CN115590831A - Dimethyl fumarate sustained-release micro-tablets and preparation method thereof - Google Patents
Dimethyl fumarate sustained-release micro-tablets and preparation method thereof Download PDFInfo
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/225—Polycarboxylic acids
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Abstract
The invention provides a dimethyl fumarate slow-release micro-tablet and a preparation method thereof. The sustained-release micro-tablet can achieve 24h sustained-release effect without adding sustained-release matrix material, and the sustained-release effect is not easily affected by mechanical pressure, and has small dosage dumping risk and reduced adverse reactions such as gastrointestinal irritation.
Description
Technical Field
The invention relates to a dimethyl fumarate sustained-release micro-tablet and a preparation method thereof, belonging to the technical field of pharmacy.
Background
Fumaric acid dimethyl ester (C) 6 H 8 O 4 ) The first-line oral therapeutic drug for the relapsing multiple sclerosis is an oral therapeutic drug, wherein the peak arrival time is about 2-2.5 h, the peak concentration of blood plasma and the area under a curve when the drug is applied are greatly influenced by dose and food, and obvious 'wave crest and trough effects' exist, so that the recommended dose of the original grinding capsule preparation (Tecfidera) of dimethyl fumarate (Tecfidera) is 120mg (the first 7 days) or 240mg (the second 7 days) every time, and the oral therapeutic drug is taken 2 times a day. The frequency and the pharmacokinetic characteristics of the administration bring much inconvenience to the use of patients, and the drugs stimulate epithelial cells of the gastrointestinal tract and induce the generation of tumor necrosis factors, thereby causing adverse reactions such as abdominal pain, diarrhea, nausea, hot flashes and the like. Therefore, the dimethyl fumarate is suitable for being prepared into a sustained-release preparation, can effectively reduce the incidence rate of adverse reactions, reduce the administration times, improve the compliance of patients and has obvious clinical advantages.
In the existing dimethyl fumarate sustained-release preparation, the adopted technologies mainly comprise a corrosion skeleton technology and a microtablet technology. The common erosion skeleton tablet has low content of active ingredients, and needs to be added with a large amount of sustained-release materials to ensure the sustained-release effect of the medicine, so that the prepared sustained-release tablet has larger tablet weight and diameter, the sustained-release effect is easily influenced by mechanical pressure, the tablet has hidden danger of dose dumping, patients have dysphagia or need to take medicine in batches, and the compliance of the patients is greatly reduced. Particularly for dimethyl fumarate which is a medicine active ingredient with gastrointestinal tract stimulation, tablets with the diameter of more than 6mm are not easy to pass through pylorus, and gastrointestinal tract stimulation is easy to increase to cause adverse reaction. The prior dimethyl fumarate micro-tablet has the following defects: 1. under the production conditions, especially when the active component of the raw material dimethyl fumarate is more than 80%, the raw material dimethyl fumarate is not easy to be pressed and formed, even if the hardness and the friability of the raw material dimethyl fumarate are obviously insufficient, a large amount of fillers such as starch, polyvinylpyrrolidone and the like and auxiliary materials such as a buffer matrix and the like need to be added, and the total content of the monoalkyl fumarate and the salt thereof is often lower than 50%; 2. after a large amount of sustained-release matrix and other auxiliary materials are added, the sustained-release effect is still poor, the unit dose weight is larger, and the compliance of a patient is reduced; 3. in the prior art, the slow release effect mainly depends on the erosion of the slow release matrix and the adhesion on the surface of the gastrointestinal tract, and the effect is greatly influenced by mechanical force and is easy to cause the difference between tablets.
Disclosure of Invention
The invention provides a dimethyl fumarate sustained-release micro-tablet and a preparation method thereof, which can effectively solve the problems.
The invention is realized by the following steps:
a method for preparing dimethyl fumarate sustained-release micro-tablets comprises the steps of putting dimethyl fumarate, a lubricant and a flow aid into a mixer, mixing, and directly pressing by using a micro-tablet punch.
As a further improvement, the lubricant is selected from one or more of magnesium stearate, calcium stearate, sodium hard fumarate and polyethylene glycol.
As a further improvement, the glidant is selected from one or more of silicon dioxide, talcum powder and micro-powder silica gel.
As a further improvement, the mass percentages of the dimethyl fumarate, the lubricant and the flow aid are respectively 90.0-99.6%, 0.5-2.5% and 0.1-0.5%.
As a further improvement, the mass percentages of the dimethyl fumarate, the lubricant and the flow aid are respectively 97.0-99.6%, 0.5-2.5% and 0.1-0.5%.
As a further improvement, the d90 of the bulk drug of the dimethyl fumarate is 100-180 μm, the d50 is 40-80 μm, and the angle of repose is less than or equal to 38 degrees.
As a further improvement, the main pressure value of the pressing is in the range of 0.5-2 kN.
As a further improvement, the three-dimensional motion mixer has the mixing speed of 10-20 rpm and the mixing time of 10-20 min.
As a further improvement, the micro sheet punch is cylindrical, the diameter is 1-2 mm, the height is 1-2 mm, and the two surfaces are convex up and down.
The dimethyl fumarate sustained-release micro-tablets prepared by the method.
The beneficial effects of the invention are:
the dimethyl fumarate sustained-release micro-tablet is prepared by a powder direct compression method, can achieve the sustained-release effect for 24 hours without adding a sustained-release matrix material, has the sustained-release effect which is not easily influenced by mechanical pressure, has small dose dumping risk, and can reduce adverse reactions such as gastrointestinal irritation and the like.
The dimethyl fumarate sustained-release micro-tablets have stable drug action curve and no obvious wave crest and wave trough phenomenon.
The dimethyl fumarate sustained-release micro-tablet does not contain hydrophilic sustained-release matrix materials, so the dimethyl fumarate sustained-release micro-tablet is not influenced by the environmental humidity in the storage process and is easy to store.
The medicine carrying proportion of the invention is up to more than 90.0 percent, the tablet weight can be obviously reduced, the size is small, the medicine is easier to swallow, and the taking compliance of patients is greatly improved.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are required to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
Fig. 1 shows the release comparison of the high drug-loading dimethyl fumarate micro-tablets (F8), the common micro-tablets (F2) and the common tablets (F1) provided in example 1.
FIG. 2 shows the 24-hour dissolution curves (F3-F8) of the dimethyl fumarate micro-tablets provided in example 1 with different drug loading rates.
FIG. 3 is a plot of the time course of the dimethyl fumarate micro-tablets (F8) and the reference formulation Tecfidera provided in example 1.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions of the embodiments of the present invention will be described clearly and completely with reference to the accompanying drawings of the embodiments of the present invention, and it is obvious that the described embodiments are some, but not all embodiments of the present invention. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention. Thus, the following detailed description of the embodiments of the present invention, presented in the figures, is not intended to limit the scope of the invention, as claimed, but is merely representative of selected embodiments of the invention. All other embodiments, which can be obtained by a person skilled in the art without inventive efforts based on the embodiments of the present invention, are within the scope of protection of the present invention.
The embodiment of the invention provides a preparation method of a dimethyl fumarate slow-release micro-tablet, which comprises the steps of putting dimethyl fumarate, a lubricant and a flow aid into a mixer, mixing, and directly pressing by using a micro-tablet punch.
In some embodiments, the mixer is a three-dimensional motion mixer.
In some embodiments, the lubricant is selected from one or more of magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycols.
In some embodiments, the glidant is selected from one or more of silicon dioxide, talc, aerosil.
In some embodiments, the dimethyl fumarate sustained-release micro-tablets further comprise other necessary auxiliary materials. Such as microcrystalline cellulose lactose complex, crospovidone, and the like.
In some embodiments, the mass percentages of the dimethyl fumarate, the lubricant and the glidant are 90.0 to 99.6%, 0.5 to 2.5%, 0.1 to 0.5%, more preferably 97.0 to 99.6%, 0.5 to 2.5%, and 0.1 to 0.5%, respectively. Within this range, the micro-tablets have strong sustained-release capability.
In some embodiments, the dimethyl fumarate bulk drug has a d90 of 100-180 μm, a d50 of 40-80 μm, and an angle of repose of not more than 38 °. The particle size and the angle of repose of the raw material medicine have important influence on the sustained release capability of the micro-tablets, and the sustained release effect is optimal within the range. The raw material medicine particles with too large particle size or angle of repose are easy to cause poor fluidity, uneven filling and weak compressibility, and cannot be pressed to obtain high medicine-loading rate; however, the active pharmaceutical ingredient with too small particle size and too small angle of repose cannot be extruded into micro-tablets with 24h sustained release effect.
In some embodiments, the main pressure value of the pressing is in the range of 0.5 to 2kN. Within the range of the main pressure value, the hardness range of the micro-tablets is ensured to be 10-40N and the friability, the requirements of pharmacopoeia are met, and the sustained-release effect within 24h can be maintained.
In some embodiments, the mixer mixes at 10 to 20rpm for 10 to 20min.
In some embodiments, the microplate punch is cylindrical, 1-2 mm in diameter, 1-2 mm in height, and convex on both sides. The shape of the micro-tablets, the diameter of the micro-tablets and the height of the micro-tablets have important influence on the slow release capability of the micro-tablets, and the slow release effect is optimal within the range.
The embodiment of the invention also provides the dimethyl fumarate sustained-release micro-tablets prepared by the method. The dimethyl fumarate sustained-release micro-tablet is prepared by a powder direct compression method, can achieve a 24-hour sustained-release effect without adding a sustained-release matrix material, is not easily affected by mechanical pressure, has small dose dumping risk, and can reduce adverse reactions such as gastrointestinal irritation; the curve is stable during administration, and no obvious wave crest and wave trough phenomenon exists; the water-based organic fertilizer does not contain hydrophilic sustained-release matrix materials, is not influenced by the environmental humidity in the storage process, and is easy to store; the medicine carrying ratio is as high as more than 90.0 percent, the tablet weight can be obviously reduced, the size is small, the medicine is easier to swallow, and the administration compliance of patients is greatly improved.
EXAMPLE 1 high drug-load dimethyl fumarate sustained-release minitablets
In order to examine the influence of the content of the ingredients of the formula on the sustained-release effect, a series of screening experiments were carried out, and the formula of this example is shown in table 1.
Is prepared by a powder direct compression method. Adding dimethyl fumarate, silicon dioxide, magnesium stearate and other adjuvants into three-dimensional motion mixer (SKH-50) at 15rpm, mixing for 15min, punching with phi 2 shallow punch at main pressure of 1kN, and directly pressing. The dissolution (cumulative release) of each formulation of the mini-tablets was tested. The test method is Chinese pharmacopoeia paddle method (2 method), pH6.8 medium, rotating speed 50rpm, and dissolving volume 1000ml. Dissolution sampling time is 0.5,1, 2, 3, 4,6, 10, 16, 24h. Dissolution test data are shown in table 2 and figures 1-2.
TABLE 1 high drug loading dimethyl fumarate microtablet compositional review
Note 1: f1 is a common tablet with the diameter of 7mm.
TABLE 2 dissolution of dimethyl fumarate microtablets of different compositions
As can be seen from fig. 1, the sustained-release effect of the high drug-loading rate dimethyl fumarate micro-tablet (F8) is better than that of the conventional tablet (F1) and conventional micro-tablet (F2).
As can be seen from Table 2 and FIG. 2, the sustained release capacity of the micro-tablets is gradually enhanced with the increase of the content of the active ingredients of the drug, the plateau period is reached when the content reaches 90%, and the dissolution curve is not changed obviously any more after the content is higher than 92%. The common dimethyl fumarate tablet (F1) can be rapidly disintegrated in water within 30min, the cumulative release degree within 30min is higher than 85%, while the high drug-loading rate micro-tablet (F8) prepared in the embodiment can realize 24h sustained release without adding any sustained release matrix, and the in vitro active ingredients of the high drug-loading rate micro-tablet can be released in 3h (20.18 +/-1.43)%, 10h (69.32 +/-2.11)%, and 24h (97.35 +/-3.59)%.
The dimethyl fumarate micro-tablets prepared in this example and reference formulation Tecfidera were tested for their main pharmacokinetic parameters and the results are shown in table 3 and fig. 3.
The test method is as follows: 8 beagle dogs were randomly divided into 1 test group and 1 control group, with 4 dogs each. All beagle dogs were fasted overnight, and the test group was given 1 prescription F8 (240 mg) and the control group was given 1 Tecficdera capsule (240 mg). At 14 blood collection time points, 0,0.5,1,1.5,2,2.5,3,3.5,4,6,8, 12, 16, 24h, approximately 1ml of blood was taken from each beagle femoral vein into tubes containing heparin sodium anticoagulant. The samples were centrifuged at 1500rpm for 15min at 4 ℃ over 30min, and the upper plasma was collected and stored at-80 ℃ for testing. MMF-d5 was used as an internal standard under conditions of theoretical concentration ranging from 25 to 2500ng/mL with a lower limit of quantitation of 25 ng/mL. Identification and quantification of compounds by liquid chromatography-tandem mass spectrometry (LC-MS/MS), column: kinetex 2.6um EVO c18 column (100 x 2.1mm), mobile phase: a:0.1% formic acid water, B:0.1% formic acid acetonitrile, flow rate: 0.4mL/min. Statistical analysis of PK parameters was performed using analysis of variance (ANOVA) on AUC 0-t, AUC0-inf, and Cmax for natural log (ln) transformations.
TABLE 3 Main pharmacokinetic parameters of the dimethyl fumarate mini-tablets prepared in this example and the reference formulation Tecfidera
| Pharmacokinetic parameters | Control group (Tecfidera) | Experimental group (dimethyl fumarate micro-tablets F8) |
| C max (mg/L) | 2.07±0.68 | 0.60±0.32 |
| t max (h) | 2.50±0.59 | 4.31±0.14 |
| t 1/2 (h) | 2.01±0.19 | 6.44±0.23 |
| t 75％ (h) | 1.63±0.31 | 7.69±0.35 |
| AUC 0-∞ (mg*h/L) | 6.28±0.73 | 6.50±1.23 |
| PTF(％) | 72.94±0.22 | 28.69±2.27 |
Wherein PTF (%) is the percent mean blood concentration, C max The peak concentration (mg/L) of the curve at the time of administration, C min The time curve is Gu Nongdu (mg/L), AUC 0-t The area under the curve (mg × h/L) indicates the time (h) of the experiment.
t 75％ Refers to the time at which the plasma drug concentration is greater than 75% of the peak concentration.
As can be seen from table 3 and fig. 3, compared with Tecfidera, the dimethyl fumarate micro-tablet (F8) of the present example shows a significant sustained release effect, and the percentage of the in vivo average plasma concentration (PTF value) is less than 60%, the curve is smooth during drug administration, no significant peak and trough phenomenon occurs, and the drug efficacy can be significantly improved.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A preparation method of dimethyl fumarate sustained-release micro-tablets is characterized in that dimethyl fumarate, a lubricant and a flow aid are put into a mixer to be mixed, and then a micro-tablet punch is used for direct compression to obtain the dimethyl fumarate sustained-release micro-tablets.
2. The method of claim 1, wherein the lubricant is selected from one or more of magnesium stearate, calcium stearate, sodium stearyl fumarate, and polyethylene glycol.
3. The method of claim 1, wherein the glidant is selected from one or more of silicon dioxide, talcum powder and silica gel micropowder.
4. The method for sustained release of the dimethyl fumarate micro-tablets according to claim 1, wherein the mass percentages of the dimethyl fumarate, the lubricant and the glidant are 90.0-99.6%, 0.5-2.5% and 0.1-0.5%, respectively.
5. The method for sustained release of the dimethyl fumarate micro-tablets according to claim 1, wherein the mass percentages of the dimethyl fumarate, the lubricant and the glidant are 97.0-99.6%, 0.5-2.5% and 0.1-0.5%, respectively.
6. The method of claim 1, wherein the dimethyl fumarate slow-release micro-tablets have a d90 of 100-180 μm, a d50 of 40-80 μm and an angle of repose of not more than 38 °.
7. The method of claim 1, wherein the compressed main pressure value is in the range of 0.5-2 kN.
8. The method of claim 1, wherein the number of mixing revolutions of the mixer is 10 to 20rpm, and the mixing time is 10 to 20min.
9. The method of claim 1, wherein the micro tablet punch is cylindrical, has a diameter of 1-2 mm and a height of 1-2 mm, and has two convex surfaces.
10. A sustained-release micro-tablet of dimethyl fumarate prepared by the method of any one of claims 1 to 9.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04253922A (en) * | 1991-02-05 | 1992-09-09 | Tokuyama Soda Co Ltd | Sustained release preparation |
| CN1325302A (en) * | 1998-11-19 | 2001-12-05 | 富马法姆股份公司 | Use of dialkylfumarates |
| CN104220061A (en) * | 2012-02-07 | 2014-12-17 | 比奥根艾迪克依蒙菲利亚公司 | Pharmaceutical compositions containing dimethyl fumarate |
| CN104470518A (en) * | 2012-02-27 | 2015-03-25 | 沃泰克斯药物股份有限公司 | Pharmaceutical composition and administration thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04253922A (en) * | 1991-02-05 | 1992-09-09 | Tokuyama Soda Co Ltd | Sustained release preparation |
| CN1325302A (en) * | 1998-11-19 | 2001-12-05 | 富马法姆股份公司 | Use of dialkylfumarates |
| CN104220061A (en) * | 2012-02-07 | 2014-12-17 | 比奥根艾迪克依蒙菲利亚公司 | Pharmaceutical compositions containing dimethyl fumarate |
| CN104470518A (en) * | 2012-02-27 | 2015-03-25 | 沃泰克斯药物股份有限公司 | Pharmaceutical composition and administration thereof |
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