CN115957206A - Tranexamic acid composition and preparation method thereof - Google Patents
Tranexamic acid composition and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the technical field of medicinal preparations, in particular to a tranexamic acid composition and a preparation method thereof, wherein the tranexamic acid composition comprises the following components in parts by weight: 100 parts of tranexamic acid, 5-9 parts of polyvinyl alcohol, 1-3 parts of corn starch, 4-8 parts of low-substituted hydroxypropyl cellulose and 1-4 parts of lubricant; the lubricant comprises glyceryl behenate. The tranexamic acid composition has less impurities than a reference preparation, and has no obvious change in dissolution under the high-temperature condition; through the research of accelerated and long-term tests, the evaluation indexes of dissolution curve, content, dissolution rate, related substances and the like meet the requirements, have no obvious change compared with 0 day, have stable quality, have consistent quality with a reference preparation and are in vivo bioequivalence with the reference preparation, realize clinical substitution with the reference preparation, have lower price and high accessibility, and reduce the medication burden of common people.
Description
Technical Field
The invention relates to a tranexamic acid composition and a preparation method thereof, belonging to the technical field of pharmaceutical preparations.
Background
Tranexamic acid (C) 8 H 15 NO 2 ) Structural formula (la):
molecular weight: 157.21, lysine derivatives, an antifibrinolytic agent, reversibly binds to lysine sites on plasmin, blocks the binding of plasminogen to fibrin, exerts antifibrinolytic action and thereby exerts hemostatic action. Tranexamic acid tablets were originally marketed by the first Sanko corporation of Japan, and were published as reference preparations in the catalog of imitation pharmaceutical reference preparations (twentieth lot) in the specifications of 250mg and 500 mg.
Currently, the tranexamic acid is marketed in the form of common tablets, capsules, powder for injection and injection, and is generally used for hemostasis.
The patent publication CN102525878A discloses a tranexamic acid slow release solid composition and a preparation method thereof, wherein tranexamic acid is taken as a raw material, and the tranexamic acid, a hydrophilic gel slow release framework material, a filling agent, an adhesive, a glidant and a lubricant respectively account for the following weight proportions: 50-70%, 7-20%, 10-40%, 0-10%, 0-2%, 0.5-2%. The prepared sustained-release solid preparation can achieve zero-order release within 3h, and maintain stable blood concentration.
The patent publication CN104414991A discloses a tranexamic acid solid sustained-release tablet and a preparation method thereof, which comprises 40-60% of tranexamic acid, 35-55% of insoluble sustained-release framework material and 0.5-5% of lubricant by weight percentage, and is obtained by carrying out granulation through wet granulation, dry granulation or melt granulation processes and then tabletting;
the publication patent CN104490752A discloses a tranexamic acid composition freeze-dried tablet and a preparation method thereof, wherein the tablet comprises tranexamic acid, starch and sucrose, the starch and the sucrose are used as auxiliary materials, and the common corn starch is subjected to heating process treatment, so that the adhesion and disintegration effects of the starch in the tablet can be improved, and the forming of the tablet is improved;
the patent publication CN103054861A discloses a compound solid preparation containing tranexamic acid, which contains tranexamic acid, vitamin C, vitamin B6, L-cysteine, calcium pantothenate and pharmaceutical excipients suitable for preparing solid preparations, and the compound solid preparation is prepared by the preparation technology.
Publication CN106265581A discloses a tranexamic acid tablet, which contains: 2.5kg of tranexamic acid, 0.3-0.8kg of microcrystalline cellulose, 0.1-0.4kg of low-substituted hydroxypropyl cellulose, 0.01-0.05kg of hydroxypropyl methylcellulose (HPMC), 0.05-0.2kg of sodium dodecyl sulfate (K12) and 0.3-0.7kg of ethanol (30-70 percent), wherein micronized tranexamic acid is subjected to spray granulation by dissolving the sodium dodecyl sulfate into adhesive slurry, and then is mixed with magnesium stearate for tabletting.
The patent publication CN110721169A discloses a preparation method of tranexamic acid tablets, which comprises 100 parts of tranexamic acid, 1.2-4 parts of polyvinyl alcohol, 1.2-4 parts of low-substituted hydroxypropylcellulose, 1.2-4 parts of carboxymethyl starch sodium, 4-12 parts of hydrogenated vegetable oil, 12-40 parts of purified water, 4-12 parts of corn starch and 1.2-4 parts of magnesium stearate. The tablets are prepared by the steps of weighing raw and auxiliary materials, sieving, wet granulation, drying, granulation, mixing, tabletting and the like.
Although many patents are published on tranexamic acid preparations, none of these preparations is reported to pass consistency evaluation and have no product equivalent to the original research (first third co-company, japan) in vitro and in vivo. According to the exempt guiding principle of human body bioequivalence test issued by CFDA, the solubility and permeability of tranexamic acid are analyzed, and the tranexamic acid is presumed to be a high-solubility and low-permeability drug and belongs to BCS classification 3.
Tranexamic acid is a drug with excellent water solubility, but as a low-permeability drug, if the drug is to achieve an equivalent product in the original research body, the product to be developed is similar to the original research in each medium (the similarity factor f2 is more than or equal to 50). Only solving the similarity of dissolution curves in various media is the premise of bioequivalence to the original research under the in vivo environment.
Tranexamic acid original ground tablets (specification 250mg, tablet weight 290 mg), the proportion of raw material medicines is large (86.2%), the proportion of auxiliary materials is small, the properties of the prepared preparation mostly depend on the properties of the raw material medicines, and through preliminary trials, the tranexamic acid is singly tabletted, has serious sticking and puckering, cannot be formed, the compressibility and fluidity of mixed powder of the raw material and the auxiliary materials are poor, the friability is easy to exceed the standard, and the process requirement of directly tabletting powder cannot be met.
In the research process of tranexamic acid tablets, the dissolution curve of a reference preparation is found to have a descending trend after the reference preparation is placed at a high temperature of 60 ℃ for 10 days, and the data of the dissolution curve is different from that of the reference preparation in 0 day. Although the dissolution profile is not a quality standard test item, it is particularly important as a key index of in vivo bioequivalence. In order to solve the stability problem of tranexamic acid tablets under high temperature conditions, the formula process optimization of the variety is carried out to meet the requirements of equivalent quality and in-vivo biological equivalence with a reference preparation.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides the tranexamic acid composition and the preparation method thereof, the tranexamic acid composition is similar to a reference preparation in dissolution in different media in vitro and is equivalent to the reference preparation in vivo, the clinical substitutability of the tranexamic acid composition and the reference preparation is realized, and the treatment cost is reduced.
The technical scheme for solving the technical problems is as follows: a tranexamic acid composition comprises the following components in parts by weight: 100 parts of tranexamic acid, 5-9 parts of polyvinyl alcohol, 1-3 parts of corn starch, 4-8 parts of low-substituted hydroxypropyl cellulose and 1-4 parts of a lubricant; the lubricant comprises glyceryl behenate.
On the basis of the technical scheme, the invention can be further improved as follows:
further, the lubricant is glyceryl behenate or a combination of glyceryl behenate and magnesium stearate.
Furthermore, the granularity of the tranexamic acid is 60-100 meshes.
Preferably, the particle size of the tranexamic acid is 60-80 meshes.
Furthermore, the type of the low-substituted hydroxypropylcellulose is any one or combination of LH-B1, LH11, LH22 and LH21, but the low-substituted hydroxypropylcellulose is not limited to the specific types.
The polyvinyl alcohol is 05-88, 03-88 and 17-88, but not limited to the polyvinyl alcohol.
The invention also discloses a preparation method of the tranexamic acid composition, which comprises the following steps: adding the sieved tranexamic acid into a high-efficiency mixing granulator, adding corn starch and polyvinyl alcohol into the high-efficiency mixing granulator, stirring and mixing uniformly, adding an adhesive solution, stirring and wet granulating, drying, granulating, adding low-substituted hydroxypropyl cellulose and a lubricant into a three-dimensional mixer, mixing to obtain total mixed powder, and tabletting or filling capsules.
Further, the adhesive solution is one or a combination of two of polyvinyl alcohol solution and starch slurry.
The mass concentration of the polyvinyl alcohol solution and the starch slurry is 5-10 percent, namely, the polyvinyl alcohol or the corn starch is prepared into solution to be used as an adhesive solution; the dosage of the polyvinyl alcohol or the corn starch as the adhesive is 50 to 100 percent of the total weight of the adhesive, namely: the dosage of the polyvinyl alcohol as the adhesive is 50 to 100 percent of the total weight of the polyvinyl alcohol in the raw material components of the formula, and the dosage of the corn starch as the adhesive is 50 to 100 percent of the total weight of the corn starch in the raw material components of the formula
Further, adding the sieved tranexamic acid into a high-efficiency mixing granulator, adding corn starch and polyvinyl alcohol into the high-efficiency mixing granulator, uniformly stirring and mixing at 100-150 r/min, adding an adhesive solution, stirring at 100-150 r/min, shearing at 800-1000 r/min for 3-5min for wet granulation, drying at 50-70 ℃, after 20-mesh granulation, adding low-substituted hydroxypropyl cellulose and a lubricant into a three-dimensional mixer, mixing for 3-5min to obtain total mixed powder, and tabletting or encapsulating.
The beneficial effects of the invention are:
(1) The tranexamic acid composition has less impurities than a reference preparation, and has no obvious change in dissolution under the high-temperature condition; through the research of accelerated and long-term tests, the evaluation indexes of dissolution curves, contents, dissolution rates, related substances and the like all meet the requirements, and the evaluation indexes have no obvious change compared with 0 day and stable quality.
(2) The tranexamic acid composition provided by the invention passes BE tests (no other manufacturers are reported to pass at present), has consistent quality with a reference preparation and is in vivo bioequivalent with the reference preparation, realizes clinical substitution with the reference preparation, has lower price and high accessibility, and reduces the medication burden of common people.
(3) The tranexamic acid composition disclosed by the invention adopts a hydrophilic gel framework material polyvinyl alcohol as an adhesive and a thickening agent, a hydrophilic gel layer is formed when the composition meets water, meanwhile, the dissolution behavior of the tranexamic acid is controlled by optimizing the formula component proportion, adjusting the dosage of the adhesive and process parameters, the slow dissolution is released, the irritation to the stomach is relieved, and the difficulty that the tranexamic acid is easily dissolved in water, is dissolved too fast when meeting water, and is difficult to maintain stable blood concentration is solved.
(4) The glyceryl behenate is adopted in the tranexamic acid composition, so that the problems of sticking and puckering of tabletting are solved, the smooth large-scale production of tabletting is ensured, the synergistic effect of the glyceryl behenate and the polyvinyl alcohol plays a role in regulating and controlling the dissolution behavior of the tranexamic acid, the tranexamic acid can have good dissolution property, and the condition that the tranexamic acid is too fast dissolved to cause irritation to the stomach can be avoided.
(5) The tranexamic acid in the tranexamic acid composition is 60-100 meshes, so that a final product has proper dissolution, the smooth operation of a preparation process is ensured, and if the mesh number of the tranexamic acid is too small, the grain size of the tranexamic acid is too large, so that the uneven mixing is easily caused, and the quality of the product is finally influenced; if the mesh number of the tranexamic acid is too large, the particle size of the tranexamic acid is too small, so that the dissolution property is easily influenced, in addition, the preparation process is easily influenced by static electricity in the preparation process, the original drug of the tranexamic acid is astringent, and if the particle size is too small, a punch is very astringent, so that the process cannot be smoothly carried out.
Drawings
FIG. 1 concentration of tranexamic acid in plasma versus time curve after oral administration of test formulation example 1 and reference formulation;
FIG. 2 concentration of tranexamic acid in plasma versus time curve after oral administration of test formulation example 2 and reference formulation;
FIG. 3 concentration of tranexamic acid in plasma after oral administration of test formulation example 3 and reference formulation versus time;
figure 4 concentration of tranexamic acid in plasma versus time curve after oral administration of test formulation example 4 and reference formulation.
Detailed Description
The following is a detailed description of specific embodiments of the invention. This invention can be embodied in many different forms than those herein described and many modifications may be made by those skilled in the art without departing from the spirit of the invention and the scope of the invention is therefore not limited to the specific embodiments disclosed.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
1. Preparation examples
Example 1
The tranexamic acid composition in the embodiment comprises the following raw materials: the composition comprises, by weight, 100 parts of tranexamic acid, 5 parts of polyvinyl alcohol (17-88), 3 parts of corn starch, 4 parts of low-substituted hydroxypropylcellulose (LH-B1), 2.5 parts of magnesium stearate and 1.5 parts of glyceryl behenate, wherein the selected granularity of the tranexamic acid is 60 meshes.
The specific process steps are as follows:
screening tranexamic acid by a sieve of 60 meshes, adding the tranexamic acid into a high-efficiency mixing granulator, adding corn starch and polyvinyl alcohol into the high-efficiency mixing granulator, uniformly stirring and mixing at a set rotating speed of 100 r/min, adding adhesive starch slurry (the mass concentration of the starch slurry is 5%, the using amount of the corn starch as the adhesive is 80% of the total weight of the corn starch in the raw material composition), stirring at 100 r/min, shearing at 800 r/min for 3min, wet granulating, drying at 50 ℃, granulating by 20 meshes, adding low-substituted hydroxypropylcellulose, magnesium stearate and glyceryl behenate into a three-dimensional mixer, mixing for 3min, and obtaining the total mixed powder tablet.
Example 2
The tranexamic acid composition in the embodiment comprises the following raw materials: the composition comprises, by weight, 100 parts of tranexamic acid, 7 parts of polyvinyl alcohol (05-88), 2 parts of corn starch, 6 parts of low-substituted hydroxypropylcellulose (LH-11) and 2.5 parts of glyceryl behenate, wherein the selected granularity of the tranexamic acid is 80 meshes. The specific process steps are as follows:
screening tranexamic acid by 80 meshes, adding the tranexamic acid into a high-efficiency mixing granulator, adding corn starch and polyvinyl alcohol into the high-efficiency mixing granulator, setting the rotation speed to be 120 r/min, stirring and mixing uniformly, adding an adhesive polyvinyl alcohol solution (the mass concentration of the polyvinyl alcohol solution is 10%, the dosage of the polyvinyl alcohol as the adhesive is 50% of the total weight of the polyvinyl alcohol in the raw material composition), stirring at 120 r/min, shearing at 900 r/min for 4min, carrying out wet granulation, drying at 60 ℃, grading by 20 meshes, adding low-substituted hydroxypropyl cellulose and glyceryl behenate into a three-dimensional mixer, mixing for 4min, and obtaining total mixed powder and filling capsules.
Example 3
The tranexamic acid composition in the embodiment comprises the following raw materials: the composition comprises, by weight, 100 parts of tranexamic acid, 9 parts of polyvinyl alcohol (03-88), 1 part of corn starch, 8 parts of low-substituted hydroxypropylcellulose (LH-22), 1 part of magnesium stearate and 3 parts of glyceryl behenate, wherein the selected granularity of the tranexamic acid is 100 meshes. The specific process steps are as follows:
sieving tranexamic acid by a 100-mesh sieve, adding the screened tranexamic acid into a high-efficiency mixing granulator, adding corn starch and polyvinyl alcohol into the high-efficiency mixing granulator, setting the rotating speed to be 150 r/min, stirring and mixing uniformly, adding an adhesive polyvinyl alcohol aqueous solution (the mass concentration of the polyvinyl alcohol solution is 5%, the dosage of the polyvinyl alcohol as the adhesive is 50% of the total weight of the polyvinyl alcohol in the raw material composition), stirring at 150 r/min, shearing at 1000 r/min for 5min, wet granulating, drying at 70 ℃, adding starch slurry (the mass concentration of the starch slurry is 10%, the dosage of the corn starch as the adhesive is 50% of the total weight of the corn starch in the raw material composition), repeating the wet granulating process, drying for 20-mesh granulation, adding low-substituted hydroxypropylcellulose, magnesium stearate and glyceryl behenate into a three-dimensional mixer, mixing for 5min, and obtaining the total mixed powder tabletting.
Example 4
The tranexamic acid composition in the embodiment comprises the following raw materials: the composition comprises, by weight, 100 parts of tranexamic acid, 8 parts of polyvinyl alcohol (03-88), 3 parts of corn starch, 7 parts of low-substituted hydroxypropylcellulose (LH-21) and 1 part of glyceryl behenate, wherein the selected granularity of the tranexamic acid is 80 meshes.
The specific process steps are as follows:
screening tranexamic acid by a sieve of 80 meshes, adding the tranexamic acid into a high-efficiency mixing granulator, adding corn starch and polyvinyl alcohol into the high-efficiency mixing granulator, setting the rotating speed to be 150 r/min, stirring and mixing uniformly, adding adhesive starch slurry (the mass concentration of the starch slurry is 5%, and the using amount of the corn starch as an adhesive is 60% of the total weight of the corn starch in the raw material composition), stirring at 100 r/min, shearing at 900 r/min for 5min, wet granulating, drying at 60 ℃, grading by a sieve of 20 meshes, adding low-substituted hydroxypropyl cellulose and glyceryl behenate into a three-dimensional mixer, mixing for 3min, and obtaining the total mixed powder tabletting.
Comparative example 1
A tranexamic acid composition was prepared by the same method as in example 1, except that: adding 2 parts of hydrogenated vegetable oil on the basis of the formula, wherein the specific method comprises the following steps:
the tranexamic acid composition in this comparative example had the following composition of raw materials: the composition comprises, by weight, 100 parts of tranexamic acid, 5 parts of polyvinyl alcohol (17-88), 3 parts of corn starch, 4 parts of low-substituted hydroxypropyl cellulose (LH-B1), 2 parts of hydrogenated vegetable oil, 2.5 parts of magnesium stearate and 1.5 parts of glyceryl behenate, wherein the selected granularity of the tranexamic acid is 60 meshes. The specific process steps are as follows:
screening tranexamic acid by a sieve of 60 meshes, adding the tranexamic acid into a high-efficiency mixing granulator, adding corn starch, polyvinyl alcohol and hydrogenated vegetable oil into the high-efficiency mixing granulator, uniformly stirring and mixing at a set rotating speed of 100 revolutions per minute, adding adhesive starch slurry (the mass concentration of the starch slurry is 5%, and the using amount of the corn starch as the adhesive is 80% of the total weight of the corn starch in the raw material composition), stirring at 100 revolutions per minute, shearing at 800 revolutions per minute for 3min for wet granulation, drying at 50 ℃, granulating at 20 meshes, adding low-substituted hydroxypropyl cellulose, magnesium stearate and glyceryl behenate into a three-dimensional mixer, mixing for 3min, and obtaining the total mixed powder tablet.
Comparative example 2
The tranexamic acid composition in this comparative example had the following raw material composition: according to the weight parts, 100 parts of tranexamic acid, 2.6 parts of polyvinyl alcohol (17-88), 2.6 parts of low-substituted hydroxypropyl cellulose (LH-B1), 2.6 parts of carboxymethyl starch sodium, 8 parts of hydrogenated vegetable oil, 28 parts of purified water, 8 parts of corn starch and 2.6 parts of magnesium stearate.
Stirring and mixing sieved tranexamic acid, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and hydrogenated vegetable oil for 5min at 200 revolutions per minute, uniformly mixing, adding adhesive starch slurry (the mass concentration of the starch slurry is 5%, the weight of corn starch serving as an adhesive is 80% of the weight of corn starch in the raw material composition), stirring at 250 revolutions per minute, shearing at 400 revolutions per minute, and granulating for 4min, carrying out 18-mesh swing granulation on wet granules, drying and granulating by a fluidized bed, and sequentially adding the corn starch and magnesium stearate to carry out mixed tabletting.
Comparative example 3
A tranexamic acid composition was prepared by the same procedure as in example 1, except that: glyceryl behenate is not added in the formula, and the specific method is as follows:
the tranexamic acid composition in this comparative example had the following raw material composition: weighing 100 parts of tranexamic acid, 5 parts of polyvinyl alcohol (17-88), 3 parts of corn starch, 4 parts of low-substituted hydroxypropyl cellulose (LH-B1) and 2.5 parts of magnesium stearate according to parts by weight, wherein the selected granularity of the tranexamic acid is 60 meshes. The specific process steps are as follows:
screening tranexamic acid by a 60-mesh sieve, adding the tranexamic acid into a high-efficiency mixing granulator, adding corn starch and polyvinyl alcohol into the high-efficiency mixing granulator, setting the rotating speed to be 100 r/min, stirring and mixing uniformly, adding adhesive starch slurry (the mass concentration of the starch slurry is 5%, and the weight of the corn starch as an adhesive is 80% of the weight of the corn starch in the raw material composition), stirring at 100 r/min, shearing at 800 r/min for 3min, carrying out wet granulation, drying at 50 ℃, grading by 20 meshes, adding low-substituted hydroxypropyl cellulose and magnesium stearate into a three-dimensional mixer, mixing for 3min, and obtaining the total mixed powder tablet.
The comparative example has serious unsmooth punching during tabletting, and the lower punch cannot fall back smoothly and cannot carry out large-scale tabletting smoothly.
Comparative example 4
A tranexamic acid composition was prepared by the same method as in example 1, except that: 1.5 parts of glyceryl behenate is replaced by 1.5 parts of hydrogenated vegetable oil, and the specific method is as follows:
the tranexamic acid composition in this comparative example had the following raw material composition: the composition comprises, by weight, 100 parts of tranexamic acid, 5 parts of polyvinyl alcohol (17-88), 3 parts of corn starch, 4 parts of low-substituted hydroxypropyl cellulose (LH-B1), 2.5 parts of magnesium stearate and 1.5 parts of hydrogenated vegetable oil, wherein the selected granularity of the tranexamic acid is 60 meshes.
The specific process steps are as follows:
screening tranexamic acid by a 60-mesh sieve, adding the tranexamic acid into a high-efficiency mixing granulator, adding corn starch and polyvinyl alcohol into the high-efficiency mixing granulator, setting the rotating speed to be 100 r/min, stirring and mixing uniformly, adding adhesive starch slurry (the mass concentration of the starch slurry is 5%, the weight of the corn starch as an adhesive is 80% of the weight of the corn starch in the raw material composition), stirring at 100 r/min, shearing at 800 r/min for 3min, carrying out wet granulation, drying at 50 ℃, grading by 20 meshes, adding low-substituted hydroxypropyl cellulose, magnesium stearate and hydrogenated vegetable oil into a three-dimensional mixer, mixing for 3min, and obtaining the total mixed powder tablet.
Comparative example 5
A tranexamic acid composition was prepared by the same procedure as in example 1, except that: to ensure that the total weight of starting materials is the same as that of example 1, without addition of glyceryl behenate, "2.5 parts of magnesium stearate" are replaced by 4 parts of magnesium stearate "(to ensure that the amount of lubricant is the same as that of example 1) in the following manner:
the tranexamic acid composition in this comparative example had the following composition of raw materials: the composition comprises, by weight, 100 parts of tranexamic acid, 5 parts of polyvinyl alcohol (17-88), 3 parts of corn starch, 4 parts of low-substituted hydroxypropylcellulose (LH-B1) and 4 parts of magnesium stearate, wherein the selected granularity of the tranexamic acid is 60 meshes.
The specific process steps are as follows:
screening tranexamic acid by a 60-mesh sieve, adding the tranexamic acid into a high-efficiency mixing granulator, adding corn starch and polyvinyl alcohol into the high-efficiency mixing granulator, setting the rotating speed to be 100 r/min, stirring and mixing uniformly, adding adhesive starch slurry (the mass concentration of the starch slurry is 5%, and the weight of the corn starch as an adhesive is 80% of the weight of the corn starch in the raw material composition), stirring at 100 r/min, shearing at 800 r/min for 3min, carrying out wet granulation, drying at 50 ℃, grading by 20 meshes, adding low-substituted hydroxypropyl cellulose and magnesium stearate into a three-dimensional mixer, mixing for 3min, and obtaining the total mixed powder tablet.
Comparative example 6
A tranexamic acid composition was prepared by the same procedure as in example 1, except that: polyvinyl alcohol was not added, but in order to ensure that the total weight of the raw materials was the same as that of example 1, "corn starch 8 parts" was replaced with "3 parts of corn starch", as follows:
the tranexamic acid composition in this comparative example had the following composition of raw materials: the composition comprises, by weight, 100 parts of tranexamic acid, 8 parts of corn starch, 4 parts of low-substituted hydroxypropylcellulose (LH-B1), 2.5 parts of magnesium stearate and 1.5 parts of glyceryl behenate, wherein the selected granularity of the tranexamic acid is 60 meshes.
The specific process steps are as follows:
screening tranexamic acid by a 60-mesh sieve, adding the screened tranexamic acid into a high-efficiency mixing granulator, adding corn starch into the high-efficiency mixing granulator, uniformly stirring and mixing at a set rotating speed of 100 r/min, adding adhesive starch slurry (the mass concentration of the starch slurry is 5%, and the weight of the corn starch serving as an adhesive is 80% of the weight of the corn starch in the raw material composition), stirring at 100 r/min, shearing at 800 r/min for 3min for wet granulation, drying at 50 ℃, grading by 20 meshes, adding low-substituted hydroxypropyl cellulose, magnesium stearate and glyceryl behenate into a three-dimensional mixer, mixing for 3min, and obtaining the total mixed powder tabletting.
Comparative example 7
A tranexamic acid composition was prepared by the same procedure as in example 1, except that: the tranexamic acid is sieved by a 40-mesh sieve. When the comparative example is mixed, the particle size difference of the raw material medicine and other auxiliary materials is large, the mixing is not uniform, and the layering phenomenon occurs.
Comparative example 8
A tranexamic acid composition was prepared by the same procedure as in example 1, except that: tranexamic acid is sieved by a 120-mesh sieve. In the comparative example, during tabletting operation, the phenomenon of sluggish punching occurs, the lower punch cannot fall back smoothly, and a large amount of tabletting cannot be performed smoothly.
2. Dissolution Curve testing
In vitro dissolution profile tests are commonly used to assess quality consistency between drugs. Comparative similarity factor (f) of dissolution Curve similarity 2 ) The method is to compare the average elution amount of a test sample with the average elution amount of a reference sample. Using a similarity factor (f) 2 ) When methods compare similarity, in general, when the similarity factor (f) 2 ) When the value is not less than 50, the dissolution curves are considered to be similar.
The tranexamic acid compositions of examples 1-4 and comparative examples 1-8 were dissolved out at high temperature (60 ℃) in a medium having a pH of 6.8 as shown in Table 1.
TABLE 1 dissolution Curve of tranexamic acid formulations in pH6.8 media at elevated temperatures
Examples 1-4 dissolution profiles in media at pH6.8 on day 0 are very similar to the reference formulation (f) 2 More than or equal to 82) and provides guarantee for the biological equivalence of the preparation and a reference preparation in vivo.
After being placed at the high temperature of 60 ℃ for 10 days, compared with the same batch for 0 day, the samples of examples 1-4 have no obvious change (f 2 is more than or equal to 85) and good stability; the dissolution curve of the reference formulation shows a downward trend (f) 2 = 72); comparative example 1 hydrogenated vegetable oil was added to example 1, and after the high temperature test, the oil was dissolved outThe curve has a downward trend (f) compared to day 0 2 = 55), comparative example 2 has hydrogenated vegetable oil in the prescription, and the dissolution is also influenced and shows a decreasing trend in the verification test (f) 2 = 51). Comparative example 3 was adjusted based on example 1, and the formulation contained no glyceryl behenate, so that the tablet was severely astringent, and the undershoot could not fall back smoothly, and a large amount of tablets could not be performed smoothly.
In comparative example 4, glyceryl behenate was replaced with hydrogenated vegetable oil, and after the high temperature test, the dissolution curve showed a downward trend compared to 0 days, and slight astringent impact was observed during the tabletting operation; in the comparative example 5, the lubricant does not use glyceryl behenate, only uses magnesium stearate and supplements the amount of the glyceryl behenate in the original place, after a high-temperature test, compared with 0 day, the dissolution curve shows a descending trend, and in the tabletting operation process, the slightly astringent impact phenomenon also exists; in comparative example 6, no polyvinyl alcohol was added, and the dissolution curve after the high-temperature test also showed a tendency to decrease compared with 0 day.
As can be seen from the data of example 1, comparative example 3, comparative example 4 and comparative example 5: the glyceryl behenate is added in the preparation process of the tranexamic acid composition, so that a good lubricating effect can be achieved, and the smooth tabletting process is ensured. In addition, as can be seen from the data of example 1, comparative example 5 and comparative example 6: when glyceryl behenate and polyvinyl alcohol exist in the prescription at the same time, the dissolution curve is good in similarity with a reference preparation, and the dissolution stability is good.
The comparison of the experimental data of the embodiment 1 and the comparative examples 7 and 8 shows that the tranexamic acid with the mesh number is more beneficial to obtaining a tranexamic acid composition preparation with good dissolution behavior, and the smooth tabletting process and the smooth proceeding of the process are ensured.
3. Stability test
Stability examination and accelerated test are carried out on examples 1 to 4 according to 9001 guiding principles of stability test of raw material drugs and preparations in the pharmacopoeia of the people's republic of China, 2020 edition, four general guidelines: 40 plus or minus 2 ℃ and 75 percent plus or minus 5 percent RH; and (3) long-term test: 30 +/-2 ℃ and RH 65% +/-5%. The results are shown in tables 2, 3 and 4.
TABLE 2 accelerated test data
TABLE 3 Long term test data
TABLE 4 stability test pH6.8 media dissolution Curve data
The results of accelerated and long-term stability test data show that the in-vitro dissolution curve behavior of the prepared examples is similar to that of the examples in 0 day (f) in a medium with pH6.8 after the examples 1 to 4 are respectively placed for 6 months and 24 months under accelerated and long-term conditions (f) 2 Not less than 80), no obvious change in the dissolution rate, content and other data, no detection of related substances, and good stability of the medicine.
4. Bioequivalence evaluation
The biological equivalence research is carried out on the tested preparation examples 1-4 and the reference preparation prepared by the invention, the pharmacokinetic parameter results after the tested preparation and the reference preparation are orally taken are summarized, the preparation prepared in the examples 1-4 is biologically equivalent to the reference preparation, and the specific comparison curve conditions are shown in figures 1-4.
The technical features of the embodiments described above may be arbitrarily combined, and for brevity of description, all possible combinations of the technical features in the embodiments described above are not exhaustive, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
It will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention as defined in the following claims.
Claims (8)
1. A tranexamic acid composition is characterized by comprising the following components in parts by weight: 100 parts of tranexamic acid, 5-9 parts of polyvinyl alcohol, 1-3 parts of corn starch, 4-8 parts of low-substituted hydroxypropyl cellulose and 1-4 parts of lubricant; the lubricant comprises glyceryl behenate.
2. The tranexamic acid composition as claimed in claim 1, wherein said lubricant is glyceryl behenate or a combination of glyceryl behenate and magnesium stearate.
3. Tranexamic acid composition according to claim 1, wherein said tranexamic acid has a particle size of 60 to 100 mesh.
4. The tranexamic acid composition as claimed in claim 1, wherein said tranexamic acid has a particle size of 60-80 mesh.
5. The tranexamic acid composition as claimed in claim 1, wherein the low-substituted hydroxypropylcellulose is selected from the group consisting of LH-B1, LH-11, LH-22 and LH-21.
6. A process for the preparation of a tranexamic acid composition as claimed in any one of claims 1 to 5, characterized in that it comprises: adding the sieved tranexamic acid into a high-efficiency mixing granulator, adding corn starch and polyvinyl alcohol into the high-efficiency mixing granulator, stirring and mixing uniformly, adding an adhesive solution, stirring and wet granulating, drying, granulating, adding low-substituted hydroxypropyl cellulose and a lubricant into a three-dimensional mixer, mixing to obtain total mixed powder, and tabletting or filling capsules.
7. The method of claim 6, wherein the binder solution is one or a combination of polyvinyl alcohol solution and starch slurry.
8. The method for preparing the tranexamic acid composition according to claim 6, wherein the screened tranexamic acid is added into a high-efficiency mixing granulator, corn starch and polyvinyl alcohol are added into the high-efficiency mixing granulator, the mixture is uniformly stirred at a speed of 100-150 rpm, then a binder solution is added, the mixture is stirred at a speed of 100-150 rpm and is sheared at a speed of 800-1000 rpm for 3-5min for wet granulation, the mixture is dried at 50-70 ℃, after 20 meshes of granulation, low-substituted hydroxypropyl cellulose and a lubricant are added into a three-dimensional mixer for mixing for 3-5min, and then the total mixed powder is obtained for tabletting or encapsulating.
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| CN117731649A (en) * | 2023-12-21 | 2024-03-22 | 博济医药科技股份有限公司 | Tranexamic acid pharmaceutical composition and preparation process thereof |
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| CN117731649A (en) * | 2023-12-21 | 2024-03-22 | 博济医药科技股份有限公司 | Tranexamic acid pharmaceutical composition and preparation process thereof |
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