4-aminopyridine sustained release preparation and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a 4-aminopyridine sustained release preparation and a preparation method thereof. The sustained release preparation comprises 4-aminopyridine, ethyl-beta cyclodextrin-calcium carbonate microspheres, a filler, an adhesive, a disintegrating agent and a lubricant. According to the sustained-release preparation, the sustained-release time can be prolonged, the medicine taking frequency is reduced, the content uniformity of the preparation is improved, meanwhile, the preparation process is improved, and stimulation to operators, environment control in a production workshop and equipment cost are reduced.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a 4-aminopyridine sustained-release preparation and a preparation method thereof. Background Art

[0002] Multiple sclerosis (MS) is a chronic inflammatory demyelinating, chronically disabling autoimmune disease of the central nervous system. Multiple sclerosis primarily affects the spinal cord, brain, brainstem, cerebellum, and optic nerves. Clinical manifestations include progressive difficulty walking, fatigue, loss of body coordination, decreased vision and memory, and accompanied by heat sensitivity.

[0003] 4-Aminopyridine (Dalfampridine, 4-AP) is a broad-spectrum cell membrane potassium channel blocker. By inhibiting potassium channels and reducing ion current outflow, it improves the propagation of action potentials in demyelinated axons and overcomes the conduction disorders of demyelinated neurons. It is mainly used to treat multiple sclerosis, Alzheimer's disease, and myasthenia gravis. This product's sustained-release tablets were launched in the United States on January 24, 2010, and were subsequently approved for marketing in the European Union and other countries. It was launched in China on May 11, 2021. The recommended dose is 10 mg twice daily, taken orally, 12 hours apart (one tablet in the morning and one in the evening).

[0004] 4-Aminopyridine is a white to pale yellow needle-shaped crystal, soluble in water, ether, and benzene, easily soluble in ethanol, and easily hygroscopic.

[0005] US5370879A discloses a pharmaceutical formulation containing a mono- or di-aminopyridine active agent. 4-AP, talc, and lactose are mixed, ground into a uniform powder, granulated, and coated with an isopropyl alcohol / acetone solution containing polyvinyl pyrrolidone. The organic solvent used in this process has the disadvantages of being highly toxic, volatile, flammable, and explosive, and posing a potential environmental risk.

[0006] US Patent No. 8,007,826B discloses a sustained-release aminopyridine composition. The tablet size is relatively small, at 10 mg. This places high demands on the mixing equipment and process, and is prone to poor content uniformity. The preparation process utilizes direct powder compression, requiring the API to undergo grinding, sieving, weighing, and mixing. This process is prone to dust formation. Furthermore, 4-aminopyridine powder is highly irritating to the eyes and skin, and dust generated during the preparation process can cause digestive and respiratory irritation in operators, leading to severe lung damage and even fatality from excessive inhalation. Therefore, the direct powder compression process places high demands on personnel and equipment isolation. Production workshops and laboratories require large-scale isolation systems to control dust levels and strengthen personnel protection, which also increases production costs.

[0007] CN106511293B discloses a sustained-release oral Dafang pyridine pharmaceutical preparation comprising a core and a semi-permeable membrane, having a certain delayed release effect, but the late release is not complete, and the process operation is difficult.

[0008] Therefore, it is urgent to provide a 4-aminopyridine sustained-release preparation for improving the content uniformity of the preparation and prolonging the sustained-release time, and to provide a preparation process for reducing the irritation to operators and the environmental control and equipment cost in the production workshop as much as possible. SUMMARY

[0009] In view of the deficiencies of the existing 4-aminopyridine sustained-release preparation, the present application provides a 4-aminopyridine sustained-release preparation which can prolong the sustained-release time, reduce the frequency of taking medicine, improve the content uniformity of the preparation, and improve the preparation process, reduce the irritation to operators and the environmental control and equipment cost in the production workshop.

[0010] The technical scheme of the present application is as follows:

[0011] A 4-aminopyridine sustained-release preparation comprises 4-aminopyridine, ethyl-beta cyclodextrin-calcium carbonate microspheres, a filler, a binder, a disintegrant and a lubricant.

[0012] Preferably, in the sustained-release preparation, the filler is selected from one or more of lactose, microcrystalline cellulose, mannitol or pregelatinized starch.

[0013] Preferably, in the sustained-release preparation, the binder is selected from one or more of povidone, copovidone, glyceryl behenate or methyl cellulose.

[0014] Preferably, in the sustained-release preparation, the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose or sodium carboxymethyl starch.

[0015] Preferably, in the sustained-release preparation, the lubricant is selected from one or more of sodium stearyl fumarate, polyethylene glycol, stearic acid, magnesium stearate or talc.

[0016] Preferably, in the sustained-release preparation, the components are as follows:

[0017]

[0018] Preferably, in the sustained-release preparation, the ethyl-beta cyclodextrin-calcium carbonate microspheres are diethyl-beta cyclodextrin-calcium carbonate microspheres or triethyl-beta cyclodextrin-calcium carbonate microspheres.

[0019] Preferably, the diameter of the ethyl-β-cyclodextrin-calcium carbonate microspheres in the sustained-release preparation is 100-150 nm, and the pore size is 4-8 nm. The ethyl-β-cyclodextrin-calcium carbonate microspheres can be self-made porous microspheres or commercially available products.

[0020] Preferably, the preparation method of the ethyl-β-cyclodextrin-calcium carbonate microspheres in the sustained-release preparation comprises the following steps: preparing a 20 mM potassium carbonate solution, adding the DMSO solution of ethyl-β-cyclodextrin to the potassium carbonate solution under the condition of stirring at a speed of 500 rpm, stirring until the ethyl-β-cyclodextrin-calcium carbonate mixed solution is completely dissolved, wherein the final concentration of ethyl-β-cyclodextrin is 5-10 mM; then continuing to stir, adding the obtained mixed solution to a 20 mM calcium chloride solution, and after the addition is completed, standing, centrifuging, filtering, washing the filter cake with purified water, and drying to remove the solvent to obtain the ethyl-β-cyclodextrin-calcium carbonate microspheres, wherein the diameter of the microspheres is 100-150 nm, and the pore size is 4-8 nm.

[0021] The present application also provides a preparation method of the above-mentioned 4-aminopyridine sustained-release preparation, comprising the following steps:

[0022] At room temperature, 4-aminopyridine is prepared into a saturated ethanol solution, ethyl-β-cyclodextrin-calcium carbonate microspheres are added, and the pores and surface of the microspheres are fully contacted with the active ingredient by stirring. After saturation loading, the filter cake is filtered, vacuum dried to obtain drug-loaded 4-aminopyridine microspheres; the drug-loaded microspheres are fully mixed with a filler, a binder, and a disintegrating agent, and then a lubricant is added to uniformly mix and prepare a 4-aminopyridine sustained-release preparation.

[0023] Preferably, the 4-aminopyridine sustained-release preparation is a tablet or a capsule.

[0024] Preferably, a preparation method of a 4-aminopyridine sustained-release tablet comprises the following steps:

[0025] At room temperature, 4-aminopyridine is prepared into a saturated ethanol solution, ethyl-β-cyclodextrin-calcium carbonate microspheres are added, and the pores and surface of the microspheres are fully contacted with the active ingredient by stirring. After saturation loading, the filter cake is filtered, vacuum dried to obtain drug-loaded 4-aminopyridine microspheres; the drug-loaded microspheres are fully mixed with a filler, a binder, and a disintegrating agent, and then a lubricant is added to uniformly mix and prepare a 4-aminopyridine sustained-release preparation.

[0026] Further preferably, the ethanol solution is an ethanol aqueous solution with a volume ratio of 90-95%.

[0027] Compared with the prior art, the present application has the following outstanding advantages:

[0028] 1. The sustained-release preparation of the application, using self-made ethyl-beta cyclodextrin-calcium carbonate microspheres to load 4-aminopyridine, solves the problem of uneven mixing caused by the small amount of main drug compared with the amount of auxiliary material in the preparation process, and the calcium carbonate microspheres used also solve the problem of moisture absorption of API.

[0029] 2. The sustained-release preparation of the application, the preparation process is simple and easy to operate, the main drug is prepared into a solution and simultaneously loaded on the microspheres, avoiding dust flying in the preparation process, greatly reducing the irritation of API to the operating personnel, the environmental control in the production workshop and the equipment cost.

[0030] 3. The sustained-release preparation obtained by the application has high content uniformity, good stability, relatively prolonged sustained-release time, reduces the frequency of taking medicine, and improves the compliance of patients with long-term medication. BRIEF DESCRIPTION OF DRAWINGS

[0031] Figure 1 : In-vitro release curve of the obtained preparation DETAILED DESCRIPTION

[0032] The specific embodiments listed below further illustrate the application, but in no way limit the scope of the application, and those skilled in the art can make various modifications or improvements based on the basic idea of the application, as long as they do not deviate from the basic idea of the application, which are within the scope of the application.

[0033] Example 1 Preparation of ethyl-beta cyclodextrin-calcium carbonate microspheres

[0034] Preparation of diethyl-beta cyclodextrin-calcium carbonate microspheres: prepare a 20mM potassium carbonate solution, under the condition of stirring speed 500rpm, add the DMSO solution of diethyl-beta cyclodextrin to the above potassium carbonate solution, stir until the diethyl-beta cyclodextrin-potassium carbonate mixed solution is dissolved, the final concentration of diethyl-beta cyclodextrin is 5mM; then continue to stir, and add the obtained mixed solution to a 20mM calcium chloride solution, after the addition is completed, stand for 0.5h, centrifugal filtration, wash the filter cake with purified water for three times, dry to remove the solvent and water, obtain diethyl-beta cyclodextrin-calcium carbonate microspheres, the microspheres have a diameter of 100-140nm and a pore size of 5-7nm.

[0035] Preparation of triethyl-β-cyclodextrin-CaCO3 microspheres: a 20 mM potassium carbonate solution was prepared, and a DMSO solution of triethyl-β-cyclodextrin was added to the potassium carbonate solution under stirring at a speed of 500 rpm. After the triethyl-β-cyclodextrin was completely dissolved, a 20 mM calcium chloride solution was added to the resulting mixture under stirring. After the addition was completed, the mixture was allowed to stand for 0.5 h, and then centrifuged and washed with purified water three times. The solvent and water were removed by drying to obtain triethyl-β-cyclodextrin-CaCO3 microspheres. The microspheres had a diameter of 110-150 nm and a pore size of 4-8 nm.

[0036] Example 2

[0037] 1) Formulation

[0038]

[0039] 2) Preparation process

[0040] A saturated solution of the prescription amount of 4-aminopyridine in 95% ethanol was prepared, and the diethyl-β-cyclodextrin-CaCO3 microspheres prepared in Example 1 were added. The microspheres were stirred to allow the active ingredient to fully contact the pores and surface of the microspheres. After saturation, the microspheres were filtered and vacuum dried to obtain 4-aminopyridine-loaded microspheres. The drug-loaded microspheres were mixed with lactose, povidone, and low-substituted hydroxypropyl cellulose in a mixer at 175 rpm for 2-3 min. Appropriate amount of ethanol was added as a wetting agent to prepare a soft material. The soft material was sieved through a 1 mm sieve, and then dried in a vacuum drying oven to remove the solvent. The material was sieved through a 16 mesh sieve, and then magnesium stearate was added. The mixture was further mixed in a mixer at 100 rpm for 2-3 min. The mixture was tableted to obtain 1000 tablets. The tableting pressure was 5.0-8.0 KN, and the specification was 10 mg of 4-aminopyridine per tablet.

[0041] Example 3

[0042] 1) Formulation

[0043]

[0044] 2) Preparation process

[0045] The prescription amount of 4-aminopyridine is prepared into saturated aqueous solution with 95% ethanol solution, and the diethyl-β-cyclodextrin-calcium microspheres prepared in Example 1 are added. The pores and surface of the microspheres are fully contacted with the active ingredient by stirring. After saturation loading, filtration and vacuum drying are performed to obtain the 4-aminopyridine microspheres loaded with drugs. The drug-loaded microspheres, microcrystalline cellulose, copovidone and sodium croscarmellose are mixed in a mixer at 175 rpm for 2-3 min, and then an appropriate amount of ethanol is added as a wetting agent to prepare a soft material. The granules are prepared through a 1 mm sieve, dried in a vacuum drying oven to remove the solvent, and then sieved through a 16 mesh sieve. Polyethylene glycol is added, and the mixture is further mixed in a mixer at 100 rpm for 2-3 min. Then, 1000 tablets are pressed at a tabletting pressure of 5.0-8.0 KN, and the specification is 4 mg of 4-aminopyridine per tablet.

[0046] Example 4

[0047] 1) Prescription

[0048]

[0049] 2) Preparation process

[0050] The prescription amount of 4-aminopyridine is prepared into saturated aqueous solution with 95% ethanol solution, and the diethyl-β-cyclodextrin-calcium microspheres prepared in Example 1 are added. The pores and surface of the microspheres are fully contacted with the active ingredient by stirring. After saturation loading, filtration and vacuum drying are performed to obtain the 4-aminopyridine microspheres loaded with drugs. The drug-loaded microspheres, microcrystalline cellulose, copovidone and sodium croscarmellose are mixed in a mixer at 175 rpm for 2-3 min, and then an appropriate amount of ethanol is added as a wetting agent to prepare a soft material. The granules are prepared through a 1 mm sieve, dried in a vacuum drying oven to remove the solvent, and then sieved through a 16 mesh sieve. Polyethylene glycol is added, and the mixture is further mixed in a mixer at 100 rpm for 2-3 min. Then, 1000 tablets are pressed at a tabletting pressure of 5.0-8.0 KN, and the specification is 4 mg of 4-aminopyridine per tablet.

[0051] Example 5

[0052] 1) Prescription

[0053]

[0054] 2) Preparation process

[0055] The prescription amount of 4-aminopyridine is prepared into saturated aqueous solution with 90% ethanol solution, and the prepared triethyl-β-cyclodextrin-calcium microspheres in Example 1 are added, and the microspheres are stirred to make the active ingredient fully contact with the pores and surface of the microspheres. After saturation, filtration and vacuum drying are performed to obtain the 4-aminopyridine microspheres loaded with drugs. The drug-loaded microspheres, pregelatinized starch, methylcellulose, sodium carboxymethyl starch, and an appropriate amount of ethanol as a wetting agent are mixed in a mixer at 175 rpm for 2-3 min to prepare a soft material, which is granulated through a 1 mm sieve, dried in a vacuum drying oven to remove the solvent, and sieved through a 16 mesh sieve. Stearyl fumarate sodium is added, and the mixture is continuously mixed in a mixer at 100 rpm for 2-3 min. Then, 1000 tablets are pressed at a tablet pressing pressure of 5.0-8.0 KN, and the specification is 10 mg of 4-aminopyridine per tablet.

[0056] Example 6

[0057] 1) Prescription

[0058]

[0059]

[0060] 2) Preparation process

[0061] The prescription amount of 4-aminopyridine is prepared into saturated aqueous solution with 90% ethanol solution, and the prepared triethyl-β-cyclodextrin-calcium microspheres in Example 1 are added, and the microspheres are stirred to make the active ingredient fully contact with the pores and surface of the microspheres. After saturation, filtration and vacuum drying are performed to obtain the 4-aminopyridine microspheres loaded with drugs. The drug-loaded microspheres, pregelatinized starch, methylcellulose, sodium carboxymethyl starch, and an appropriate amount of ethanol as a wetting agent are mixed in a mixer at 175 rpm for 2-3 min to prepare a soft material, which is granulated through a 1 mm sieve, dried in a vacuum drying oven to remove the solvent, and sieved through a 16 mesh sieve. Stearyl fumarate sodium is added, and the mixture is continuously mixed in a mixer at 100 rpm for 2-3 min. Then, 1000 tablets are pressed at a tablet pressing pressure of 5.0-8.0 KN, and the specification is 10 mg of 4-aminopyridine per tablet.

[0062] Example 7

[0063] 1) Prescription

[0064]

[0065] 2) Preparation process

[0066] The prescription amount of 4-aminopyridine is prepared into saturated aqueous solution with 95% ethanol solution, and the diethyl-β-cyclodextrin-calcium microspheres prepared in Example 1 are added. The microspheres are stirred to make the active ingredient fully contact with the pores and surface of the microspheres. After saturation, the loaded 4-aminopyridine microspheres are filtered and vacuum dried. The loaded microspheres are mixed with lactose, povidone, and low-substituted hydroxypropyl cellulose in a mixer at 175 rpm for 2-3 minutes. Appropriate amount of ethanol is added as a wetting agent to make soft material. The soft material is granulated through a 1 mm sieve. The granules are dried in a vacuum drying oven to remove the solvent. The granules are sieved through a 16 mesh sieve. Magnesium stearate is added, and the mixture is continuously mixed in the mixer at 100 rpm for 2-3 minutes. 1000 tablets are pressed. The tablet pressing pressure is 5.0-8.0 KN. The specification is that each tablet contains 10 mg of 4-aminopyridine.

[0067] Example 8

[0068] 1) Prescription

[0069]

[0070] 2) Preparation process

[0071] The prescription amount of 4-aminopyridine is prepared into saturated aqueous solution with 95% ethanol solution, and the diethyl-β-cyclodextrin-calcium microspheres prepared in Example 1 are added. The microspheres are stirred to make the active ingredient fully contact with the pores and surface of the microspheres. After saturation, the loaded 4-aminopyridine microspheres are filtered and vacuum dried. The loaded microspheres are mixed with lactose, povidone, and low-substituted hydroxypropyl cellulose in a mixer at 175 rpm for 2-3 minutes. Appropriate amount of ethanol is added as a wetting agent to make soft material. The soft material is granulated through a 1 mm sieve. The granules are dried in a vacuum drying oven to remove the solvent. The granules are sieved through a 16 mesh sieve. Magnesium stearate is added, and the mixture is continuously mixed in the mixer at 100 rpm for 2-3 minutes. 1000 tablets are pressed. The tablet pressing pressure is 5.0-8.0 KN. The specification is that each tablet contains 10 mg of 4-aminopyridine.

[0072] Comparative Example 1

[0073] 1) Prescription

[0074]

[0075] 2) Preparation process

[0076] The prescription amount of 4-aminopyridine is prepared into saturated solution with 95% ethanol solution, and then diethyl-β-cyclodextrin and calcium carbonate (microspheres with diameter of 200 nm) are added and stirred to make them fully contact with the active ingredient. The solid mixture is obtained by vacuum drying under reduced pressure. Then the obtained solid mixture, lactose, povidone and low-substituted hydroxypropyl cellulose in the prescription are mixed in a mixer at 175 rpm for 2-3 min, and then an appropriate amount of ethanol is added as a wetting agent to make soft material. The granules are prepared by passing through a 1 mm sieve, and then dried in a vacuum drying oven to remove the solvent. The granules are sieved through a 16 mesh sieve, and then magnesium stearate is added. The mixture is continuously mixed in the mixer at 100 rpm for 2-3 min, and then 1000 tablets are pressed. The tablet pressing pressure is 5.0-8.0 KN, and the specification is that each tablet contains 10 mg of 4-aminopyridine.

[0077] Comparative Example 2

[0078] 1) Prescription

[0079]

[0080] 2) Preparation process

[0081] Preparation of acetyl-α-cyclodextrin-calcium carbonate microspheres: a 20 mM potassium carbonate solution is prepared, and then an acetyl-α-cyclodextrin DMSO solution is added to the above potassium carbonate solution under stirring at a stirring speed of 500 rpm. The acetyl-α-cyclodextrin-acetyl-α-cyclodextrin-potassium carbonate mixed solution is obtained by fully dissolving the acetyl-α-cyclodextrin, and the final concentration of acetyl-α-cyclodextrin is 5 mM. Then the mixture is continuously stirred, and then added to a 20 mM calcium chloride solution. After the addition is completed, the mixture is left to stand for 0.5 h, centrifuged and filtered, and the filter cake is washed with purified water for three times. The acetyl-α-cyclodextrin-calcium carbonate microspheres are obtained by drying to remove the solvent. The microspheres have a diameter of 300-450 nm and a pore size of 10-15 nm.

[0082] The prescription amount of 4-aminopyridine is prepared into saturated aqueous solution with 95% ethanol solution, and then acetyl-α-cyclodextrin-calcium carbonate microspheres are added and stirred to make the pores and surface of the microspheres fully contact with the active ingredient. After the saturation loading, the mixture is filtered and vacuum dried to obtain drug-loaded 4-aminopyridine microspheres. Then the drug-loaded microspheres, lactose, povidone and low-substituted hydroxypropyl cellulose are mixed in a three-dimensional motion mixer at 175 rpm for 15 min, and then an appropriate amount of ethanol is added as a wetting agent to make soft material. The granules are prepared by passing through a 1 mm sieve, and then dried in a vacuum drying oven to remove the solvent. The granules are sieved through a 16 mesh sieve, and then magnesium stearate is added. The mixture is continuously mixed in the mixer at 100 rpm for 5 min, and then 1000 tablets are pressed. The tablet pressing pressure is 5.0-8.0 KN, and the specification is that each tablet contains 10 mg of 4-aminopyridine.

[0083] Comparative Example 3

[0084] 1) Prescription

[0085]

[0086]

[0087] 2) Preparation process

[0088] The prescription amount of 4-aminopyridine is prepared into saturated solution with 95% ethanol solution, diethyl-β-cyclodextrin is added, and the two are fully contacted with the active ingredient by stirring, and the solid mixture is obtained by vacuum drying under reduced pressure; then the obtained solid mixture, lactose, povidone, low-substituted hydroxypropyl cellulose in the prescription are mixed in a mixer at 175 rpm for 2-3 min, and then an appropriate amount of ethanol is added as a wetting agent to make a soft material, granulated through a 1 mm sieve, placed in a vacuum drying oven for drying to remove the solvent, and then sieved through a 16 mesh sieve, and then magnesium stearate is added and mixed in the mixer at 100 rpm for 2-3 min, and then 1000 tablets are pressed, with a tablet pressing pressure of 5.0-8.0 KN, and a specification of 10 mg of 4-aminopyridine per tablet.

[0089] Comparative Example 4

[0090] 1) Prescription

[0091]

[0092] 2) Preparation process

[0093] The prescription amount of 4-aminopyridine and povidone are dissolved in 40% ethanol aqueous solution as a drug-containing binder; hydroxypropyl methyl cellulose, microcrystalline cellulose, and lactose are placed in a wet granulator and mixed uniformly, the drug-containing binder is sprayed into the high-shear wet granulator at a constant speed to granulate, and then dried in a fluidized bed; after drying, the granules are sieved, and then colloidal silicon dioxide and magnesium stearate are added and mixed, and then 1000 tablets are pressed, with a tablet pressing pressure of 5.0-8.0 KN, and a specification of 10 mg of 4-aminopyridine per tablet.

[0094] Comparative Example 5

[0095] 1) Prescription

[0096]

[0097]

[0098] 2) Preparation process

[0099] The prescription amount of 4-aminopyridine is ground through a 50-mesh sieve first, then half of the prescription amount of hydroxypropyl methyl cellulose K100LV, microcrystalline cellulose PH101, colloidal silicon dioxide and the ground 4-aminopyridine are sequentially added into a mixer, the remaining hydroxypropyl methyl cellulose K100LV is added; the mixture is mixed at 175 rpm for 15 min, then magnesium stearate is added and further mixed at 100 rpm for 5 min, 1000 tablets are compressed, the tablet compression pressure is 5.0-8.0 KN, and the specification is 5 mg of 4-aminopyridine per tablet.

[0100] Verification example

[0101] Experimental example 1: comparison of appearance, hardness and content uniformity of the obtained tablets

[0102] Appearance: The appearance of the tablets should be complete and smooth, with uniform color, and appropriate hardness to prevent wear or breakage during packaging and transportation.

[0103] Hardness determination: According to the hardness requirements of tablets in the Chinese Pharmacopoeia 2020 edition, the hardness of ordinary tablets should be between 40-150 N, while the hardness of special preparations (such as sustained-release tablets, controlled-release tablets, etc.) needs to be determined according to their special properties. Based on the need for certain hardness of sustained-release tablets to prevent breakage or wear during packaging, transportation, etc., while ensuring good release in the stomach or intestine, the hardness range of sustained-release tablets is generally 150-260 N. The determination method is as follows: using a tablet hardness tester, under the conditions of 20±1℃ and humidity 45-75%, 10 tablets are measured continuously at a time, and the average hardness and hardness values of each tablet are recorded.

[0104] Content uniformity determination: According to the content uniformity test method in the Chinese Pharmacopoeia 0941, the standard is A+2.2S≤15.

[0105] Table 1 Comparison of appearance, hardness and content uniformity of the obtained preparations

[0106]

[0107]

[0108] The results show that the appearance of the preparations obtained in each example is good, the hardness is moderate, and the content uniformity is high; Comparative Example 1 does not prepare ethyl-beta cyclodextrin-calcium carbonate microspheres, and directly prepares wet granules, and the obtained tablets are unevenly colored, have a large hardness, and are not uniformly mixed; in Comparative Example 2, acetyl-alpha-cyclodextrin is used instead of ethyl-beta cyclodextrin, which may affect the mixing effect due to the preparation of large calcium carbonate microspheres, and the content uniformity is slightly poor; in Comparative Example 3, only diethyl-beta cyclodextrin is used, and the API cannot be uniformly mixed, the obtained tablets have a large hardness and poor content uniformity; in Comparative Example 4, the API, hydroxypropyl methylcellulose E5Lv and ethanol are dissolved to prepare a drug-containing adhesive, then hydroxypropyl methylcellulose K100Lv and pregelatinized starch are placed in a fluidized bed and uniformly mixed, and the drug-containing adhesive is sprayed into the fluidized bed at a constant speed to prepare granules, which improves the content uniformity to a certain extent, but the preparation method is complex, and the obtained tablets have a large hardness; in Comparative Example 5, although the API is added after the excipients are added, the mixing effect is improved, but the defect of uneven mixing caused by small API amount is not completely solved, and the obtained tablets have a large hardness and poor content uniformity.

[0109] Experimental Example 2: Investigation of in vitro release characteristics

[0110] Dissolution test: The tablets obtained in each example and comparative example (6 tablets were determined) were taken, the test device was referred to the second method of dissolution test in Chinese Pharmacopoeia 2020 edition Part IV 0931, 500 mL of pH 6.8 phosphate buffer was used as the dissolution medium, the rotation speed was 50 revolutions per minute, 5 mL of sample was taken at 1, 2, 3, 4, 8, 12, 16, 22, 30, 38 and 48 h (the same amount of medium was added in time), and the filtrate was filtered through a 0.45 μm microporous filter, the filtrate was taken as a blank control with the dissolution medium, the absorbance was measured at a wavelength of 245 nm, and the cumulative dissolution was calculated by entering the standard curve equation, and the results are shown in Table 2 and FIG. 1. Figure 1

[0111] Table 2: Dissolution test results of the obtained preparations

[0112]

[0113]

[0114] Note: "-" in the table means that the previous time point has been basically released, and the time point is not measured

[0115] ​The results show that the sustained-release time of the preparations of Examples 1-6 is prolonged compared with the prior art; the sustained-release time of the preparation of Example 7 is shortened due to insufficient amount of ethyl-β-cyclodextrin-calcium carbonate microspheres; the preparation of Example 8 has the defect of incomplete release due to the use of excessive ethyl-β-cyclodextrin-calcium carbonate microspheres; the sustained-release time of the preparations of Comparative Examples 1 and 3 is significantly shortened because no ethyl-β-cyclodextrin-calcium carbonate microspheres are prepared; in Comparative Example 2, acetyl-α-cyclodextrin is used to replace ethyl-β-cyclodextrin, although cyclodextrin calcium carbonate microspheres are prepared, the sustained-release effect is relatively poor; the sustained-release time of the preparations of Comparative Examples 4 and 5 is relatively short.

[0116] Experimental Example 3: Stability Investigation

[0117] The tablets obtained in Examples 1-6 are packaged in polyamide / aluminum / polyethylene cold-stamped solid pharmaceutical composite hard sheet boxes and pharmaceutical aluminum foils (the same packaging materials as the marketed product), and the marketed AMPYRA preparation is placed under the conditions of temperature 40±2°C and relative humidity 75±5% (accelerated) for 6 months, and samples are taken at the end of the 0th, 3rd and 6th months, and the impurities A, B and C and total impurities of Dalfampridine and the water content in the USP 2023 edition of the Pharmacopoeia Standard are determined, wherein the preparations obtained in the following examples and the marketed product do not contain impurities B and C, and the results are shown in Table 3.

[0118] Table 3: Stability determination results of the obtained preparations

[0119]

[0120] The results show that the preparations obtained in Examples 2-6 do not contain the specific impurities in the Pharmacopoeia before and after being placed under accelerated conditions, have low total impurity content, high stability and are not easy to absorb moisture; the marketed AMPYRA preparation contains impurity A and has high total impurity content, poor stability and is easy to absorb moisture.

Claims

1. A 4-aminopyridine sustained-release preparation, characterized in that: The sustained-release preparation comprises 4-aminopyridine, ethyl-β-cyclodextrin-calcium carbonate microspheres, a filler, a binder, a disintegrant and a lubricant.

2. The sustained-release preparation according to claim 1, wherein The ethyl-β-cyclodextrin-calcium carbonate microspheres are diethyl-β-cyclodextrin-calcium carbonate microspheres or triethyl-β-cyclodextrin-calcium carbonate microspheres.

3. The sustained-release preparation according to claim 1, wherein The binder is selected from one or more of povidone, copovidone, glyceryl behenate or methylcellulose.

4. The sustained-release preparation according to claim 1, wherein The disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose or sodium carboxymethyl starch.

5. The sustained-release preparation according to claim 1, wherein The filler is selected from one or more of lactose, microcrystalline cellulose, mannitol or pregelatinized starch.

6. The sustained-release preparation according to claim 1, wherein The lubricant is selected from one or more of sodium stearyl fumarate, polyethylene glycol, stearic acid, magnesium stearate or talc.

7. The sustained-release preparation according to claim 1, wherein The sustained-release preparation contains the following components in percentage by weight:

8. The sustained-release preparation according to claim 1, wherein The diameter of the ethyl-β-cyclodextrin-calcium carbonate microspheres is 100-150 nm, and the pore size is 4-8 nm.

9. The sustained-release preparation according to claim 8, wherein The preparation method of the ethyl-β-cyclodextrin-calcium carbonate microspheres comprises the following steps: preparing a potassium carbonate solution, adding a DMSO solution of ethyl-β-cyclodextrin to the potassium carbonate solution under stirring conditions, and stirring to completely dissolve the ethyl-β-cyclodextrin-potassium carbonate mixed solution; then continuing to stir, and adding the obtained mixed solution to a calcium chloride solution. After the addition is completed, the mixture is allowed to stand, centrifuged, filtered, the filter cake is washed with purified water, and the solvent is removed by drying to obtain the ethyl-β-cyclodextrin-calcium carbonate microspheres.

10. The sustained-release preparation according to any one of claims 1 to 9, characterized in that: The preparation method of the sustained-release preparation comprises the following steps: Prepare 4-aminopyridine into a saturated ethanol solution, add ethyl-β-cyclodextrin-calcium carbonate microspheres, stir to make the pores and surface of the microspheres fully contact with the active ingredient, filter after saturation, and vacuum dry to obtain drug-loaded 4-aminopyridine microspheres; The drug-loaded microspheres are fully mixed with the filler, binder, and disintegrant, and then a lubricant is added and mixed evenly to prepare a 4-aminopyridine sustained-release preparation.

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