Preparation method of galanthamine hydrobromide capsule

Abstract

The invention relates to a preparation method of a galanthamine hydrobromide capsule. The capsule prepared by the method is good in particle roundness and uniform in particle size, the drug loading capacity, the yield and the dissolution rate are greatly improved, and the cost is saved. The method is simple in process, easy to operate, good in reproducibility and suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, and in particular to a method for preparing galantamine hydrobromide capsules. Background Technology

[0002] Galantamine hydrobromide is a phenanthridine alkaloid derived from plants of the genus *Lycoris*, its structure shown in (II). It is a selective, reversible, and competitive inhibitor of acetylcholinesterase, competitively binding to cholinesterase in the synaptic cleft to reduce acetylcholine degradation and thus maintain or increase the level of cholinergic neurotransmitters within the synaptic cleft. Galantamine is also a regulator of N-type acetylcholine receptors, increasing the release of acetylcholine from cholinergic terminals by binding to nicotinic-like acetylcholine receptors (nAChRs). It exhibits a dual mechanism of action in regulating acetylcholine concentration in the brain. Its hydrobromide form was approved by the US FDA in 2001 for improving cognitive impairments such as memory and learning, and for slowing the progression of brain cell function decline; it is one of the important drugs for treating early or mid-stage Alzheimer's disease.

[0003] Galantamine preparations are available in ordinary tablets and capsules. Due to their short biological half-life, they are eliminated from the body quickly after oral administration, resulting in a short duration of effective blood drug concentration. They need to be taken more frequently, which causes many inconveniences for patients. In addition, the frequent use often leads to large fluctuations in the blood drug concentration. Summary of the Invention

[0004] The purpose of this invention is to provide a method for preparing galantamine hydrobromide capsules, the method comprising the following steps:

[0005] 1) Preparation of pellet cores: Mix hydrobromic acid galantamine, diluent, binder, flow aid and lubricant, sieve and mix, add purified water, mix, granulate and dry to make pellet cores;

[0006] 2) Prepare coating solution 1 by mixing PEG6000, disodium hydrogen phosphate and 12% hydroxypropyl methylcellulose;

[0007] 3) The pellet cores prepared in step 1) are placed in a fluidized bed and coated with the coating solution 1 prepared in step 2) to produce coated pellet cores 1;

[0008] 4) Prepare coating solution 2 by mixing PEG6000, talc and 15% Eudragit L30D-55 solution;

[0009] 5) Place the coated pellet core 1 obtained in step 3) into a fluidized bed and use the coating solution 2 obtained in step 4) to coat it to make coated pellet core 2;

[0010] 6) The coated pellet core 2 prepared in step 5) is filled into an empty capsule to obtain the final product.

[0011] Preferably, the diluent is selected from dicalcium phosphate, calcium silicate, calcium carbonate, lactose, mannitol, sucrose, starch, or mixtures thereof; preferably, it is a mixture of sucrose and starch.

[0012] Preferably, the adhesive is selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, starch, povidone, copovidone, microcrystalline cellulose, pregelatinized starch, or mixtures thereof; preferably from microcrystalline cellulose.

[0013] Preferably, the flow aid is selected from talc, sodium dodecyl sulfate, colloidal silica, or magnesium trisilicate; more preferably from colloidal silica.

[0014] Preferably, the lubricant is selected from sodium stearoyl fumarate, magnesium stearate, calcium stearate, hydrogenated vegetable oil, stearic acid, glyceryl behenate, talc, or a mixture thereof; preferably magnesium stearate.

[0015] Preferably, in step 1), the mass ratio of galantamine hydrobromide, diluent, adhesive, flow aid, and lubricant is 1:(2-10):(0.5-5):(0.01-0.05):(0.01-0.05).

[0016] Preferably, in step 2), the mass ratio of PEG6000 to disodium hydrogen phosphate is 1:(0.5-1).

[0017] Preferably, in step 4), the mass ratio of PEG6000 to talc is 1:(1-5).

[0018] Another object of the present invention is to provide galantamine hydrobromide capsules prepared by the above method.

[0019] Another object of the present invention is to provide the use of galantamine hydrobromide capsules obtained by the above method or the above capsules in acetylcholinesterase inhibitors.

[0020] The effects of the invention

[0021] The method provided by this invention yields capsules with good sphericity, uniform particle size, and significantly improved drug loading, yield, and dissolution, while saving costs. This method is simple, readily operable, and highly reproducible, making it suitable for industrial production. Detailed Implementation

[0022] To make the technical solution and beneficial effects of the present invention more apparent and understandable, a detailed description is provided below by listing specific embodiments. Unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application pertains.

[0023] The purpose of this invention is to provide a method for preparing galantamine hydrobromide capsules, the method comprising the following steps:

[0024] 1) Preparation of pellet cores: Mix hydrobromic acid galantamine, diluent, binder, flow aid and lubricant, sieve and mix, add purified water, mix, granulate and dry to make pellet cores;

[0025] 2) Prepare coating solution 1 by mixing PEG6000, disodium hydrogen phosphate and 12% hydroxypropyl methylcellulose;

[0026] 3) The pellet cores prepared in step 1) are placed in a fluidized bed and coated with the coating solution 1 prepared in step 2) to produce coated pellet cores 1;

[0027] 4) Prepare coating solution 2 by mixing PEG6000, talc and 15% Eudragit L30D-55 solution;

[0028] 5) Place the coated pellet core 1 obtained in step 3) into a fluidized bed and use the coating solution 2 obtained in step 4) to coat it to make coated pellet core 2;

[0029] 6) The coated pellet core 2 prepared in step 5) is filled into an empty capsule to obtain the final product.

[0030] In some embodiments, the diluent is selected from dicalcium phosphate, calcium silicate, calcium carbonate, lactose, mannitol, sucrose, starch, or mixtures thereof.

[0031] In some embodiments, the diluent is selected from a mixture of sucrose and starch.

[0032] In some embodiments, the adhesive is selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, starch, povidone, copovidone, microcrystalline cellulose, pregelatinized starch, or mixtures thereof.

[0033] In some embodiments, the adhesive is selected from microcrystalline cellulose.

[0034] In some embodiments, the flow aid is selected from talc, sodium dodecyl sulfate, colloidal silica, or magnesium trisilicate.

[0035] In some embodiments, the flow aid is selected from colloidal silica.

[0036] In some embodiments, the lubricant is selected from sodium stearoyl fumarate, magnesium stearate, calcium stearate, hydrogenated vegetable oil, stearic acid, glyceryl behenate, talc, or mixtures thereof.

[0037] In some embodiments, the lubricant is selected from magnesium stearate.

[0038] In some embodiments, the mass ratio of galantamine hydrobromide, diluent, adhesive, flow aid, and lubricant in step 1) is 1:(2-10):(0.5-5):(0.01-0.05):(0.01-0.05).

[0039] In some embodiments, the mass ratio of galantamine hydrobromide, diluent, binder, flow aid, and lubricant in step 1) is 1:(2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4... 4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8 9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0):(0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2. 8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0):(0.01, 0.02, 0.03, 0.04, 0.05):(0.01, 0.02, 0.03, 0.04, 0.05).

[0040] In some embodiments, the mass ratio of PEG6000 to disodium hydrogen phosphate in step 2) is 1:(0.5-1).

[0041] In some embodiments, the mass ratio of PEG6000 to disodium hydrogen phosphate in step 2) is 1:(0.5, 0.6, 0.7, 0.8, 0.9, 1).

[0042] In some embodiments, the mass ratio of PEG6000 to talc in step 4) is 1:(1-5).

[0043] In some embodiments, the mass ratio of PEG6000 to talc in step 4) is 1:(10, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4. 9, 5.0):(0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0).

[0044] Another object of the present invention is to provide galantamine hydrobromide capsules prepared by the above method.

[0045] Another object of the present invention is to provide the use of galantamine hydrobromide capsules obtained by the above method or the above capsules in acetylcholinesterase inhibitors.

[0046] In the following examples, unless otherwise specified, all temperatures are in Celsius; unless otherwise specified, all starting materials and reagents are commercially available or synthesized according to known methods; commercially available materials and reagents are used directly without further purification; unless otherwise specified, commercially available manufacturers include, but are not limited to, Sinopharm Group, Bailingwei Technology Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Shanghai BIDE Pharmaceutical Technology Co., Ltd., and Shanghai Mairui Chemical Technology Co., Ltd.

[0047] Example 1

[0048]

[0049] Preparation method:

[0050] 1) Preparation of pellet cores: Mix hydrobromic acid galantamine, diluent, binder, flow aid and lubricant, sieve and mix, add purified water and mix, granulate through a 20-mesh sieve and dry at 50℃ to make pellet cores;

[0051] 2) Prepare coating solution 1 by mixing PEG6000, disodium hydrogen phosphate and 12% hydroxypropyl methylcellulose;

[0052] 3) The pellet cores prepared in step 1) are placed in a fluidized bed and coated with the coating liquid 1 prepared in step 2) to form coated pellet cores 1. The parameters of the fluidized bed are: air inlet temperature 55℃, material temperature 35℃, air volume 12-15Hz, atomizing air pressure 0.15-0.25MPa, nozzle inner diameter 0.8mm, and spraying speed 4-10g / min.

[0053] 4) Prepare coating solution 2 by mixing PEG6000, talc and 15% Eudragit L30D-55 solution;

[0054] 5) Place the coated pellet core 1 obtained in step 3) into a fluidized bed and coat it with the coating liquid 2 obtained in step 4) to form coated pellet core 2; the parameters of the fluidized bed are: air inlet temperature 55℃, material temperature 35℃, air volume 12-15Hz, atomizing air pressure 0.15-0.25MPa, nozzle inner diameter 0.8mm, and spraying speed 1-5g / min.

[0055] 6) The coated pellet core 2 prepared in step 5) is filled into an empty capsule to obtain the final product.

[0056] Example 2

[0057]

[0058] Preparation method:

[0059] 1) Preparation of pellet cores: Mix hydrobromic acid galantamine, diluent, binder, flow aid and lubricant, sieve and mix, add purified water and mix, granulate through a 20-mesh sieve and dry at 50℃ to make pellet cores;

[0060] 2) Prepare coating solution 1 by mixing PEG6000, disodium hydrogen phosphate and 12% hydroxypropyl methylcellulose;

[0061] 3) The pellet cores prepared in step 1) are placed in a fluidized bed and coated with the coating liquid 1 prepared in step 2) to form coated pellet cores 1. The parameters of the fluidized bed are: air inlet temperature 55℃, material temperature 35℃, air volume 12-15Hz, atomizing air pressure 0.15-0.25MPa, nozzle inner diameter 0.8mm, and spraying speed 4-10g / min.

[0062] 4) Prepare coating solution 2 by mixing PEG6000, talc and 15% Eudragit L30D-55 solution;

[0063] 5) Place the coated pellet core 1 obtained in step 3) into a fluidized bed and coat it with the coating liquid 2 obtained in step 4) to form coated pellet core 2; the parameters of the fluidized bed are: air inlet temperature 55℃, material temperature 35℃, air volume 12-15Hz, atomizing air pressure 0.15-0.25MPa, nozzle inner diameter 0.8mm, and spraying speed 1-5g / min.

[0064] 6) The coated pellet core 2 prepared in step 5) is filled into an empty capsule to obtain the final product.

[0065] Example 3

[0066]

[0067]

[0068] Preparation method:

[0069] 1) Preparation of pellet cores: Mix hydrobromic acid galantamine, diluent, binder, flow aid and lubricant, sieve and mix, add purified water and mix, granulate through a 20-mesh sieve and dry at 50℃ to make pellet cores;

[0070] 2) Prepare coating solution 1 by mixing PEG6000, disodium hydrogen phosphate and 12% hydroxypropyl methylcellulose;

[0071] 3) The pellet cores prepared in step 1) are placed in a fluidized bed and coated with the coating liquid 1 prepared in step 2) to form coated pellet cores 1. The parameters of the fluidized bed are: air inlet temperature 55℃, material temperature 35℃, air volume 12-15Hz, atomizing air pressure 0.15-0.25MPa, nozzle inner diameter 0.8mm, and spraying speed 4-10g / min.

[0072] 4) Prepare coating solution 2 by mixing PEG6000, talc and 15% Eudragit L30D-55 solution;

[0073] 5) Place the coated pellet core 1 obtained in step 3) into a fluidized bed and coat it with the coating liquid 2 obtained in step 4) to form coated pellet core 2; the parameters of the fluidized bed are: air inlet temperature 55℃, material temperature 35℃, air volume 12-15Hz, atomizing air pressure 0.15-0.25MPa, nozzle inner diameter 0.8mm, and spraying speed 1-5g / min.

[0074] 6) The coated pellet core 2 prepared in step 5) is filled into an empty capsule to obtain the final product.

[0075] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations included in the claims. Various modifications and changes can be made to the above embodiments without departing from the scope of this disclosure. Similarly, the various technical features of the above embodiments can be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only illustrate several implementations of the present invention and do not limit the scope of protection of this patent.

Claims

1. A method for preparing galantamine hydrobromide capsules, characterized in that, The method includes the following steps: 1) Preparation of pellet cores: Mix hydrobromic acid galantamine, diluent, binder, flow aid and lubricant, sieve and mix, add purified water, mix, granulate and dry to make pellet cores; 2) Prepare coating solution 1 by mixing PEG6000, disodium hydrogen phosphate and 12% hydroxypropyl methylcellulose; 3) The pellet cores prepared in step 1) are placed in a fluidized bed and coated with the coating solution 1 prepared in step 2) to produce coated pellet cores 1; 4) Prepare coating solution 2 by mixing PEG6000, talc and 15% Eudragit L30D-55 solution; 5) Place the coated pellet core 1 obtained in step 3) into a fluidized bed and use the coating solution 2 obtained in step 4) to coat it to make coated pellet core 2; 6) The coated pellet core 2 prepared in step 5) is filled into an empty capsule to obtain the final product.

2. The method according to claim 1, characterized in that, The diluent is selected from dicalcium phosphate, calcium silicate, calcium carbonate, lactose, mannitol, sucrose, starch, or mixtures thereof; preferably a mixture of sucrose and starch.

3. The method according to any one of claims 1-2, characterized in that, The adhesive is selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, starch, povidone, copovidone, microcrystalline cellulose, pregelatinized starch, or mixtures thereof; preferably microcrystalline cellulose.

4. The method according to any one of claims 1-3, characterized in that, The flow aid is selected from talc, sodium dodecyl sulfate, colloidal silica, or magnesium trisilicate; preferably from colloidal silica.

5. The method according to any one of claims 1-4, characterized in that, The lubricant is selected from sodium stearoyl fumarate, magnesium stearate, calcium stearate, hydrogenated vegetable oil, stearic acid, glyceryl behenate, talc, or a mixture thereof; preferably magnesium stearate.

6. The method according to any one of claims 1-5, characterized in that, In step 1), the mass ratio of galantamine hydrobromide, diluent, adhesive, flow aid, and lubricant is 1:(2-10):(0.5-5):(0.01-0.05):(0.01-0.05).

7. The method according to any one of claims 1-6, characterized in that, In step 2), the mass ratio of PEG6000 to disodium hydrogen phosphate is 1:(0.5-1).

8. The method according to any one of claims 1-7, characterized in that, In step 4), the mass ratio of PEG6000 to talc is 1:(1-5).

9. Galantamine hydrobromide capsules prepared by the method according to any one of claims 1-8.

10. The use of the hydrobromide galantamine capsule prepared by the method according to any one of claims 1-8 or the capsule according to claim 9 in the field of acetylcholinesterase inhibitors.

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