CN109864971A - A kind of granule and preparation method thereof of Lamotrigine solid dispersions - Google Patents
A kind of granule and preparation method thereof of Lamotrigine solid dispersions Download PDFInfo
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- CN109864971A CN109864971A CN201910275593.5A CN201910275593A CN109864971A CN 109864971 A CN109864971 A CN 109864971A CN 201910275593 A CN201910275593 A CN 201910275593A CN 109864971 A CN109864971 A CN 109864971A
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Abstract
The present invention relates to a kind of granules and preparation method thereof of Lamotrigine solid dispersions, belong to medicine preparation field.The granule of Lamotrigine solid dispersions provided by the invention, it is mainly made of Lamotrigine solid dispersions and pharmaceutically acceptable additive, wherein, Lamotrigine solid dispersions are made of active medicine Lamotrigine and pharmaceutically acceptable water-solubility carrier；Additive includes filler, adhesive, disintegrating agent, lubricant and corrigent.The solubility of granule prepared by the present invention increases by 30% or so, improves the solubility and bioavilability of Lamotrigine, compared to other oral dosage forms, have absorb it is fast, effective rapidly, convenient for taking, the advantages such as in good taste.Using the preparation method of granule provided by the invention, simple process, the quality of the pharmaceutical preparations is stablized, and is suitble to industrialized production.
Description
Technical field
The invention belongs to medicine preparation fields, and in particular to a kind of granule of Lamotrigine solid dispersions and its preparation
Method.
Background technique
Choke fear (fear of choking) caused by dyscatabrosis be all in all age groups it is relatively conventional,
And dyscatabrosis caused by epileptic attack is also more universal, seriously hampers the curative effect of oral preparation.It is main for epileptic
Wanting therapeutic purposes is exactly to maintain enough antiepileptic levels and prevent subsequent epileptic attack.Therefore, dosage regimen is improved
Compliance is required to maintenance therapy blood concentration.
Lamotrigine, chemical name 3,5- diamino -6- (2,3- dichlorophenyl) -1,2,4- triazines, molecular formula are
C9H7N5Cl2, molecular weight 256.09 is a kind of wide spectrum antiepileptic of benzene triazines.Its indication includes simple partial
Epileptic attack, complex partial seizure, secondary generalized tonic-clonic epileptic attack, primary generalized tonic-clonic spasm
Property epileptic attack and the epileptic attack etc. for being associated with Lennox-Gastaut syndrome.
The antiepileptic containing Lamotrigine clinically used earliest is by the trade name of GSK company production listing
LAMICTALTMConventional tablet.So far, there are the various oral preparations containing Lamotrigine in the market, including ordinary tablet,
Oral disnitegration tablet, bite-dispersion tablets and sustained release tablets.And found when clinical administration, the administration compliance of these oral preparations is too
Difference, it is difficult to which control dosage, dosage is very few to lead to unsatisfactory curative effect, and dosage excessively then will lead to the side reactions such as serious fash.
In water phase be in view of Lamotrigine slightly dissolve very much (in 25 DEG C of about 0.17mg/mL, about at 37 DEG C
0.57mg/mL), therefore, it is necessary to use a kind of preparation technique to improve solubility of the Lamotrigine in water phase, a kind of side is prepared
Just the oral granular formulation being administered while to expect to improve administration compliance, and can reach expected therapeutic effect, avoid or subtract
The generation of few side effect.
Summary of the invention
The purpose of the present invention is on the basis of existing technology, providing a kind of granule of Lamotrigine solid dispersions,
The solubility and bioavilability for improving Lamotrigine solve the problems, such as that Lamotrigine solubility in water phase is low.
It is a further object of the present invention to provide a kind of Lamotrigine solid dispersions.
Technical scheme is as follows:
A kind of granule of Lamotrigine solid dispersions, it can mainly connect by Lamotrigine solid dispersions and pharmaceutically
The additive received is made, wherein Lamotrigine solid dispersions are by active medicine Lamotrigine and pharmaceutically acceptable water-soluble
Property carrier is made；Additive includes filler, adhesive, disintegrating agent, lubricant and corrigent.
The water-solubility carrier that the present invention uses includes but is not limited to polyethylene glycol, povidone, poloxamer, organic acid, urine
One or more of element or cellulose derivative.
The granule of Lamotrigine solid dispersions provided by the invention, compared with prior art, mainly by Lamotrigine
Solid dispersions and pharmaceutically acceptable additive are made, and under the cooperation of other conditions, solve Lamotrigine in water phase
The low problem of middle solubility improves the solubility and bioavilability of Lamotrigine, have absorb it is fast, effective rapidly, be convenient for
The advantages such as take, be in good taste.Compared with the Lamotrigine of equivalent, the granule of Lamotrigine solid dispersions prepared by the present invention
Solubility increase by 30% or so.
The present invention can not influence the organic acid of effect of the present invention using any one, such as: citric acid, tartaric acid, horse
Come sour, succinic acid, fumaric acid.In a preferred embodiment, the organic acid that the present invention uses is fumaric acid.
The cellulose derivative that the present invention uses is mainly cellulose ether, such as: methylcellulose, carboxymethyl cellulose,
Ethyl cellulose, hydroxyethyl cellulose, cyanethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose.A kind of preferred
In scheme, cellulose derivative is hydroxypropyl methyl cellulose, as hydroxypropyl methylcellulose.
The weight ratio of active medicine Lamotrigine and water-solubility carrier in Lamotrigine solid dispersions provided by the invention
For 1:1~1:10, preferably 1:3~1:7；More preferably 1:5.
The granule of Lamotrigine solid dispersions prepared by the present invention, wherein filler is calcium carbonate, microcrystalline cellulose
Or one or more of starch.
In further preferred scheme, adhesive is povidone.
Further, disintegrating agent is low-substituted hydroxypropyl cellulose, carboxyrnethyl starch sodium or combinations thereof object.
Further, lubricant is magnesium stearate.
Further, corrigent is saccharin sodium, essence or combinations thereof object.
The granule of Lamotrigine solid dispersions prepared by the present invention, it is comprised the following components in parts by weight: Rameau three
110~130 parts of piperazine solid dispersions, 36~52 parts of filler, 20~40 parts of disintegrating agent, 3~6 parts of adhesive, corrigent 0.4~
4 parts, 1.0~6 parts of lubricant.
The granule of Lamotrigine solid dispersions prepared by the present invention, it is comprised the following components in parts by weight: Rameau three
115~125 parts of piperazine solid dispersions, 40~48 parts of filler, 20~30 parts of disintegrating agent, 4~6 parts of adhesive, corrigent 1~3
Part, 2~4 parts of lubricant.
The granule of Lamotrigine solid dispersions prepared by the present invention, 120 parts of Lamotrigine solid dispersions, filler
45~46 parts, 23~25 parts of disintegrating agent, 5~6 parts of adhesive, 2 parts of corrigent, 3 parts of lubricant.
A kind of preparation method of the granule of Lamotrigine solid dispersions, it is mainly comprised the steps that
Wet mixing pelletizer is added in interior plus supplementary material, stirring 3r/s is opened, while shearing 15r/s, mixes five minutes,
It opens stirring 3r/s and shearing 20r/s simultaneously again, water softwood is added, timing 4 minutes, the granulation of 24 meshes was crossed in discharging, and baking oven is dry
It is dry then to be moved into hopper mixing machine to moisture 5% hereinafter, after 24 mesh sieves, the lubricant of formula ratio is added, 15r/s's
Speed mixes 10 minutes, thus obtains the granule of Lamotrigine solid dispersions.
A kind of Lamotrigine solid dispersions, it is by active medicine Lamotrigine and pharmaceutically acceptable water-solubility carrier
It is made, the weight ratio of the active medicine Lamotrigine and water-solubility carrier is 1:1~1:10；Preferably 1:3~1:7；It is more excellent
It is selected as 1:5.Wherein, water-solubility carrier is in polyethylene glycol, povidone, poloxamer, organic acid, urea or cellulose derivative
One or more.
In Lamotrigine solid dispersions, cellulose derivative is mainly cellulose ether, such as: methylcellulose, carboxylic
Methylcellulose, ethyl cellulose, hydroxyethyl cellulose, cyanethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl fiber
Element.In a preferred embodiment, cellulose derivative is hydroxypropyl methyl cellulose, as hydroxypropyl methylcellulose.
In Lamotrigine solid dispersions, cellulose derivative is mainly cellulose ether, such as: methylcellulose, carboxylic
Methylcellulose, ethyl cellulose, hydroxyethyl cellulose, cyanethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl fiber
Element.In a preferred embodiment, cellulose derivative is hydroxypropyl methyl cellulose, as hydroxypropyl methylcellulose.
Lamotrigine solid dispersions provided by the invention, are made of hot-melt extruded method.Hot-melt extruded method is by equipment
It is heated on the glass transition temperature of carrier, softens carrier, and then drug is sufficiently merged with carrier, and squeezed by the screw rod of machine
A kind of method that is cooling out and preparing solid dispersions.
The method for increasing drug solubility includes physical modification such as solid dispersions, nano particle, eutectic；Chemical modification is such as
At salt or prodrug is made；Carrier system such as inclusion complex, polymer micelle, amphiphilic polymer, micro emulsion；Change solvent group
At such as solubilizer, cosolvent, cosolvent and wetting agent etc..
Solid dispersions can increase the dissolubility of slightly solubility active pharmaceutical ingredient, improve the stability of drug, reduce poison
Side effect.Drug is highly dispersed in solid matrix, increases the specific surface area of drug, accelerates the dissolution rate of drug, is improved
The bioavilability of drug.
The solubility of active pharmaceutical ingredient can be effectively improved using solid dispersions technique, improve active pharmaceutical ingredient
Bioavilability.Granule is made in drug, have absorb it is fast, effective rapidly, convenient for taking, the advantages such as in good taste.
Using technical solution of the present invention, advantage is as follows:
The granule of Lamotrigine solid dispersions provided by the invention, compared with the Lamotrigine of equivalent, system of the present invention
The solubility of standby granule increases by 30% or so, improves the solubility and bioavilability of Lamotrigine.
The granule of Lamotrigine solid dispersions provided by the invention can be used for oral granular formulation, compared to other mouths
Oral solid dosage form, have absorb it is fast, effective rapidly, convenient for taking, the advantages such as in good taste.
The preparation method of granule provided by the invention, simple process, the quality of the pharmaceutical preparations are stablized, and industrialized production is suitble to.
Specific embodiment
It is further described by granule of the following embodiment to Lamotrigine solid dispersions of the invention, but this
A little embodiments do not form any restrictions to the present invention.Those skilled in the art can not depart from the spirit and scope of the present invention
In the case of be changed and improve.All these improvements and changes are intended to be included within the scope of the present invention.
The component and dosage of Lamotrigine solid dispersions provided by the invention, as shown in table 1.
1 solid dispersions formula composition of table
Above-described embodiment 1~6 is prepared in accordance with the following methods:
The preparation method of Lamotrigine solid dispersions provided by the invention, includes the following steps: according to recorded in table 1
It for the amount of the formula of each embodiment, adds it in hot-melt extruded machine, sets barrel temperature as 140 DEG C -175 DEG C, if
Determining screw rod rotation speed is 60-90rpm, thus obtains the formed body of solid dispersions.By gained formed body powder in the ball mill
It is broken, then smashed product is sieved, the product of sieving is collected, thus obtains solid dispersion powder.
The component and dosage of the granule of Lamotrigine solid dispersions provided by the invention, as shown in table 2.
2 Granular formulations of table composition
Above-described embodiment 7~9 is prepared in accordance with the following methods:
The process for producing granula of Lamotrigine solid dispersions provided by the invention includes the following steps: interior plus original
Wet mixing pelletizer is added in auxiliary material, opens stirring 3r/s, while shearing 15r/s, mixes five minutes, then opens stirring simultaneously
3r/s and shearing 20r/s, be added water softwood, timing 4 minutes, discharging, cross 24 meshes granulation, oven drying to moisture 5% with
Under, it after 24 mesh sieves, then moves into hopper mixing machine, the lubricant of formula ratio is added, the speed of 15r/s mixes 10 points
Thus clock obtains the granule of Lamotrigine solid dispersions.
The granule embodiment 7 and comparative example 1, comparative example 2, comparative example of Lamotrigine solid dispersions provided by the invention
3, the formula composition of comparative example 4 is as shown in table 3, and the preparation method of comparative example 1~3 is referring to embodiment 7.
3 Granular formulations of table composition
Compared with Example 7, the granule that prepared by comparative example 1 does not add corrigent, and mouthfeel is difficult to receive, the bitter taste of bulk pharmaceutical chemicals
It is difficult to cover, oral administration compliance is poor.
Compared with Example 7, the granule that prepared by comparative example 2 does not add magnesium stearate lubricant, when causing to place for a long time
The phenomenon that showing the moisture absorption and largely agglomerating, it is unfavorable for saving.
Compared with Example 7, the granule that prepared by comparative example 3 does not add adhesive povidone, leads to the particle being prepared
Fine powder accounts for the overwhelming majority in agent, does not have the granule character having.
Compared with Example 7, adhesive is excessively added in comparative example 4, causes to hinder when softwood sieving granulation larger and dry
Particle after dry is harder, is not easy to carry out whole grain by sieve, technical process is not easy to operate.
Embodiment 10: analysis control methods: solubility studies.
Reference substance solution is prepared: precision weighs Lamotrigine raw material about 20mg, is placed in 10mL volumetric flask, and 6mL purifying is added
Water, ultrasound 15 minutes dissolve, be cooled to room temperature, then plus purified water be settled to 10mL, shake up.0.45 μm of membrane filtration, takes filtrate
1mL is placed in 100mL volumetric flask, adds purified water dilution and constant volume, shakes up to obtain the final product.
Test solution is prepared: precision weighs granule (embodiment 7) about 200mg and (is approximately equivalent to raw material containing Lamotrigine
20mg), be placed in 10mL volumetric flask, 6mL purified water be added, dissolve within ultrasound 15 minutes, be cooled to room temperature, then plus purified water be settled to
10mL shakes up.0.45 μm of membrane filtration, takes filtrate 1mL to be placed in 100mL volumetric flask, adds purified water dilution and constant volume, shakes up i.e.
?.
Absorbance detection is carried out using ultraviolet-uisible spectrophotometer, wavelength 306nm measures test sample dissolution as the result is shown
Degree is higher than reference substance 30% or so.
| Sample name | Sample weighting amount (mg) | Absorbance |
| Reference substance 1 | 20.05 | 0.460 |
| Reference substance 2 | 20.00 | 0.456 |
| Reference substance 3 | 20.07 | 0.462 |
| Test sample 1 (embodiment 7) | 200.10 | 0.596 |
| Test sample 2 (embodiment 7) | 200.01 | 0.590 |
| Test sample 3 (embodiment 7) | 200.03 | 0.591 |
Embodiment 11: analysis control methods: solubility studies.
Lamotrigine material solution is prepared: precision weighs Lamotrigine raw material about 20mg, is placed in 10mL volumetric flask, is added
6mL purified water, ultrasound 15 minutes dissolve, be cooled to room temperature, then plus purified water be settled to 10mL, shake up.0.45 μm of membrane filtration,
It takes filtrate 1mL to be placed in 100mL volumetric flask, adds purified water dilution and constant volume, shake up to obtain the final product.
Lamotrigine solid dispersions solution is prepared: precision weighs Lamotrigine solid dispersions (embodiment 6) about 120mg
(being approximately equivalent to the raw material 20mg containing Lamotrigine) is placed in 10mL volumetric flask, and 6mL purified water is added, and dissolves within ultrasound 15 minutes, cooling
To room temperature, then plus purified water be settled to 10mL, shake up.0.45 μm of membrane filtration, takes filtrate 1mL to be placed in 100mL volumetric flask, adds pure
Change water dilution and constant volume, shake up to obtain the final product.
The particle agent solution of Lamotrigine solid dispersions is prepared: precision weighs the granule of Lamotrigine solid dispersions
(embodiment 9) about 200mg (is approximately equivalent to the raw material 20mg containing Lamotrigine), is placed in 10mL volumetric flask, and 6mL purified water is added, and surpasses
Sound 15 minutes dissolve, be cooled to room temperature, then plus purified water be settled to 10mL, shake up.0.45 μm of membrane filtration, takes filtrate 1mL to set
In 100mL volumetric flask, add purified water dilution and constant volume, shake up to obtain the final product.
Absorbance detection is carried out using ultraviolet-uisible spectrophotometer, it is solid to measure Lamotrigine as the result is shown by wavelength 306nm
Body dispersion and the solubility of granule are suitable, and solubility is all higher than Lamotrigine raw material 30% or so.
Claims (10)
1. a kind of granule of Lamotrigine solid dispersions, which is characterized in that it mainly by Lamotrigine solid dispersions and
Pharmaceutically acceptable additive is made, and the Lamotrigine solid dispersions can connect by active medicine Lamotrigine and pharmaceutically
The water-solubility carrier received is made, and the additive includes filler, adhesive, disintegrating agent, lubricant and corrigent.
2. the granule of Lamotrigine solid dispersions according to claim 1, which is characterized in that the water-solubility carrier
For one or more of polyethylene glycol, povidone, poloxamer, organic acid, urea or cellulose derivative.
3. the granule of Lamotrigine solid dispersions according to claim 2, which is characterized in that the organic acid is lemon
Lemon acid, tartaric acid, maleic acid, succinic acid or fumaric acid；Preferably fumaric acid；The cellulose derivative be methylcellulose,
Carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, cyanethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl fiber
Element；Preferably hydroxypropyl methylcellulose.
4. the granule of Lamotrigine solid dispersions according to claim 1, which is characterized in that the Lamotrigine is solid
The weight ratio of active medicine Lamotrigine and water-solubility carrier is 1:1~1:10 in body dispersion；Preferably 1:3~1:7；It is more excellent
It is selected as 1:5.
5. the granule of Lamotrigine solid dispersions according to claim 1, which is characterized in that the filler is carbon
One or more of sour calcium, microcrystalline cellulose or starch；Described adhesive is povidone；The disintegrating agent is low-substituted hydroxypropyl
Cellulose, carboxyrnethyl starch sodium or combinations thereof object；The lubricant is magnesium stearate；The corrigent be saccharin sodium, essence or its
Composition.
6. the granule of Lamotrigine solid dispersions according to claim 1, which is characterized in that it includes following weight
The component of part: 110~130 parts of Lamotrigine solid dispersions, 36~52 parts of filler, 20~40 parts of disintegrating agent, adhesive 3~
6 parts, 0.4~4 part of corrigent, 1.0~6 parts of lubricant.
7. the granule of Lamotrigine solid dispersions according to claim 1, which is characterized in that it includes following weight
The component of part: 115~125 parts of Lamotrigine solid dispersions, 40~48 parts of filler, 20~30 parts of disintegrating agent, adhesive 4~
6 parts, 1~3 part of corrigent, 2~4 parts of lubricant.
8. the granule of Lamotrigine solid dispersions according to claim 1, which is characterized in that it includes following weight
The component of part: 120 parts of Lamotrigine solid dispersions, 45~46 parts of filler, 23~25 parts of disintegrating agent, 5~6 parts of adhesive,
2 parts of corrigent, 3 parts of lubricant.
9. the granule of Lamotrigine solid dispersions according to claim 1, which is characterized in that use wet-mixing system
Grain machine preparation.
10. a kind of Lamotrigine solid dispersions, which is characterized in that it is by active medicine Lamotrigine and pharmaceutically acceptable
Water-solubility carrier is made, and the weight ratio of the active medicine Lamotrigine and water-solubility carrier is 1:1~1:10；Preferably 1:3
~1:7；More preferably 1:5；Wherein, water-solubility carrier is polyethylene glycol, povidone, poloxamer, organic acid, urea or fiber
One or more of plain derivative.
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