR) signaling pathways, extend lifespan and healthspan in invertebrates. These pathways have also been evaluated in mammalian models, where genetic manipulation or drugs have been used to extend healthspan and lifespan. This raises hopes for new interventions, including drugs that slow the aging process and delay the appearance of age-related diseases by modulating conserved aging pathways; however, to date, with the exception of some symptomatic treatments, unfortunately, no known interventions have been shown to effectively slow the aging process in humans. Ultimately, there is a growing need and demand for measures to maintain health and slow aging, in addition to medically treating existing diseases and disorders.

[0003] Metformin is widely used and approved as an antidiabetic drug for the treatment of type 2 diabetes. Metformin enhances 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 also been shown to target many aging mechanisms. Specifically, in the context of aging, 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 (Non-Patent Document 1). Using a C. elegans model system, the health-promoting and life-extending effects of metformin in type 2 diabetes have also been confirmed. Human studies have also shown that metformin significantly reduces the risk of cancer in diabetic patients (Non-Patent Document 2) and reduces the risk of coronary artery disease (Non-Patent Document 3). However, these effects have only been observed when metformin is administered at fairly high therapeutic doses of at least 850 mg / day. In addition, to date, no synergistic effects of metformin in combination with another compound against age-related diseases have been identified.

[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, as in humans, and rescue the paralysis phenotype in a transgenic C. elegans model of Alzheimer's disease (Non-Patent Document 4). However, galantamine has been reported to have no effect on locomotor activity, motor activity, or other forms of age-related decline in C. elegans. In humans, galantamine has been shown to significantly reduce deaths from myocardial infarction (Non-Patent Document 5). Furthermore, galantamine alleviates inflammation and insulin resistance in subjects with metabolic syndrome (Non-Patent Document 6). However, all of these effects were observed when galantamine was administered at a fairly high therapeutic dose of at least 24 mg / day. Furthermore, no synergistic effects against age-related diseases were identified when galantamine was combined with another compound.

[0005] In the applicant's previous study (Patent Document 1), the biguanide metformin was shown to have a potentiating and even synergistic effect against age-related diseases 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] Mini-tablets are promising patient-friendly drug delivery systems to overcome therapeutic barriers such as dysphagia and polypharmacy, as well as to offer several therapeutic benefits such as dosage flexibility and combination release patterns (Non-Patent Document 7). Mini-tablets are generally tablets with a diameter of 3 mm or less and are produced in conventional tablet presses equipped with multiple tooling. The production of mini-tablets is similar to the production of standard tablets, except that the smaller tooling requires very good powder flow, precise control of process parameters, and special care during tablet press assembly to avoid damage to the tooling. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] European Patent No. 3813882 [Non-patent literature]

[0008] [Non-Patent Document 1] Barzilai et al., Cell Metab. 2016 [Non-patent document 2] Fuming et al. Oncol Lett. 2018 [Non-patent document 3] Hong et al., Diabetes Care. 2014 [Non-patent document 4] Xin et al., Plos One, 2013 [Non-Patent Document 5] Nordstroem et al., 2013 [Non-patent document 6] Consolim-Colombo et al.; JCI Insight. 2017 [Non-Patent Document 7] Aleksovski et al. Expert Opinion on Drug Delivery 2014 12, 65 Summary of the Invention [Problem to be solved by the invention]

[0009] It is therefore an object of the present invention to address the challenges associated with mini-tablet production by providing a method for producing novel galantamine mini-tablets, the mini-tablets obtained thereby, and the use of galantamine mini-tablets as a sole therapeutic agent 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 an immediate-release pharmaceutical composition for oral administration comprising galantamine or a pharmaceutical salt thereof as an active pharmaceutical ingredient, the method comprising the steps of: (1) preparing a suspension comprising the active pharmaceutical ingredient and a binder; (2) adding the suspension to a first filler; (3) granulating the mixture formed in step (2), thereby forming granules; (4) blending the granules of step (3) with a second filler and a disintegrant; (5) blending the granules of step (4) with a lubricant; and (6) tableting the granules formed in step (5), thereby forming mini-tablets.

[0011] In particular, the present invention provides a method for preparing an immediate-release pharmaceutical composition for oral administration comprising galantamine or a pharmaceutical salt thereof as an active pharmaceutical ingredient, the method comprising the steps of: (1) preparing a dispersion / solution comprising water and a binder; (2) adding the active ingredient in the form of a dry powder to the dispersion / solution of step (1) to form a suspension of the active pharmaceutical ingredient; (3) adding the suspension of step (2) to a first powder filler; (4) granulating the mixture formed in step (3), thereby forming granules; (5) blending the granules of step (4) with a second filler and a disintegrant; (6) blending the granules of step (5) with a lubricant; and (7) tableting the granules formed in step (6), thereby forming mini-tablets.

[0012] According to an embodiment of the present invention, granulation is carried out by fluidized air bed and drying in the same equipment, by high shear granulation and fluidized bed air drying, or by high shear granulation and tray drying, preferably by fluidized air bed and drying in the same equipment.

[0013] In various embodiments of the present invention, the average particle size of the granules is in the range of 100 micrometers to 400 micrometers.

[0014] According to various embodiments of the present invention, the mini-tablets have an average diameter in the range of 1 mm to 3 mm, preferably in the range of 1.5 mm to 2.5 mm, more preferably in the range of 1.8 mm to 2.2 mm.

[0015] In various embodiments of the present invention, the mini-tablets comprise 15% to 35% by weight of an active pharmaceutical ingredient, 1% to 5% by weight of a binder, 25% to 50% by weight of a first filler, 20% to 40% by weight of a second filler, 1% to 5% by weight of a disintegrant, and 0.5% to 5% by weight of a lubricant.

[0016] In various embodiments of the invention, the binder is selected from the list including 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 binder is hydroxypropyl methylcellulose.

[0017] In various embodiments of the invention, the first filler is selected from the list including microcrystalline cellulose, calcium carbonate, calcium phosphate (dibasic), calcium phosphate (tribasic), calcium sulfate, cellulose, microcrystalline cellulose, silicified microcrystalline 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 certain embodiments, the first filler is microcrystalline cellulose.

[0018] In various embodiments of the invention, the second filler is selected from the list including microcrystalline cellulose, calcium carbonate, calcium phosphate (dibasic), calcium phosphate (tribasic), calcium sulfate, cellulose, microcrystalline cellulose, silicified microcrystalline 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 certain embodiments, the second filler is microcrystalline cellulose.

[0019] In various embodiments of the present invention, the disintegrant is selected from the list comprising cross-linked sodium carboxymethylcellulose (croscarmellose sodium), cross-linked polyvinylpyrrolidone (crospovidone), sodium starch glycolate, calcium alginate, calcium sodium alginate, calcium carboxymethylcellulose, calcium cellulose glycolate, calcium carmellose, microcrystalline cellulose, powdered cellulose, chitosan hydrochloride, corn starch, pregelatinized starch, and mixtures thereof. According to a particular embodiment, the disintegrant is croscarmellose sodium.

[0020] In various 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 oil, 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 magnesium stearate.

[0021] According to a further aspect, the present invention provides mini-tablets obtainable by the above process.

[0022] According to yet another aspect, the present invention provides mini-tablets comprising 15% to 35% by weight of galantamine or a pharmaceutical salt thereof as an active pharmaceutical ingredient, 1% to 5% by weight of a binder, 25% to 50% by weight of a first filler, 20% to 40% by weight of a second filler, 1% to 5% by weight of a disintegrant, and 0.5% to 5% by weight of a lubricant.

[0023] According to yet another aspect, the present invention provides a pharmaceutical composition comprising a mini-tablet according to various aspects and embodiments of the present invention. [Brief explanation of the drawings]

[0024] [Figure 1] (A) illustrates granulation using dry addition, i.e., the active compound (Gal.HBr) is added as a dry mixture with the filler to the manufacturing vessel and the binder solution is sprayed into the granulation chamber. (B) illustrates granulation using wet addition, i.e., the filler alone is added to the manufacturing vessel and a suspension of the active compound (Gal.HBr) in the binder solution is sprayed into the granulation chamber. [Figure 2] 1 is a graph showing the particle size distribution of Example 1. [Figure 3] 1 is a graph showing the dissolution profile of Example 1 in phosphate buffer at pH 6.8. DETAILED DESCRIPTION OF THE INVENTION

[0025] The present invention will now be further described. In the following paragraphs, various aspects of the present invention are defined in more detail. Each aspect so defined can be combined with any other aspect or aspects, unless expressly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous can be combined with any other feature or features indicated as being preferred or advantageous.

[0026] 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. By way of example, "a compound" means one compound or more than one compound. The above terms, and others used herein, are well understood by those of ordinary skill in the art.

[0027] According to a first aspect, the present invention provides a method for preparing an immediate-release pharmaceutical composition for oral administration comprising galantamine or a pharmaceutical salt thereof as an active pharmaceutical ingredient, the method comprising the steps of: (1) preparing a suspension comprising the active pharmaceutical ingredient and a binder; (2) adding the suspension to a first filler; (3) granulating the mixture formed in step (2), thereby forming granules; (4) blending the granules of step (3) with a second filler and a disintegrant; (5) blending the granules of step (4) with a lubricant; and (6) tableting the granules formed in step (5), thereby forming mini-tablets.

[0028] In particular, the present invention provides a method for preparing an immediate-release pharmaceutical composition for oral administration comprising galantamine or a pharmaceutical salt thereof as an active pharmaceutical ingredient, the method comprising the steps of: (1) preparing a dispersion / solution comprising water and a binder; (2) adding the active ingredient in the form of a dry powder to the dispersion / solution of step (1) to create a suspension of the active pharmaceutical ingredient; (3) adding the suspension of step (2) to a first powder filler; (4) granulating the mixture formed in step (3), thereby forming granules; (5) blending the granules of step (4) with a second filler and a disintegrant; (6) blending the granules of step (5) with a lubricant; and (7) tableting the granules formed in step (6), thereby forming mini-tablets.

[0029] In certain embodiments, the powdered active ingredient is added to a dispersion / solution (eg, suspension) of a binder in water, without the need to disperse, suspend, or dissolve the active ingredient in a solvent such as alcohol.

[0030] In another embodiment, the active ingredient is added to the water / binder solution at a weight percent of about 30%, for example, between 10% and 50%, particularly between 20% and 50%, and the resulting solution is stirred in a high-speed mixer for about 10 to 30 minutes, particularly about 15 minutes, followed by stirring in an overhead mixer for about 60 to 180 minutes, particularly about 120 minutes.

[0031] According to an embodiment of the present invention, granulation is carried out by fluidized air bed and drying in the same equipment, by high shear granulation and fluidized bed air drying, or by high shear granulation and tray drying, preferably by fluidized air bed and drying in the same equipment.

[0032] In certain embodiments, granulation is performed by air fluidized bed using a first powder filler (typical particle size 20 μm to 400 μm), without the need for beads or tablets (typical particle size 500 μm to 710 μm). The advantage of this granulation is that smaller particle sizes can be obtained, which allows for easier further processing. In certain embodiments, the particle size of the first powder filler is between 20 μm and 400 μm, particularly between 30 μm and 200 μm, and particularly between 50 μm and 100 μm.

[0033] In a particular embodiment, a first powder filler is added to the vessel of a fluidized bed apparatus and granulation is carried out using a suspension of water, binder and active ingredient, wherein the weight percentage of the filler relative to the suspension is about 50% by weight, particularly between 30% and 70% by weight, for example between 40% and 60% by weight.

[0034] In various embodiments of the present invention, the average particle size of the granules is in the range of 100 micrometers to 400 micrometers.

[0035] According to various embodiments of the present invention, the mini-tablets have an average diameter in the range of 1 mm to 3 mm, preferably in the range of 1.5 mm to 2.5 mm, more preferably in the range of 1.8 mm to 2.2 mm.

[0036] In various embodiments of the present invention, the mini-tablets comprise 15% to 35% by weight of an active pharmaceutical ingredient, 1% to 5% by weight of a binder, 25% to 50% by weight of a first filler, 20% to 40% by weight of a second filler, 1% to 5% by weight of a disintegrant, and 0.5% to 5% by weight of a lubricant.

[0037] In various embodiments of the invention, the 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 binder is hydroxypropyl methylcellulose.

[0038] In certain embodiments, the weight percent of the suspension containing water and binder is about 4% by weight, for example, between 1% and 10% by weight, between 2% and 8% by weight, and in particular between 3% and 6% by weight.

[0039] In various embodiments of the present invention, the first filler is selected from the list including microcrystalline cellulose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose monohydrate, magnesium carbonate, maltitol, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, and xylitol. According to certain embodiments, the first filler is microcrystalline cellulose. In a preferred embodiment, the first filler is a powdered filler.

[0040] In various embodiments of the present invention, the second filler is selected from the list including microcrystalline cellulose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose monohydrate, magnesium carbonate, maltitol, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, and xylitol. According to certain embodiments, the second filler is microcrystalline cellulose. In a preferred embodiment, the second filler is a powdered filler.

[0041] In a specific embodiment, after the first granulation step, the second filler, the disintegrant, and the granules obtained in the first granulation step are blended in a ratio of about 10 / 1 / 20, particularly about 9.6 / 0.9 / 18.9, to prepare a pre-blend. After this blending step, a lubricant can be added.

[0042] In various embodiments of the present invention, the disintegrant is selected from the list comprising cross-linked sodium carboxymethylcellulose (croscarmellose sodium), cross-linked polyvinylpyrrolidone (crospovidone), sodium starch glycolate, calcium alginate, calcium sodium alginate, calcium carboxymethylcellulose, calcium cellulose glycolate, calcium carmellose, microcrystalline cellulose, powdered cellulose, chitosan hydrochloride, corn starch, pregelatinized starch, and mixtures thereof. According to a particular embodiment, the disintegrant is croscarmellose sodium.

[0043] In various 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 magnesium stearate.

[0044] According to a further aspect, the present invention provides mini-tablets obtainable by the above process.

[0045] According to a particular embodiment of the present invention, the mini-tablets comprise galantamine or a pharmaceutical salt thereof, hydroxypropyl methylcellulose, microcrystalline cellulose, croscarmellose sodium and magnesium stearate.

[0046] According to a particular embodiment of the present invention, the mini-tablets comprise 15% to 35% by weight of galantamine or a pharmaceutical salt thereof, 1% to 5% by weight of hydroxypropylmethylcellulose, 50% to 87.5% by weight of microcrystalline cellulose, 1% to 5% by weight of croscarmellose sodium, and 0.5% to 5% by weight of magnesium stearate.

[0047] According to yet another aspect, the present invention provides mini-tablets comprising 15% to 35% by weight of galantamine or a pharmaceutical salt thereof as an active pharmaceutical ingredient, 1% to 5% by weight of a binder, 25% to 50% by weight of a first filler, 20% to 40% by weight of a second filler, 1% to 5% by weight of a disintegrant, and 0.5% to 5% by weight of a lubricant.

[0048] The mini-tablets obtained using the method defined herein have been shown to have a very fast release profile, with about 100% of the active ingredient being released within a time frame of only about 10 minutes, as is evident from the Examples section.

[0049] In yet another aspect, the present invention provides pharmaceutical compositions comprising the mini-tablets described above according to various aspects and embodiments of the present invention. Such pharmaceutical compositions can be prepared and formulated by methods known in the art and may take a variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are preferably in a unit dosage form suitable for systemic administration, e.g., oral, transdermal, or parenteral administration.

[0050] 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.

[0051] According to embodiments of the present invention, the pharmaceutical composition can be used by itself or in pharmaceutical combination with another agent used to prevent, stabilize, and / or alleviate age-related complaints, degenerative dysfunction, and / or degenerative complaints. According to embodiments of the present invention, the pharmaceutical composition can be used by itself or in pharmaceutical combination with another agent to improve measures of lifespan and / or healthspan. According to certain embodiments, the pharmaceutical composition comprises as another agent a biguanide compound, and / or an N-oxide, hydrate, pharmaceutically acceptable salt, or solvate thereof. According to further particular embodiments, the pharmaceutical composition comprises as another agent metformin. [Example]

[0052] material Galantamine.HBr (Gal.HBr) was purchased from Fagron. Croscarmellose sodium (Ac-di-sol SD-711) and microcrystalline cellulose (MCC-Avicel™ PH102) were purchased from FMC Health and Nutrition. Magnesium stearate (Ligamed MF-2-V) was purchased from IMCD Benelux. Colloidal hydrous silica (Syloied 244FP) was purchased from Grace Davison. Hydroxypropyl methylcellulose (HPMC E5) was purchased from Colorcon.

[0053] method Bulk density and tapped density The bulk and tapped densities of powders were determined using a Tap Density Tester TD1 (Sotax, Allschwil, Switzerland) equipped with a 25 mL graduated cylinder (readable to 0.5 mL increments). The tap height and tapping speed were set at 3 mm and 250 taps per minute, respectively. Approximately 25 mL of material was poured into the 25 mL graduated cylinder. The weight and exact volume of the powder 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 unit. If the difference between V500 and V1250 was 2 mL or less, V1250 was retained as the tapped volume. If the difference between the volume after 500 taps and the volume obtained after 1250 taps was greater than 2 mL, an additional 1250 taps were performed. The volume read was 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: Hausner ratio=ρT / ρB Compression index = 100 × (ρT-ρB) / ρT

[0054] size Immediately after tabletting, the diameter and height of the mini-tablets (n=20 per batch) were recorded using digital calipers (Mahr, Gottingen, Germany).

[0055] weight The individual weights of 30 mini-tablets (each batch) were recorded using an analytical 5d balance (Sartorius ME235P, Gottingen, Germany).

[0056] Hardness Test The diametric breaking force of mini-tablets (n=6 per batch) was measured using a pharmaceutical tablet hardness tester (Sotax HT10, Basel, Switzerland).

[0057] Disintegration test The disintegration time of mini-tablets (n=3 per batch) was determined using a European Pharmacopoeia-compliant disintegration tester (Sotax DT2, Basel, Switzerland). To account for the smaller diameter of the mini-tablets, the sieve opening size was reduced to 1.4 x 1.4 mm. All tests were carried out using discs in elix™ water at a temperature of 37±0.5°C.

[0058] Friability measurement The friability of the mini-tablets was determined by subjecting approximately 6.5 g of mini-tablets (according to the European Pharmacopoeia standard) to friability measurement using a friability measuring device (Sotax FT2, Basel, Switzerland) set at a speed of 25 rpm for 4 minutes. The percentage of weight loss was expressed as tablet friability.

[0059] Quantitative Testing Galantamine was quantified using ultra-performance liquid chromatography (UPLC) (European Pharmacopoeia section 2.2.29) using UV-absorbance measurement at 230 nm. Evaluation was based on the external standard method using peak area measurements and relative sensitivity.

[0060] Particle size distribution The particle size distribution was obtained by sieving the particles using a RETSCH type sieving machine with different mesh sizes and weighing the different fractions.

[0061] Example 1 - Granulation (wet addition) Stage 1 - Suspension The suspension was prepared in two stages. In the first step, a 4 wt. % binder solution was prepared by stirring Methocel E5 Premium LV and purified water for approximately 45 minutes. In the second step, Gal.HBr (approximately 167 g) was added to the binder solution (approximately 550 g), followed by stirring in a high-speed mixer (Silverson™ L4R, Silverson Machines, Waterside, Chetham, Buckinghamshire, UK) for approximately 15 minutes, and finally degassed using an overhead stirrer for approximately 120 minutes.

[0062] Stage 2 - Granulation Avicel PH102 (approximately 333 g) was weighed and introduced into a suitable manufacturing vessel for a fluidized bed apparatus (Oystar Huettlin Mycrolab). Granulation was carried out using the suspension prepared in the previous step (approximately 702 g) according to the parameters listed in Table 1, resulting in white, uniform granules with a yield of 90%. Figure 1B illustrates the wet addition method of granulation.

[0063] Table 1. Granulation parameters [Table 1] Granulation parameter: Inlet flow rate: Inlet flow rate (m 3 / time) Inlet temperature: Inlet temperature (℃) Product temperature: Product temperature (℃) Outlet temperature: Outlet temperature (℃) Solution flow rate: Solution flow rate (g / min) Duration: Duration (minutes) Pre-heating: 10 to 20 minutes Wetting: Wet 30 to 60 minutes 45 to 75 minutes Drying:Dry method 1 to 10 minutes

[0064] The composition data of the resulting suspension and granules are presented in Table 2.

[0065] Table 2. Composition data of suspension and granules according to Example 1 [Table 2] Suspension Compound: Compound Mass total Batch: Total mass of the batch (g) Relative: Relative (%) (4% by weight) Granules Gal.HBr Suspension: Subtotal: Subtotal

[0066] The analytical data of the resulting granules are presented in Table 3.

[0067] Table 3. Analytical data of the granules according to Example 1 [Table 3] Bulk density: bulk density (g / ml) Tapped density: Tapped density (g / ml) Compressibility index: Compressibility index (%) Hausner ration: Hausner ratio Assay value: Quantitative value (%)

[0068] The particle size distribution of the resulting granules is presented in Table 4 and FIG.

[0069] Table 4. Particle size distribution of granules according to Example 1 [Table 4] Screen size: Sieve size (μm) Retained particles: Retained particles (%) Bottom: bottom Total: Grand total

[0070] Observation: Galantamine HBr Granules successfully passed the powder characterization test, with good galantamine assay values ​​(i.e., 92.86%, 95.12%, and 92.75%). This was attributed to the larger particle size distribution and reduced loss of fine galantamine HBr powder in the filter of the fluidized bed equipment. Therefore, the assay values ​​obtained after assay-purity determination on the material collected from the fluidized bed filter were 103.50%, 100.96%, and 103.07%.

[0071] Stage 3 - Premix A pre-blend was prepared by weighing out (and sieving at 600 μm) Avicel PH102 (approximately 9.6 g), Ac-Di-Sol (approximately 0.9 g) and the granules prepared in the previous step (approximately 18.9 g), introducing them into a suitable container and blending them for approximately 10 minutes using a Turbula blender type T2F (WAB, Switzerland).

[0072] Stage 4 - Admixture A blend was prepared by weighing out magnesium stearate MF2V (approximately 0.9 g), sieving it through a 600 μm sieve, introducing it into the pan containing the preblend, and blending for a further approximately 5 minutes to obtain a white, homogeneous blend.

[0073] The compositional data of the resulting blends are presented in Table 5.

[0074] Table 5. Composition data of preblends and blends according to Example 1 [Table 5] Pre-blend: Pre-mix Compound: Compound Mass total batch: Total mass of the batch (g) Mass (mean) per minitablet: Mass (mean) per minitablet (mg) Relative: Relative (%) Gal.HBr granules: granules Subtotal: Subtotal Blend:Admixture Magnesium stearate: Magnesium stearate MF2V Total blend: Total blend

[0075] The analytical data of the resulting blend are presented in Table 6.

[0076] Table 6. Analytical data of the admixture according to Example 1 [Table 6] Bulk density: bulk density (g / ml) Tapped density: Tapped density (g / ml) Compressibility index: Compressibility index (%) Hausner ratio:

[0077] Stage 5 - Tableting The tableting process was carried out in an eccentric tablet press (Korsch XP1, Korsch AG, Berlin, Germany) equipped with eight 2 mm diameter punches. Tableting parameters: average compression force: 5.5 kN to 6.5 kN.

[0078] The analytical data of the obtained tablets are presented in Table 7.

[0079] Table 7. Analytical data for tablets according to Example 1 [Table 7] Appearance: White round brightening tablets: White, round, glossy tablets Friability: Friability (n=20) Hardness: Hardness (n=6, average ± SD) Height: Height (n=20, mean ± SD) Mass: Mass (n=20, mean ± SD) Disintegration time: Disintegration time (n=3, mean ± SD) 153±4 seconds

[0080] Observations: The mini-tablets obtained have high abrasion resistance. Therefore, the friability of the mini-tablets is well below 1.0 (European Pharmacopoeia standard for tablets). 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), thus resulting in an aspect ratio of approximately 1. Furthermore, the disintegration time of the mini-tablets is well below 15 minutes.

[0081] Step 6 - Dissolution Testing The mini-tablets were filled into capsules (12 mg equivalent dose strength) and subjected to in vitro dissolution testing using phosphate buffer at pH 6.8.

[0082] Observations: As shown in Figure 3, rapid release kinetics were observed.

[0083] Example 2 - Granulation (wet addition) Stage 1 - Suspension A suspension according to Example 1 was prepared by adding Gal.HBr (about 67 g) to a 4 wt % binder solution (about 219.50 g).

[0084] Stage 2 - Granulation Avicel PH102 (approximately 133 g) was weighed and introduced into a suitable container. Granulation was carried out using the suspension prepared in the previous step according to Example 1 (approximately 274 g).

[0085] The composition data of the resulting suspensions and granules are presented in Table 8.

[0086] Table 8. Composition data of suspension and granules according to Example 2 [Table 8] Suspension Compound: Compound Mass total batch: Total mass of the batch (g) Relative: Relative (%) (4% by weight) Granules Gal.HBr suspension: Subtotal: Subtotal

[0087] The analytical data of the resulting granules are presented in Table 9.

[0088] Table 9. Analytical data of granules according to Example 2 [Table 9] Bulk density: bulk density (g / ml) Tapped density: Tapped density (g / ml) Compressibility index: Compressibility index (%) Housner ratio: Assay value: Quantitative value (%)

[0089] Observation: Galantamine HBr granules successfully passed the powder characterization test, and the quantitative values ​​of galantamine were acceptable (i.e., 78.83%, 79.30%, 80.93%).

[0090] Comparative Example 3 - Direct Compression Stage 1 - Premix A preblend was prepared by weighing (and sieving at 600 μm) Syloied 244FP (approximately 2 g) and Gal.HBr (approximately 98 g), then blending for approximately 10 minutes using a Turbula T2A blender.

[0091] Stage 2 - Admixture Avicel PH102 (approximately 25.5 g), pre-blend (approximately 3 g), Ac-di-sol (approximately 0.9 g) and Ligamed MF-2-V (approximately 0.6 g) were weighed (and sieved at 600 μm), then introduced into a suitable container in the following order: 1 / 2 of Avicel PH102, Ac-di-sol, pre-blend, 1 / 2 of Avicel PH102, blended for approximately 10 minutes using a Turbula T2A blender, Ligamed MF-2-V was added to the container and finally blended for approximately 5 minutes to prepare the blend.

[0092] The compositional data for the resulting blends are presented in Table 10.

[0093] Table 10. Composition data of preblends and blends according to Comparative Example 3 [Table 10] Pre-Blend: Pre-mixture Compound: Compound Mass total batch: Total mass of the batch (g) Relative: Relative (%) Subtotal: Subtotal Blend:Admixture Gal.HBr pre-blend: Pre-mix Magnesium stearate: Magnesium stearate MF2V Total Blend: Total blend

[0094] Analytical data for the resulting blend are presented in Table 11.

[0095] Table 11. Analytical data for the blend of Comparative Example 3 [Table 11] Housner ratio:

[0096] Stage 3 - Tableting The tableting process was carried out in an eccentric tablet press (Korsch XP1, Korsch AG, Berlin, Germany) equipped with eight 2 mm diameter punches. Tableting parameters: average compression force: 5.5 kN to 6.5 kN.

[0097] Observations: poor powder flow properties (due to Hausner ratio of 1.28), rat-holing of the powder layer in the hopper, and therefore uneven filling of the mortar.

[0098] Comparative Example 4 - Direct Compression Stage 2 - Admixture A blend was prepared by weighing out (and sieving at 600 μm) Avicel PH102 (approximately 26.4 g), the preblend of Comparative Example 1 (approximately 1.5 g), Ac-di-sol (approximately 0.9 g), Ligamed MF-2-V (approximately 0.6 g) and Syloied 244FP (approximately 0.6 g), then introducing them into a suitable container in the following order: 1 / 2 of Avicel PH102, Ac-di-sol, preblend, Syloied 244FP, 1 / 2 of Avicel PH102, blending for approximately 10 minutes using a Turbula T2A blender, adding Ligamed MF-2-V to the container and finally blending for approximately 5 minutes.

[0099] The compositional data for the resulting blends are presented in Table 12.

[0100] Table 12. Composition data of preblends and blends according to Comparative Example 4 [Table 12] Pre-Blend: Pre-mixture Compound: Compound Mass total batch: Total mass of the batch (g) Relative: Relative (%) Subtotal: Subtotal Blend:Admixture Gal.HBr pre-blend: Pre-mix Magnesium stearate: Magnesium stearate MF2V Total Blend: Total blend

[0101] Analytical data for the resulting blend are presented in Table 13.

[0102] Table 13. Analytical data for the blend of Comparative Example 4 [Table 13] Compressibility index: Compressibility index (%) Housner ratio:

[0103] Stage 3 - Tableting The tableting process was carried out in an eccentric tablet press (Korsch XP1, Korsch AG, Berlin, Germany) equipped with eight 2 mm diameter punches. Tableting parameters: average compression force: 5.5 kN to 6.5 kN.

[0104] Observations: Although the powder flow properties based on bulk / tapped density measurements were acceptable (attributed to a Hausner ratio of 1.31 and a compaction index of 23.69), rat-holing of the powder layer in the hopper and therefore uneven filling of the die still occurred.

[0105] Comparative Example 5 - Granulation (dry addition) Stage 2 - Granulation A dry blend of Gal.HBr (approximately 67 g) and Avicel PH102 (approximately 33 g) was weighed and introduced into a suitable manufacturing vessel for a fluidized bed apparatus (Oystar Huettlin Mycrolab). Granulation was carried out using a 4 wt. % binder solution (approximately 107.7 g) (see Example 1) and sieved through a 500 μm sieve to obtain white, uniform granules with a yield of 66%. Figure 1A illustrates the dry addition method of granulation.

[0106] The compositional data of the resulting suspensions and granules are presented in Table 14.

[0107] Table 14. Composition data of granules according to Comparative Example 5 [Table 14] Dry Blend: Dry blend Compound: Compound Mass total batch: Total mass of the batch (g) Relative: Relative (%) Subtotal: Subtotal Granules Gal.HBr dry mixture (4% by weight)

[0108] The analytical data of the resulting granules are presented in Table 15.

[0109] Table 15. Analytical data of granules of Comparative Example 5 [Table 15] Bulk density: bulk density (g / ml) Tapped density: Tapped density (g / ml) Compressibility index: Compressibility index (%) Housner ratio: Assay value: Quantitative value (%)

[0110] Observation: Galantamine HBr granules successfully passed the powder characterization test, but the quantitative values ​​of galantamine were low (i.e., 56.85%, 57.52% and 55.01%).

[0111] Comparative Example 6 - Granulation (dry addition) Stage 2 - Granulation A dry blend of Gal.HBr (approximately 133 g) and Avicel PH102 (approximately 67 g) was weighed and introduced into a suitable manufacturing vessel for a fluidized bed apparatus (Oystar Huettlin Mycrolab). Granulation was carried out using a 4% by weight binder solution (approximately 219.2 g) (see Example 1) and sieved through a 500 μm sieve to obtain white, uniform granules with a yield of 80%.

[0112] The compositional data of the resulting suspensions and granules are presented in Table 16.

[0113] Table 16. Composition data of granules according to Comparative Example 6 [Table 16] Dry Blend: Dry blend Compound: Compound Mass total batch: Total mass of the batch (g) Relative: Relative (%) Subtotal: Subtotal Granules Gal.HBr dry mixture (4% by weight)

[0114] The analytical data of the resulting granules are presented in Table 17.

[0115] Table 17. Analytical data of granules of Comparative Example 6 [Table 17] Bulk density: bulk density (g / ml) Tapped density: Tapped density (g / ml) Compressibility index: Compressibility index (%) Housner ratio: Assay value: Quantitative value (%)

[0116] Observation: Galantamine HBr granules successfully passed the powder characterization test, but the quantitative values ​​of galantamine were still low (ie, 70.16%, 70.53% and 71.62%). [Explanation of symbols]

[0117] Drawing translation Figure 1 Galantamine Hbr / MCC PH102 Galantamine Hbr / MCC PH102 4% (w / w) HPMC E5 solution 4% by weight HPMC E5 solution Galantamine Hbr dispersed in 4% (w / w) HPMC E5 Galantamine dispersed in 4% (w / w) HPMC E5 Figure 2 Retained particles Screen size Bottom Figure 3 Drug release Time (min) Example 1

Claims

1. 1. A method for preparing an immediate-release pharmaceutical composition for oral administration comprising galantamine or a pharmaceutical salt thereof as an active pharmaceutical ingredient, comprising: (1) preparing a dispersion / solution comprising water and a binder; (2) adding an active pharmaceutical ingredient in the form of a dry powder to the dispersion / solution of step (1) to produce a suspension of the active pharmaceutical ingredient; (3) adding the suspension of step (2) to a first powder filler; (4) granulating the mixture formed in step (3), thereby forming granules; (5) blending the granules of step (4) with a second filler and a disintegrant; (6) blending the granules of step (5) with a lubricant; (7) tableting the granules formed in step (6), thereby forming mini-tablets; A method comprising:

2. 10. The method of claim 1, wherein the average particle size of the granules is in the range of 100 micrometers to 400 micrometers.

3. 3. The method according to claim 1 or 2, wherein the mini-tablets have an average diameter in the range of 1 mm to 3 mm, preferably in the range of 1.5 mm to 2.5 mm, more preferably in the range of 1.8 mm to 2.2 mm.

4. 4. The method according to any one of claims 1 to 3, wherein the mini-tablets comprise 15% to 35% by weight of the active pharmaceutical ingredient, 1% to 5% by weight of a binder, 25% to 50% by weight of a first filler, 20% to 40% by weight of a second filler, 1% to 5% by weight of a disintegrant, and 0.5% to 5% by weight of a lubricant.

5. 5. The method according to any one of claims 1 to 4, wherein the granulation is carried out by fluidized air bed and drying in the same equipment, by high shear granulation and fluidized bed air drying, or by high shear granulation and tray drying, preferably by fluidized air bed and drying in the same equipment.

6. 6. The method according to any one of claims 1 to 5, wherein the 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, preferably wherein the binder is hydroxypropyl methylcellulose.

7. 7. The method of any one of claims 1 to 6, wherein the first filler and the second filler are each independently selected from the list comprising: microcrystalline cellulose, calcium carbonate, calcium phosphate (dibasic), calcium phosphate (tribasic), calcium sulfate, cellulose, microcrystalline cellulose, silicified microcrystalline 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, preferably the first filler and / or the second filler is microcrystalline cellulose.

8. 8. The method according to any one of claims 1 to 7, wherein the disintegrant is selected from the list comprising cross-linked sodium carboxymethylcellulose (croscarmellose sodium), cross-linked polyvinylpyrrolidone (crospovidone), sodium starch glycolate, calcium alginate, calcium sodium alginate, calcium carboxymethylcellulose, calcium cellulose glycolate, carmellose calcium, microcrystalline cellulose, powdered cellulose, chitosan hydrochloride, corn starch, pregelatinized starch and mixtures thereof, preferably wherein the disintegrant is croscarmellose sodium.

9. 9. The method according to any one of claims 1 to 8, wherein 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 sulphate, magnesium stearate, sodium lauryl sulphate, sodium stearyl fumarate, starch, stearic acid, talc, zinc stearate and mixtures thereof, preferably wherein the lubricant is magnesium stearate.

10. Mini-tablets obtainable by the method according to any one of claims 1 to 9.

11. A mini-tablet comprising 15% to 35% by weight of galantamine or a pharmaceutical salt thereof as an active pharmaceutical ingredient, 1% to 5% by weight of a binder, 25% to 50% by weight of a first filler, 20% to 40% by weight of a second filler, 1% to 5% by weight of a disintegrant, and 0.5% to 5% by weight of a lubricant.

12. 12. Mini-tablets according to claim 11, having an average diameter in the range of 1 mm to 3 mm, preferably in the range of 1.5 mm to 2.5 mm, more preferably in the range of 1.8 mm to 2.2 mm.

13. 13. Mini-tablets according to claim 11 or 12, wherein the 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, preferably the binder is hydroxypropyl methylcellulose.

14. 14. The mini-tablet of any one of claims 10 to 13, wherein the first filler and the second filler are each independently selected from the list comprising: microcrystalline cellulose, calcium carbonate, calcium phosphate (dibasic), calcium phosphate (tribasic), calcium sulfate, cellulose, microcrystalline cellulose, silicified microcrystalline 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, preferably the first filler and / or the second filler is microcrystalline cellulose.

15. A pharmaceutical composition comprising the mini-tablet of any one of claims 10 to 14.

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