Galanthamine micro tablet

Abstract

The present invention relates to a process for obtaining microtablets of galanthamine, microtablets obtainable by this process and the use of these microtablets as monotherapeutics or in combination with other active agents.

Description

Technical Field

[0001] The present invention relates to a method for obtaining galantamine microtablets, the microtablets obtainable by this method, and the use of these microtablets as a single therapy or in combination with other active drugs. Background Art

[0002] Aging is the progressive loss and deterioration of functions at the cellular, tissue, and organ levels, leading to a progressive loss of physiological integrity, increased susceptibility to diseases and external stressors, and ultimately death. With the increasing aging of the global population, the incidence of age-related diseases is expanding every year. Therefore, many attempts have been made to treat age-related diseases and to delay the onset of this complex process of aging. As a result, multiple age-related pathways have been identified, which may become targets for extending lifespan and healthspan. 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 the mechanistic target of rapamycin (mTOR) in the rapamycin signaling pathway) extend the lifespan and healthspan of invertebrates. These pathways have also been evaluated in mammalian models, in which healthspan and lifespan have been extended through genetic manipulation or drugs. Although this offers hope for new interventions, including drugs that slow down the aging process and the emergence of age-related diseases by modulating conserved aging pathways, unfortunately, to date, except for some symptomatic treatments, there are no known interventions that effectively slow down the aging process in humans. After all, in addition to treating existing diseases and disorders with drugs, the need and demand for measures to maintain health and delay aging are increasing.

[0003] Metformin has been widely used and approved as an anti-diabetic drug for the treatment of type 2 diabetes. It increases insulin sensitivity, thereby improving insulin action at the cellular level without affecting insulin secretion. It has also been shown that metformin has a positive effect on several cardiovascular risk factors. In addition, it has been shown that metformin also targets multiple aging mechanisms. Specifically for aging, metformin leads to reduced insulin levels, reduced IGF-1 signaling, inhibition of mTOR, inhibition of mitochondrial complex I in the electron transport chain and reduction of the production of endogenous reactive oxygen species, activation of AMP-activated kinase (AMPK), and reduction of DNA damage. It has also been shown that metformin favorably affects metabolic and cellular processes closely related to the development of age-related diseases, such as inflammation, autophagy, and cellular senescence (Barzilai et al., Cell Metab. 2016). Using the Caenorhabditis elegans (C. elegans) model system, the health-promoting and lifespan-extending effects of metformin in type 2 diabetes have also been confirmed. Human studies have further shown that metformin significantly reduces the risk of cancer in diabetic patients (Fuming et al., Oncol Lett. 2018), and reduces the risk of coronary disease (Hong et al., Diabetes Care. 2014). However, all of these effects were observed when metformin was administered at a relatively high therapeutic dose, which is at least 850 mg / day or more. Additionally, to date, the synergistic effect of metformin in combination with another compound on age-related diseases has not been determined.

[0004] Galantamine is an acetylcholinesterase inhibitor that allosterically modulates nicotinic receptors and is widely known as a drug administered to patients with Alzheimer's disease. Galantamine has been shown to promote cholinergic neurotransmission in C. elegans in a manner similar to that in humans, and to rescue the paralytic phenotype in a transgenic C. elegans Alzheimer's disease model (Xin et al., Plos One, 2013), however, it has been described that galantamine has no effect on locomotion, movement, or other forms of decline related to age in C. elegans. In humans, it has been shown that galantamine significantly reduces death caused by myocardial infarction ( et al., 2013). In addition, galantamine alleviates inflammation and insulin resistance in subjects with metabolic syndrome (Consolim-Colombo et al.; JCI Insight. 2017). However, all of these effects were observed when galantamine was administered at a relatively high therapeutic dose, which is at least 24 mg / day or more. Additionally, when galantamine is combined with another compound, the synergistic effect of galantamine on age-related diseases has also not been determined.

[0005] Earlier work of the present applicant (EP3813882A1) has shown an enhanced or even synergistic effect of the combination of the biguanide metformin with the acetylcholinesterase inhibitor galantamine on age-related diseases. In particular, this effect was observed when at least one or both compounds were administered at their sub-therapeutic doses.

[0006] To overcome treatment barriers such as impaired swallowing and polypharmacy, and also to provide some therapeutic benefits such as dosing flexibility and combination release patterns, minitablets are a promising patient-friendly drug delivery system (Aleksovski et al., Expert Opinion on Drug Delivery 2014 12, 65). Minitablets are tablets typically with a diameter ≤3 mm, which are produced on a conventional tableting machine equipped with various tools. The production of minitablets is similar to that of standard tablets, but due to the small dies, excellent powder flow, precise control of process parameters and special care during tableting assembly are required to avoid tool damage.

[0007] Accordingly, the object of the present invention is to solve the problems associated with the production of minitablets by providing a new method for producing galantamine minitablets, the minitablets obtainable by this method, and the use of galantamine minitablets as a single therapy or in combination with other therapies in the treatment of age-related diseases. Summary of the Invention

[0008] According to a first aspect, the present invention provides a method for preparing an orally administrable immediate-release pharmaceutical composition, the pharmaceutical composition comprising galantamine or a pharmaceutically acceptable 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; (6) tableting the granules formed in step (5), thereby forming minitablets.

[0009] In particular, the present invention provides a method for preparing an orally administered immediate-release pharmaceutical composition comprising galantamine or a pharmaceutically acceptable 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 dry powder form 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 powdered filler; (4) granulating the mixture formed in step (3) to form 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) to form microtablets.

[0010] According to one 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.

[0011] In various embodiments of the present invention, the granules have an average particle size in the range of 100 to 400 microns.

[0012] According to various embodiments of the present invention, the microtablets 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.

[0013] In various embodiments of the present invention, the microtablets comprise 15 - 35% w / w active pharmaceutical ingredient, 1 - 5% w / w binder, 25 - 50% w / w first filler; 20 - 40% w / w second filler, 1 - 5% w / w disintegrant and 0.5 - 5% w / w lubricant.

[0014] In various embodiments of the present invention, the binder is selected from the list comprising: hydroxypropyl methylcellulose, gum arabic, alginic acid, carbomer, calcium carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), magnesium aluminum silicate, maltodextrin, methyl cellulose, polydextrose, polyethylene oxide, polyvinylpyrrolidone, copovidone, sodium alginate, starch paste, pregelatinized starch, sucrose (syrup), and mixtures thereof. According to a particular embodiment, the binder is hydroxypropyl methylcellulose.

[0015] In various embodiments of the present invention, the first filler is selected from the list comprising: microcrystalline cellulose, calcium carbonate, calcium hydrogen phosphate, tricalcium phosphate, calcium sulfate, cellulose, microcrystalline cellulose, siliconized microcrystalline cellulose, powdered cellulose, glucose binder, 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.

[0016] In various embodiments of the present invention, the second filler is selected from the list comprising: microcrystalline cellulose, calcium carbonate, calcium hydrogen phosphate, tricalcium phosphate, calcium sulfate, cellulose, microcrystalline cellulose, siliconized microcrystalline cellulose, powdered cellulose, glucose binder, 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 second filler is microcrystalline cellulose.

[0017] In various embodiments of the present invention, the disintegrant is selected from the list comprising: croscarmellose sodium (cross-linked carboxymethylcellulose sodium), crospovidone (cross-linked polyvinylpyrrolidone), sodium starch glycolate, calcium alginate, calcium sodium alginate, carboxymethylcellulose calcium, calcium cellulose glycolate, croscarmellose calcium, microcrystalline cellulose, powdered cellulose, chitosan hydrochloride, corn starch, pregelatinized starch, and mixtures thereof. According to a particular embodiment, the disintegrant is croscarmellose sodium.

[0018] In various embodiments of the present 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.

[0019] According to another aspect, the present invention provides microtablets obtainable by the method.

[0020] According to yet another aspect, the present invention provides microtablets comprising 15 - 35% w / w galantamine or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient, 1 - 5% w / w binder, 25 - 50% w / w first filler; 20 - 40% w / w second filler, 1 - 5% w / w disintegrant and 0.5 - 5% w / w lubricant.

[0021] According to yet another aspect, the present invention provides a pharmaceutical composition comprising microtablets according to different aspects and embodiments of the present invention.

[0022] Brief Description of the Drawings

[0023] Figure 1 . (A) shows a schematic diagram of granulation with dry addition, i.e., where the active compound (Gal.HBr) and the filler are added as a dry blend to the product container, and the binder solution is sprayed into the granulation chamber; (B) shows a schematic diagram of granulation with wet addition, i.e., where only the filler is added to the product container, and a suspension of the active compound (Gal.HBr) in the binder solution is sprayed into the granulation chamber.

[0024] Figure 2 Shows the particle size distribution of Example 1.

[0025] Figure 3 Shows the dissolution curve of Example 1 in phosphate buffer at pH 6.8. Detailed Description of the Invention

[0027] The present invention will now be further described. In the following paragraphs, different aspects of the present invention are defined in more detail. Unless explicitly stated to the contrary, each aspect so defined can be combined with any other one or more aspects. In particular, any feature specified as being preferred or advantageous can be combined with any other one or more features specified as being preferred or advantageous.

[0028] Unless the context clearly dictates otherwise, the singular forms "a / an" and "the" as used in this specification and the appended claims include plural referents. By way of example, "a compound" means one compound or more than one compound. Those skilled in the art will fully understand the terms described above and other terms used in the specification.

[0029] According to a first aspect, the present invention provides a method for preparing an orally administrable immediate-release pharmaceutical composition, the immediate-release pharmaceutical composition comprising galantamine or a pharmaceutically acceptable 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; (6) tableting the granules formed in step (5), thereby forming microtablets.

[0030] In particular, the present invention provides a method for preparing an orally administered immediate-release pharmaceutical composition, the pharmaceutical composition comprising galantamine or a pharmaceutically acceptable 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 dry powder form 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 powdered filler; (4) granulating the mixture formed in step (3) to thereby form 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) tabletting the granules formed in step (6) to thereby form microtablets.

[0031] In a specific embodiment, the powdered active ingredient is added to a dispersion / solution of the binder in water (such as a suspension), and there is no need to disperse, suspend or dissolve the active ingredient in a solvent (such as an alcohol).

[0032] In another embodiment, the active ingredient is added to the water / binder solution at about 30% w / w, such as between 10 and 50% w / w, particularly between 20 and 50% w / w % w / w. The resulting solution is stirred with a high-speed mixer for about 10 - 30 min, particularly about 15 min; then stirred with an overhead stirrer for about 60 - 180 min, particularly about 120 min.

[0033] According to one embodiment of the present invention, granulation is carried out by a 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 a fluidized air bed and drying in the same equipment.

[0034] In a specific embodiment, granulation is carried out by a fluidized air bed using a first powdered filler (typical particle size 20 - 400 μm), and there is no need to use beads or tablets (typical particle size 500 - 710 μm). The advantage is that smaller particle sizes can be obtained, allowing for easier further processing steps. In a specific embodiment, the particle size of the first powdered filler is between 20 - 400 μm, particularly between 30 - 200 μm, more particularly between 50 - 100 μm.

[0035] In a specific embodiment, the first powdered filler is added to the container of the fluidized bed equipment, and granulation is carried out using a suspension of water, binder and active ingredient, wherein the % w / w of the filler to the suspension is about 50% w / w, particularly between 30 and 70% w / w, such as between 40 and 60% w / w.

[0036] In various embodiments of the present invention, the particles have an average particle size in the range of 100 microns to 400 microns.

[0037] According to various embodiments of the present invention, the microtablets 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.

[0038] In various embodiments of the present invention, the microtablets comprise 15 - 35% w / w active pharmaceutical ingredient, 1 - 5% w / w binder, 25 - 50% w / w first filler; 20 - 40% w / w second filler, 1 - 5% w / w disintegrant and 0.5 - 5% w / w lubricant.

[0039] In various embodiments of the present invention, the binder is selected from the list comprising: hydroxypropyl methylcellulose, gum arabic, alginic acid, carbomer, calcium carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), magnesium aluminum silicate, maltodextrin, methyl cellulose, polydextrose, polyethylene oxide, polyvinylpyrrolidone, copovidone, sodium alginate, starch paste, pregelatinized starch, sucrose (syrup) and mixtures thereof. According to a particular embodiment, the binder is hydroxypropyl methylcellulose.

[0040] In a particular embodiment, the suspension containing water and binder has a % w / w of about 4% w / w, such as between 1 and 10% w / w, between 2 and 8% w / w, particularly between 3 and 6% w / w.

[0041] In various embodiments of the present invention, the first filler is selected from the list comprising: microcrystalline cellulose, calcium carbonate, calcium hydrogen phosphate, tricalcium phosphate, calcium sulfate, cellulose, microcrystalline cellulose, siliconized microcrystalline cellulose, powdered cellulose, glucose binder, 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. In a preferred embodiment, the first filler is a powdered filler.

[0042] In various embodiments of the present invention, the second filler is selected from the list comprising: microcrystalline cellulose, calcium carbonate, dibasic calcium phosphate, tricalcium phosphate, calcium sulfate, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, glucose binder, 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 second filler is microcrystalline cellulose. In a preferred embodiment, the second filler is a powdered filler.

[0043] In a specific embodiment, after the first granulation step, a pre - blend is prepared by blending the second filler, the disintegrant, and the granules obtained in the first granulation step at a ratio of about 10 / 1 / 20, particularly about 9.6 / 0.9 / 18.9. After this blending step, a lubricant can be added.

[0044] In various embodiments of the present invention, the disintegrant is selected from the list comprising: sodium carboxymethylcellulose cross - linked (croscarmellose sodium), polyvinylpyrrolidone cross - linked (cross - linked povidone), sodium starch glycolate, calcium alginate, calcium sodium alginate, calcium carboxymethylcellulose, calcium glycolate cellulose, cross - linked calcium carboxymethylcellulose (carmellosumcalcium), microcrystalline cellulose, powdered cellulose, chitosan hydrochloride, corn starch, pregelatinized starch, and mixtures thereof. According to a particular embodiment, the disintegrant is croscarmellose sodium.

[0045] In various embodiments of the present 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.

[0046] According to another aspect, the present invention provides micro - tablets obtainable by the method.

[0047] According to a particular embodiment of the present invention, the micro - tablets comprise galantamine or a pharmaceutically acceptable salt thereof, hydroxypropylmethylcellulose, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

[0048] According to a particular embodiment of the present invention, the micro - tablets comprise 15 - 35% w / w galantamine or a pharmaceutically acceptable salt thereof, 1 - 5% w / w hydroxypropylmethylcellulose, 50 - 87.5% w / w microcrystalline cellulose, 1 - 5% w / w croscarmellose sodium, and 0.5 - 5% w / w magnesium stearate.

[0049] According to yet another aspect, the present invention provides a microtablet comprising 15-35% w / w galantamine or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient, 1-5% w / w binder, 25-50% w / w first filler; 20-40% w / w second filler, 1-5% w / w disintegrant and 0.5-5% w / w lubricant.

[0050] The microtablets obtained using the method as defined herein have been shown to have a very rapid release profile, wherein approximately 100% of the active ingredient is released within a period of only about 10 min, as shown in the Examples section.

[0051] According to yet another aspect, the present invention provides a pharmaceutical composition comprising the microtablets according to different aspects and embodiments of the present invention. Such pharmaceutical compositions can be prepared and formulated by methods known in the art and can take various forms depending on the desired formulation for administration. These pharmaceutical compositions are desirably in unit dosage forms suitable for preferably systemic administration, such as oral, transdermal or parenteral administration.

[0052] For example, the microtablets can be formulated with common excipients, diluents or carriers and formed into oral tablets, capsules, sprays, mouthwashes, oral liquids (such as suspensions, solutions, emulsions), powders or any other suitable dosage forms.

[0053] According to one embodiment of the present invention, the pharmaceutical composition can be used alone or as a pharmaceutical combination with another agent for the prevention, stabilization and / or reduction of age-related diseases, degenerative dysfunctions and / or degenerative diseases. According to one embodiment of the present invention, the pharmaceutical composition can be used alone or as a pharmaceutical combination with another agent for improving measures of lifespan and / or healthspan. According to a particular embodiment, the pharmaceutical composition comprises a biguanide compound, and / or its N-oxide, hydrate, pharmaceutically acceptable salt or solvate as another agent. According to a more particular embodiment, the pharmaceutical composition comprises metformin as another agent. Examples

[0054] Materials

[0055] Galantamine.HBr (Gal.HBr) was purchased from Fagron. Croscarmellose sodium (Ac-di-sol SD-711) and microcrystalline cellulose ( PH102) were purchased from FMC Health and Nutrition. Magnesium stearate (Ligamed MF-2-V) was purchased from IMCD Benelux. Colloidal hydrated silica ( 244FP) was purchased from Grace Davison. Hydroxypropyl methylcellulose (HPMC E5) was purchased from Colorcon.

[0056] Methods

[0057] Bulk density and tapped density

[0058] The bulk density and tapped density of the powder were determined using a Tap Density Tester TD1 (Sotax, Allschwil, Switzerland) equipped with a 25 mL graduated cylinder (readable to 0.5 mL). The tapping height and frequency were set to 3 mm and 250 times / min. Approximately 25 mL of the material was poured into the 25 mL graduated cylinder. The bulk density (ρB) was calculated using the powder weight and the exact volume. Subsequently, the sample was subjected to 10, 500, and 1250 taps, and the corresponding volumes V10, V500, and V1250 were determined to the nearest graduation unit. If the difference between V500 and V1250 was less than or equal to 2 mL, V1250 was retained as the tapped volume. When 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. Then the tapped density (ρT) was determined using the volume reading. Finally, the Hausner ratio (HR) and the compression index (CI) were calculated and used as measures of powder flowability:

[0059]

[0060] Dimensions

[0061] The diameter and height of the microtablets (n = 20 per batch) were recorded immediately after tableting using a digital caliper (Mahr, Germany).

[0062] Weight

[0063] The individual weights of 30 microtablets (per batch) were recorded using an analytical grade 5d balance (Sartorius ME235P, Germany).

[0064] Hardness test

[0065] The radial fracture force of the microtablets (n = 6 per batch) was measured using a pharmaceutical tablet hardness tester (Sotax HT10, Basel, Switzerland).

[0066] Disintegration test

[0067] The disintegration time of the microtablets (n = 3 per batch) was determined using a Ph.Eur. disintegration apparatus (Sotax DT2, Basel, Switzerland). Considering the small diameter of the microtablets, the sieve opening size was reduced to 1.4 × 1.4 mm. All tests were carried out using a disk in elixTM water at a temperature of 37 ± 0.5 °C.

[0068] Friability measurement

[0069] The friability of the microtablets was determined using a friabilator apparatus (Sotax FT2, Basel, Switzerland), set to run at 25 rpm for 4 min, by subjecting approximately 6.5 g of microtablets (according to Ph.Eur. standards). The percentage weight loss was expressed as tablet friability.

[0070] Assay test

[0071] Galantamine was quantified by ultra - performance liquid chromatography - UPLC (Ph Eur 2.2.29) using UV absorption measurement at 230 nm. This evaluation was based on peak area measurement and the external standard method with relative response.

[0072] Particle size distribution

[0073] The particle size distribution was performed by sieving particles with different mesh sizes using a RETSCH - type sieve shaker and weighing the different fractions.

[0074] Example 1 - Granulation (Wet Addition)

[0075] Phase 1 - Suspension

[0076] The suspension was prepared in two steps. In the first step, a 4% w / w binder solution was prepared by stirring Methocel E5 Premium LV and purified water for approximately 45 min. In the second step, Gal.HBr (approx. 167 g) was added to the binder solution (approx. 550 g), then stirred for approximately 15 min using a high - speed mixer (SilversonTM L4R, Silverson Machines, Waterside, Chesham, Bucks, UK), and finally degassed for approximately 120 min using an overhead stirrer.

[0077] Phase 2 - Granulation

[0078] Weigh Avicel PH102 (about 333 g) and introduce it into a suitable product container of a fluidized bed device (Oystar Hüttlin Mycrolab). Granulate with the suspension prepared in the previous stage (about 702 g) according to the parameters listed in Table 1 to obtain white and uniform granules with a yield of 90%. Figure 1 B illustrates the wet addition method for granulation.

[0079] Table 1. Granulation parameters

[0080]

[0081] The composition data of the obtained suspension and granules are provided in Table 2.

[0082] Table 2. Composition data of the suspension and granules according to Example 1

[0083]

[0084] The analysis data of the obtained granules are provided in Table 3.

[0085] Table 3. Analysis data of the granules according to Example 1

[0086]

[0087] Table 4 and Figure 2 provide the particle size distribution of the obtained granules.

[0088] Table 4. Particle size distribution of the granules according to Example 1

[0089] Sieve Size (μm) Retained Particles (%) 710 0.00 500 0.70 355 10.69 250 33.99 180 24.36 125 15.07 90 6.30 Bottom 8.89 Total 100.00

[0090] Observation Results : The galantamine HBr granules successfully passed the powder property test, and the galantamine content determination values were good (i.e., 92.86, 95.12, 92.75%). This is attributed to the larger particle size (distribution) and the reduced loss of fine galantamine HBr powder in the filter of the fluidized bed device. Therefore, after the content determination - purity measurement of the material collected from the fluidized bed filter, the content determination values of 103.50, 100.96, 103.07% were obtained.

[0091] Stage 3 - Premix

[0092] Prepare the premix by weighing (and sieving on 600 μm) Avicel PH102 (about 9.6 g), Ac - Di - Sol (about 0.9 g) and the granules prepared in the previous stage (about 18.9 g), introducing them into a suitable container, and blending for about 10 min using a Turbula mixer model T2F (WAB, Switzerland).

[0093] Stage 4 - Blend

[0094] The blend was prepared by weighing and sieving magnesium stearate MF2V (approx. 0.9 g) on a 600 μm sieve, introducing it into a container containing the pre - blend and further blending for about 5 min to obtain a white, homogeneous blend.

[0095] The composition data of the obtained blend are provided in Table 5.

[0096] Table 5. Composition data of the pre - blend and blend according to Example 1

[0097]

[0098] The analysis data of the obtained blend are provided in Table 6.

[0099] Table 6. Analysis data of the blend according to Example 1

[0100] Bulk Density (g / ml) 0.36 Tap Density (g / ml) 0.47 Compression Index (%) 22 Hausner Ratio 1.28 LOD (%) 4.18

[0101] Stage 5 - Tabletting

[0102] The tabletting step was carried out on an eccentric tabletting machine (Korsch XP1, Korsch AG, Berlin, Germany) equipped with 8 D2 mm punches. Tabletting parameters: average pressing force: 5.5 - 6.5 kN.

[0103] The analysis data of the obtained tablets are provided in Table 7.

[0104] Table 7. Analysis data of the tablets according to Example 1

[0105] Appearance White Round Brightened Tablets Friability (n = 20) 0.000％ Hardness (n = 6, Mean ± SD (Standard Deviation)) 26±4N Height (n = 20, Mean ± SD) 1.99 ± 0.04 mm Mass (n = 20, Mean ± SD) 7.05 ± 0.21 mg Disintegration Time (n = 3, Mean ± SD) 153 ± 4 sec

[0106] Observation Results : The obtained micro - tablets have high abrasion resistance. Therefore, the friability of the micro - tablets is much lower than 1.0 (Ph.Eur. tablet standard). In addition to the low friability value, the height of the micro - tablets is similar to the diameter of the tablets (i.e., 2.0 mm), which results in an aspect ratio of approximately 1. Moreover, the disintegration time of the micro - tablets is much lower than 15 minutes.

[0107] Stage 6 - Dissolution test

[0108] The micro - tablets were filled into capsules (dose strength equal to 12 mg) and an in vitro dissolution test was carried out using phosphate buffer at pH 6.8.

[0109] Observation Results : As Figure 3 shown, rapid - release kinetics were observed.

[0110] Example 2 - Granulation (Wet Addition)

[0111] Stage 1 - Suspension

[0112] A suspension was prepared according to Example 1 by adding Gal.HBr (about 67 g) to a 4% w / w binder solution (about 219.50 g).

[0113] Stage 2 - Granulation

[0114] Avicel PH102 (about 133 g) was weighed and introduced into a suitable container. Granulation was carried out with the suspension (about 274 g) prepared in the previous stage according to Example 1.

[0115] Table 8 provides the compositional data of the obtained suspension and granules.

[0116] Table 8. Compositional data of the suspension and granules according to Example 2

[0117]

[0118] Table 9 provides the analytical data of the obtained granules.

[0119] Table 9. Analytical data of the granules according to Example 2

[0120]

[0121] Observation Results : The galantamine HBr granules successfully passed the powder property tests, and the galantamine assay values were acceptable (i.e., 78.83, 79.30, 80.93%).

[0122] Comparative Example 3 - Direct Compression

[0123] Stage 1 - Premix

[0124] By weighing (and sieving on 600 μm) 244FP (about 2 g) and Gal.HBr (about 98 g), and then blending for about 10 min using a Turbula T2A mixer to prepare the premix.

[0125] Stage 2 - Blend

[0126] By weighing (and sieving on 600 μm) Avicel PH102 (about 25.5 g), the pre - blend (about 3 g), Ac - di - sol (about 0.9 g) and Ligamed MF - 2 - V (about 0.6 g), and then introducing them into a suitable container in the following order: 1 / 2 Avicel PH102, Ac - di - sol, pre - blend, 1 / 2 Avicel PH102, blending with a Turbula T2A mixer for about 10 min, adding Ligamed MF - 2 - V to the container, and finally blending for about 5 min to prepare the blend.

[0127] Table 10 provides the composition data of the obtained blends.

[0128] Table 10. Composition data of the pre - blend and blends according to Comparative Example 3

[0129]

[0130] Table 11 provides the analysis data of the obtained blends.

[0131] Table 11. Analysis data of the blends of Comparative Example 3

[0132] Hausner Ratio 1.28

[0133] Stage 3 - Tabletting

[0134] The tabletting step was carried out on an eccentric tabletting machine (Korsch XP1, Korsch AG, Berlin, Germany) equipped with 8 D2 mm punches. Tabletting parameters: average compaction force: 5.5 - 6.5 kN.

[0135] Observation Results : Poor powder flowability (attributed to a Hausner ratio of 1.28), rat - holing of the powder bed in the hopper and thus uneven die cavity filling.

[0136] Comparative Example 4 - Direct Compression

[0137] Stage 2 - Blend

[0138] By weighing (and sieving on 600 μm) Avicel PH102 (about 26.4 g), the pre - blend of Comparative Example 1 (about 1.5 g), Ac - di - sol (about 0.9 g), Ligamed MF - 2 - V (about 0.6 g) and 244FP (about 0.6 g), and then introducing them into a suitable container in the following order: 1 / 2 Avicel PH102, Ac - di - sol, pre - blend, 244FP, 1 / 2 Avicel PH102, were blended for about 10 min using a Turbula T2A blender. Ligamed MF-2-V was added to the container and finally blended for about 5 min to prepare the blend.

[0139] Table 12 provides the compositional data of the obtained blends.

[0140] Table 12. Compositional data of the premixes and blends according to Comparative Example 4

[0141]

[0142] Table 13 provides the analytical data of the obtained blends.

[0143] Table 13. Analytical data of the granules according to Comparative Example 4

[0144] Compression Index (%) 23.69 Hausner Ratio 1.31

[0145] Stage 3 - Tabletting

[0146] The tabletting step was carried out on an eccentric tabletting machine (Korsch XP1, Korsch AG, Berlin, Germany) equipped with 8 D2 mm punches. Tabletting parameters: average compaction force: 5.5 - 6.5 kN.

[0147] Observation Results : Qualified powder flowability based on loose / tap density measurements (attributed to a Hausner ratio of 1.31 and a compression index of 23.69), however, rat holing of the powder bed in the hopper and thus uneven die cavity filling still occurred.

[0148] Comparative Example 5 - Granulation (Dry Addition)

[0149] Stage 2 - Granulation

[0150] The dry blend of Gal.HBr (about 67 g) and Avicel PH102 (about 33 g) was weighed and introduced into a suitable product container of a fluidized bed device (Oystar Hüttlin Mycrolab). Granulation was carried out with a 4% w / w binder solution (about 107.7 g) (see Example 1) and sieved at 500 μm to obtain white, uniform granules with a yield of 66%. Figure 1 A illustrates the dry addition method for granulation. Table 14 provides the compositional data of the obtained suspensions and granules.

[0151] Table 14. Compositional data of the granules according to Comparative Example 5

[0152]

[0153] Table 15 provides the analysis data of the obtained particles.

[0154] Table 15. Analysis data of the particles of Comparative Example 5

[0155]

[0156] Observation Results : Although the galantamine HBr particles successfully passed the powder property test, the determined galantamine content was low (i.e., 56.85; 57.52 and 55.01%).

[0157] Comparative Example 6 - Granulation (Dry Addition)

[0158] Phase 2 - Granulation

[0159] Weigh the dry blend of Gal.HBr (about 133 g) and Avicel PH102 (about 67 g) and introduce it into a suitable product container of a fluidized bed equipment (Oystar Hüttlin Mycrolab). Granulation was carried out with a 4% w / w binder solution (about 219.2 g) (see Example 1), and sieved at 500 μm to obtain white, uniform particles with a yield of 80%.

[0160] Table 16 provides the composition data of the obtained suspension and particles.

[0161] Table 16. Composition data of the particles according to Comparative Example 6

[0162]

[0163] Table 17 provides the analysis data of the obtained particles.

[0164] Table 17. Analysis data of the particles of Comparative Example 6

[0165]

[0166] Observation Results : Although the galantamine HBr particles successfully passed the powder property test, the determined galantamine content was still low (i.e., 70.16; 70.53 and 71.62%).

Claims

1. A method for preparing an orally administrable immediate-release pharmaceutical composition, said immediate-release pharmaceutical composition comprising galantamine or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient, said method comprising the following steps: (1) preparing a dispersion / solution comprising water and a binder; (2) adding the active pharmaceutical ingredient in dry powder form 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 powdered 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) tabletting the granules formed in step (6), thereby forming microtablets.

2. The method according to claim 1, wherein the granules have an average particle size in the range of 100 to 400 microns.

3. The method according to any one of claims 1 to 2, wherein the microtablets 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.

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

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. 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, calcium carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropyl methylcellulose (hypromellose), magnesium aluminum silicate, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, polyvinylpyrrolidone, copovidone, sodium alginate, starch paste, pregelatinized starch, sucrose (syrup), and blends thereof; preferably wherein the binder is hydroxypropyl methylcellulose.

7. The method according to 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 hydrogen phosphate, tricalcium phosphate, calcium sulfate, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, glucose binder, dextrose, fructose, lactitol, lactose monohydrate, magnesium carbonate, maltitol, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, xylitol; preferably wherein the first filler and / or the second filler is microcrystalline cellulose.

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

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 oil, magnesium lauryl sulfate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, starch, stearic acid, talc, zinc stearate, and mixtures thereof; preferably wherein the lubricant is magnesium stearate.

10. A microtablet obtainable by the method according to any one of claims 1 to 9.

11. A microtablet comprising 15 - 35% w / w galantamine or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient, 1 - 5% w / w binder, 25 - 50% w / w first filler, 20 - 40% w / w second filler, 1 - 5% w / w disintegrant, and 0.5 - 5% w / w lubricant.

12. The microtablet according to claim 11, having 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.

13. The microtablet according to any one of claims 11 to 12, wherein the binder is selected from the list comprising: hydroxypropyl methylcellulose, gum arabic, alginic acid, carbomer, calcium carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropyl methylcellulose (hypromellose), magnesium aluminum silicate, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, polyvinylpyrrolidone, copovidone, sodium alginate, starch paste, pregelatinized starch, sucrose (syrup), and mixtures thereof; preferably wherein the binder is hydroxypropyl methylcellulose.

14. The microtablet according to any one of claims 10 to 13, wherein the first filler and the second filler are each independently selected from the list consisting of: microcrystalline cellulose, calcium carbonate, calcium hydrogen phosphate, tricalcium phosphate, calcium sulfate, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, glucose binder, dextrose, fructose, lactitol, lactose monohydrate, magnesium carbonate, maltitol, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, xylitol; preferably wherein the first filler and / or the second filler is microcrystalline cellulose.

15. A pharmaceutical composition comprising the microtablet according to any one of claims 10 to 14.

Images