CN110507617A - Dimethylcurcumin solid dispersions, Dimethylcurcumin solid dispersion tablet and preparation method thereof - Google Patents
Dimethylcurcumin solid dispersions, Dimethylcurcumin solid dispersion tablet and preparation method thereof Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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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
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
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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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- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention belongs to solid dispersion tablet technical field, it is related to a kind of Dimethylcurcumin solid dispersions, Dimethylcurcumin solid dispersion tablet and preparation method thereof.Steps are as follows: according to a certain percentage, water soluble carrier material is added to the container heating melting, add Dimethylcurcumin, agitating and heating 20-60min, 60~85 DEG C of heating temperature, after defoamed, place 2h-8h at 0~4 DEG C, by pulverizing and sieving to get the Dimethylcurcumin solid dispersions；The water soluble carrier material is PEG 6000 or PLURONICS F87.Dimethylcurcumin solid dispersions prepared by the present invention improve the solubility and dissolution in vitro of Dimethylcurcumin, and the prescription Primary Study of dry method direct tablet compressing solid dispersion tablet also provides partial condition for the research of Dimethylcurcumin dosage form, the utilization for Dimethylcurcumin in anticancer therapy provides theoretical basis.
Description
Technical field
The invention belongs to solid dispersion tablet technical fields, and in particular to a kind of Dimethylcurcumin solid dispersions, two
Methyl curcumin solid Disket and preparation method thereof.
Background technique
Curcumin is one of turmeric rhizome medicinal herbs (turmeric) main component, has been widely used as food dye
And flavouring.In addition, curcumin and its derivative also have the multiple pharmacological effects such as antitumor, anti-inflammatory, antiviral, and bad anti-
Should be slight less, medicine source is sufficient, great development prospect.Wherein, research finds that Dimethylcurcumin is a kind of effective androgen
Receptor degradation reinforcing agent, it can mainly interrupt androgen receptor and expression in the selection of Prostate gland stroma or luminal epithelial cell
Interaction between the property co-activation factor (ARA55 or ARA70).Have found Dimethylcurcumin to controlling in current research
It treats prostate cancer and spinobulbar muscular atrophy has shown beneficial effect.For cell line in vitro and internal mice study
In, Dimethylcurcumin, which has shown that, has good effect to treatment prostate cancer and spinobulbar muscular atrophy.But
The problems such as poorly water-soluble of Dimethylcurcumin, oral administration biaavailability is low, gastrointestinal tract absorption difference need to be improved.
Summary of the invention
A kind of Dimethylcurcumin solid dispersions, diformazan are provided the purpose of the present invention is overcome the deficiencies in the prior art
Base curcumin solid Disket and preparation method thereof, the present invention has successfully dispersed insoluble drug Dimethylcurcumin, is made
Dimethylcurcumin solid dispersion tablet solubility with higher and dissolution in vitro.
The present invention adopts the following technical scheme:
The preparation method of Dimethylcurcumin solid dispersions, steps are as follows: according to a certain percentage, by water-solubility carrier material
Material is added to the container heating melting, adds Dimethylcurcumin, agitating and heating 20-60min, and 60~85 DEG C of heating temperature, after
It is defoamed, places 2h-8h at 0~4 DEG C, by pulverizing and sieving to get the Dimethylcurcumin solid dispersions；It is described
Water soluble carrier material is PEG 6000 or PLURONICS F87.
Further, the mass ratio of the PEG 6000 and Dimethylcurcumin is 10:1~50:1.
Further, the mass ratio of the PLURONICS F87 and Dimethylcurcumin is 5:1~20:1.
Further, the temperature when heating melting is 60~85 DEG C.
The present invention also provides dimethyl ginger made from a kind of preparation method as above-mentioned Dimethylcurcumin solid dispersions
Flavine solid dispersions.
The present invention also provides a kind of Dimethylcurcumin solid dispersion tablets, include above-mentioned Dimethylcurcumin solid point
Granular media.
Further, the Dimethylcurcumin solid dispersion tablet, including according to mass fraction meter such as the following group
Point: 2.2-10.2 parts of Dimethylcurcumin solid dispersions, 9.4-13.4 parts of disintegrating agent, 9.4-13.4 parts of filler, flavoring agent
1-6 parts, 0.2-0.5 parts of glidant, 0.1-0.5 parts of lubricant, 1-4 parts of raising agent.
Further, the Dimethylcurcumin solid dispersion tablet, including according to mass fraction meter such as the following group
Point: 2.2 parts of Dimethylcurcumin solid dispersions, 13.4 parts of disintegrating agent, 13.4 parts of filler, 6 parts of flavoring agent, glidant 0.5
Part, 0.5 part of lubricant, 4 parts of raising agent.
Further, the disintegrating agent is microcrystalline cellulose, and the filler is pregelatinized starch, the flavoring agent is
Lactis Anhydrous；The glidant is superfine silica gel powder, and the lubricant is magnesium stearate, and the raising agent is calcium monohydrogen phosphate.
Further, the Dimethylcurcumin solid dispersion tablet further includes coating, and the coating material is hydroxyl first
Base sodium cellulosate.
Compared with the prior art, the present invention has the following beneficial effects:
Solid dispersion technology refers to drug with molecule, colloidal state, crystallite or amorphous state, is dispersed in a kind of carrier Jie
One carrier solids dispersion of drug formed in matter can be effectively improved the dissolution of insoluble drug, improve bioavilability.
Therefore, in order to improve water-soluble Dimethylcurcumin and bioavilability the problems such as, this research is for the first time by Dimethylcurcumin
It is prepared respectively with hydrophilic carrier material Macrogol 6000 (PEG 6000) and PLURONICS F87 by solid dispersion technology
At solid dispersion tablet, to reach the solubility and dissolution rate in vitro that improve Dimethylcurcumin, thus for improve its
Intracorporal bioavilability lays the foundation.
Preparing solid dispersions using high molecular material is the water-soluble of current most effective most convenient and fast change insoluble drug
One of Xie Du and the method for bioavilability.Selection carrier is very crucial when preparing the solid dispersions of different pharmaceutical, often by medicine
The limitation of the conditions such as object self-characteristic and prescription proportion, preparation process.And the present invention is successfully by two kinds of common medicinal macromolecules
Carrier material PEG6000 and PLURONICS F87 have successfully dispersed insoluble drug dimethyl respectively by solid dispersion technology
Curcumin.By the comparison of solubility at room temperature, it is better than with the solid dispersions that PEG 6000 disperses with PLURONICS F87 point
Scattered solid dispersions, and find that solubility is best when Dimethylcurcumin and PEG 6000 carry medicine ratio as 1:50.And moor Lip river sand
Nurse 188 is used as carrier, when preparing solid dispersions with Dimethylcurcumin ratio for 5:1,10:1 and 20:1, ratio 10:1
When drug solubility it is best, this result illustrates that the content for increasing PLURONICS F87 cannot be further added by the solubility of drug, institute
Not study further in follow-up study, and directly select PEG 6000 as the load of Dimethylcurcumin solid dispersions
Body material.PEG6000 clinical application is relatively broad, general feature be fusing point is low, non-toxic, gastrointestinal tract easily absorbs, thermostabilization,
It is soluble easily in water and can with a variety of organic solvents altogether it is molten.The PEG6000 of preparation is that the Dimethylcurcumin solid dispersions of carrier mention
The high solubility and dissolution in vitro of Dimethylcurcumin, and the prescription Primary Study of dry method direct tablet compressing solid dispersion tablet
Also the research for Dimethylcurcumin dosage form provides partial condition, and the utilization for Dimethylcurcumin in anticancer therapy provides
Theoretical basis.
In addition, the present invention has obtained the optimization tablet proportion of Dimethylcurcumin solid dispersion tablet after study, use
Additive of tablet proportion of the present invention, can make tablet reach preferable hardness and dissolution rate, reach preferable quality.
Detailed description of the invention
Fig. 1 is the comparison of ASC-J9 (Dimethylcurcumin) different dosage forms；
Fig. 2 is influence of PEG6000 (Macrogol 6000) different proportion to solubility；
Fig. 3 is PEG6000: the comparison of PLURONICS F87 (4:5) different dosage forms；
Fig. 4 PEG6000: PLURONICS F87 solid disperses that influence of body different proportion to solubility；
Fig. 5 is the comparison of PLURONICS F87 (1:10) different dosage forms；
Fig. 6 is the comparison of PLURONICS F87 solid dispersions different proportion；
Fig. 7 is the comparison of PEG6000 (1:50) different system dissolution rates；
Fig. 8 is dissolution rate curve；
Fig. 9 is accumulation Dissolution profiles figure；
Figure 10 is accumulation dissolution rate；
Figure 11 is the accumulation dissolution rate of different proportion solid dispersions.
Specific embodiment
Below by specific embodiment, invention is further described in detail, but those skilled in the art will manage
Solution, the following example is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.
Instrument used in the present invention and material are as follows:
1 key instrument of table
2 primary raw material of table and reagent
The preparation of 1 Dimethylcurcumin solid dispersions of embodiment
Weigh Dimethylcurcumin, PEG 6000 and PLURONICS F87 according to a certain percentage respectively.By PEG 6000 and pool
For Luo Shamu 188 respectively into beaker, the heating melting under 85 DEG C of water-baths is separately added into Dimethylcurcumin later, sufficiently heats
20min is stirred, after taking-up, 5min is defoamed with ultrasonic wave defoaming instrument, is put into refrigerator freezing 2h.It is drawn off, crushes later, cross 5
Number mesh is placed spare in drier.
The different solid dispersions of embodiment 2 select excellent and quality testing
The measurement of the solubility of different solid dispersions and compare
Start to prepare the monomer solution of 7.5 μ g/mL (theory): taking main ingredient 7.5mg in 100mL volumetric flask, constant volume is used
Ultrasonic oscillation 1h mixes, stands 30min later.
To the physical mixture of different proportion, SD is calculated according to dissolution 0.75mg in 10mL water, as shown in table 3.
The weighed quality of 3 different proportion of table
| Ratio | Weigh quality (mg) |
| 1:5 | 4.5 |
| 1:10 | 8.25 |
| 1:20 | 15.75 |
| 1:50 | 38.25 |
It is put into 10mL centrifuge tube by the different material that the measurement in table accurately weighs different proportion, is accurately moved with pipette
10mL distilled water is taken, is put into centrifuge tube, is put into ultrasonoscope and shakes 30min, is substantially dissolved in it in water.
Centrifuge tube equipped with liquid after dissolution is put into a centrifuge, centrifugal rotational speed 8000r/min, time 10min,
It takes supernatant to carry out the measurement of absorbance at absorbing wavelength after centrifugation, by the relationship of standard curve, concentration is carried out
It calculates and compares.
The repeatability for carrying out solubility to the SD drug of different carriers different proportion compares, and compares special ratios monomer,
Physical mixture, the difference of the solubility of SD.
Monomer, object is mixed, the measurement of SD dissolution rate
Dissolution determination: being measured, temperature (37.5) DEG C, revolving speed 50r/min using paddle method, since ASC-J9 is insoluble in artificial
Gastric juice and simulated intestinal fluid when measuring dissolution rate to above-mentioned sample, select the simulated gastric fluid containing 0.2% lauryl sodium sulfate
(solubility that lauryl sodium sulfate can increase ASC-J9) carries out dissolution determination as dissolution medium, and by monomer, object is mixed, Gu
It is in bulk enter 1,2, No. 3 capsules, be placed in 1 000mL dissolution medium, every 5min sample, every sub-sampling 10mL.It is supplemented after sampling
Fresh dissolution medium.The solution of acquirement, which is put into 10mL centrifuge tube, to be centrifuged (8000r/min, 10min) and takes supernatant, is carried out
The measurement of absorbance, concentration for the treatment of data carry out the drafting of Dissolution profiles.
Accumulate the calculating of dissolution rate: accumulation the amount of dissolution=dissolution total material amount ÷ input amount × 100%
The total material amount of dissolution=current sample point concentration of medium × medium volume+(sample point concentration of medium before × it takes
Sample amount) }
Accumulation dissolution rate is carried out according to formula to calculate, and draws curve.
The preparation of 3 SD tablet of embodiment
The selection of auxiliary material
This experiment carries out wet granulation and direct compression method and carries out tablet compression to SD, prepare PEG6000SD 3 kinds (1:
10,1:20,1:50) tablet
Wet granulation process:
100 every ASC-J9 content 5mg (total 30g auxiliary material) of auxiliary material proportion of 1:10PEG6000SD
4 prescription 1 of table
Direct compression method
100 every ASC-J9 content 5mg (total 30g auxiliary material) of auxiliary material proportion of 1:10PEG6000SD.
5 prescription 2 of table
Replace partial supplementary material: sucrose → lactose, talcum powder → magnesium stearate.
6 prescription 3 of table
Add auxiliary material: superfine silica gel powder, calcium monohydrogen phosphate remove sodium carboxymethylcellulose.(monolithic weight 200mg is controlled, it is a piece of
ASC-J9 dosage is 1mg).200 amounts (40g auxiliary material)
7 prescription 4 of table
200 tablet amounts of 1:10SD (monolithic weight 200mg, monolithic ASC-J9 dosage are 1mg), by microcrystalline cellulose and cream
Sugared ratio is prepared (1:1) (2:1).
8 prescription 5 of table
By pregelatinized starch, microcrystalline cellulose is used in mixed way as filler 1:10SD (monolithic 1mgASC-J9, slice weight
200mg) auxiliary material ratio
8 prescription 6 of table
Different tablets are placed on high humility, a period of time under room temperature, hardness test is carried out, selects best auxiliary material scheme.
The quality testing of tablet
Tablet weight variation inspection: test sample 20 are taken.Claiming its gross mass, is averaging slice weight, precision weighs every sheet weight, due to
Indicate slice weight < 0.3g therefore weight differential ± 7.5% for qualification.
The inspection of friability: taking test sample 10, and precision weighs gross mass, is placed in cylinder, and 100 circle of rotation takes out, removes
Remove dust, precise weighing.Reducing quality needs < 1%.
Tablet hardness inspection: taking 3 to carry out Determination of Hardness respectively, when observation tablet cracking, the maximum pressure that can bear.
The inspection of tablet disintegration time limit: 6 tablets being put into and are turned in basket, observes 6 times being all disintegrated.
The examination of Dissolution of Tablet:
Monomer tablet, physical mixture tablet, the comparison of SD Dissolution of Tablet
Dissolution determination: it is measured using Rotating shaker method, temperature (37.5) DEG C, revolving speed 50r/min, since ASC-J9 is not dissolved in
Simulated gastric fluid and simulated intestinal fluid when measuring dissolution rate to above-mentioned sample, select the artificial stomach containing 0.2% lauryl sodium sulfate
Liquid (solubility that lauryl sodium sulfate can increase ASC-J9) carries out dissolution determination as dissolution medium, and by monomer, object is mixed,
Admittedly dissipating 1,2, No. 3 capsules of each 10 loadings, it is placed in 1000mL dissolution medium, is sampled every 5min, every sub-sampling 10mL.Sampling
After supplement fresh dissolution medium.The solution of acquirement, which is put into 10mL centrifuge tube, to be centrifuged (8000r/min, 10min) and takes supernatant
Liquid, carries out the measurement of absorbance, and concentration for the treatment of data draw Dissolution profiles.
Similarly, the measurement (carrying out 3 repeated experiments) for carrying out dissolution rate to 3 kinds of ratio SD tablets is compared, and is drawn
Dissolution profiles.
The stability study (influence factor experiment) of SD
Content detection is carried out to the SD tablet of selection, takes 10 tablets to be respectively put into 1. into 10. number 10mL centrifuge tube, adds
10mL ethyl alcohol constant volume, ultrasonoscope concussion, dissolves it sufficiently, puts into a centrifuge (8000r/min, 10min) and be centrifuged.
It takes supernatant to dilute 100 times, carries out absorbance measurement.
The examination of disintegration time limited and hardness is carried out simultaneously.
High-temperature experiment
It taking test sample 20 to take pictures, weighs, be put into stability test case, setting temperature is 60 DEG C, at the 5th day, the
Sampling in 10 days is analyzed.
It is sampled after 5th day, claims its gross mass, taken out 10, weigh 10 sheet weights, content was carried out to the 5th day sample,
Disintegration time limited, the measurement of hardness
It is sampled after 10th day, weighs gross mass, content, disintegration time limited, the measurement of hardness were carried out to the 10th day sample.
High humility experiment
It takes test sample 20 to take pictures, weighs, be put into culture dish, one is placed in 1000mL beaker equipped with saturation
In the 50mL beaker of NaCl, culture dish is put into 1000mL beaker, room temperature is protected from light, and is sealed.
It is sampled after 5th day, claims its gross mass, taken out 10, weigh 10 sheet weights, content was carried out to the 5th day sample,
Disintegration time limited, the measurement of hardness
It is sampled after 10th day, weighs gross mass, content, disintegration time limited, the measurement of hardness were carried out to the 10th day sample.
Strong illumination experiment
It takes test sample 20 to take pictures, weighs, be put into light in stability test case and be set as 4800lx, at the 5th day
It is sampled analysis within tenth day.
It samples, takes pictures after 5th day, claim its gross mass, take out 10, weigh 10 sheet weights, the 5th day sample is carried out
Content, disintegration time limited, the measurement of hardness.
It is sampled after 10th day, takes pictures, weigh gross mass, content, disintegration time limited, the survey of hardness were carried out to the 10th day sample
It is fixed.
Experimental result and analysis
One .PEG6000 monomer, physical mixture, the comparison of SD solubility can be obtained three by the experiment of multiplicating property
The concentration of ASC-J9 is monomer (2.6 μ g/mL) in kind solution, and object mixes (9.2 μ g/mL), SD (34 μ g/mL), as shown in Figure 1.
Compare the solubility of the SD of three kinds of different proportions (1:10,1:20,1:50), wherein 1:10SD (13 μ g/mL), 1:
20SD (22 μ g/mL), 1:50SD (35 μ g/mL), as shown in Figure 2.
By can be seen that the solubility of PEG6000:ASC-J9 physical mixture is higher than ASC-J9 monomer in water in Fig. 1
Solubility, and the solubility of PEG6000:ASC-J9SD is significantly larger than the solubility of monomer and physical mixture.By can in Fig. 2
To find out, according to identical theoretical content ASC-J9SD solubility relatively in, 1:50ASC-J9SD solubility is best.
Two .PEG6000: the monomer of PLURONICS F87 (4:5), physical mixture, the comparison of SD solubility, by multiple
Repeated experiment, the concentration that ASC-J9 in three kinds of solution can be obtained is monomer (2.5g/mL), and object mixes (10 μ g/mL), SD (22 μ g/
ML) as shown in Figure 3.
Compare three kinds of different proportions (1:(1:1)；1:(2:5) 1:(4:5)) SD solubility, wherein 1:(1:1) SD
(17.2μg/mL),1:(2:5)SD(17.7μg/mL),1:(4:5)SD(23μg/mL).As shown in Figure 4.
The solubility that can be seen from figure 3 (PEG6000: PLURONICS F87) ASC-J9 physical mixture is higher than
The solubility of ASC-J9 monomer in water, and the solubility of (PEG6000: PLURONICS F87) ASC-J9SD is significantly larger than monomer
With the solubility of physical mixture.Compare it can be seen from Fig. 4 according to the solubility of the ASC-J9SD of identical theoretical content
In, 1:(4:5) ASC-J9SD solubility is best.
Three .F68 (1:10) monomer, physical mixture, the comparison of SD solubility can be obtained by the experiment of multiplicating property
The concentration of ASC-J9 is monomer (2.3 μ g/mL) in three kinds of solution, and object mixes (5.5 μ g/mL), and SD (17 μ g/mL) is as shown in Figure 5.
Compare the solubility of the SD of three kinds of different proportions (1:5,1:10,1:20), wherein 1:5SD (12.1 μ g/mL), 1:
10SD (22 μ g/mL), 1:20SD (12.6 μ g/mL) are as shown in Figure 6.
By can be seen that PLURONICS F87 in Fig. 5: the solubility of ASC-J9 physical mixture is higher than ASC-J9 monomer and exists
Solubility in water, and PLURONICS F87: the solubility of ASC-J9SD is significantly larger than the solubility of monomer and physical mixture.
It can be seen from Fig. 6 according to the solubility of the ASC-J9SD of identical theoretical content relatively in, 1:10 PLURONICS F87 ASC-
J9SD solubility is best.
Repeated experiment is carried out to different batches drug, the solubility for obtaining 1:50PEG6000SD is best, preparation
PEG6000SD, physical mixture carry out it shown in reperformance test table 9, shown in dissolution rate histogram 7.(7.5 μ of theoretical value
g/mL)。
9 dissolution rate of table
As shown in Figure 7, the dissolution rate of 1:50PEG6000ASC-J9SD mixes monomer in water much higher than object 47% or so
In dissolution rate, substantially increase the solubility of ASC-J9 in water.
Select the analysis of dissolution of excellent rear SD
Dissolution determination: being measured, temperature (37.5) DEG C, revolving speed 50r/min using paddle method, since ASC-J9 is insoluble in artificial
Gastric juice and simulated intestinal fluid when measuring dissolution rate to above-mentioned sample, select the simulated gastric fluid containing 0.2% lauryl sodium sulfate
(solubility that lauryl sodium sulfate can increase ASC-J9) carries out dissolution determination as dissolution medium, and by monomer, object is mixed, Gu
It is in bulk enter 1,2, No. 3 capsules, be placed in 1 000ml dissolution medium, every 5min sample, every sub-sampling 10mL.It is supplemented after sampling
Fresh dissolution medium.Wherein the amount of ASC-J9 monomer is 0.02g (calculating by ASC-J9 content 2% in SD), physical mixture and
Each 1g of SD.The solution of acquirement, which is put into 10mL centrifuge tube, to be centrifuged (8000r/min, 10min) and takes supernatant, and absorbance is carried out
Measurement, the data of processing are as shown in table 10, draw dissolution rate curve it is as shown in Figure 8.
The concentration of 10 different time of table
As seen from Figure 8, the dissolution rate of 1:50ASC-J9SD is significantly larger than the dissolution speed of physical mixture and monomer
Rate.
The dissolution rate of different time can be found out according to the calculation formula of the accumulation dissolution rate of offer, thus calculate data such as
Shown in table 11, and draw shown in accumulation Dissolution profiles Fig. 9.
11 intermediate data of table is accumulation dissolution rate %
By in Fig. 9 it can be seen that the accumulation dissolution rate of 1:50ASC-J9SD reaches 70%, significantly larger than physical mixture and
The accumulation dissolution rate of monomer.
The result and optimization of tablet quality detection
Different tablet formulation 2.5.1 are placed on high humility, a period of time under room temperature, carry out hardness test, selection is best
For the auxiliary material scheme of auxiliary material scheme prescription 6 compared with other schemes, hardness is good, is not easy to be deliquesced, admittedly select this scheme to carry out experiment system
Standby 1:10SD tablet is 1.；1:20SD tablet is 2.；3., each 200, each auxiliary material amount is as shown in table 12 for 1:50SD tablet:
The additive of tablet content of 12 3 kinds of SD of table
Prepare monomer tablet I, 1:50 physical mixture tablet II, each 100.Shown in each auxiliary material amount such as table 3.4 (b)
Prepare monomer tablet I, 1:50 physical mixture tablet II, each 100.Each auxiliary material amount is as shown in table 13
13 monomer of table mixes additive of tablet content
To 1:50SD tablet weight Difference test, friability detection is as follows:
The inspection of friability: taking test sample 10, and precision weighs gross mass, is placed in cylinder, and 100 circle of rotation takes out, removes
Remove dust, precise weighing.Reducing quality needs < 1%.
14 1:50SD tablet friability of table measures table
By table 14 it can be concluded that, friability passed examination.
Tablet weight variation inspection: test sample 20 are taken.Claiming its gross mass, is averaging slice weight, precision weighs every sheet weight, due to
Indicate slice weight < 0.3g therefore weight differential ± 7.5% for qualification.
15 1:50SD tablet weight difference of table measures table (gross mass 4.08g, average value 0.204g)
Continued 15
As can be seen from Table 15, the weight differential of 20 test samples is respectively less than ± 7.5%, and tablet weight variation is qualified.
Tablet hardness inspection: it takes 3 to carry out Determination of Hardness respectively, observes maximum pressure.3 pressure are respectively 144.1N,
147.2N,143.1N。
The inspection of tablet disintegration time limit: 6 have been disintegrated the time all for 12min or so.Monomer tablet, physical mixture piece
Agent, the comparison of 1:50SD Dissolution of Tablet
Dissolution determination: it is measured using Rotating shaker method, temperature (37.5) DEG C, revolving speed 50r/min, since ASC-J9 is not dissolved in
Simulated gastric fluid and simulated intestinal fluid when measuring dissolution rate to above-mentioned sample, select the artificial stomach containing 0.2% lauryl sodium sulfate
Liquid (solubility that lauryl sodium sulfate can increase ASC-J9) carries out dissolution determination as dissolution medium, and by monomer, object is mixed,
Admittedly dissipating turning in basket for each 11,2, No. 3 capsule of loading, it is placed in 1000mL dissolution medium, is sampled every 5min, every sub-sampling
10mL.Fresh dissolution medium is supplemented after sampling.The solution of acquirement be put into 10mL centrifuge tube and be centrifuged (8000r/min,
Supernatant 10min) is taken, the measurement of absorbance is carried out, draws Dissolution profiles.
The data of processing are as follows:
16 absorbance data of table
Concentration is obtained through standard curve A=0.1432C conversion.
The concentration in different time periods of table 17 (μ g/mL)
Calculate the accumulation dissolution rate of each time point:
Table 18 accumulates dissolution rate %
As seen from Figure 10, it is left that 70% is up to after the accumulation dissolution rate morning 25min of 1:50ASC-J9PEG6000SD tablet
The dissolution rate on the right side, significantly larger than monomer (5% or so) and physical mixture (10% or so).
Similarly, to 1:10,1:20, the measurement (carrying out 3 repeated experiments) of 1:50SD tablet progress dissolution rate
Absorbance (1. 3. experiment for the first time tests 2. third time experiment second)
19 absorbance of table (1. 3. experiment for the first time tests 2. third time experiment second)
Continued 19
Concentration is obtained through standard curve A=0.1432C conversion.
20 concentration μ g/mL of table (1. 3. experiment for the first time tests 2. third time experiment second)
Calculate accumulation dissolution rate:
Table 21 accumulates dissolution rate % (1. 3. experiment for the first time tests 2. third time experiment second)
Accumulate the drafting of Dissolution profiles: by the repeated experiment table 20 of dissolution rate, the Drawing of Curve figure of table 21 and Figure 11
It can be seen that the dissolution rate of 1:50SD tablet 70% or so, 1:20SD tablet dissolution rate in 50% or so, 1:10SD tablet
Dissolution rate it is best in the dissolution rate of 40% or so, 1:50SD tablet.
The research (influence factor experiment) of stability experiment
Content detection is carried out to 1:50SD tablet, takes 10 tablets to be respectively put into 1. into 10. number 10mL centrifuge tube, adds
10mL ethyl alcohol constant volume, ultrasonoscope concussion, dissolves it sufficiently, puts into a centrifuge (8000r/min, 10min) and be centrifuged.
It takes supernatant to dilute 100 times, carries out absorbance measurement.
Absorbance is as follows:
The measurement of 22 tablet content of table
10 μ g/mL of theoretical value, actual content is in 0.99mg/ piece or so.
For hardness about in 130N or so, disintegration time limited is 11min45s or so before sampling.
High-temperature experiment
It taking test sample 20 to take pictures, weighs, be put into stability test case, setting temperature is 60 DEG C, at the 5th day, the
Sampling in 10 days is analyzed.
It is put into 20 gross masses of stability experiment case: 4.012g；
The 5th day test sample taken out, claims its gross mass: 3.982g, 10 test samples is taken to claim its quality: 1.873g.
Hardness test: 75N
The test of disintegration: 11min30s or so
Above detection, photo find out color without significant change, and Mass lost 0.03g, disintegration time limited and high temperature are tested
Preceding roughly the same, hardness has dropped as many as 50N.
It samples within tenth day, claims its 10 gross masses: 2.102g, Theoretical Mass 2.109g.
Hardness test: 70N
The test of disintegration: 11min23s or so.
Assay: it takes 3 tablets to be respectively put into 1. into 3. number 10mL centrifuge tube, adds 10mL ethyl alcohol constant volume, ultrasonic wave
Instrument oscillation, dissolves it sufficiently, puts into a centrifuge (8000r/min, 10min) and be centrifuged.Supernatant is taken to dilute 100 times
(0.1mL+9.9mL ethyl alcohol) carries out absorbance measurement.
The assay of sampling in table 23 10 days
According to above detection, Mass lost 0.007g, disintegration time limited is roughly the same with before high temperature experiment, hardness decline
As many as 55N, content is in 0.8mg/ piece.
Table comparison in 24 10 days
It being obtained by table 24, under hot conditions, the content of ASC-J9 has small-scale reduction in tablet, and hardness reduces, other
Part difference is little.
High humility experiment
It takes test sample 20 to take pictures, weighs, the 1000mL that the 50mL container of saturation NaCl solution is put at one is burnt
In cup, it is put into test sample, is sealed under normal temperature conditions.At the 5th day, sampling in the 10th day was analyzed.
It is put into 20 gross mass 4.034g of container；
5th day, claim its gross mass: 4.322g, (hydroscopicity 6%) takes 10 test samples to claim its quality: 2.259g.
Hardness test 15N
Disintegration time limited 3min43s
According to above detection, photo finds out that color is deepened, and hydroscopicity reaches 6%, and disintegration time limited and hardness substantially reduce.
10th day, claim its 10 gross masses: 2.235g, Theoretical Mass 2.063g.Hydroscopicity 8%.
Hardness test: 7N
The test of disintegration: 11min23s or so
Assay: it takes 3 tablets to be respectively put into 1. into 3. number 10mL centrifuge tube, adds 10mL ethyl alcohol constant volume, ultrasonic wave
Instrument concussion, dissolves it sufficiently, puts into a centrifuge (8000r/min, 10min) and be centrifuged.Supernatant is taken to dilute 100 times
(0.1mL+9.9mL ethyl alcohol) carries out absorbance measurement.
The assay of sampling in table 25 10 days
According to above detection, photo finds out that color is deepened, and hydroscopicity 8%, disintegration time limited hardness reduction amount is big, and content exists
0.65mg/ piece or so.
Table comparison in 26 10 days
It is obtained by table 26, under super-humid conditions, the content of ASC-J9 is reduced in tablet, and hardness reduces, and disintegration time limited shortens, moisture absorption
Rate is 8% or so.
Strong light experiment
It takes test sample 20 to take pictures, stability experiment case is put into, under the conditions of 4800lx strong illumination.At the 5th day,
Sampling in 10th day is analyzed.
It is put into 20 gross mass 4.060g of container；
5th day, claim its gross mass: 3.975g, (Mass lost 0.103g) takes 10 test samples to claim its quality: 1.983g.
Hardness test 120N
Disintegration time limited 9min30s
Assay: it takes 3 tablets to be respectively put into 1. into 3. number 10mL centrifuge tube, adds 10mL ethyl alcohol constant volume, ultrasonic wave
Instrument concussion, dissolves it sufficiently, puts into a centrifuge (8000r/min, 10min) and be centrifuged.Supernatant is taken to dilute 100 times
(0.1mL+9.9mL ethyl alcohol) carries out absorbance measurement.
The assay of sampling in table 27 the 5th day
According to above detection, quality hardness reduces, and there be certain shorten in disintegration time limited.Content reduces obviously, is
0.5mg/ piece or so.
Tenth day, claim its 10 gross masses: 1.974g, Theoretical Mass 1.936g.
Hardness test: 117N；
The test of disintegration: 11min20s or so；
Assay: it takes 3 tablets to be respectively put into 1. into 3. number 10mL centrifuge tube, adds 10mL ethyl alcohol constant volume, ultrasonic wave
Instrument concussion, dissolves it sufficiently, puts into a centrifuge (8000r/min, 10min) and be centrifuged.Supernatant is taken to dilute 100 times
(0.1mL+9.9mL ethyl alcohol) carries out absorbance measurement.
The assay of sampling in table 28 10 days
According to above detection, quality hardness disintegration time limited changes less than before, and content reduces greatly, in 0.25mg/ piece
Left and right.
Table comparison in 29 10 days
It is obtained by table 29, under the conditions of strong illumination, the content of ASC-J9 reduces obvious, quality, hardness, disintegration time limited in tablet
Change small.
The tablet should be placed on low temperature, be protected from light, and encapsulation saves.
Discuss the Optimizing Suggestions with auxiliary material to the unstability of this tablet: the purpose of influence factor experiment is to investigate system
The reasonability and production technology and terms of packing of agent prescription.The tablet is in high temperature, high humility, under strong illumination, content, character meeting
It changes, influences the drug effect of ASC-J9.For this disadvantage, coating can be made and be protected.The purpose of coating: 1. be protected from light,
It is moisture-proof, to improve the stability of drug.2. changing rate of release and the position of drug.3. enhancing drug recognition capability, improves and use
The safety of medicine.Using the water-soluble material of film coating, sodium cellulose glycolate is as coating material, and talcum powder is as lubrication
Agent, water colo(u)r are coloured.Carry out the preparation of tablet.
Embodiment described above is only to absolutely prove preferred embodiment that is of the invention and being lifted, and protection scope is unlimited
In this.Those skilled in the art's made equivalent substitute or transformation on the basis of the present invention, in protection of the invention
Within the scope of, protection scope of the present invention is subject to claims.
Claims (10)
1. the preparation method of Dimethylcurcumin solid dispersions, which is characterized in that steps are as follows: according to a certain percentage, by water
Solubleness carrier material is added to the container heating melting, adds Dimethylcurcumin, agitating and heating 20-60min, heating temperature 60
~85 DEG C, after defoamed, 2h-8h is placed at 0~4 DEG C, by pulverizing and sieving to get the Dimethylcurcumin solid point
Granular media；The water soluble carrier material is PEG 6000 or PLURONICS F87.
2. the preparation method of Dimethylcurcumin solid dispersions according to claim 1, which is characterized in that described
The mass ratio of PEG6000 and Dimethylcurcumin is 10:1~50:1.
3. the preparation method of Dimethylcurcumin solid dispersions according to claim 1, which is characterized in that the pool Lip river
The mass ratio of husky nurse 188 and Dimethylcurcumin is 5:1~20:1.
4. the preparation method of Dimethylcurcumin solid dispersions according to claim 1-3, which is characterized in that
The temperature when heating melting is 60~85 DEG C.
5. the dimethyl ginger as made from the preparation method of the described in any item Dimethylcurcumin solid dispersions of claim 1-4
Flavine solid dispersions.
6. Dimethylcurcumin solid dispersion tablet, the dimethyl turmeric obtained comprising any one of claim 1-5 preparation method
Plain solid dispersions.
7. Dimethylcurcumin solid dispersion tablet according to claim 6, which is characterized in that the Dimethylcurcumin
Solid dispersion tablet includes the following component according to mass fraction meter: 2.2-10.2 parts of Dimethylcurcumin solid dispersions collapse
Solution agent 9.4-13.4 parts, 9.4-13.4 parts of filler, 1-6 parts of flavoring agent, 0.2-0.5 parts of glidant, 0.1-0.5 parts of lubricant,
1-4 parts of raising agent.
8. Dimethylcurcumin solid dispersion tablet according to claim 7, which is characterized in that the Dimethylcurcumin
Solid dispersion tablet includes the following component according to mass fraction meter: 2.2 parts of Dimethylcurcumin solid dispersions, disintegrating agent
13.4 parts, 13.4 parts of filler, 6 parts of flavoring agent, 0.5 part of glidant, 0.5 part of lubricant, 4 parts of raising agent.
9. Dimethylcurcumin solid dispersion tablet according to claim 7, which is characterized in that the disintegrating agent is crystallite
Cellulose, the filler is pregelatinized starch, the flavoring agent is Lactis Anhydrous；The glidant is superfine silica gel powder, described
Lubricant is magnesium stearate, and the raising agent is calcium monohydrogen phosphate.
10. Dimethylcurcumin solid dispersion tablet according to claim 7, which is characterized in that the dimethyl turmeric
Plain solid dispersion tablet further includes coating, and the coating material is sodium cellulose glycolate.
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Application publication date: 20191129 |