CN107875128A - A kind of pomalidomide oral disintegrating tablet and preparation method thereof - Google Patents
A kind of pomalidomide oral disintegrating tablet and preparation method thereof Download PDFInfo
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- CN107875128A CN107875128A CN201711279224.0A CN201711279224A CN107875128A CN 107875128 A CN107875128 A CN 107875128A CN 201711279224 A CN201711279224 A CN 201711279224A CN 107875128 A CN107875128 A CN 107875128A
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- Prior art keywords
- disintegrating tablet
- pomalidomide
- oral disintegrating
- tablet according
- mannitol
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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
- A61K31/435—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
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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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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Abstract
The invention discloses a kind of pomalidomide oral disintegrating tablet and preparation method thereof.The oral disintegrating tablet is a kind of comprising pomalidomide, filler, disintegrant, wetting agent and adhesive, flavouring, the pharmaceutical composition of lubricant, and the preparation method uses wet granule compression tablet method.It is an object of the invention to provide the pomalidomide oral disintegrating tablet that a kind of preparation technology is simple, cost is cheap, convenient to take, action is rapid, bioavilability is high, the formulation can improve the Compliance of patient.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, is related to a kind of oral disintegrating tablet comprising pomalidomide and preparation method thereof.
Background technology
U.S. FDA approval on January 8th, 2013 Pomalyst（Pomalidomide, pomalidomide）Treat other anticarcinogens
The multiple myeloma patients that the state of an illness is still in progress after treatment.
Huppert's disease is a kind of leukemia, mainly influences older population, is induced from the thick liquid cell of marrow.According to American National
Cancer research institute estimates, there are about 2.17 ten thousand Americans every year and is diagnosed with Huppert's disease, 1.071 ten thousand are died from this
Kind disease.
Pomalyst is a kind of pill, and it adjusts the immune system of human body, destroys cancer cell and suppresses its growth.It is suitable
For previously at least having received two kinds of medicines, including lenalidomide（lenalidomide）And bortezomib
（bortezomib）, to treating no response（Fail of the effect）It is in progress with after last time is treated in 60 days（Recur and refractory
Property）Patient.Pomalyst is immunomodulator one kind, after lenalidomide and Thalidomide（thalidomide）Afterwards
Three medicines.Multiple myeloma needs " customizing ", to meet the needs of patient out of the ordinary, Pomalyst be approved for
The invalid patient of other medicines treatment provides new selection.In July, 2012, FDA once ratify Kyprolis
（carfilzomib）Treat Huppert's disease.Similar with Kyprolis, Pomalyst is also to be examined by FDA acceleration
Program gets the Green Light, and obtains seldom used medicine treatment.Pomalyst security and validity has 221 recurrences or difficult at one
Assessed in the clinical test that the property controlled multiple myeloma patients participate in.The purpose of the experiment is observation cancer after treatment
The patient's number to disappear completely or partially（Objective response rate, or ORR）.Patient be probabilistically assigned receive independent Pomalyst or
Pomalyst adds low dose corticosteroid dexamethasone（dexamethasone）.As a result show：Receive that Pomalyst is single to be controlled
The patient 7.4% for the treatment of reaches ORR.Response time median is not yet drawn a conclusion in these patients（Still there is response during statistics）.
Pomalyst, which adds in the patient that low dose dexamethasone is treated, 29.2% display ORR, response duration median 7.4
Month.Pomalyst label reminds patient and the medical personnel medicine to be used to pregnant woman with one plus frame caveat, because
It may result in the Severe birth defect of threat to life, and the medicine may cause blood clotting.
Because Pomalyst is risky to fetus, Pomalyst is planned by risk assessment and abatement（REMS）Allot：Press
According to REMS requirements, doctor signs with patient.Particular without pregnancy can conceptive female patient, need to make pregnancy tests and to keep away
Pregnant, male patient must take contraceptives as requested.Pharmacy need to according to REMS certifications, the medicine can only prescription to being met the requirements
Patient.Common side effect has the white blood corpuscle for resisting infection（Neutrophil leucocyte）Reduce, tired and weak, red blood cell count(RBC)
Reduce（Anaemia）, constipation, diarrhoea, decrease of platelet decline（Thrombopenia）, the infection of the upper respiratory tract, back pain and hair
Burn.
Clinical advantage 1, II clinical trial phase prove pomalidomide（2mg/d）Combined with Dexamethasone（40mg/ weeks）To RRMM
There are the effect of fine and tolerance.2nd, the clinical test of III phase demonstrates POM+LoDEX Regimen Chemotherapies RRMM, especially right
Lenalidomide and（Or）The RRMM of bortezomib drug resistant, there are the effect of encouraging and controllable toxic side effect.
The content of the invention
The invention provides a kind of oral disintegrating tablet comprising pomalidomide and preparation method thereof.It is produced according to the present invention to obtain
Pomalidomide oral disintegrating tablet has the characteristics of disintegration is rapid, and good mouthfeel, bioavilability height, toxic side effect is small, convenient to take, and
And preparation technology is simple, cost is cheap, suitable for industrialized production.
The component and its percentage by weight that pomalidomide oral disintegrating tablet provided by the invention is included are as follows：
Pomalidomide 0.1-10%
Filler 20-90%
Disintegrant 5-20%
Wetting agent and adhesive 1-10%
Flavouring 2-6%
Lubricant 0.5-5%
The particle size range of heretofore described pomalidomide is 1 ~ 20 μm, preferably 1 ~ 10 μm.
Heretofore described filler be selected from lactose, dextrin, pregelatinized starch, microcrystalline cellulose, mannitol, sorbierite,
One or more in xylitol, calcium monohydrogen phosphate, preferably mannitol and lactose or the mixture of mannitol and xylitol, enter one
Step preferably mannitol is 2 with the weight ratio of lactose or xylitol:1~6:1.
Heretofore described disintegrant is selected from dried starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, the poly- dimension of crosslinking
One or more in ketone, Ac-Di-Sol, preferably sodium carboxymethyl starch or PVPP, further preferably
Feed postition for sodium carboxymethyl starch or PVPP is interior additional.
Heretofore described wetting agent is selected from purified water, ethanol, starch slurry, sodium carboxymethylcellulose, poly- dimension with adhesive
One or more in ketone, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, preferably PVP or hydroxypropyl
The water or ethanol water of ylmethyl cellulose.
Heretofore described flavouring is selected from sorbierite, mannitol, stevioside, saccharin sodium, aspartame, menthol, perfume (or spice)
One or more in essence.
Heretofore described lubricant is selected from magnesium stearate, sodium stearyl fumarate, superfine silica gel powder, talcum powder, hydrogenated vegetable
One or more in oil, polyethylene glycol, magnesium laurylsulfate.
Heretofore described pomalidomide oral disintegrating tablet preparation method comprises the following steps：
（1）By bulk drug micronization processes, remaining auxiliary material distinguishes the finely ground mesh sieve of mistake 100；
（2）After adding material sieving well mixed in recipe quantity, the water or ethanol water of the adhesive of recipe quantity, system are added
Standby softwood；
（3）The granulation of 20 mesh sieves is crossed, is dried in 50 DEG C of baking ovens to pellet moisture between 1.5 ~ 3.5%, crosses 24 mesh sieve whole grains；
（4）To（3）The additional material of recipe quantity is added in middle gained dry particl, is well mixed；
（5）Determine intermediates content, determine piece weight after tabletting produce.
Using technical scheme, the pomalidomide oral disintegrating tablet of different content specification, its taste can be prepared
Fragrant salubrious, no sand type, disintegration time is short, is easily swallowed after taking and dissolution rate meets the requirements.The present invention uses simultaneously
Preparation technology is simple and easy to do, has good promotion prospect.
Embodiment
With reference to specific embodiment, the invention will be further described, so that those skilled in the art can be more preferable
Understand the present invention and can be practiced, but illustrated embodiment is not as a limitation of the invention.
Embodiment 1：
Components Name part by weight（%）10% PVP of pomalidomide 0.1% mannitol, 60% lactose, 30% sodium carboxymethyl starch 3% Ah
The magnesium stearate 1% of 1% superfine silica gel powders of Si Patan 1%
Preparation method：
（1）By pomalidomide micronization processes, remaining auxiliary material distinguishes the finely ground mesh sieve of mistake 100；
（2）After pomalidomide, mannitol, lactose, the sodium carboxymethyl starch of recipe quantity 5%, aspartame sieving are well mixed,
The PVP ethanol water that recipe quantity concentration is 20% is added, prepares softwood；
（3）The granulation of 20 mesh sieves is crossed, is dried in 50 DEG C of baking ovens to pellet moisture between 1.5 ~ 3.5%, crosses 24 mesh sieve whole grains；
（4）To（3）Superfine silica gel powder, magnesium stearate, the sodium carboxymethyl starch of surplus are added in middle gained dry particl, mixing is equal
It is even；
（5）Determine intermediates content, determine piece weight after tabletting produce.
Embodiment 2：
Components Name part by weight（%）The hydroxypropyl of 25% Ac-Di-Sol of pomalidomide 0.2% mannitol, 55% lactose 10%
The magnesium stearate 1% of 2% aspartame of base cellulose 2%
Preparation method：
（1）By pomalidomide micronization processes, remaining auxiliary material distinguishes the finely ground mesh sieve of mistake 100；
（2）Pomalidomide, mannitol, lactose, the Ac-Di-Sol of recipe quantity 5%, aspartame sieving mixing is equal
After even, the hydroxypropyl cellulose ethanol water that recipe quantity concentration is 25% is added, prepares softwood；
（3）The granulation of 20 mesh sieves is crossed, is dried in 50 DEG C of baking ovens to pellet moisture between 1.5 ~ 3.5%, crosses 24 mesh sieve whole grains；
（4）To（3）Magnesium stearate, the Ac-Di-Sol of surplus are added in middle gained dry particl, is well mixed；
（5）Determine intermediates content, determine piece weight after tabletting produce.
Embodiment 3：
Components Name part by weight（%）The hydroxypropyl cellulose of 31% PVPP of pomalidomide 0.6% mannitol, 50% xylitol 6%
The magnesium stearate 1% of 4% aspartame, 2% lemon extract, 1% superfine silica gel powder 1%
Preparation method：
（1）By pomalidomide micronization processes, remaining auxiliary material distinguishes the finely ground mesh sieve of mistake 100；
（2）Pomalidomide, mannitol, xylitol, the PVPP of recipe quantity 3%, aspartame, lemon extract sieving is mixed
After closing uniformly, the hydroxypropyl cellulose ethanol water that recipe quantity concentration is 20% is added, prepares softwood；
（3）The granulation of 20 mesh sieves is crossed, is dried in 50 DEG C of baking ovens to pellet moisture between 1.5 ~ 3.5%, crosses 24 mesh sieve whole grains；
（4）To（3）Superfine silica gel powder, magnesium stearate, the PVPP of surplus are added in middle gained dry particl, is well mixed；
（5）Determine intermediates content, determine piece weight after tabletting produce.
Embodiment 4：
Components Name part by weight（%）The hydroxypropyl methyl fiber of 0.6% microcrystalline cellulose of pomalidomide, 72% sodium carboxymethyl starch 5%
The magnesium stearate 0.5% of 0.5% superfine silica gel powder of plain 2% stevioside 1%
Preparation method：
（1）By pomalidomide micronization processes, remaining auxiliary material distinguishes the finely ground mesh sieve of mistake 100；
（2）After pomalidomide, microcrystalline cellulose, the sodium carboxymethyl starch of recipe quantity 4%, stevioside sieving are well mixed, add
Recipe quantity concentration is 20% hydroxypropyl methyl cellulose ethanol water, prepares softwood；
（3）The granulation of 20 mesh sieves is crossed, is dried in 50 DEG C of baking ovens to pellet moisture between 1.5 ~ 3.5%, crosses 24 mesh sieve whole grains；
（4）To（3）Superfine silica gel powder, magnesium stearate, the sodium carboxymethyl starch of surplus are added in middle gained dry particl, mixing is equal
It is even；
（5）Determine intermediates content, determine piece weight after tabletting produce.
Claims (8)
1. a kind of oral disintegrating tablet of pomalidomide, using pomalidomide as active drug composition, it is characterised in that used in prescription and medicine
The good pharmaceutic adjuvant of thing compatibility collectively constitutes, including filler, disintegrant, wetting agent and adhesive, flavouring, lubricant
Deng by weight percentage, the ratio of each component is as follows：
Pomalidomide 0.1-10%
Filler 20-90%
Disintegrant 5-20%
Wetting agent and adhesive 1-10%
Flavouring 2-6%
Lubricant 0.5-5%.
2. oral disintegrating tablet according to claim 1, it is characterised in that the particle size range of pomalidomide be 1 ~ 20 μm, preferably 1 ~
10μm。
3. oral disintegrating tablet according to claim 1, it is characterised in that the filler be selected from lactose, dextrin, pregelatinized starch,
One or more in microcrystalline cellulose, mannitol, sorbierite, xylitol, calcium monohydrogen phosphate, preferably mannitol and lactose or sweet
Reveal the mixture of alcohol and xylitol, more preferably mannitol and the weight ratio of lactose or xylitol are 2:1~6:1.
4. oral disintegrating tablet according to claim 1, it is characterised in that the disintegrant be selected from dried starch, sodium carboxymethyl starch,
One or more in low-substituted hydroxypropyl cellulose, PVPP, Ac-Di-Sol, preferably carboxymethyl are formed sediment
The feed postition of powder sodium or PVPP, more preferably sodium carboxymethyl starch or PVPP is interior additional.
5. oral disintegrating tablet according to claim 1, it is characterised in that the wetting agent and adhesive be selected from purified water, ethanol,
One kind in starch slurry, sodium carboxymethylcellulose, PVP, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose
Or several, the preferably water or ethanol water of PVP or hydroxypropyl methyl cellulose.
6. oral disintegrating tablet according to claim 1, it is characterised in that the flavouring be selected from sorbierite, mannitol, stevioside,
One or more in saccharin sodium, aspartame, menthol, essence.
7. oral disintegrating tablet according to claim 1, it is characterised in that the lubricant is selected from magnesium stearate, stearyl fumarate
One or more in sodium, superfine silica gel powder, talcum powder, hydrogenated vegetable oil, polyethylene glycol, magnesium laurylsulfate.
8. oral disintegrating tablet according to claim 1, it is characterised in that the preparation method comprises the following steps：
（1）By bulk drug micronization processes, remaining auxiliary material distinguishes the finely ground mesh sieve of mistake 100；
（2）After adding material sieving well mixed in recipe quantity, the water or ethanol water of the adhesive of recipe quantity, system are added
Standby softwood；
（3）The granulation of 20 mesh sieves is crossed, is dried in 50 DEG C of baking ovens to pellet moisture between 1.5 ~ 3.5%, crosses 24 mesh sieve whole grains；
（4）To（3）The additional material of recipe quantity is added in middle gained dry particl, is well mixed；
（5）Determine intermediates content, determine piece weight after tabletting produce.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711279224.0A CN107875128A (en) | 2017-12-06 | 2017-12-06 | A kind of pomalidomide oral disintegrating tablet and preparation method thereof |
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| CN201711279224.0A CN107875128A (en) | 2017-12-06 | 2017-12-06 | A kind of pomalidomide oral disintegrating tablet and preparation method thereof |
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| CN107875128A true CN107875128A (en) | 2018-04-06 |
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| CN201711279224.0A Pending CN107875128A (en) | 2017-12-06 | 2017-12-06 | A kind of pomalidomide oral disintegrating tablet and preparation method thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090317385A1 (en) * | 2008-01-29 | 2009-12-24 | Brady Helen A | Methods Using Immunomodulatory Compounds for Modulating Level of CD59 |
| CN104224723A (en) * | 2014-10-14 | 2014-12-24 | 北京科莱博医药开发有限责任公司 | Pomalidomide nanoparticle and preparation and preparation method thereof |
| CN105246480A (en) * | 2013-04-02 | 2016-01-13 | 细胞基因公司 | Methods and compositions using 4-amino-2-(2, 6-dioxo-piperidine-3-yl)-isoindoline-1, 3-dione for treatment and management of central nervous system cancers |
| CN105496977A (en) * | 2015-12-18 | 2016-04-20 | 北京万全德众医药生物技术有限公司 | Succinic acid trelagliptin orally-disintegrating tablets and preparing method thereof |
-
2017
- 2017-12-06 CN CN201711279224.0A patent/CN107875128A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090317385A1 (en) * | 2008-01-29 | 2009-12-24 | Brady Helen A | Methods Using Immunomodulatory Compounds for Modulating Level of CD59 |
| CN105246480A (en) * | 2013-04-02 | 2016-01-13 | 细胞基因公司 | Methods and compositions using 4-amino-2-(2, 6-dioxo-piperidine-3-yl)-isoindoline-1, 3-dione for treatment and management of central nervous system cancers |
| CN104224723A (en) * | 2014-10-14 | 2014-12-24 | 北京科莱博医药开发有限责任公司 | Pomalidomide nanoparticle and preparation and preparation method thereof |
| CN105496977A (en) * | 2015-12-18 | 2016-04-20 | 北京万全德众医药生物技术有限公司 | Succinic acid trelagliptin orally-disintegrating tablets and preparing method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 吴灵静，等: "制粒工艺对泊马度胺胶囊质量的影响", 《中国医药工业杂志》 * |
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Application publication date: 20180406 |