CN114796127A - Iloxamine sustained-release dry suspension and preparation method thereof - Google Patents
Iloxamine sustained-release dry suspension and preparation method thereof Download PDFInfo
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- CN114796127A CN114796127A CN202210527516.6A CN202210527516A CN114796127A CN 114796127 A CN114796127 A CN 114796127A CN 202210527516 A CN202210527516 A CN 202210527516A CN 114796127 A CN114796127 A CN 114796127A
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- dry suspension
- sustained
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- release dry
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- 238000013268 sustained release Methods 0.000 title claims abstract description 32
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- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims abstract description 12
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- Animal Behavior & Ethology (AREA)
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- Pharmacology & Pharmacy (AREA)
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- Public Health (AREA)
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- Molecular Biology (AREA)
- Pain & Pain Management (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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- Organic Chemistry (AREA)
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Abstract
The invention provides an iloxamine sustained-release dry suspension which comprises the following components in percentage by mass: 10 to 30 percent of the ilexlyamine, 30 to 60 percent of the slow release carrier, 10 to 57 percent of the filling agent, 1 to 5 percent of the suspending agent, 1 to 4 percent of the pH regulator, 0.2 to 1 percent of the flavoring agent and 0.2 to 1 percent of the aromatic flavoring agent; wherein, the slow release carrier is selected from one or two of stearic acid and glycerin monostearate; 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 being added with water, no precipitation and layering problems, good sustained-release performance and no spicy taste.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to an ilexlyamine sustained-release dry suspension and a preparation method thereof.
Background
Epilepsy is a chronic disorder of the central nervous system and requires long-term drug therapy. The effective rate of the antiepileptic drugs clinically used at present is only 70-80%, and the antiepileptic drugs cannot prevent the formation of epileptic foci and the progressive course of disease and can only relieve symptoms. In addition, antiepileptic drugs have many adverse reactions, which relate to a plurality of systems of human bodies, and the common adverse reactions include rash, dizziness, nausea, anorexia, abnormal psychobehavior, abnormal liver and kidney functions, dysfunction of endocrine system, enlargement of lymph nodes and the like. Moreover, epileptics often need to take medicines for a long time or several anti-epileptic medicines simultaneously, which aggravates the adverse reaction of the medicines. The childhood phase is an important growth and development phase, the treatment of children epileptic patients is different from that of adults, and for children epileptic patients, the treatment of children epileptic patients by adopting antiepileptic drugs with obvious application effect and less adverse reactions is more important.
Pepper belongs to a segetalis plant, is an evergreen vine plant of the Piperaceae family, is applied to folk therapy for controlling epileptic seizure and is continuously delivered in Xishuangbanna of Yunnan province of China, and is discovered and concerned by experts of the university of Beijing medical science later, effective, broad-spectrum and low-toxicity piperine novel domestic plant antiepileptic drug ilalumide tablets are developed through continuous efforts, and the good news is brought to epileptics, especially children epileptics.
The ilacetin is a chemical derivative of piperineBiological, also called as antiepileptic, is chemically named 3- (3 ', 4' -methylenedioxyphenyl) -acryloyl piperidine or 3 ', 4' -methylenedioxycinnamoyl piperidine with molecular formula C 15 H 17 NO 3 . The alexan can inhibit the generation and development of epilepsy by acting on sodium channels to inhibit the generation of sodium current, and is a novel antiepileptic drug acting on the sodium channels. The chemical structure of the alexidine comprises two benzene ring-like structures divided by 4C-C or C-N single bonds. The structure is very similar to that of the traditional antiepileptic drug carbamazepine and lamotrigine, and the two benzene ring structures are divided by one or more C-C or C-N single bonds, namely the two benzene ring structures play an important role in the antiepileptic effect of the drug. Since carbamazepine and lamotrigine can prevent generalized tonic clonic seizures and partial seizures by inhibiting sodium channel high-frequency discharge, it is speculated that ilazepine may have a comparable therapeutic effect on partial seizures.
However, since the ilexamine is derived from pepper, the drug has a strong pungent taste, thereby making pediatric epileptic patients poorly compliant with it. And the traditional ilex preparations are all tablets, and have no special dosage form for children. The therapeutic window of antiepileptic drugs is generally narrow, and the adult dosage of the marketed ilazeramine tablets is as follows: the dosage is not accurate enough because the tablet is taken for children 2 times a day and 1-3 tablets (50-150mg) are taken once. The traditional Chinese medicine composition is taken for a plurality of times a day, the blood concentration of children patients fluctuates greatly, if the blood concentration is too high, great toxic and side effects exist, and if the blood concentration is too low, an ideal curative effect cannot be achieved.
Aiming at children, the old and epileptic patients with difficulty in swallowing, patent CN102697779B discloses an ilexlyamine pharmaceutical composition with high dissolution rate and a preparation method thereof, wherein the ilexlyamine with 80-120 meshes and auxiliary materials are prepared into particles with 30-50 meshes, and the preferable formulation is dry suspension. However, the iloxamine preparation obtained by the technology has the problem of poor suspension uniformity due to the characteristics of difficult solubility and strong hydrophobicity of the iloxamine. In addition, this document employs conventional flavoring methods such as addition of sweeteners or flavors without masking the pungent taste, and testers test that the formula does not mask the pungent taste.
Disclosure of Invention
Based on the above, the invention provides the ilex slow-release dry suspension which is good in suspension uniformity after being added with water, free of the problems of precipitation and layering, good in slow-release performance and free of pungent taste.
The invention is realized by the following technical scheme.
The slow-release dry suspension of the iloxamine comprises the following components in percentage by mass:
wherein, the slow release carrier is selected from one or two of stearic acid and glycerin monostearate;
the suspending agent is selected from one or more of xanthan gum, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and sodium alginate.
In one embodiment, the slow-release dry suspension of the ilamex comprises the following components in percentage by mass:
in one embodiment, the bulking agent is selected from one or both of sorbitol and mannitol.
In one embodiment, the pH adjusting agent is selected from one or more of anhydrous monosodium citrate, sodium citrate and sodium bicarbonate.
In one embodiment, the flavoring agent is selected from one or more of sodium saccharin, sucrose, and aspartame;
the aromatic flavoring agent is selected from one or more of orange powder essence, juicy peach powder essence, vanilla essence and mouthfeel essence.
In one embodiment, the suspending agent is xanthan gum.
In one embodiment, the xanthan gum has a molecular weight of 6 × 10 6 ～10×10 6 Or 10X 10 6 ～25×10 6 ；
The molecular weight of the hydroxypropyl methyl cellulose is 10000-150000; and/or the viscosity of the 1% aqueous solution of the hydroxypropyl methyl cellulose is 12-18 mPa.s;
the molecular weight of the sodium carboxymethylcellulose is 90000-200000 or 200000-700000;
the molecular weight of the sodium alginate is 4000-185000; and/or the viscosity of the 1% aqueous solution of the sodium alginate is 20 mPa.s-400 mPa.s.
The invention also provides a preparation method of the slow-release dry suspension of the ilexemide, which comprises the following steps:
heating the sustained-release carrier to prepare a molten liquid;
mixing the molten liquid with the ilacetamide, and then carrying out hot-melt spraying treatment to prepare an ilacetamide solid dispersion;
mixing the filler, the suspending agent and the flavoring agent, performing wet granulation, and then drying to prepare auxiliary material granules;
mixing the solid dispersion of the ilex, the auxiliary material particles, the pH regulator and the aromatic flavoring agent.
In one embodiment, the temperature of the heating is 70 ℃ to 100 ℃.
In one embodiment, the conditions of the hot melt spray process include a low temperature refrigerated air temperature of-10 ℃ to 15 ℃.
Compared with the prior art, the slow-release dry suspension of the ilex has the following beneficial effects:
the sustained-release dry suspension of the ilaemide adopts a specific preparation formula, further limits that the suspending agent is one or more of xanthan gum, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and sodium alginate, and the sustained-release carrier is one or two of stearic acid and glyceryl monostearate, and cooperates with the filling agent, the pH regulator, the flavoring agent and the aromatic flavoring agent, thereby solving the characteristics of insolubility and strong hydrophobicity of the ilaemide, and the obtained slow-release dry suspension of the ilaemide has good suspension uniformity, no precipitation and layering problems after water is added, and has better sustained-release performance. Meanwhile, the suspending agent high molecular material in the prescription of the iloxamine sustained-release dry suspension can also obviously improve the strong spicy taste of iloxamine, thereby improving the compliance of patients, especially children patients.
Drawings
Fig. 1 is a release curve chart of an iloxelamine slow-release dry suspension provided by the embodiment of the invention;
FIG. 2 is a graph representing the strong hydrophobicity of an ilamicine starting material provided by the present invention.
Detailed Description
To facilitate an understanding of the invention, the invention will now be described more fully with reference to the accompanying drawings. Preferred embodiments of the present invention are shown in the drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
Mode of administration
As used herein, "drug" includes any agent, compound, composition, or mixture that provides a physiological and/or pharmacological effect, either in vivo or in vitro, and often provides a beneficial effect. The "drug" is not particularly limited in the range that produces physiological and/or pharmacological effects in vivo, and may be systemic or local. 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 with other substances.
As used herein, "therapeutically effective amount" refers to an amount of a compound of the invention that will elicit the biological or medical response of an individual, e.g., an amount of a compound of the invention that will bring a physiologically and/or pharmacologically positive effect to the individual, including but not limited to reducing or inhibiting enzyme or protein activity or ameliorating symptoms, alleviating a condition, slowing or delaying the progression of a disease or preventing a disease, etc.
The invention provides an ilosamine slow-release dry suspension which comprises the following components in percentage by mass:
wherein, the slow release carrier is selected from one or two of stearic acid and glycerin monostearate;
the suspending agent is selected from one or more of xanthan gum, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and sodium alginate.
The alexandrine has the characteristics of poor solubility and strong hydrophobicity, as shown in figure 2, so that the problem of poor suspension uniformity exists in the ilexandrine dry suspension preparation obtained by the conventional technology.
In a specific example, the slow-release dry suspension of the ilamex comprises the following components in percentage by mass:
in a particular example, the bulking agent is selected from one or both of sorbitol and mannitol.
In a specific example, the pH adjusting agent is selected from one or more of anhydrous monosodium citrate, sodium citrate, and sodium bicarbonate.
In a particular example, the flavoring agent is selected from one or more of sodium saccharin, sucrose, and aspartame.
In one particular example, the aromatic flavoring agent is selected from one or more of orange powder essence, honey peach powder essence, vanilla essence, and mouth feel essence.
In one particular example, the suspending agent is xanthan gum.
In one specific example, the molecular weight of xanthan gum is 6 x 10 6 ～10×10 6 Or 10X 10 6 ～25×10 6 。
In a specific example, the hydroxypropyl methylcellulose has a molecular weight of 10000-150000; and/or the viscosity of a 1% aqueous solution of hydroxypropyl methylcellulose is 12 to 18 mPa.s.
In a specific example, the molecular weight of the sodium carboxymethylcellulose is 90000-200000 or 200000-700000.
In a specific example, the molecular weight of the sodium alginate is 4000-185000; and/or the viscosity of the 1% aqueous solution of sodium alginate is 20 mPa.s-400 mPa.s.
The invention also provides a preparation method of the ilexlyamine sustained-release dry suspension, which comprises the following steps:
heating the sustained-release carrier to prepare a molten liquid;
mixing the molten liquid with the ilacetamide, and then carrying out hot-melt spraying treatment to prepare an ilacetamide solid dispersion;
mixing the filler, the suspending agent and the flavoring agent, performing wet granulation, and then drying to prepare auxiliary material granules;
mixing the solid dispersion of the ilex, the auxiliary material particles, the pH regulator and the aromatic flavoring agent.
The invention solves the problem of strong pungent taste brought by the ilex by screening the high-molecular suspending agent material and combining the inclusion effect of the solid dispersion technology, thereby greatly improving the compliance of patients.
In one specific example, the temperature of heating is 70 ℃ to 100 ℃. It is understood that the heating temperature includes, but is not limited to, 70 deg.C, 72 deg.C, 74 deg.C, 76 deg.C, 78 deg.C, 80 deg.C, 81 deg.C, 82 deg.C, 83 deg.C, 84 deg.C, 85 deg.C, 86 deg.C, 87 deg.C, 88 deg.C, 89 deg.C, 90 deg.C, 92 deg.C, 94 deg.C, 96 deg.C, 98 deg.C, and 100 deg.C.
In one particular example, the conditions of the hot melt spray process include: the air temperature of the low-temperature freezing is-10 ℃ to 15 ℃. As will be understood, the air temperature of the low temperature freezing includes, but is not limited to, -10 ℃, -9 ℃, -8 ℃, -7 ℃, -6 ℃, -5 ℃, -4 ℃, -3 ℃, -2 ℃, -1 ℃, 0 ℃, 2 ℃, 3 ℃,4 ℃, 5 ℃, 7 ℃, 9 ℃, 11 ℃, 13 ℃, 15 ℃.
In the invention, the low-temperature freezing technology directly prepares the fine powder, and can solve the common aging problem caused by high humidity and high heat in the solid dispersion crushing process, thereby obviously improving the stability of the medicine.
In a more specific example, the preparation method of the sustained-release dry suspension of the ilexlyamine comprises the following steps:
heating the sustained-release carrier to 70-100 ℃ for melting to prepare a molten liquid;
adding the ilamex into the molten liquid under the stirring state, and uniformly stirring; conveying the mixture to a two-flow gas type spray gun by an MS220 hot-melt sprayer through a double screw, atomizing the mixture into fog drops through compressed air, and solidifying the fog drops and air frozen at the low temperature of-10-15 ℃ into solid powder to prepare an alexandrine solid dispersion;
adding a flavoring agent into water, dissolving, and preparing an adhesive;
adding the filler into a wet granulator, adding the suspending agent, starting stirring and shearing at the stirring speed of 130-160 rpm and the shearing speed of 1500-1800 rpm, mixing for 3-5 min, and adding the adhesive to prepare a soft material; carrying out 30-mesh granulation on the soft material swing granulator, drying by a fluidized bed until the moisture is not more than 1%, and carrying out 30-mesh dry granulation on the swing granulator to prepare auxiliary material particles;
adding the solid dispersion of the ilazeamide, the auxiliary material particles, the pH regulator and the aromatic flavoring agent into a three-dimensional mixer, and mixing for 10-15 min under the condition of 13-15 rpm.
The iloxamine sustained-release dry suspension and the preparation method thereof of the present invention are further described in detail with reference to the following specific examples. The starting materials used in the following examples are all commercially available products unless otherwise specified.
Example 1
The embodiment provides an iloxamine sustained-release dry suspension, which specifically comprises the following components in percentage by weight as shown in table 1:
TABLE 1
The preparation method comprises the following steps:
s1, heating the glyceryl monostearate to 85 ℃ to melt;
s2, adding the ilamex into the melted glycerin monostearate in the step S1 under the stirring state, and uniformly stirring;
s3, conveying the mixture to a two-flow gas type spray gun through a double screw by using an MS220 hot-melt sprayer, atomizing the mixture into fog drops through compressed air, and solidifying the fog drops and air frozen at low temperature (-10-15 ℃) into solid powder to prepare fine powder of the solid dispersion of the ilex;
s4, preparing auxiliary material particles: the prescribed amount of aspartame is added to water and dissolved to be used as a binder for standby. Adding sorbitol into wet granulator, adding carboxymethylcellulose sodium, stirring and shearing (stirring speed 130rpm, shearing speed 1500rpm), mixing for 3min, adding binder, and making into soft material. Carrying out 30-mesh granulation on the wet soft material by using a swing granulator, drying the wet soft material by using a fluidized bed until the moisture is not more than 1%, and carrying out 30-mesh dry granulation by using the swing granulator for later use;
s5, adding the fine powder of the solid dispersion of the ilex, the auxiliary material particles, the sodium citrate and the juicy peach powder essence into a three-dimensional mixer, and mixing for 10min at 13 rpm;
s6, packaging the granules: packaging into different bags of 1g, 2g and the like according to different dosages by using a particle packaging machine ZKB-180F.
Example 2
The embodiment provides an iloxamine sustained-release dry suspension, and the component contents of the suspension are specifically shown in table 2:
TABLE 2
| Composition (I) | Content% |
| Ilexlyamine | 15 |
| |
40 |
| |
40 |
| Xanthan gum | 2 |
| Anhydrous monosodium citrate | 2 |
| Saccharin sodium salt | 0.5 |
| Taste essence | 0.5 |
The preparation method comprises the following steps:
s1, heating the stearic acid to 80 ℃ for melting;
s2, adding the ilamex into the stearic acid melt in the step S1 under the stirring state, and uniformly stirring;
s3, conveying the mixture to a two-flow gas type spray gun through a double screw by using an MS220 hot-melt sprayer, atomizing the mixture into fog drops through compressed air, and solidifying the fog drops and air frozen at low temperature (-10-15 ℃) into solid powder to prepare fine powder of the solid dispersion of the ilex;
s4, preparing auxiliary material particles: adding the saccharin sodium salt with the prescription amount into water, dissolving, and using as a binder for standby. Adding sorbitol into a wet granulator, adding xanthan gum, starting stirring and shearing (the stirring speed is 150rpm, the shearing speed is 1500rpm, mixing for 5min, adding an adhesive, preparing a soft material, carrying out 30-mesh granulation on the wet soft material by a swing granulator, drying by a fluidized bed until the moisture is not more than 1%, and carrying out 30-mesh dry granulation by the swing granulator for later use.
S5, adding the fine powder of the solid dispersion of the alexidine, the auxiliary material particles, the anhydrous monosodium citrate and the taste essence into a three-dimensional mixer, and mixing for 10min at 15 rpm.
S6, packaging the granules: packaging into different bags of 1g, 2g and the like according to different dosages by using a particle packaging machine ZKB-180F.
Example 3
The embodiment provides an iloxamine sustained-release dry suspension, and the component contents of the suspension are specifically shown in table 3:
TABLE 3
| Composition (I) | |
| Ilexlyamine | |
| 30 | |
| Stearic acid | 55 |
| Mannitol | 12 |
| Xanthan gum | 1.5 |
| Citric acid sodium salt | 1 |
| Saccharin sodium salt | 0.2 |
| Juicy peach powder essence | 0.3 |
The preparation method comprises the following steps:
s1, heating the stearic acid to 80 ℃ for melting;
s2, adding the ilamex into the stearic acid melt in the step S1 under the stirring state, and uniformly stirring;
s3, conveying the mixture to a two-flow gas type spray gun through a double screw by using an MS220 hot-melt sprayer, atomizing the mixture into fog drops through compressed air, and solidifying the fog drops and air frozen at low temperature (-10-15 ℃) into solid powder to prepare fine powder of the solid dispersion of the ilex;
s4, preparing auxiliary material particles: adding the saccharin sodium salt with the prescription amount into water, dissolving, and using as a binder for standby. Adding mannitol into a wet granulator, adding xanthan gum, starting stirring and shearing (stirring speed is 160rpm, shearing speed is 1800rpm, mixing for 5min, adding an adhesive, and preparing a soft material, carrying out 30-mesh granulation on the wet soft material by a swing granulator, drying by a fluidized bed until the moisture is not more than 1%, and carrying out 30-mesh dry granulation by the swing granulator for later use;
s5, adding the fine powder of the solid dispersion of the ilex, the auxiliary material particles, the sodium citrate and the juicy peach powder essence into a three-dimensional mixer, and mixing for 15min at 13 rpm;
s6, packaging the granules: packaging with granule packaging machine ZKB-180F into different bags such as 1g, 2g, etc. according to different dosages.
Example 4
The embodiment provides an iloxamine sustained-release dry suspension, and the component contents of the suspension are specifically shown in table 4:
TABLE 4
| Composition (I) | Content% |
| Ilexlyamine | 10 |
| |
30 |
| Sorbitol | 50 |
| Xanthan gum | 5 |
| Anhydrous monosodium citrate | 3 |
| Saccharin sodium salt | 1 |
| Vanilla essence | 1 |
The preparation method comprises the following steps:
s1, heating the stearic acid to 80 ℃ for melting;
s2, adding the ilamex into the stearic acid melt in the step S1 under the stirring state, and uniformly stirring;
s3, conveying the mixture to a two-flow gas type spray gun through a double screw by using an MS220 hot-melt sprayer, atomizing the mixture into fog drops through compressed air, and solidifying the fog drops and air frozen at low temperature (-10-15 ℃) into solid powder to prepare fine powder of the solid dispersion of the ilex;
s4, preparing auxiliary material particles: adding the saccharin sodium salt with the prescription amount into water, dissolving, and using as a binder for standby. Adding sorbitol into wet granulator, adding xanthan gum, stirring and shearing (stirring speed 150rpm, shearing speed 1500rpm), mixing for 3min, adding binder, and making into soft material. Carrying out 30-mesh granulation on the wet soft material by using a swing granulator, drying the wet soft material by using a fluidized bed until the moisture is not more than 1%, and carrying out 30-mesh dry granulation by using the swing granulator for later use;
s5, adding the fine powder of the solid dispersion of the ilex, the auxiliary material particles, the anhydrous monosodium citrate and the vanilla essence into a three-dimensional mixer, and mixing for 10min at 13 rpm;
s6, packaging the granules: packaging into different bags of 1g, 2g and the like according to different dosages by using a particle packaging machine ZKB-180F.
Example 5
The embodiment provides an iloxamine sustained-release dry suspension, the component contents of which are specifically shown in table 5:
TABLE 5
The preparation method comprises the following steps:
s1, heating the stearic acid to 80 ℃ for melting;
s2, adding the ilamex into the stearic acid melt in the step S1 under the stirring state, and uniformly stirring;
s3, conveying the mixture to a two-flow gas type spray gun through a double screw by using an MS220 hot-melt sprayer, atomizing the mixture into fog drops through compressed air, and solidifying the fog drops and air frozen at low temperature (-10-15 ℃) into solid powder to prepare fine powder of the solid dispersion of the ilex;
s4, preparing auxiliary material particles: adding the saccharin sodium salt with the prescription amount into water, dissolving, and using as a binder for standby. Adding mannitol into wet granulator, adding hydroxypropyl methylcellulose E15, stirring and shearing (stirring speed 150rpm, shearing speed 1500rpm), mixing for 3min, adding binder, and making into soft material. Carrying out 30-mesh granulation on the wet soft material by using a swing granulator, drying the wet soft material by using a fluidized bed until the moisture is not more than 1%, and carrying out 30-mesh dry granulation by using the swing granulator for later use;
s5, adding the fine powder of the solid dispersion of the ilex, the auxiliary material particles, the anhydrous monosodium citrate and the orange powder essence into a three-dimensional mixer, and mixing for 10min at 13 rpm;
s6, packaging the granules: packaging into different bags of 1g, 2g and the like according to different dosages by using a particle packaging machine ZKB-180F.
Example 6
The embodiment provides an iloxamine sustained-release dry suspension, the component contents of which are specifically shown in table 6:
TABLE 6
The preparation method comprises the following steps:
s1, heating the stearic acid to 80 ℃ for melting;
s2, adding the ilamex into the stearic acid melt in the step S1 under the stirring state, and uniformly stirring;
s3, conveying the mixture to a two-flow gas type spray gun through a double screw by using an MS220 hot-melt sprayer, atomizing the mixture into fog drops through compressed air, and solidifying the fog drops and air frozen at low temperature (-10-15 ℃) into solid powder to prepare fine powder of the solid dispersion of the ilex;
s4, preparing auxiliary material particles: the prescribed amount of sucrose was added to water, dissolved, and used as a binder for future use. Adding mannitol into wet granulator, adding sodium alginate, stirring and shearing (stirring speed 130rpm, shearing speed 1500rpm), mixing for 5min, adding binder, and making into soft material. Carrying out 30-mesh granulation on the wet soft material by using a swing granulator, drying the wet soft material by using a fluidized bed until the moisture is not more than 1%, and carrying out 30-mesh dry granulation by using the swing granulator for later use;
s5, adding the fine powder of the solid dispersion of the ilex, the auxiliary material particles, the sodium bicarbonate and the orange powder essence into a three-dimensional mixer, and mixing for 10min at 15 rpm;
s6, packaging the granules: packaging into different bags of 1g, 2g and the like according to different dosages by using a particle packaging machine ZKB-180F.
Comparative example 1
The comparative example provides an iloxamine sustained-release dry suspension, the component contents of which are specifically shown in table 7:
TABLE 7
The preparation method comprises the following steps:
s1, preparation of the ilazeamide particles:
povidone K30 with the prescription amount is added into water for dissolution, and 5% povidone K30 solution is prepared and used as an adhesive for standby;
uniformly mixing the ilaminnesamine, the cane sugar and the hydroxypropyl methylcellulose K100M, adding a binder to prepare a soft material, and finishing the particles by a wet soft material swing granulator with 30 meshes. Drying the mixture by a fluidized bed until the water content is 1 to 3 percent, and performing dry granulation by a swing granulator with 30 meshes for later use;
s2, preparing auxiliary material particles:
adding saccharin sodium in a prescribed amount into water, and dissolving to serve as an adhesive for later use;
adding mannitol into wet granulator, adding xanthan gum, stirring and shearing (stirring speed 160rpm, shearing speed 1800rpm), mixing for 3min, adding binder, and making into soft material. Carrying out 30-mesh granulation on the wet soft material by using a swing granulator, drying the wet soft material by using a fluidized bed until the moisture is not more than 1%, and carrying out 30-mesh dry granulation by using the swing granulator for later use;
s3, adding the alexidine granules, the auxiliary material granules, the anhydrous monosodium citrate and the orange powder essence into a three-dimensional mixer, and mixing for 10min at 13 rpm;
s4, packaging the granules: packaging into different bags of 1g, 2g and the like according to different dosages by using a particle packaging machine ZKB-180F.
Comparative example 2
The comparative example provides an iloxamine sustained-release dry suspension, the component contents of which are specifically shown in table 8:
TABLE 8
| Composition (I) | Content% |
| Ilexlyamine | 15 |
| |
40 |
| Sorbitol | 39 |
| Xanthan gum | 1 |
| Anhydrous monosodium citrate | 4 |
| Saccharin sodium salt | 0.5 |
| Orange powder essence | 0.5 |
The preparation method comprises the following steps:
s1, heating the stearic acid to 80 ℃ for melting;
s2, adding the iracetamide into the stearic acid melt obtained in the step S1 under the stirring state, and uniformly stirring;
s3, preparing a bar-shaped solid dispersion by using a hot-melt extruder;
s4, crushing the mixture by using a mechanical crusher and screening the mixture by using a 80-mesh screen to obtain fine powder of the solid dispersion of the ilex;
s5, preparing auxiliary material particles: adding the saccharin sodium salt with the prescription amount into water, dissolving, and using as a binder for standby. Adding sorbitol into wet granulator, adding xanthan gum, stirring and shearing (stirring speed 150rpm, shearing speed 1500rpm), mixing for 3min, adding binder, and making into soft material. Carrying out 30-mesh granulation on the wet soft material by using a swing granulator, drying the wet soft material by using a fluidized bed until the moisture is not more than 1%, and carrying out 30-mesh dry granulation by using the swing granulator for later use;
s5, adding the fine powder of the solid dispersion of the ilex, the auxiliary material particles, the anhydrous monosodium citrate and the orange powder essence into a three-dimensional mixer, and mixing for 10min at 13 rpm;
s6, packaging the granules: packaging into different bags of 1g, 2g and the like according to different dosages by using a particle packaging machine ZKB-180F.
Comparative example 3
The comparative example provides an iloxamine sustained-release dry suspension, the component contents of which are specifically shown in table 9:
TABLE 9
| Composition (I) | Content% |
| Ilexlyamine | 15 |
| Co-polyvidone S630 | 45 |
| Sorbitol | 35 |
| Xanthan gum | 1 |
| Citric acid sodium salt | 3 |
| Saccharin sodium salt | 0.5 |
| Orange powder essence | 0.5 |
The preparation method comprises the following steps:
s1, heating the copovidone S630 to 100 ℃ for melting;
s2, adding the ilolexan into the molten solution of the copovidone S630 obtained in the step S1 under the stirring state, and uniformly stirring;
s3, conveying the mixture to a two-flow gas type spray gun through a double screw by using an MS220 hot-melt sprayer, atomizing the mixture into fog drops through compressed air, and solidifying the fog drops and air frozen at low temperature (-10-15 ℃) into solid powder to prepare fine powder of the solid dispersion of the ilex;
s4, preparing auxiliary material particles: adding saccharin sodium in the prescription dose into water, dissolving and using as an adhesive for standby. Adding sorbitol into wet granulator, adding xanthan gum, stirring and shearing (stirring speed 130rpm, shearing speed 1500rpm), mixing for 5min, adding binder, and making into soft material. Carrying out 30-mesh granulation on the wet soft material by using a swing granulator, drying the wet soft material by using a fluidized bed until the moisture is not more than 1%, and carrying out 30-mesh dry granulation by using the swing granulator for later use;
s5, adding the fine powder of the solid dispersion of the ilex, the auxiliary material particles, the sodium citrate and the orange powder essence into a three-dimensional mixer, and mixing for 10min at 15 rpm.
S6, packaging the granules: packaging into different bags of 1g, 2g and the like according to different dosages by using a particle packaging machine ZKB-180F.
Comparative example 4
The comparative example provides an iloxamine sustained-release dry suspension, the component contents of which are specifically shown in table 10:
watch 10
| Composition (I) | Content% |
| Ilexlyamine | 15 |
| |
40 |
| Sorbitol | 35 |
| Hydroxypropyl cellulose | 5 |
| Anhydrous monosodium citrate | 4 |
| Aspartame | 0.5 |
| Juicy peach powder essence | 0.5 |
The preparation method comprises the following steps:
s1, heating the stearic acid to 80 ℃ for melting;
s2, adding the ilamex into the stearic acid melt in the step S1 under the stirring state, and uniformly stirring;
s3, conveying the mixture to a two-flow gas type spray gun through a double screw by using an MS220 hot-melt sprayer, atomizing the mixture into fog drops through compressed air, and solidifying the fog drops and air frozen at low temperature (-10-15 ℃) into solid powder to prepare fine powder of the solid dispersion of the ilex;
s4, preparing auxiliary material particles: the prescribed amount of aspartame is added to water and dissolved to be used as a binder for standby. Adding sorbitol into wet granulator, adding hydroxypropyl cellulose, stirring and shearing (stirring speed 130rpm, shearing speed 1500rpm), mixing for 3min, adding binder, and making into soft material. Carrying out 30-mesh granulation on the wet soft material by using a swing granulator, drying the wet soft material by using a fluidized bed until the moisture is not more than 1%, and carrying out 30-mesh dry granulation by using the swing granulator for later use;
s5, adding the fine powder of the solid dispersion of the ilex, the auxiliary material particles, the anhydrous monosodium citrate and the juicy peach powder essence into a three-dimensional mixer, and mixing for 15min at 13 rpm;
s6, packaging the granules: packaging into different bags of 1g, 2g and the like according to different dosages by using a particle packaging machine ZKB-180F.
Test example 1
Sedimentation volume ratio test: according to the requirement of 0123 of the national pharmacopoeia 2020 edition four-part general rule, the oral suspension should be subjected to sedimentation volume ratio inspection, and the standard limit is not lower than 0.90.
The products obtained in examples 1 to 6 and comparative examples 1 to 4 were examined as described above, and the results are shown in Table 11.
TABLE 11 sedimentation volume ratio results
| Sample (I) | 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 example3 | 0.95a |
| Comparative example 4 | 0.82b |
Between groups marked with different letters, p <0.05, with significant differences.
Test example 2
Taste testing
Samples of the iloxamine sustained-release dry suspension prepared in examples 1 to 6 and comparative examples 1 to 4 were suspended by adding warm water. The oral sensation was tested by selecting 24 testers, and the results are shown in table 12 below:
table 12 taste test results
The taste test result of the comparative example 1 also proves that the product of the granules with 30-50 meshes is prepared by mixing 80-120 meshes of the ilamex and the conventional auxiliary materials and then carrying out wet granulation in the prior patent, and the spicy taste of the ilamex cannot be covered.
Test example 3
Release Curve determination
(1) Instrument and reagent
The instrument comprises: RCZ-8A Intelligent medicine dissolving instrument (precision instruments factory of Tianjin university)
Reagent testing: iloxamine slow-release dry suspension
Sample amount: 0.5g was taken for example 3, 1.5g was taken for example 4, 1.0g was taken for other examples, and 1.0g was taken for comparative examples 1 to 4.
(2) The detection method comprises the following steps: ultraviolet-visible spectrophotometry
Detection wavelength: 326nm
The dissolution method comprises the following steps: paddle method
Dissolution medium: 900ml of phosphate buffer, pH6.80
Rotating speed: 50 revolutions per minute
Sampling time points are as follows: 5. 15, 30, 45, 60, 120, 240, 360 and 480min
The detection method comprises the following steps: test solution: 10ml of the solution is taken out of each sample, filtered, 5ml of the subsequent filtrate is taken out, placed in a 50ml measuring flask and diluted to the scale with the solvent. Control solution: taking an alexanide reference substance of about 10mg, precisely weighing, placing in a 50ml measuring flask, adding 20ml of methanol to dissolve, diluting with methanol to scale, and shaking up; precisely measuring 5ml of the above solution, placing in a 50ml measuring flask, and taking the dissolution medium as solvent as control solution.
The results of the release profile measurements are shown in table 13 and in figure 1.
TABLE 13 Release Curve test results
| 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 |
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, so as to understand the technical solutions of the present invention specifically and in detail, but not to be understood as the limitation of the protection scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. It should be understood that the technical solutions provided by the present invention, which are obtained by logical analysis, reasoning or limited experiments, are within the scope of the appended claims. Therefore, the protection scope of the present invention should be subject to the content of the appended claims, and the description and the drawings can be used for explaining the content of the claims.
Claims (10)
1. The slow-release dry suspension of the iloxamine is characterized by comprising the following components in percentage by mass:
wherein, the slow release carrier is selected from one or two of stearic acid and glycerin monostearate;
the suspending agent is selected from one or more of xanthan gum, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and sodium alginate.
2. The iloxamine sustained-release dry suspension according to claim 1, wherein the iloxamine sustained-release dry suspension comprises the following components in percentage by mass:
3. the slow-release dry suspension of ilalumide of claim 1, wherein said filler is selected from one or both of sorbitol and mannitol.
4. The slow-release dry suspension of alexidine according to claim 1, wherein said pH adjusting agent is selected from one or more of anhydrous monosodium citrate, sodium citrate and sodium bicarbonate.
5. The slow release dry suspension of ilaemide of claim 1 wherein the flavoring agent is selected from one or more of saccharin sodium, sucrose, and aspartame; and/or
The aromatic flavoring agent is selected from one or more of orange powder essence, juicy peach powder essence, vanilla essence and mouthfeel essence.
6. The slow release dry suspension of ilalumide of claim 1 wherein said suspending agent is xanthan gum.
7. The slow-release dry suspension of ilexamine according to any one of claims 1 to 6, wherein the xanthan gum has a molecular weight of 6 x 10 6 ～10×10 6 Or 10X 10 6 ～25×10 6 ；
The molecular weight of the hydroxypropyl methyl cellulose is 10000-150000; and/or the viscosity of the 1% aqueous solution of the hydroxypropyl methyl cellulose is 12-18 mPa.s;
the molecular weight of the sodium carboxymethylcellulose is 90000-200000 or 200000-700000;
the molecular weight of the sodium alginate is 4000-185000; and/or the viscosity of the 1% aqueous solution of the sodium alginate is 20 mPa.s-400 mPa.s.
8. A preparation method of the slow-release dry suspension of the ilex according to any one of claims 1 to 7, which is characterized by comprising the following steps:
heating the sustained-release carrier to prepare a molten liquid;
mixing the molten liquid with the alexanil, and then carrying out hot-melt spraying treatment to prepare an alexanil solid dispersion;
mixing the filler, the suspending agent and the flavoring agent, performing wet granulation, and then drying to prepare auxiliary material granules;
mixing the solid dispersion of the ilex, the auxiliary material particles, the pH regulator and the aromatic flavoring agent.
9. The method for preparing an ilexlyamine sustained-release dry suspension according to claim 8, wherein the heating temperature is 70-100 ℃.
10. The method for preparing an ilexlyamine sustained-release dry suspension according to claim 8, wherein the conditions of the hot-melt spray treatment comprise: the air temperature of the low-temperature freezing is-10 ℃ to 15 ℃.
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| CN101810592A (en) * | 2000-12-07 | 2010-08-25 | 尼科梅德有限责任公司 | Contain the pharmaceutical preparation that is dispersed in the active matter in the substrate |
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| CN101810592A (en) * | 2000-12-07 | 2010-08-25 | 尼科梅德有限责任公司 | Contain the pharmaceutical preparation that is dispersed in the active matter in the substrate |
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