CN105919958A - Preparation method of lenalidomide capsules - Google Patents

Preparation method of lenalidomide capsules Download PDF

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Publication number
CN105919958A
CN105919958A CN201610419048.5A CN201610419048A CN105919958A CN 105919958 A CN105919958 A CN 105919958A CN 201610419048 A CN201610419048 A CN 201610419048A CN 105919958 A CN105919958 A CN 105919958A
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CN
China
Prior art keywords
lenalidomide
preparation
dispersible tablet
binding agent
prepared
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Pending
Application number
CN201610419048.5A
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Chinese (zh)
Inventor
张亮
黄懿
凌军军
谢登海
向召兰
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Priority to CN201610419048.5A priority Critical patent/CN105919958A/en
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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
    • 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
    • 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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention provides a preparation method of lenalidomide capsules, comprising the following steps: a, weighing the following materials according to parts by weight: 10-20 parts of lenalidomide, 30-80 parts of a disintegrating agent, 100-200 parts of a filler, 1-3 parts of a binder, 1.5-2.5 parts of a glidant; b, dissolving lenalidomide and the disintegrating agent in 50-95% ethanol to prepare a medicinal binder; c, screening a mixture of the filler, a lubricant and the binder, and mixing; d, adding the medicinal binder of step b into a mixture prepared in step c, granulating, drying, size-stabilizing, generally mixing, and tableting to obtain tablets. The preparation method of the lenalidomide capsules can ensure medicine content uniformity, the materials require micronization for particle size control, dissolution of refractory medicine can be improved, technical steps are reduced via co-dissolution, energy is saved, and cost is reduced.

Description

A kind of preparation method of lenalidomide dispersible tablet
Technical field
The present invention relates to the preparation method of a kind of lenalidomide dispersible tablet, belong to field of pharmaceutical preparations.
Background technology
Lenalidomide (Lenalidomide;Trade name Revlimid) be a new immunomodulator be the 4-of thalidomide Amino one glutaryl derivant.This product has anticancer and antiinflammatory action.Its mechanism is mainly by suppression cachectin (TNF-α) interleukin (IL) 1b, IL6 and IL12 and play a role, additionally to granulocyte macrophage colony stimulating factor (GM- CSF) also there is inhibitory action.This product also can stimulate iotave T lymphocytes, so that its propagation, generation cytokine and release are thin Born of the same parents' toxin, further enhances the active anticancer of T cell, it is possible to induction IL-2 mediation primary T cell propagation, thus strengthen γ- The generation of interferon, and reduce the concentration of the cell surface adhesion molecule of TNF-α induction.
Additionally this product also can suppress the angiogenesis of tumor cell, and directly hypertrophy and the induction of suppression tumor cell are abnormal thin The decomposition of born of the same parents.Compared with thalidomide, although lenalidomide structurally has slight change, but its curative effect has bigger changing Kind, and untoward reaction is less.The modal untoward reaction of this product is neutrophilic granulocytopenia and thrombocytopenia, it is possible to draw Play vasculitis, thrombosis, thromboembolism, fatigue, erythra, diarrhoea, pruritus etc..
Lenalidomide oral absorbs good, but owing to it is insoluble in water, bioavailability is low, in order to improve biological utilisation Degree, reduces untoward reaction, and the research of lenalidomide novel form is arisen at the historic moment.
Lenalidomide is insoluble in water, and ordinary preparation such as tablet or capsule slowly affect the normal of medicine because dissolving with disintegrate Absorbing, cause bioavailability low, lenalidomide dispersible tablet disintegration time compared with ordinary preparation is short, and drug-eluting is rapid, can It is greatly improved the bioavailability of medicine.
Time prepared by existing lenalidomide dispersible tablet raw material add adjuvant mixing, after soft material processed, uniformly dry, pulverize after use again Binding agent is pelletized, and is dried；Two step mixings, two steps are dried, and loaded down with trivial details being unfavorable for produces greatly process, and the easy consumption energy increases cost.
Summary of the invention
In order to solve above-mentioned technical problem, technical scheme provides the preparation side of a kind of lenalidomide dispersible tablet Method.
The invention provides a kind of method preparing lenalidomide dispersible tablet, it comprises the steps:
The preparation method of a kind of lenalidomide dispersible tablet, it comprises the steps:
A, the raw material weighing each weight proportion and adjuvant:
Lenalidomide 10-20 part, disintegrating agent 30-80 part, filler 100-200 part, binding agent 1-3 part, fluidizer 1.5-2.5 Part, lubricant 1-3 part；
B, lenalidomide and binding agent are dissolved in 50-95% ethanol, are prepared as pastille binding agent；
C, take filler, lubricant and disintegrant mixture and sieve, mixing；
D, the pastille binding agent of b step is joined in mixture prepared by step (c), pelletize, be dried, granulate, total mixed, pressure Sheet, is prepared as tablet.
As preferably, described filler is selected from least one in pregelatinized Starch, dextrin, lactose, microcrystalline Cellulose.
As preferably, described binding agent is selected from hydroxypropyl methyl cellulose, polyvidone, sodium carboxymethyl cellulose at least A kind of.
As preferably, described disintegrating agent is selected from carboxymethylstach sodium, crospolyvinylpyrrolidone, cross-linked carboxymethyl cellulose At least one in sodium, at least one in silicon dioxide, magnesium stearate of described lubricant.
As preferably, described lenalidomide dispersible tablet also includes correctives, and described correctives is selected from from aspartame, saccharin At least one in sodium.
As preferably, raw material and the part by weight of adjuvant described in step a be:
Lenalidomide 20mg, cross-linking sodium carboxymethyl cellulose 32.5mg, pregelatinized Starch 140mg, polyvidone 2.5mg, Pulvis Talci 2.5mg, magnesium stearate 2.5mg.
As preferably, the ethanol described in step b is 50% ethanol.
As preferably, the method for granulating described in step d is: pastille binding agent b step prepared and step c preparation mixing Thing is put in granulator, arranges mixing speed 400rpm, the pelletize of shear rate 1000rpm, takes out and pelletizes with 18-22 mesh sieve.
As preferably, the total mixing method of granulate described in step d is: by whole for the granule 20-25 mesh sieve after fluid bed drying Grain, addition lubricant is put mix homogeneously in Mixers with Multi-direction Movement and is obtained midbody particle.
The invention has the beneficial effects as follows: due to the difficult soluble substance of lenalidomide tablet raw material, uniformity of dosage units, dissolution are The index of the major control of lenalidomide sheet, carries out pretreatment by the method using the present invention to lenalidomide and binding agent, Can guarantee that the medicament contg uniformity, reduce principal agent particle diameter simultaneously, raw material, without micronization, increases the dissolution of insoluble drug, carries High bioavailability, and common minimizing technological operation step of dissolving, the saving energy reduces input cost.
Accompanying drawing illustrates:
Fig. 1 is the selection of principal agent dissolution solvent and investigates result figure；
Fig. 2,3,4 are the prescription map of lenalidomide sheet；
Fig. 5 grinds commercially available product stripping curve measurement result figure for self-control sample with former.
Detailed description of the invention:
Following embodiment is used for further illustrating but is not limited to the present invention.
The Selection experiment of embodiment 1 lenalidomide dissolution solvent
In taking raw material respectively about 20mg putting beaker, it is gradually added into the ethanol solution of variable concentrations (50%, 75%, 95%), shaking limit, limit Observe, until solution clarification, weigh added quantity of solvent.According to the consumption of different ethanol concentration, the mixed accessories to 180mg respectively Carrying out soft material processed, observe the humidity condition of soft material, and carry out, with 20 mesh sieves, investigation of sieving, result is shown in Fig. 1.
Result: the ethanol solution of above-mentioned variable concentrations can dissolve 20mg raw material under a certain amount of very well, good to 180mg Wetting effect, it has good formability, determines that this product granulation solvent uses the ethanol solution of 50 ~ 95% material particles.
Experimental example 2
The prescription of lenalidomide sheet one-tenth as shown in Figure 2 is grouped into.
The preparation method of above-mentioned lenalidomide dispersible tablet is as follows:
Preparation technology:
1. by the lenalidomide of recipe quantity, polyvidone, ultrasonic dissolution is in 75% ethanol solution of about 60g simultaneously, as containing principal agent Binding agent, this binding agent is water white transparency, without agglomerate and bubble.
2. take the carboxymethyl starch sodium of recipe quantity, pregelatinized Starch, Pulvis Talci, saccharin sodium mixed 100 mesh sieve 3 times.
3. being joined by the binding agent containing principal agent in the mixture of step 2, prepare soft material 20 mesh sieve and pelletize, 60 DEG C of baking oven is done Dry (moisture 1-3%).
4. granule crosses 24 mesh sieve granulate, and additional magnesium stearate mixes as midbody particle.
5. tabletting, tablet hardness scope control is at 50 ~ 70N.
Experimental example 3
The prescription of lenalidomide sheet one-tenth as shown in Figure 3 is grouped into.
The preparation method of above-mentioned lenalidomide dispersible tablet is as follows:
Preparation technology:
1. by the lenalidomide of recipe quantity, hydroxypropyl methyl cellulose ultrasonic dissolution simultaneously in 50% ethanol solution of about 60g, As the binding agent containing principal agent, this binding agent is water white transparency, without agglomerate and bubble.
2. take the microcrystalline Cellulose of recipe quantity, crospolyvinylpyrrolidone, Pulvis Talci, aspartame mixed 100 mesh Sieve 3 times.
3. being joined by the binding agent containing principal agent in the mixture of step 2, prepare soft material 20 mesh sieve and pelletize, 40 DEG C of baking oven is done Dry (moisture 1-3%).
4. granule crosses 24 mesh sieve granulate, and additional magnesium stearate mixes as midbody particle.
5. tabletting, tablet hardness scope control is at 50 ~ 70N.
Experimental example 4
The prescription of lenalidomide sheet one-tenth as shown in Figure 4 is grouped into.
The preparation method of above-mentioned lenalidomide dispersible tablet is as follows:
Preparation technology:
1., by the lenalidomide of recipe quantity, sodium carboxymethyl cellulose ultrasonic dissolution simultaneously in 85% ethanol solution of about 32g, make For the binding agent containing principal agent, this binding agent is water white transparency, without agglomerate and bubble.
2. take the lactose of recipe quantity, carboxymethylstach sodium, Pulvis Talci, aspartame mixed 100 mesh sieve 3 times.
3. being joined by the binding agent containing principal agent in the mixture of step 2, prepare soft material 20 mesh sieve and pelletize, 50 DEG C of baking oven is done Dry (moisture 1-3%).
4. granule crosses 24 mesh sieve granulate, and additional magnesium stearate mixes as midbody particle.
5. tabletting, tablet hardness scope control is at 50 ~ 70N.
The lenalidomide dispersible tablet present invention prepared grinds medicine contrast with former, the lenalidomide dispersible tablet of the present invention and former grind Medicine is shown in Fig. 5 in 0.1 hydrochloric acid solution, aqueous solution and pH4.5 buffer solution, pH6.8 phosphate buffer stripping curve result.
From figure 5 it can be seen that lenalidomide sheet of the present invention self-control sample is in different dissolution mediums, when different Between point under, dissolution is above the former dissolution grinding medicine.
The ultimate principle of the present invention and principal character and advantages of the present invention have more than been shown and described.The technology of the industry Personnel, it should be appreciated that the present invention is not restricted to the described embodiments, simply illustrating this described in above-described embodiment and description The principle of invention, without departing from the spirit and scope of the present invention, the present invention also has various changes and modifications, and these become Change and improvement both falls within scope of the claimed invention.Claimed scope by appending claims and Equivalent defines.

Claims (8)

1. the preparation method of a lenalidomide dispersible tablet, it is characterised in that: it comprises the steps:
A, the raw material weighing each weight proportion and adjuvant:
Lenalidomide 10-20 part, disintegrating agent 30-80 part, filler 100-200 part, binding agent 1-3 part, fluidizer 1.5-2.5 Part, lubricant 1-3 part；
B, lenalidomide and binding agent are dissolved in 50-95% ethanol, are prepared as pastille binding agent；
C, take filler, lubricant and disintegrant mixture and sieve, mixing；
D, the pastille binding agent of b step is joined in mixture prepared by step (c), pelletize, be dried, granulate, total mixed, pressure Sheet, is prepared as tablet.
The preparation method of a kind of lenalidomide dispersible tablet the most according to claim 1, it is characterised in that: described filler selects At least one in pregelatinized Starch, dextrin, lactose, microcrystalline Cellulose.
The preparation method of a kind of lenalidomide dispersible tablet the most according to claim 1, it is characterised in that: described binding agent selects At least one in hydroxypropyl methyl cellulose, polyvidone, sodium carboxymethyl cellulose.
The preparation method of a kind of lenalidomide dispersible tablet the most according to claim 1, it is characterised in that: described disintegrating agent At least one in carboxymethylstach sodium, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, described lubricant selects At least one in silicon dioxide, magnesium stearate.
The preparation method of a kind of lenalidomide dispersible tablet the most according to claim 1, it is characterised in that: described lenalidomide Dispersible tablet also includes correctives, described correctives selected from from Ah
At least one in this Ba Tian, saccharin sodium.
6. according to the preparation method of a kind of lenalidomide dispersible tablet described in claim 1, it is characterised in that: former described in step a The part by weight of material and adjuvant is:
Lenalidomide 20mg, cross-linking sodium carboxymethyl cellulose 32.5mg, pregelatinized Starch 140mg, polyvidone 2.5mg, Pulvis Talci 2.5mg, magnesium stearate 2.5mg.
The preparation method of a kind of lenalidomide dispersible tablet the most according to claim 1, it is characterised in that: described in step b Ethanol be 50% ethanol.
The preparation method of a kind of lenalidomide dispersible tablet the most according to claim 1, it is characterised in that: described in step d Method of granulating is pastille binding agent b step prepared and step c is prepared mixture and put in granulator, arranges mixing speed 400rpm, the pelletize of shear rate 1000rpm, take out and pelletize with 18-22 mesh sieve.
CN201610419048.5A 2016-06-13 2016-06-13 Preparation method of lenalidomide capsules Pending CN105919958A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018070671A1 (en) * 2016-10-14 2018-04-19 주식회사 삼양바이오팜 Lenalidomide oral tablet composition
JP2021070662A (en) * 2019-10-31 2021-05-06 東和薬品株式会社 Pharmaceutical composition containing lenalidomide

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101791288A (en) * 2010-04-07 2010-08-04 南京卡文迪许生物工程技术有限公司 Stable lenalidomide oral solid preparation
CN103610658A (en) * 2013-11-15 2014-03-05 广州帝奇医药技术有限公司 Immunomodulator slow-release preparation and preparation method thereof
CN103705485A (en) * 2013-12-31 2014-04-09 广州帝奇医药技术有限公司 Composite for treating myelodysplastic syndrome and preparation method thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101791288A (en) * 2010-04-07 2010-08-04 南京卡文迪许生物工程技术有限公司 Stable lenalidomide oral solid preparation
CN103610658A (en) * 2013-11-15 2014-03-05 广州帝奇医药技术有限公司 Immunomodulator slow-release preparation and preparation method thereof
CN103705485A (en) * 2013-12-31 2014-04-09 广州帝奇医药技术有限公司 Composite for treating myelodysplastic syndrome and preparation method thereof

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018070671A1 (en) * 2016-10-14 2018-04-19 주식회사 삼양바이오팜 Lenalidomide oral tablet composition
CN109843269A (en) * 2016-10-14 2019-06-04 株式会社三养生物制药 The tablets for oral use composition of lenalidomide
JP2019534887A (en) * 2016-10-14 2019-12-05 サムヤン バイオファーマシューティカルズ コーポレイションＳａｍｙａｎｇ Ｂｉｏｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｃｏｒｐｏｒａｔｉｏｎ Oral tablet composition of lenalidomide
US11077099B2 (en) 2016-10-14 2021-08-03 Samyang Holdings Corporation Oral tablet formulation of lenalidomide
JP7023945B2 (en) 2016-10-14 2022-02-22 サムヤン ホールディングス コーポレイション Oral tablet composition of lenalidomide
JP2021070662A (en) * 2019-10-31 2021-05-06 東和薬品株式会社 Pharmaceutical composition containing lenalidomide
JP7420529B2 (en) 2019-10-31 2024-01-23 東和薬品株式会社 Pharmaceutical compositions containing lenalidomide

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Application publication date: 20160907