CN113440488A - Rimiditan orally disintegrating tablet and preparation method thereof - Google Patents

Rimiditan orally disintegrating tablet and preparation method thereof Download PDF

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Publication number
CN113440488A
CN113440488A CN202010226254.0A CN202010226254A CN113440488A CN 113440488 A CN113440488 A CN 113440488A CN 202010226254 A CN202010226254 A CN 202010226254A CN 113440488 A CN113440488 A CN 113440488A
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disintegrating tablet
orally disintegrating
limpidutan
limpidan
sieving
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马艺腾
王宇杰
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Beijing Wanquan Dezhong Medical Biological Technology Co Ltd
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Beijing Wanquan Dezhong Medical Biological Technology Co Ltd
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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
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61P25/06—Antimigraine agents

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
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  • Medicinal Preparation (AREA)

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and relates to a limpidan orally disintegrating tablet preparation and a preparation method thereof, wherein the limpidan orally disintegrating tablet is prepared from 30-50% by weight of limpidan and 50-70% by weight of excipient, wherein the excipient comprises more than one of disintegrant, adhesive, flavoring agent, lubricant and glidant. The orally disintegrating tablet of limpidutan provided by the invention has the advantages of rapid disintegration, excellent taste, no grit sensation, no discomfort, stable quality, reliable curative effect, timely effect, quick absorption, greatly increased bioavailability, compliance with the requirements of patients, simple preparation process, suitability for large-scale production and the like.

Description

Rimiditan orally disintegrating tablet and preparation method thereof
Technical Field
The invention belongs to a medicinal preparation, relates to an orally disintegrating tablet preparation, and particularly relates to a limpidan orally disintegrating tablet which is tableted by a direct tabletting method and has a quick release effect.
Background
Rimiditan (Lasmidinan) is a 5-hydroxytryptamine (5-HT) 1F receptor agonist, and is suitable for acute treatment of migraine in adults. According to the population Pharmacokinetic (PK) analysis, age, sex, race/ethnicity and body weight had no significant effect on the PK (Cmax and AUC) of Rimidestan. Limpidutan was developed and marketed by american gifts corporation (ELI LILLY) and approved by the U.S. Food and Drug Administration (FDA) in 2019 in 10 months under the trade name REYVOW.
Limpidan, lasiditan, chemical name: 2,4, 6-trifluoro-N- [6- (1-methylpiperidine-4-carbonyl) pyridin-2-yl ] benzamide hemisuccinate having CAS number: 380917-97-5, molecular formula: C19H18F3N3O2.0.5 [ C4H6O4], molecular weight: 436.41 (hemisuccinate) having the chemical formula:
Figure DEST_PATH_IMAGE001
the currently clinically available dosage form is the REYVOW tablet, which is a film-coated tablet. Orally disintegrating tablets are new dosage forms that have recently emerged that exhibit rapid onset of action. Orally disintegrating tablets are tablets which do not require water or only a small amount of water, do not require chewing, are placed on the tongue surface, dissolve or disintegrate rapidly in the presence of saliva, and can be swallowed to achieve the effect in the stomach. Compared with the common tablet, the preparation has the advantages of quick absorption, high bioavailability and quick response, and the modification of the tablet into the limpidutan orally disintegrating tablet is of great clinical significance in view of the fact that the tablet is mainly used for patients with acute migraine.
Disclosure of Invention
The invention aims to provide a limpidan orally disintegrating tablet and a preparation method thereof.
The invention is realized by the following technical scheme:
the oral disintegrating tablet preparation of limpidutan is prepared from the following components in percentage by weight:
30-50% of limpidan
20 to 70 percent of filler
5 to 30 percent of disintegrating agent
1-10% of flavoring agent
0.5 to 5 percent of lubricant
0.01 to 5 percent of adhesive
0.01 to 2 percent of glidant
The disintegrant is one or more selected from dry starch, hydroxypropyl starch, sodium carboxymethyl starch, croscarmellose sodium, crospovidone or low-substituted hydroxypropyl cellulose.
The adhesive is one or more selected from polyethylene glycol 6000, microcrystalline cellulose, sodium carboxymethylcellulose, polyvidone or hydroxypropyl cellulose.
The flavoring agent is one or more selected from sorbitol, mannitol, stevioside, saccharin sodium or xylitol.
The lubricant is one or more selected from magnesium stearate, superfine silica gel powder, talcum powder and calcium stearate.
The glidant is selected from one or more of talc, starch, stearic acid or anhydrous colloidal silicon dioxide.
The preparation method of the lamidottan orally disintegrating tablet comprises wet granulation, dry granulation and powder direct compression.
A method for preparing the limpidutan orally disintegrating tablet by adopting wet granulation comprises the following steps:
(1) weighing the raw materials of the components according to the proportion, and respectively sieving;
(2) uniformly mixing the limpiditan (30-50%), the flavoring agent (1-10%) and the disintegrating agent (5-30%) in the proportion of the raw materials and the auxiliary materials, adding the adhesive (0.01-5%) to prepare a soft material;
(3) sieving the obtained soft material, granulating, drying, sieving, and grading;
(4) adding 0.5-5% of lubricant and 80-90% of disintegrating agent in the proportion of raw materials and auxiliary materials into the dry granules obtained in the step (3), and uniformly mixing;
(5) tabletting to obtain the limpidutan orally disintegrating tablet.
In the step (1), the limpidan is sieved by a 60-mesh sieve, and the excipient is ground and sieved by a 100-mesh sieve;
in the step (3), the prepared soft material is sieved by a 20-mesh sieve, then is granulated, is dried in an oven at 50 ℃ until the moisture of the granules is 1.0-3.0%, and is sieved by a 24-mesh sieve for finishing.
A method for preparing the limpidutan orally disintegrating tablet by adopting dry granulation comprises the following steps:
(1) weighing the raw materials of the components according to the proportion, sieving and uniformly mixing the limpiditentan (30-50%), the disintegrating agent (5-30%), the flavoring agent (1-10%), the lubricant (0.5-5%) and the glidant (0.01-2%);
(2) carrying out dry granulation;
(3) tabletting to obtain the limpidutan orally disintegrating tablet.
A method for preparing the orally disintegrating tablet of limpidutan by adopting a powder direct compression method comprises the following steps:
(1) weighing the raw materials of the components according to the proportion, and respectively sieving the lamidottan (30-50%), the disintegrant (5-30%), the flavoring agent (1-10%), the lubricant (0.5-5%) and the glidant (0.01-2%);
(2) mixing uniformly;
(3) and directly pressing the powder to obtain the limpidutan orally disintegrating tablet.
The invention has the following beneficial effects:
the orally disintegrating tablet of limpidutan provided by the invention has the advantages of rapid disintegration, excellent taste, no grit sensation, no discomfort, stable quality, reliable curative effect, timely effect, quick absorption, greatly increased bioavailability, compliance with the requirements of patients, simple preparation process and suitability for large-scale production.
Detailed Description
The invention will be further illustrated with reference to the following specific examples.
The present invention is described in further detail below by way of examples, but it should be noted that these examples are only for illustrating the present invention and do not limit the scope of the present invention, and all the technologies realized based on the above-mentioned contents of the present invention belong to the scope of the present invention.
Example 1
The oral disintegrating tablet of the limpidutan is prepared by wet granulation and comprises the following components in percentage by weight:
500g of limpidutan (67.57%),
170g (22.97%) of dry starch,
polyethylene glycol 600015 g (2.03%),
mannitol 45g (6.08%),
magnesium stearate 10g (1.35%);
(1) the preparation method of the lamidottan orally disintegrating tablet in the embodiment comprises the following steps: weighing the raw materials of the components according to the proportion provided by the embodiment; sieving the limpidan with a 60-mesh sieve, and respectively grinding the rest auxiliary materials and sieving with a 100-mesh sieve;
(2) sieving and mixing the limpidan, the mannitol and 10% of dry starch in the raw material and auxiliary material ratio uniformly, and adding 30% of polyethylene glycol 6000 aqueous solution in the raw material ratio to prepare a soft material;
(3) sieving with a 20-mesh sieve for granulation, drying in a 50-DEG C oven until the moisture of the granules is 1.5-3.5%, and sieving with a 24-mesh sieve for granulation;
(4) adding magnesium stearate and 90% of dry starch in the proportion of raw materials and auxiliary materials into the dry granules obtained in the step (3), and uniformly mixing;
(5) and tabletting after the mixed uniformity and content are detected to be qualified, wherein the theoretical amount is 1000 tablets.
Example 2
The oral disintegrating tablet of the limpidutan is prepared by dry granulation and comprises the following components in percentage by weight:
500g of limpidutan (67.57%),
hydroxypropyl starch 100g (13.51%),
120g (16.21%) of xylitol,
15g of talcum powder (2.03%),
talc 5g (0.68%);
the preparation method of the lamidottan orally disintegrating tablet in the embodiment comprises the following steps:
(1) sieving the limpidan with a 60-mesh sieve, and respectively grinding the rest auxiliary materials and sieving with a 100-mesh sieve.
(2) The raw material of the limpidan and the internal addition material are uniformly mixed, and then dry granulation is carried out to prepare 20-mesh granules.
(3) And tabletting after the mixed uniformity and content are detected to be qualified, wherein the theoretical amount is 1000 tablets.
Example 3
The oral disintegration tablet of limpidutan is prepared by adopting powder direct compression and comprising the following components in percentage by weight:
500g of limpidutan (67.57%),
40g (5.6%) of sodium carboxymethyl starch,
sorbitol 190g (9.6%),
4g of superfine silica gel powder (2.88%),
starch 6g (0.81%);
the preparation method of the lamidottan orally disintegrating tablet in the embodiment comprises the following steps:
(1) sieving the limpidan with a 60-mesh sieve, and respectively grinding the rest auxiliary materials and sieving with a 100-mesh sieve.
(2) The raw material of the limpidan and the internal material are mixed evenly.
(3) And tabletting after the mixed uniformity and content are detected to be qualified, wherein the theoretical amount is 1000 tablets.
Example 4
The oral disintegrating tablet of the limpidutan is prepared by wet granulation and comprises the following components in percentage by weight:
500g of limpidutan (67.57%),
40g (5.41%) of croscarmellose sodium,
microcrystalline cellulose 35g (4.73%),
stevioside 145g (19.59%),
magnesium stearate 20g (2.70%);
the preparation method of the lamidottan orally disintegrating tablet in the embodiment comprises the following steps:
(1) sieving the limpidan with a 60-mesh sieve, and respectively grinding the rest auxiliary materials and sieving with a 100-mesh sieve.
(2) Sieving and mixing the limpidan, stevioside and 15% of croscarmellose sodium in the raw material and auxiliary material ratio uniformly, and adding a microcrystalline cellulose aqueous solution with the concentration of 30% in the raw material ratio to prepare a soft material;
(3) sieving with a 20-mesh sieve for granulation, drying in a 50-DEG C oven until the moisture of the granules is 1.5-3.5%, and sieving with a 24-mesh sieve for granulation;
(4) adding magnesium stearate and 85% of croscarmellose sodium in the proportion of raw materials and auxiliary materials into the dry granules obtained in the step (3), and uniformly mixing;
(5) and tabletting after the mixed uniformity and content are detected to be qualified, wherein the theoretical amount is 1000 tablets.
The disintegration time measuring method comprises the following steps: taking the samples in the examples, the disintegration time was determined as the time required for the granules to completely pass through the mesh screen, measured from the time when the tablets were exposed to water, according to the disintegration time limit inspection method (0921, second part of the pharmacopoeia 2015), and the disintegration times of the orally disintegrating tablets of lamidipitan prepared in examples 1 to 4 are shown in table 1.
Table 1: disintegration time of each example
Name (R) Disintegration time (seconds)
Example 1 26
Example 2 32
Example 3 35
Example 4 33
Through investigation and analysis on the aspects of disintegration time, appearance, taste and the like of samples prepared in the embodiments, the orally disintegrating tablet of the invention has the advantages of rapid disintegration and rapid release, can be completely disintegrated within 5-40 seconds, can be completely released within 10 minutes, can take effect in time, has good taste, no gravel feeling, no uncomfortable feeling and rapid absorption, greatly increases the bioavailability, and conforms to the requirements of patients. And the preparation process is simple and is suitable for large-scale production.
The foregoing description of the embodiments is provided to enable any person skilled in the art to make or use the present invention
And (5) clearing. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the embodiments described herein, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.

Claims (8)

1. The oral disintegrating tablet preparation of limpidutan is prepared from the following components in percentage by weight:
30-50% of limpidan
20 to 70 percent of filler
5 to 30 percent of disintegrating agent
1-10% of flavoring agent
0.5 to 5 percent of lubricant
0.01 to 5 percent of adhesive
0.01 to 2 percent of glidant
2. The orally disintegrating tablet of limpidutan according to claim 1, characterized in that: the disintegrating agent is selected from one or more of dry starch, hydroxypropyl starch, sodium carboxymethyl starch, croscarmellose sodium, crospovidone or low-substituted hydroxypropyl cellulose; or the flavoring agent is one or more selected from sorbitol, mannitol, stevioside, saccharin sodium or xylitol; or the lubricant is one or more selected from magnesium stearate, silica gel micropowder, talcum powder and calcium stearate.
3. The orally disintegrating tablet of limpidutan according to claim 1, characterized in that: the adhesive is one or more selected from polyethylene glycol 6000, microcrystalline cellulose, sodium carboxymethylcellulose, polyvidone or hydroxypropyl cellulose.
4. The orally disintegrating tablet of limpidutan according to claim 1, characterized in that: the glidant is selected from one or more of talc, starch, stearic acid or anhydrous colloidal silicon dioxide.
5. A process for preparing the orally disintegrating tablet of limpidutan according to claim 1 by wet granulation, comprising the steps of:
(1) weighing the raw materials of the components according to the proportion of claim 1, and respectively sieving;
(2) uniformly mixing the limpidan, the flavoring agent and the disintegrating agent accounting for 10-20% of the raw and auxiliary materials, and adding the adhesive to prepare a soft material;
(3) sieving the obtained soft material, granulating, drying, sieving, and grading;
(4) adding a lubricant and 80-90% of a disintegrating agent in the proportion of raw materials and auxiliary materials into the dry granules obtained in the step (3), and uniformly mixing;
(5) tabletting to obtain the limpidutan orally disintegrating tablet.
6. The method of claim 5, wherein: in the step (1), the limpidan is sieved by a 60-mesh sieve, and the excipient is ground and sieved by a 100-mesh sieve; or in the step (3), the prepared soft material is sieved by a 20-mesh sieve, then is granulated, is dried in an oven at 50 ℃ until the moisture of the granules is 1.0-3.0%, and is sieved by a 24-mesh sieve for finishing.
7. A process for preparing the orally disintegrating tablet of limpidutan according to claim 1 by dry granulation, characterized in that: comprises the following steps:
(1) weighing the raw materials of the components according to the proportion of claim 1, respectively sieving the lamidottan, the disintegrant, the flavoring agent, the lubricant and the glidant, and uniformly mixing;
(2) carrying out dry granulation;
(3) tabletting to obtain the limpidutan orally disintegrating tablet.
8. A process for preparing the orally disintegrating tablet of limpidan according to claim 1 by powder direct compression, characterized in that: comprises the following steps:
(1) weighing the raw materials of the components according to the proportion of the components in the claim 1, and respectively sieving the lamidottan, the disintegrant, the flavoring agent, the lubricant and the glidant;
(2) mixing uniformly;
(3) and directly pressing the powder to obtain the limpidutan orally disintegrating tablet.
CN202010226254.0A 2020-03-27 2020-03-27 Rimiditan orally disintegrating tablet and preparation method thereof Pending CN113440488A (en)

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Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202010226254.0A CN113440488A (en) 2020-03-27 2020-03-27 Rimiditan orally disintegrating tablet and preparation method thereof

Publications (1)

Publication Number Publication Date
CN113440488A true CN113440488A (en) 2021-09-28

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Country Status (1)

Country Link
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Application publication date: 20210928