CN108853042B - Mirtazapine freeze-dried orally disintegrating tablet and preparation method and application thereof - Google Patents
Mirtazapine freeze-dried orally disintegrating tablet and preparation method and application thereof Download PDFInfo
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- CN108853042B CN108853042B CN201811101902.9A CN201811101902A CN108853042B CN 108853042 B CN108853042 B CN 108853042B CN 201811101902 A CN201811101902 A CN 201811101902A CN 108853042 B CN108853042 B CN 108853042B
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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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
- A61P25/24—Antidepressants
Abstract
The invention discloses a mirtazapine freeze-dried orally disintegrating tablet and a preparation method thereof. The mirtazapine freeze-dried orally disintegrating tablet comprises 15 parts of mirtazapine, 5-10 parts of a skeleton supporting agent, 10-20 parts of a freeze-drying protective agent, 39-45 parts of a solubilizer and 1.5-2 parts of a flavoring agent, wherein the particle size of the mirtazapine is less than or equal to 50 microns, the mirtazapine freeze-dried orally disintegrating tablet is prepared by a freeze-drying method, and the application of the mirtazapine freeze-dried orally disintegrating tablet in preparation of an antidepressant is provided.
Description
Technical Field
The invention relates to a mirtazapine freeze-dried orally disintegrating tablet, and a preparation method and application thereof, and belongs to the field of oral preparations.
Background
Mirtazapine tablets are a novel antidepressant drug, the active ingredient mirtazapine of which produces antidepressant action by antagonizing central autologous and allogeneic adrenergic alpha 2 receptors and increasing the release of norepinephrine and 5-hydroxytryptamine (5-HT). Moreover, the effect of releasing 5-HT is that the specific 5-HT1 receptor has blocking effect on 5-HT2 and 5-HT3 receptors, and the affinity to adrenergic alpha 1 receptor and M-receptor is very low, so orthostatic hypotension and anticholinergic adverse reaction do not exist. Although having a relatively strong affinity for histamine receptors, it does not cause clinically excessive sedation.
After oral administration of a mirtazapine tablet, the active ingredient mirtazapine is rapidly absorbed (bioavailability about 50%), the plasma concentration peaks after about two hours, about 85% binds to plasma proteins, the mean half-life is 20-40 hours, occasionally up to 65 hours, and occasionally shorter half-lives are seen in young people. The elimination half-life is sized to be suitable for once-a-day dosing. The blood concentration reaches a steady state three to four days after the administration, and no in vivo accumulation occurs thereafter. Within the recommended dosage range, the pharmacokinetic form of mirtazapine is linear and mirtazapine is mostly metabolized and excreted in the body via urine and faeces within a few days after administration. The main biochemical modes are demethylation and oxidation reactions followed by conjugation. The demethylated metabolite remains pharmacologically active as the original compound.
Mirtazapine is marketed in China as 15mg mirtazapine tablets, and is not orally disintegrating tablets, or freeze-dried orally disintegrating tablets. By comparing the in vitro dissolution behavior of the example 1 of the invention with that of a 15mg mirtazapine tablet on the market in China, the dissolution rate of the example 1 of the invention is far faster than that of the mirtazapine tablet, and the in vitro dissolution behavior can reflect the absorption speed in vivo, so that the invention can effectively improve the bioavailability of the mirtazapine, and the freeze-dried orally disintegrating tablet is convenient to carry and take without water, and is more beneficial to patients to take.
Disclosure of Invention
The invention aims to provide a mirtazapine freeze-dried orally disintegrating tablet and a preparation method and application thereof.
In order to achieve the purpose, the invention provides mirtazapine freeze-dried orally disintegrating tablets which comprise, by weight, 15 parts of mirtazapine, 5-10 parts of a skeleton supporting agent, 10-20 parts of a freeze-drying protective agent, 39-45 parts of a solubilizer and 1.5-2 parts of a flavoring agent; and the particle size of the mirtazapine is less than or equal to 50 um.
Preferably, the composition comprises 15 parts of mirtazapine, 6 parts of skeleton propping agent, 15 parts of freeze-drying protective agent, 40 parts of solubilizer and 1.8 parts of flavoring agent in parts by weight.
Preferably, the skeleton propping agent is selected from one of gelatin, hydroxypropyl methylcellulose, xylitol, trehalose and pullulan or the combination thereof; more preferably, the skeletal proppant is hydroxypropylmethylcellulose E5. The matrix proppant is to prevent the tablet from collapsing after dehydration by lyophilization and is used to maintain the tablet shape.
Preferably, the lyoprotectant is mannitol or pullulan; more preferably, the lyoprotectant is mannitol.
Preferably, the solubilizer is selected from glacial acetic acid, citric acid or tartaric acid; more preferably, the solubilizer is citric acid.
Preferably, the flavoring agent is selected from one of sucralose, steviosin and essence or the combination thereof; more preferably, the flavoring agent is sucralose and black cherry essence.
The invention also provides a preparation method of the mirtazapine freeze-dried orally disintegrating tablet, which comprises the following steps:
(1) adding the solubilizer and mirtazapine in the weight parts according to claim 1 into a proper amount of water to be fully dissolved, adding the skeleton propping agent, the freeze-drying protective agent and the flavoring agent to be fully and uniformly dissolved, and adding water to a constant volume of 300 ml;
(2) sucking the liquid medicine prepared in the step (1), and adding the liquid medicine into a tablet die;
(3) quickly freezing and forming the mould loaded with the liquid medicine obtained in the step (2) in an environment of-75 to-120 ℃;
(4) putting the quick-frozen and molded solid liquid medicine obtained in the step (3) into a freeze dryer, keeping the liquid medicine at-40 ℃ for 30 minutes, vacuumizing the liquid medicine until the vacuum degree is 10-20 Pa, keeping the vacuum degree for 120 minutes, heating the liquid medicine to-25 to-15 ℃ for 120 minutes, heating the liquid medicine to-15 to 0 ℃ for 120 minutes, heating the liquid medicine to 5-10 ℃ for 120 minutes, heating the liquid medicine to 20-25 ℃ for 120 minutes, and heating the liquid medicine to 30-35 ℃ for 180 minutes;
(5) and discharging, laminating, blanking and printing batch numbers.
The invention also provides application of the mirtazapine freeze-dried orally disintegrating tablet in preparation of an antidepressant.
Drawings
FIG. 1 is a graph of the in vitro dissolution profile of a commercial product of mirtazapine and example 1 in 0.1M hydrochloric acid solution;
FIG. 2 is a graph of the in vitro dissolution profile of commercially available mirtazapine and example 1 in acetate buffer at pH 4.0;
FIG. 3 is an in vitro dissolution profile of a commercial product of mirtazapine and example 1 in phosphate buffer at pH 4.5;
FIG. 4 is a graph of the in vitro dissolution profile of a commercial product of mirtazapine and example 1 in phosphate buffer at pH 6.8;
FIG. 5 is a graph of the time course of the meal prodrug of the pharmacokinetic index test of example 1(T) and Remeturon (R);
FIG. 6 is a graph of the post-prandial dose-time for the pharmacokinetic index test of example 1(T) and Remeturon (R).
Detailed Description
The invention will be further described with reference to specific embodiments, and the advantages and features of the invention will become apparent as the description proceeds. These examples are illustrative only and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
Selection of solubilizers by solubility
Because the mirtazapine material is slightly soluble in water and because the amount of solvent used to prepare the lyophilized orally disintegrating tablet is low, it cannot be completely dissolved, a certain amount of solubilizer has to be added.
The solubility of the raw material medicine is investigated in the experimental example, and the research shows that the mirtazapine has the best solubility in a slightly acidic environment. Because the function principle of the solubilizer is to increase the solubility of the drug in water, the proper solubilizer is investigated according to the solubility of the mirtazapine, and good solubilizers such as glacial acetic acid, citric acid, tartaric acid and the like are obtained. Citric acid is most widely used in food and medicine, and has a taste-modifying effect, so citric acid is preferably used in the invention.
The amount of citric acid was further examined and the results are shown in table 1.
Table 1 citric acid dosage test results
| Mirtazapine is used in an amount | Type of solvent | Amount of solvent used | Amount of citric acid | Phenomenon of dissolution |
| 0.15g | Purified water | 3ml | 0.15g | Can not be completely dissolved |
| 0.15g | Purified water | 3ml | 0.24g | Can not be completely dissolved |
| 0.15g | Purified water | 3ml | 0.3g | Can not be completely dissolved |
| 0.15g | Purified water | 3ml | 0.39g | Completely dissolve |
| 0.15g | Purified water | 3ml | 0.45g | Completely dissolve |
The citric acid dosage is finally optimized through the experiment.
Example 1
When the mirtazapine freeze-dried orally disintegrating tablet is prepared, the dosage of each component is as follows:
15g of mirtazapine
Citric acid 40g
Hydroxypropyl methylcellulose 6g
Mannitol 15g
0.9g of sucralose
Black cherry essence 0.9g
The purified water is fixed to the volume of 300ml
The preparation method comprises the following steps:
(1) dissolving citric acid in water, adding mirtazapine raw material, stirring uniformly to form a solution, adding mannitol, hypromellose, sucralose and black cherry essence, stirring uniformly, and diluting to a constant volume of 300ml with water;
(2) sucking the liquid medicine prepared in the step (1), and injecting 300ul of the liquid medicine into each blister mould;
(3) quickly freezing and forming the mould loaded with the liquid medicine obtained in the step (2) in an environment of-90 ℃;
(4) and (4) putting the quick-frozen and molded solid liquid medicine obtained in the step (3) into a freeze dryer, storing for 30 minutes at a low temperature of-40 ℃, vacuumizing until the vacuum degree is 15Pa, keeping for 120 minutes, heating to-15 ℃, keeping for 120 minutes, heating to 0 ℃, keeping for 120 minutes, heating to 10 ℃, keeping for 120 minutes, heating to 20 ℃, keeping for 120 minutes, heating to 35 ℃, and keeping for 80 minutes.
(5) And discharging, laminating, blanking and printing batch numbers.
This example prepares orally disintegrating tablets with a white band flavor, which disintegrate in water at 37 ℃ within 5-10 s.
Example 2
When the mirtazapine freeze-dried orally disintegrating tablet is prepared, the dosage of each component is as follows:
15g of mirtazapine
Citric acid 45g
Mannitol 15g
Gelatin 6g
Stevia rebaudianum 0.9g
Black cherry essence 0.9g
The purified water is fixed to the volume of 300ml
The preparation method comprises the following steps:
(1) dissolving citric acid in water, adding mirtazapine raw material, stirring uniformly to form a solution, adding mannitol, gelatin, steviosin and black cherry essence, stirring uniformly, and diluting to a constant volume of 300ml with water;
(2) sucking the liquid medicine prepared in the step (1), and injecting 300ul of the liquid medicine into each blister mould;
(3) quickly freezing and forming the mould loaded with the liquid medicine obtained in the step (2) in an environment of-90 ℃;
(4) and (4) putting the quick-frozen and molded solid liquid medicine obtained in the step (3) into a freeze dryer, storing for 30 minutes at a low temperature of-40 ℃, vacuumizing until the vacuum degree is 15Pa, keeping for 120 minutes, heating to-15 ℃, keeping for 120 minutes, heating to 0 ℃, keeping for 120 minutes, heating to 10 ℃, keeping for 120 minutes, heating to 20 ℃, keeping for 120 minutes, heating to 35 ℃, and keeping for 80 minutes.
(5) And discharging, laminating, blanking and printing batch numbers.
The product is white orally disintegrating tablet with fragrance, and can disintegrate in water at 37 deg.C for 10-15 s.
Example 3
When the mirtazapine freeze-dried orally disintegrating tablet is prepared, the dosage of each component is as follows:
15g of mirtazapine
Citric acid 40g
Pullulan 15g
0.9g of sucralose
Black cherry essence 0.9g
The purified water is fixed to the volume of 300ml
The preparation method comprises the following steps:
(1) dissolving citric acid in water, adding mirtazapine raw material, stirring uniformly to form a solution, adding pullulan, sucralose and black cherry essence, stirring uniformly, and adding water to a constant volume of 300 ml;
(2) sucking the liquid medicine prepared in the step (1), and injecting 300ul of the liquid medicine into each blister mould;
(3) quickly freezing and forming the mould loaded with the liquid medicine obtained in the step (2) in an environment of-90 ℃;
(4) and (4) putting the quick-frozen and molded solid liquid medicine obtained in the step (3) into a freeze dryer, storing for 30 minutes at a low temperature of-40 ℃, vacuumizing until the vacuum degree is 15Pa, keeping for 120 minutes, heating to-15 ℃, keeping for 120 minutes, heating to 0 ℃, keeping for 120 minutes, heating to 10 ℃, keeping for 120 minutes, heating to 20 ℃, keeping for 120 minutes, heating to 35 ℃, and keeping for 80 minutes.
(5) And discharging, laminating, blanking and printing batch numbers.
The product is white and fragrant orally disintegrating tablet, and can disintegrate in water at 37 deg.C for 10-30 s.
Test example 1
The disintegration time test method of the freeze-dried tablet comprises the following steps: 2 slides with 70mm multiplied by 20mm multiplied by 1.0mm are bonded with one end by a transparent adhesive tape, the slide is opened, a filter paper strip with the length of 1cm multiplied by 3cm is arranged at the position 1/3 of the bonding end of the slide, the long end is about 3mm outside the slide, the tablet is arranged on the filter paper, the slide is closed, the upper slide is naturally pressed on the tablet, the opening end is opened by about 2cm, distilled water with the temperature of 37 ℃ is dripped at the end of the filter paper exposed out of the slide by a dropper, the filter paper is wetted, the freeze-dried tablet absorbs water and collapses, the opening end of the slide is closed to 2-3mm, and the disintegration end point is regarded. The test results are shown in Table 2.
TABLE 2 disintegration time test results of inventive examples 1 to 3
| Disintegration time | Appearance of the product | |
| Example 1 | Completely disintegrating in 5-10s | White sheet, smooth surface and easy demoulding |
| Example 2 | Complete disintegration in 10-15s | White sheet, smooth surface and easy demoulding |
| Example 3 | Complete disintegration in 10-30s | White sheet, smooth surface and easy demoulding |
Test example 2
Preferably, the in vitro dissolution test is performed in inventive example 1.
Samples (twenty-four tablets each of mirtazapine commercial product and product of example 1, 15mg each) were taken, and absorbance was measured at the maximum absorption wavelength of each medium by a dissolution method (0931 second method on the four parts of the chinese pharmacopoeia 2015 edition) using a 0.1M hydrochloric acid solution, a ph4.0 acetate buffer, a ph4.5 phosphate buffer, a ph6.8 phosphate buffer, 900ml each as a dissolution medium (6 tablets each of the dissolution medium commercial product and the product of example 1), a rotation speed of 50 rpm, operating according to the method, taking an appropriate amount of the solution at 5min, 10min, 15min, 20min, 30min, 45min, filtering, taking 5ml of the precise amount of the filtrate, placing in a 10ml measuring flask, diluting to a scale with the dissolution medium, shaking up, as a sample solution, and by an ultraviolet-visible spectrophotometry (0401 on the four parts of the chinese pharmacopoeia 2015 edition).
And taking a proper amount of mirtazapine reference substance, precisely weighing, adding a proper amount of methanol to dissolve, diluting with each dissolution medium to prepare a solution containing about 17 mu g of mirtazapine per 1ml, using the solution as the reference substance solution, and measuring by the same method.
Based on the above measurement results, the elution amount was calculated by a formula and an elution curve was drawn.
Calculating the formula:
(Au/As) × (CS × V/L) × 100 in% dissolution
Wherein:
absorbance of sample solution
As ═ absorbance of control solution
Concentration of CS ═ control solution (mg/ml)
V＝900ml×2
L ═ mark amount (mg/tablet)
The limit is 80% of the indicated amount and should be met.
See fig. 1-4 for each dissolution profile.
Test example 3
Preferably, the method of example 1 of the present invention is used for the study of the bioequivalence of human body, and the test study is carried out on the marketed product of Remeturon, and C is carried out before meal and after meal respectivelymaxAnd (blood peak concentration) and AUC (area under the curve of the blood concentration) pharmacokinetic index tests and grades, and finally, a 90% confidence interval is calculated, and the acceptance standard of 80.00-125.00 is considered as the biological equivalence of the tested human body and the reference human body. See fig. 5, 6, and table 3 below for test results.
Table 3 results of testing the bioequivalence of example 1 of the present invention to rimexolone in human body
Wherein T represents the test formulation (inventive example 1) and R represents the reference formulation (Remeturon).
Claims (9)
1. The mirtazapine freeze-dried orally disintegrating tablet is characterized by comprising 15 parts of mirtazapine, 5-10 parts of a skeleton propping agent, 10-20 parts of a freeze-drying protective agent, 39-45 parts of a solubilizer and 1.5-2 parts of a flavoring agent in parts by weight; and the particle size of the mirtazapine is less than or equal to 50 um; the skeleton propping agent is selected from one or the combination of gelatin, hydroxypropyl methylcellulose, xylitol, trehalose and pullulan; the freeze-drying protective agent is mannitol or pullulan; the solubilizer is selected from glacial acetic acid, citric acid or tartaric acid.
2. The freeze-dried mirtazapine orally disintegrating tablet according to claim 1, comprising 15 parts mirtazapine, 6 parts matrix proppant, 15 parts lyoprotectant, 40 parts solubilizer and 1.8 parts flavoring, by weight.
3. The freeze-dried, orally disintegrating mirtazapine tablet of claim 1, wherein the matrix proppant is hydroxypropylmethylcellulose E5.
4. The lyophilized orally disintegrating mirtazapine tablet of claim 1, wherein the lyoprotectant is mannitol.
5. The lyophilized orally disintegrating tablet of mirtazapine of claim 1, wherein the solubilizing agent is citric acid.
6. The freeze-dried orally disintegrating mirtazapine tablet of claim 1, wherein the flavoring agent is selected from one of sucralose, steviosin, flavors, or combinations thereof.
7. The mirtazapine lyophilized orally disintegrating tablet of claim 6, wherein the flavoring agent is sucralose and black cherry flavor.
8. The process for the preparation of a freeze-dried orally disintegrating tablet of mirtazapine according to any of claims 1-7, comprising the steps of:
(1) adding the solubilizer and mirtazapine in the weight parts according to claim 1 into a proper amount of water to be fully dissolved, adding the skeleton propping agent, the freeze-drying protective agent and the flavoring agent to be fully and uniformly dissolved, and adding water to a constant volume of 300 ml;
(2) sucking the liquid medicine prepared in the step (1), and adding the liquid medicine into a tablet die;
(3) carrying out quick-freezing molding on the mold loaded with the liquid medicine obtained in the step (2) in an environment of-75 to-120 ℃;
(4) putting the quick-frozen and molded solid liquid medicine obtained in the step (3) into a freeze dryer, keeping the liquid medicine at-40 ℃ for 30 minutes, vacuumizing the liquid medicine until the vacuum degree is 10-20 Pa, keeping the vacuum degree for 120 minutes, heating the liquid medicine to-25 to-15 ℃ for 120 minutes, heating the liquid medicine to-15 to 0 ℃ for 120 minutes, heating the liquid medicine to 5-10 ℃ for 120 minutes, heating the liquid medicine to 20-25 ℃ for 120 minutes, and heating the liquid medicine to 30-35 ℃ for 180 minutes;
(5) and discharging, laminating, blanking and printing batch numbers.
9. Use of a freeze-dried orally disintegrating tablet of mirtazapine according to any of claims 1-7 for the preparation of an antidepressant.
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| CN116077450A (en) * | 2022-12-24 | 2023-05-09 | 东北农业大学 | Mirtazapine taste masking orally disintegrating tablet, and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0431663A1 (en) * | 1989-12-06 | 1991-06-12 | Akzo Nobel N.V. | Stabilized solutions of psychotropic agents |
| CN101129341A (en) * | 2006-08-22 | 2008-02-27 | 上海医药工业研究院 | Intra-oral disintegration compositions and process for producing same |
| CN101433523A (en) * | 2008-12-22 | 2009-05-20 | 浙江大学 | Breviscapine freeze-dry orally disintegrating tablets and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0431663A1 (en) * | 1989-12-06 | 1991-06-12 | Akzo Nobel N.V. | Stabilized solutions of psychotropic agents |
| CN101129341A (en) * | 2006-08-22 | 2008-02-27 | 上海医药工业研究院 | Intra-oral disintegration compositions and process for producing same |
| CN101433523A (en) * | 2008-12-22 | 2009-05-20 | 浙江大学 | Breviscapine freeze-dry orally disintegrating tablets and preparation method thereof |
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