Elixiram sustained-release dry suspension and preparation method thereof

Abstract

The invention provides an eleczyme sustained-release dry suspension, which comprises the following components in percentage by mass: 10% to 30% of eleczyme, 30% to 60% of a sustained-release carrier, 10% to 57% of a filler, 1% to 5% of a suspending agent, 1% to 4% of a pH regulator, 0.2% to 1% of a flavoring agent, and 0.2% to 1% of an aromatic flavoring agent; wherein the sustained-release carrier is selected from one or both of stearic acid and glyceryl monostearate; and the suspending agent is selected from one or more of xanthan gum, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and sodium alginate. The sustained-release dry suspension has good suspension uniformity after adding water, has no precipitation or stratification problems, has good sustained-release performance, and does not have a pungent taste.

Description

Technical Field

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

[0002] Epilepsy is a chronic disease of the central nervous system that requires long-term drug treatment. The effectiveness of anti-epileptic drugs currently used clinically is only 70% to 80%. Anti-epileptic drugs cannot prevent the formation of epileptic foci and the progressive course of the disease, but can only relieve symptoms. In addition, anti-epileptic drugs have many adverse reactions, involving multiple systems of the human body. Common adverse reactions include rash, dizziness, nausea, poor appetite, mental and behavioral abnormalities, liver and kidney dysfunction, endocrine system dysfunction, lymphadenopathy, etc. Moreover, epilepsy patients often need to take medication for a long time or take several anti-epileptic drugs at the same time, which will aggravate the adverse reactions of the drugs. Childhood is an important period of growth and development. The treatment of children with epilepsy is different from that of adults. For children with epilepsy, it is more important to use anti-epileptic drugs with significant application effects and few adverse reactions.

[0003] Pepper is a genus of petal plants and an evergreen vine of the Piperaceae family. Its folk remedy for controlling epileptic seizures has been circulated in Xishuangbanna, Yunnan Province, my country. It was later discovered and paid attention to by experts from Peking Medical University. Through unremitting efforts, they developed a new type of effective, broad-spectrum, low-toxic piperine-based plant-based anti-epileptic drug, electomycin tablets, which brought good news to epilepsy patients, especially children with epilepsy.

[0004] Elixiram is a chemical derivative of piperine, also known as anti-epileptic spirit, with a chemical name of 3-(3',4'-methylenedioxyphenyl)-acryloylpiperidine or 3',4'-methylenedioxycinnamoylpiperidine, and a molecular formula of C 15 H 17 NO3. Ilecithin can inhibit the generation of sodium current by acting on sodium channels, thereby inhibiting the occurrence and development of epilepsy. It is a new anti-epileptic drug that acts on sodium channels. The chemical structure of Ilecithin contains two benzene-like ring structures separated by four CC or CN single bonds. This structure is very similar to traditional anti-epileptic drugs carbamazepine and lamotrigine, which also have two benzene-like ring structures separated by one or more CC or CN single bonds. It is these two benzene-like ring structures that play an important role in the anti-epileptic effect of the drug. Since carbamazepine and lamotrigine can prevent systemic tonic-clonic seizures and partial epileptic seizures by inhibiting high-frequency discharges of sodium channels, it is speculated that Ilecithin may have considerable efficacy in partial epileptic seizures.

[0005] However, since eleczyme is derived from pepper, the drug has a strong spicy taste, which makes it less compliant for children with epilepsy. In addition, traditional eleczyme preparations are all tablets, and there is no special dosage form for children. The therapeutic window of anti-epileptic drugs is generally narrow. The adult dosage of eleczyme tablets that have been on the market is: 1 to 3 tablets (50-150 mg) at a time, twice a day, while children need to break the tablets when taking them, so the dosage taken by children is not accurate enough. Taking multiple tablets a day and taking multiple times will cause large fluctuations in blood drug concentration for children. If the blood drug concentration is too high, there will be greater toxic side effects. If the blood drug concentration is too low, the ideal therapeutic effect will not be achieved.

[0006] For children, the elderly and epileptic patients with difficulty swallowing, patent CN102697779B discloses a pharmaceutical composition of eleczema with a high dissolution rate and a preparation method thereof, which is prepared by mixing 80-120 mesh eleczema with excipients to obtain 30-50 mesh particles, and the preferred dosage form is a dry suspension. However, due to the poor solubility and strong hydrophobicity of eleczema itself, the eleczema preparation obtained by this technology has the problem of poor suspension uniformity. In addition, the document adopts conventional flavor correction methods such as adding sweeteners or flavoring agents without masking the spicy taste. The testers tested that the prescription could not mask its spicy taste. Summary of the invention

[0007] Based on this, the present invention provides an eleciclide sustained-release dry suspension, which has good suspension uniformity after adding water, no precipitation or stratification problems, good sustained-release performance, and no pungent taste.

[0008] The present invention is achieved through the following technical solutions.

[0009] An eleczyme sustained-release dry suspension, comprising the following components in percentage by mass:

[0010]

[0011] Wherein, the sustained-release carrier is selected from one or both of stearic acid and glyceryl monostearate;

[0012] The suspending agent is selected from one or more of xanthan gum, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and sodium alginate.

[0013] In one embodiment, the eleciclib sustained-release dry suspension comprises the following components in percentage by mass:

[0014]

[0015] In one embodiment, the filler is selected from one or both of sorbitol and mannitol.

[0016] In one embodiment, the pH adjuster is selected from one or more of anhydrous monosodium citrate, sodium citrate and sodium bicarbonate.

[0017] In one embodiment, the flavoring agent is selected from one or more of saccharin sodium, sucrose and aspartame;

[0018] The aromatic flavoring agent is selected from one or more of orange powder flavor, peach powder flavor, vanilla flavor and mouthfeel flavor.

[0019] In one embodiment, the suspending agent is xanthan gum.

[0020] In one embodiment, the molecular weight of the xanthan gum is 6×10 6 ~10×10 6 or 10×10 6 ~25×10 6 ;

[0021] The molecular weight of the hydroxypropyl methylcellulose is 10,000 to 150,000; and / or the viscosity of a 1% aqueous solution of the hydroxypropyl methylcellulose is 12 mPa.s to 18 mPa.s;

[0022] The molecular weight of the sodium carboxymethyl cellulose is 90,000 to 200,000 or 200,000 to 700,000;

[0023] The molecular weight of the sodium alginate is 4000-185000; and / or the viscosity of a 1% aqueous solution of the sodium alginate is 20mPa.s-400mPa.s.

[0024] The present invention also provides a method for preparing the above-mentioned eleczema sustained-release dry suspension, comprising the following steps:

[0025] heating the sustained-release carrier to prepare a molten liquid;

[0026] The molten liquid is mixed with the eleciclide and then subjected to hot melt spraying to prepare an eleciclide solid dispersion;

[0027] The filler, the suspending agent and the flavoring agent are mixed, wet granulated, and then dried to prepare auxiliary material granules;

[0028] The eleciclib solid dispersion, the auxiliary material particles, the pH regulator and the aromatic flavoring agent are mixed.

[0029] In one embodiment, the heating temperature is 70°C to 100°C.

[0030] In one embodiment, the hot melt spraying treatment conditions include a low temperature freezing air temperature of -10°C to 15°C.

[0031] Compared with the prior art, the eleciclib sustained-release dry suspension of the present invention has the following beneficial effects:

[0032] The eleczyme sustained-release dry suspension of the present invention adopts a specific formulation prescription, further defines the suspending agent as one or more of xanthan gum, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and sodium alginate, and the sustained-release carrier as one or two of stearic acid and glyceryl monostearate, and coordinates fillers, pH regulators, flavoring agents and aromatic flavoring agents, thereby solving the poor solubility and strong hydrophobicity of eleczyme itself, and the obtained eleczyme sustained-release dry suspension has good suspension uniformity after adding water, no precipitation and stratification problems, and good sustained-release performance. At the same time, the suspending agent polymer material in the eleczyme sustained-release dry suspension prescription can also significantly improve the strong pungent taste of eleczyme, thereby improving the compliance of patients, especially children. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 A release curve diagram of the eleczema sustained-release dry suspension provided in an embodiment of the present invention;

[0034] Figure 2 This is a characterization diagram of the strong hydrophobicity of the eleciclide raw material provided by the present invention. DETAILED DESCRIPTION

[0035] In order to facilitate the understanding of the present invention, the present invention will be described more fully below with reference to the relevant drawings. The preferred embodiments of the present invention are given in the drawings. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used herein in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more related listed items.

[0037] Mode of administration

[0038] As used herein, "drug" includes any agent, compound, composition or mixture that provides physiological and / or pharmacological effects in vivo or in vitro, and often provides beneficial effects. The scope of the physiological and / or pharmacological effects produced by the "drug" in vivo is not particularly limited, and may be systemic effects or may only produce effects locally. The activity of the "drug" is not particularly limited, and may be an active substance that can interact with other substances, or an inert substance that does not interact.

[0039] As used herein, "therapeutically effective amount" refers to the amount of the compound of the present invention that will cause a biological or medical response in an individual, for example, the amount of the compound of the present invention that brings about a physiological and / or pharmacologically positive effect to an individual, wherein the physiological and / or pharmacologically positive effect includes but is not limited to reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing down or delaying disease progression, or preventing disease, etc.

[0040] The present invention provides an eleczema sustained-release dry suspension, which comprises the following components in terms of mass percentage:

[0041]

[0042] Wherein, the sustained-release carrier is selected from one or both of stearic acid and glyceryl monostearate;

[0043] The suspending agent is selected from one or more of xanthan gum, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and sodium alginate.

[0044] Ilecithin itself has the characteristics of poor solubility and strong hydrophobicity, such as Figure 2 As shown, the eleciclib dry suspension preparation obtained by the traditional technology has the problem of poor suspension uniformity.

[0045] In a specific example, the eleciclib sustained-release dry suspension comprises the following components in terms of mass percentage:

[0046]

[0047] In a specific example, the filler is selected from one or both of sorbitol and mannitol.

[0048] In a specific example, the pH adjuster is selected from one or more of anhydrous monosodium citrate, sodium citrate and sodium bicarbonate.

[0049] In a specific example, the flavoring agent is selected from one or more of saccharin sodium, sucrose and aspartame.

[0050] In a specific example, the aromatic flavoring agent is selected from one or more of orange powder flavor, peach powder flavor, vanilla flavor and mouthfeel flavor.

[0051] In one specific example, the suspending agent is xanthan gum.

[0052] In a specific example, the molecular weight of xanthan gum is 6×10 6 ~10×10 6 or 10×10 6 ~25×10 6 .

[0053] In a specific example, the molecular weight of hydroxypropyl methylcellulose is 10,000 to 150,000; and / or the viscosity of a 1% aqueous solution of hydroxypropyl methylcellulose is 12 mPa.s to 18 mPa.s.

[0054] In a specific example, the molecular weight of sodium carboxymethylcellulose is 90,000-200,000 or 200,000-700,000.

[0055] In a specific example, the molecular weight of sodium alginate is 4000-185000; and / or the viscosity of a 1% aqueous solution of sodium alginate is 20 mPa.s-400 mPa.s.

[0056] The present invention also provides a method for preparing the above-mentioned eleczema sustained-release dry suspension, comprising the following steps:

[0057] heating the sustained-release carrier to prepare a molten liquid;

[0058] The molten liquid is mixed with eleczyme C and then subjected to hot melt spraying treatment to prepare a solid dispersion of eleczyme C;

[0059] The filler, suspending agent and flavoring agent are mixed, wet granulated, and then dried to prepare auxiliary material granules;

[0060] The elecitamine solid dispersion, auxiliary material particles, pH regulator and aromatic flavoring agent are mixed.

[0061] The invention solves the strong pungent taste brought by eleczema itself by screening out a polymer suspending agent material and combining it with the inclusion effect of solid dispersion technology, thereby greatly improving the compliance of patients.

[0062] In a specific example, the heating temperature is 70° C. to 100° C. It can be understood that the heating temperature includes but is not limited to 70° C., 72° C., 74° C., 76° C., 78° C., 80° C., 81° C., 82° C., 83° C., 84° C., 85° C., 86° C., 87° C., 88° C., 89° C., 90° C., 92° C., 94° C., 96° C., 98° C., and 100° C.

[0063] In a specific example, the conditions of the hot melt spray treatment include: the low temperature freezing air temperature is -10°C to 15°C. It can be understood that the low temperature freezing air temperature includes but is not limited to -10°C, -9°C, -8°C, -7°C, -6°C, -5°C, -4°C, -3°C, -2°C, -1°C, 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 7°C, 9°C, 11°C, 13°C, 15°C.

[0064] In the present invention, the low-temperature freezing technology is used to directly prepare fine powder, which can solve the aging problem commonly existing in the solid dispersion pulverization process and high humidity and high heat, thereby significantly improving the stability of the drug.

[0065] In a more specific example, the preparation method of the above-mentioned eleczema sustained-release dry suspension comprises the following steps:

[0066] The sustained-release carrier is heated to 70-100° C. to melt to prepare a molten liquid;

[0067] Under stirring, eleczyme is added to the molten liquid and stirred evenly; using a MS220 hot melt sprayer, the liquid is transported to a two-flow gas spray gun through a twin screw, atomized into droplets by compressed air, and solidified into solid powder by low-temperature frozen air at a temperature of -10°C to 15°C, to prepare a solid dispersion of eleczyme;

[0068] The flavoring agent is added to water and dissolved to prepare an adhesive;

[0069] Add the filler to the wet granulator, then add the suspending agent, start stirring and shearing, the stirring speed is 130rpm~160rpm, the shear speed is 1500rpm~1800rpm, mix for 3min~5min, add the binder to prepare the soft material; granulate the soft material with a 30 mesh swing granulator, dry it in a fluidized bed until the moisture content is not more than 1%, and granulate it with a 30 mesh swing granulator to prepare the auxiliary material granules;

[0070] Add the eleciclib solid dispersion, auxiliary material particles, pH regulator and aromatic flavor corrective into a three-dimensional mixer and mix for 10 to 15 minutes at 13 to 15 rpm.

[0071] The eleciclide sustained-release dry suspension of the present invention and its preparation method are further described in detail below in conjunction with specific examples. The raw materials used in the following examples, unless otherwise specified, are all commercially available products.

[0072] Example 1

[0073] This embodiment provides an eleciclide sustained-release dry suspension, the component contents of which are specifically shown in Table 1:

[0074] Table 1

[0075]

[0076]

[0077] The preparation method is as follows:

[0078] S1, heating the glyceryl monostearate to 85° C. to melt;

[0079] S2. Under stirring, add elecylamine to the melt of glyceryl monostearate in step S1 and stir evenly;

[0080] S3, using MS220 hot melt sprayer, conveying to a two-flow gas spray gun through a twin screw, atomizing into droplets through compressed air, and solidifying into solid powder with low-temperature frozen air (-10°C to 15°C), to prepare eleczema solid dispersion fine powder;

[0081] S4. Prepare auxiliary material granules: Add the prescribed amount of aspartame into water, dissolve it, and use it as a binder for later use. Add sorbitol to the wet granulator, then add sodium carboxymethyl cellulose, start stirring and shearing (stirring speed 130rpm, shear speed 1500rpm), mix for 3min, add binder, and make soft material. Granulate the wet soft material with a 30-mesh swing granulator, dry it in a fluidized bed until the moisture content is no more than 1%, and granulate it with a 30-mesh swing granulator for later use;

[0082] S5, eleciclib solid dispersion fine powder, auxiliary material particles, sodium citrate, and peach powder flavor were added into a three-dimensional mixer and mixed at 13 rpm for 10 min;

[0083] S6. Granule packaging: Use granule packaging machine ZKB-180F to package into different bags of 1g, 2g, etc. according to different dosages.

[0084] Example 2

[0085] This embodiment provides an eleciclib sustained-release dry suspension, the component contents of which are specifically shown in Table 2:

[0086] Table 2

[0087] Element content% Elixiram 15 Stearic acid 40 Sorbitol 40 Xanthan gum 2 Monosodium citrate anhydrous 2 Saccharin Sodium 0.5 Taste and flavor 0.5

[0088] The preparation method is as follows:

[0089] S1, heating the stearic acid to 80° C. to melt;

[0090] S2. Under stirring, add elecylamine to the melt of stearic acid in step S1 and stir evenly;

[0091] S3, using MS220 hot melt sprayer, conveying to a two-flow gas spray gun through a twin screw, atomizing into droplets through compressed air, and solidifying into solid powder with low-temperature frozen air (-10°C to 15°C), to prepare eleczema solid dispersion fine powder;

[0092] S4. Preparation of auxiliary material granules: Add the prescribed amount of saccharin sodium into water, dissolve it, and use it as a binder for later use. Add sorbitol to a wet granulator, then add xanthan gum, start stirring and shearing (stirring speed 150rpm, shear speed 1500rpm, mix for 5min, add binder, and make soft material. Granulate the wet soft material with a 30-mesh swing granulator, dry it in a fluidized bed until the moisture content is no more than 1%, and granulate it with a 30-mesh swing granulator for later use.

[0093] S5, eleciclib solid dispersion fine powder, auxiliary material granules, anhydrous monosodium citrate, and taste flavor were added into a three-dimensional mixer and mixed at 15 rpm for 10 min.

[0094] S6. Granule packaging: Use granule packaging machine ZKB-180F to package into different bags of 1g, 2g, etc. according to different dosages.

[0095] Example 3

[0096] This embodiment provides an eleczema sustained-release dry suspension, the component contents of which are specifically shown in Table 3:

[0097] Table 3

[0098] Element content% Elixiram 30 Stearic acid 55 Mannitol 12 Xanthan gum 1.5 Sodium Citrate 1 Saccharin Sodium 0.2 Peach powder flavor 0.3

[0099] The preparation method is as follows:

[0100] S1, heating the stearic acid to 80° C. to melt;

[0101] S2. Under stirring, add elecylamine to the melt of stearic acid in step S1 and stir evenly;

[0102] S3, using MS220 hot melt sprayer, conveying to a two-flow gas spray gun through a twin screw, atomizing into droplets through compressed air, and solidifying into solid powder with low-temperature frozen air (-10°C to 15°C), to prepare eleczema solid dispersion fine powder;

[0103] S4. Prepare auxiliary material granules: Add the prescribed amount of saccharin sodium into water, dissolve it, and use it as a binder for later use. Add mannitol to the wet granulator, then add xanthan gum, start stirring and shearing (stirring speed 160rpm, shear speed 1800rpm, mix for 5min, add binder, and make soft material. Granulate the wet soft material with a 30-mesh swing granulator, dry it in a fluidized bed until the moisture is no more than 1%, and granulate it with a 30-mesh swing granulator for later use;

[0104] S5, eleciclib solid dispersion fine powder, auxiliary material particles, sodium citrate, and peach powder flavor were added into a three-dimensional mixer and mixed at 13 rpm for 15 min;

[0105] S6. Granule packaging: Use granule packaging machine ZKB-180F to package into different bags of 1g, 2g, etc. according to different dosages.

[0106] Example 4

[0107] This embodiment provides an eleciclide sustained-release dry suspension, the component contents of which are specifically shown in Table 4:

[0108] Table 4

[0109] Element content% Elixiram 10 Stearic acid 30 Sorbitol 50 Xanthan gum 5 Monosodium citrate anhydrous 3 Saccharin Sodium 1 Vanilla flavor 1

[0110] The preparation method is as follows:

[0111] S1, heating the stearic acid to 80° C. to melt;

[0112] S2. Under stirring, add elecylamine to the melt of stearic acid in step S1 and stir evenly;

[0113] S3, using MS220 hot melt sprayer, conveying to a two-flow gas spray gun through a twin screw, atomizing into droplets through compressed air, and solidifying into solid powder with low-temperature frozen air (-10°C to 15°C), to prepare eleczema solid dispersion fine powder;

[0114] S4. Prepare auxiliary material granules: Add the prescribed amount of saccharin sodium into water, dissolve it, and use it as a binder for later use. Add sorbitol to the wet granulator, then add xanthan gum, start stirring and shearing (stirring speed 150rpm, shear speed 1500rpm), mix for 3min, add binder, and make soft material. Granulate the wet soft material with a 30-mesh swing granulator, dry it in a fluidized bed until the moisture content is no more than 1%, and granulate it with a 30-mesh swing granulator for later use;

[0115] S5, eleciclib solid dispersion fine powder, auxiliary material particles, anhydrous monosodium citrate, and vanilla essence were added into a three-dimensional mixer and mixed at 13 rpm for 10 min;

[0116] S6. Granule packaging: Use granule packaging machine ZKB-180F to package into different bags of 1g, 2g, etc. according to different dosages.

[0117] Example 5

[0118] This embodiment provides an eleciclide sustained-release dry suspension, the component contents of which are specifically shown in Table 5:

[0119] Table 5

[0120]

[0121] The preparation method is as follows:

[0122] S1, heating the stearic acid to 80° C. to melt;

[0123] S2. Under stirring, add elecylamine to the melt of stearic acid in step S1 and stir evenly;

[0124] S3, using MS220 hot melt sprayer, conveying to a two-flow gas spray gun through a twin screw, atomizing into droplets through compressed air, and solidifying into solid powder with low-temperature frozen air (-10°C to 15°C), to prepare eleczema solid dispersion fine powder;

[0125] S4. Prepare auxiliary material granules: Add the prescribed amount of saccharin sodium into water, dissolve it, and use it as a binder for later use. Add mannitol to the wet granulator, then add hydroxypropyl methylcellulose E15, turn on stirring and shearing (stirring speed 150rpm, shear speed 1500rpm), mix for 3min, add binder, and make soft material. Granulate the wet soft material with a 30-mesh swing granulator, dry it in a fluidized bed until the moisture content is no more than 1%, and granulate it with a 30-mesh swing granulator for later use;

[0126] S5, eleciclib solid dispersion fine powder, auxiliary material particles, anhydrous monosodium citrate, and orange powder flavor were added into a three-dimensional mixer and mixed at 13 rpm for 10 min;

[0127] S6. Granule packaging: Use granule packaging machine ZKB-180F to package into different bags of 1g, 2g, etc. according to different dosages.

[0128] Example 6

[0129] This embodiment provides an eleciclib sustained-release dry suspension, the component contents of which are specifically shown in Table 6:

[0130] Table 6

[0131]

[0132]

[0133] The preparation method is as follows:

[0134] S1, heating the stearic acid to 80° C. to melt;

[0135] S2. Under stirring, add elecylamine to the melt of stearic acid in step S1 and stir evenly;

[0136] S3, using MS220 hot melt sprayer, conveying to a two-flow gas spray gun through a twin screw, atomizing into droplets through compressed air, and solidifying into solid powder with low-temperature frozen air (-10°C to 15°C), to prepare eleczema solid dispersion fine powder;

[0137] S4. Prepare auxiliary material granules: Add the prescribed amount of sucrose into water, dissolve it, and use it as a binder for later use. Add mannitol to the wet granulator, then add sodium alginate, start stirring and shearing (stirring speed 130rpm, shear speed 1500rpm), mix for 5 minutes, add binder, and make soft material. Granulate the wet soft material with a 30-mesh swing granulator, dry it in a fluidized bed until the moisture content is no more than 1%, and granulate it with a 30-mesh swing granulator for later use;

[0138] S5, eleczema solid dispersion fine powder, auxiliary material particles, sodium bicarbonate, and orange powder flavor were added into a three-dimensional mixer and mixed at 15 rpm for 10 min;

[0139] S6. Granule packaging: Use granule packaging machine ZKB-180F to package into different bags of 1g, 2g, etc. according to different dosages.

[0140] Comparative Example 1

[0141] This comparative example provides an eleciclib sustained-release dry suspension, the component contents of which are specifically shown in Table 7:

[0142] Table 7

[0143]

[0144]

[0145] The preparation method is as follows:

[0146] S1. Preparation of eleczema granules:

[0147] The prescribed amount of povidone K30 is added into water and dissolved to prepare a 5% povidone K30 solution, which is used as an adhesive for later use;

[0148] Mix elecicline with sucrose and hydroxypropyl methylcellulose K100M evenly, add a binder to prepare a soft material, and granulate the wet soft material with a 30-mesh swing granulator. Dry it in a fluidized bed to a moisture content of 1% to 3%, and granulate it with a 30-mesh swing granulator for later use;

[0149] S2. Preparation of auxiliary material particles:

[0150] Add the prescribed amount of saccharin sodium into water, dissolve it and use it as a binder;

[0151] Add mannitol to the wet granulator, then add xanthan gum, start stirring and shearing (stirring speed 160rpm, shearing speed 1800rpm), mix for 3min, add adhesive to make soft material. Granulate the wet soft material with a 30-mesh swing granulator, dry it in a fluidized bed until the moisture content is no more than 1%, and granulate it with a 30-mesh swing granulator for later use;

[0152] S3, eleciclib granules, auxiliary material granules, anhydrous monosodium citrate, and orange powder flavor were added into a three-dimensional mixer and mixed at 13 rpm for 10 min;

[0153] S4. Granule packaging: Use granule packaging machine ZKB-180F to package into different bags of 1g, 2g, etc. according to different dosages.

[0154] Comparative Example 2

[0155] This comparative example provides an electomycin sustained-release dry suspension, the component contents of which are specifically shown in Table 8:

[0156] Table 8

[0157] Element content% Elixiram 15 Stearic acid 40 Sorbitol 39 Xanthan gum 1 Monosodium citrate anhydrous 4 Saccharin Sodium 0.5 Orange powder flavor 0.5

[0158] The preparation method is as follows:

[0159] S1, heating the stearic acid to 80° C. to melt;

[0160] S2. Under stirring, add elecylamine to the melt of stearic acid in step S1 and stir evenly;

[0161] S3, using a hot melt extruder to prepare a strip-shaped solid dispersion;

[0162] S4, using a mechanical pulverizer to pulverize through an 80-mesh sieve to obtain a fine powder of eleczema solid dispersion;

[0163] S5. Prepare auxiliary material granules: Add the prescribed amount of saccharin sodium into water, dissolve it, and use it as a binder for later use. Add sorbitol to the wet granulator, then add xanthan gum, start stirring and shearing (stirring speed 150rpm, shear speed 1500rpm), mix for 3min, add binder, and make soft material. Granulate the wet soft material with a 30-mesh swing granulator, dry it in a fluidized bed until the moisture content is no more than 1%, and granulate it with a 30-mesh swing granulator for later use;

[0164] S5, eleciclib solid dispersion fine powder, auxiliary material particles, anhydrous monosodium citrate, and orange powder flavor were added into a three-dimensional mixer and mixed at 13 rpm for 10 min;

[0165] S6. Granule packaging: Use granule packaging machine ZKB-180F to package into different bags of 1g, 2g, etc. according to different dosages.

[0166] Comparative Example 3

[0167] This comparative example provides an electomycin sustained-release dry suspension, the component contents of which are specifically shown in Table 9:

[0168] Table 9

[0169] Element content% Elixiram 15 Copolyvinylpyrrolidone S630 45 Sorbitol 35 Xanthan gum 1 Sodium Citrate 3 Saccharin Sodium 0.5 Orange powder flavor 0.5

[0170] The preparation method is as follows:

[0171] S1, heating the copolyvidone S630 to 100° C. to melt;

[0172] S2. Under stirring, add elecicline to the melt of copolyvidone S630 in step S1 and stir evenly;

[0173] S3, using MS220 hot melt sprayer, conveying to a two-flow gas spray gun through a twin screw, atomizing into droplets through compressed air, and solidifying into solid powder with low-temperature frozen air (-10°C to 15°C), to prepare eleczema solid dispersion fine powder;

[0174] S4. Prepare auxiliary material granules: Add the prescribed amount of saccharin sodium into water, dissolve it, and use it as a binder for later use. Add sorbitol to the wet granulator, then add xanthan gum, start stirring and shearing (stirring speed 130rpm, shear speed 1500rpm), mix for 5min, add binder, and make soft material. Granulate the wet soft material with a 30-mesh swing granulator, dry it in a fluidized bed until the moisture content is no more than 1%, and granulate it with a 30-mesh swing granulator for later use;

[0175] S5, eleciclib solid dispersion fine powder, auxiliary material granules, sodium citrate, and orange powder flavor were added into a three-dimensional mixer and mixed at 15 rpm for 10 min.

[0176] S6. Granule packaging: Use granule packaging machine ZKB-180F to package into different bags of 1g, 2g, etc. according to different dosages.

[0177] Comparative Example 4

[0178] This comparative example provides an electomycin sustained-release dry suspension, the component contents of which are specifically shown in Table 10:

[0179] Table 10

[0180] Element content% Elixiram 15 Stearic acid 40 Sorbitol 35 Hydroxypropylcellulose 5 Monosodium citrate anhydrous 4 Aspartame 0.5 Peach powder flavor 0.5

[0181] The preparation method is as follows:

[0182] S1, heating the stearic acid to 80° C. to melt;

[0183] S2. Under stirring, add elecylamine to the melt of stearic acid in step S1 and stir evenly;

[0184] S3, using MS220 hot melt sprayer, conveying to a two-flow gas spray gun through a twin screw, atomizing into droplets through compressed air, and solidifying into solid powder with low-temperature frozen air (-10°C to 15°C), to prepare eleczema solid dispersion fine powder;

[0185] S4, prepare auxiliary material granules: add the prescribed amount of aspartame into water, dissolve it, and use it as a binder for later use. Add sorbitol to the wet granulator, then add hydroxypropyl cellulose, start stirring and shearing (stirring speed 130rpm, shear speed 1500rpm), mix for 3min, add binder, and make soft material. Granulate the wet soft material with a 30-mesh swing granulator, dry it in a fluidized bed until the moisture is no more than 1%, and granulate it with a 30-mesh swing granulator for later use;

[0186] S5, eleciclib solid dispersion fine powder, auxiliary material particles, anhydrous monosodium citrate, and peach powder flavor were added into a three-dimensional mixer and mixed at 13 rpm for 15 min;

[0187] S6. Granule packaging: Use granule packaging machine ZKB-180F to package into different bags of 1g, 2g, etc. according to different dosages.

[0188] Test Example 1

[0189] Sedimentation volume ratio test: According to the requirements of General Chapter 0123 of Part IV of the 2020 edition of the Chinese Pharmacopoeia, oral suspensions should be tested for sedimentation volume ratio, and the standard limit is not less than 0.90.

[0190] The products obtained in Examples 1 to 6 and Comparative Examples 1 to 4 were tested as described above, and the test results are shown in Table 11.

[0191] Table 11 Sedimentation volume ratio results

[0192] sample Sedimentation volume ratio (n=5) Example 1 0.97a Example 2 1.00a Example 3 0.95a Example 4 0.99a Example 5 0.99a Example 6 0.96a Comparative Example 1 0.41c Comparative Example 2 0.96a Comparative Example 3 0.95a Comparative Example 4 0.82b

[0193] Groups marked with different letters have significant differences at p < 0.05.

[0194] Test Example 2

[0195] Taste test

[0196] The samples of eleciclide sustained-release dry suspension prepared in Examples 1 to 6 and Comparative Examples 1 to 4 were suspended in warm water. 24 testers were selected to test the taste, and the results are shown in Table 12:

[0197] Table 12 Taste test results

[0198]

[0199]

[0200] The taste test results of Comparative Example 1 also confirmed that the product of the existing patent using 80-120 mesh eleczema mixed with conventional excipients and then wet granulated to obtain 30-50 mesh granules could not cover up the spicy taste of eleczema.

[0201] Test Example 3

[0202] Release curve determination

[0203] (1) Instruments and reagents

[0204] Instrument: RCZ-8A Intelligent Drug Dissolution Apparatus (Tianjin University Precision Instrument Factory)

[0205] Test drug: Elecithin sustained-release dry suspension

[0206] Sample amount: 0.5 g for Example 3, 1.5 g for Example 4, 1.0 g for other examples, and 1.0 g for Comparative Examples 1 to 4.

[0207] (2) Detection method: UV-visible spectrophotometry

[0208] Detection wavelength: 326nm

[0209] Dissolution method: Paddle method

[0210] Dissolution medium: pH 6.80 phosphate buffer 900ml

[0211] Speed: 50 rpm

[0212] Sampling time points: 5, 15, 30, 45, 60, 120, 240, 360 and 480 min

[0213] Detection method: Test solution: Take 10ml of each sample solution, filter, take 5ml of the filtrate, place it in a 50ml volumetric flask, and dilute to the mark with solvent. Reference solution: Take about 10mg of elecylamine reference substance, accurately weigh it, place it in a 50ml volumetric flask, add 20ml of methanol, dissolve it, dilute to the mark with methanol, and shake well; accurately measure 5ml of the above solution, place it in a 50ml volumetric flask, use the dissolution medium as the solvent, as the reference solution.

[0214] The release curve measurement results are shown in Table 13 and Table 13. Figure 1 shown.

[0215] Table 13 Release curve test results

[0216] Serial number / min 5 15 30 45 60 120 240 360 480 Example 1 15.52 29.04 40.25 50.39 56.91 66.25 78.97 88.66 98.58 Example 2 8.61 15.99 27.34 35.02 41.01 51.26 68.35 83.06 95.19 Example 3 10.91 20.01 29.88 37.71 42.97 57.44 71.32 87.25 97.20 Example 4 10.56 22.92 30.81 38.32 44.87 57.29 72.22 86.66 95.01 Example 5 9.88 20.06 26.01 36.24 40.86 53.65 69.09 83.61 94.65 Example 6 7.85 15.90 27.61 34.63 38.99 52.06 72.70 86.82 95.79 Comparative Example 1 24.11 38.47 55.56 77.9 85.38 98.80 99.26 99.93 100.1 Comparative Example 2 11.34 20.11 27.26 36.94 45.66 59.73 71.08 82.90 94.29 Comparative Example 3 21.45 37.24 52.51 75.70 92.66 99.33 100.1 99.39 99.88 Comparative Example 4 12.23 19.98 28.45 35.36 40.91 56.52 71.69 85.50 96.75

[0217] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0218] The above-described embodiments only express several implementation methods of the present invention, which are convenient for understanding the technical solutions of the present invention in detail, but they cannot be understood as limiting the scope of protection of the invention patent. It should be pointed out that for ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. It should be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided by the present invention are all within the protection scope of the claims attached to the present invention. Therefore, the protection scope of the patent of the present invention shall be based on the contents of the attached claims, and the description and drawings can be used to interpret the contents of the claims.

Claims

1. An eleciclide sustained-release dry suspension, characterized in that: The eleciclide sustained-release dry suspension comprises the following components in percentage by mass: Wherein, the sustained-release carrier is selected from stearic acid; The suspending agent is selected from xanthan gum; The flavoring agent is selected from one or more of saccharin sodium, sucrose and aspartame; The aromatic flavoring agent is selected from one or more of orange powder flavor, peach powder flavor, vanilla flavor and mouthfeel flavor; The filler is selected from sorbitol; The pH regulator is selected from anhydrous monosodium citrate; The preparation method of the eleczyme sustained-release dry suspension comprises the following steps: heating the sustained-release carrier to prepare a molten liquid; The molten liquid is mixed with the eleciclide and then subjected to hot melt spraying to prepare an eleciclide solid dispersion; The filler, the suspending agent and the flavoring agent are mixed, wet granulated, and then dried to prepare auxiliary material granules; The eleciclib solid dispersion, the auxiliary material particles, the pH regulator and the aromatic flavoring agent are mixed.

2. The eleciclide sustained-release dry suspension according to claim 1, characterized in that The molecular weight of the xanthan gum is 6×10 6 ~10×10 6 or 10×10 6 ~25×10 6 ; The molecular weight of the hydroxypropyl methylcellulose is 10,000 to 150,000; and / or the viscosity of a 1% aqueous solution of the hydroxypropyl methylcellulose is 12 mPa.s to 18 mPa.s; The molecular weight of the sodium carboxymethyl cellulose is 90,000 to 200,000 or 200,000 to 700,000; The molecular weight of the sodium alginate is 4000-185000; and / or the viscosity of a 1% aqueous solution of the sodium alginate is 20mPa.s-400mPa.s.

3. The method for preparing the eleciclib sustained-release dry suspension according to claim 1, characterized in that: The heating temperature is 70°C to 100°C.

4. The method for preparing the eleciclide sustained-release dry suspension according to claim 1, characterized in that: The conditions for the hot melt spray treatment include: the low temperature freezing air temperature is -10°C to 15°C.

Images