CN104146981A - Lipoic acid composition and preparation method thereof - Google Patents
Lipoic acid composition and preparation method thereof Download PDFInfo
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- CN104146981A CN104146981A CN201310180167.6A CN201310180167A CN104146981A CN 104146981 A CN104146981 A CN 104146981A CN 201310180167 A CN201310180167 A CN 201310180167A CN 104146981 A CN104146981 A CN 104146981A
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Abstract
The invention provides a stable lipoic acid composition and a preparation method thereof. In the composition, the weight ratio of antioxidant BHT to lipoic acid is (0.1-0.3):100, so that the product stability can be remarkably improved. In the preparation method, the BHT is dissolved in more than 70% ethyl alcohol, so as to prepare particles with lipoic acid and other auxiliary materials by virtue of a wet method, so that the product stability is further improved. Compared with traditional physical mixing, the preparation method has the advantage that the oxidized impurities are obviously improved.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of stable thioctic acid composition and method of making the same.
Background technology
Thioctic acid is that one is present in mitochondrial enzyme, and similar vitamin is eliminated accelerated ageing and pathogenic free radical.Thioctic acid enters cell in vivo after intestinal absorption, has fat-soluble and water miscible characteristic concurrently, therefore can go everywhere without any hindrance here at whole body, arrives any one cell position, provides human body comprehensive usefulness, is the fat-soluble and water miscible universal antioxidant of tool.
Thioctic acid possess general antioxidant can not and non-oxidizability, be used for the treatment of the existing many decades history of diabetic neuropathy in Germany, other medical values also just get the nod.More domestic producers are also used as hepatoprotective, and constantly have the report of new purposes
1).
Thioctic acid belongs to vitamin(e) B group compound, in the multienzyme complexs such as pyruvic dehydrogenase, ketoglurate dehydrogenase, aminocaproic acid decarboxylase, works as coenzyme.Thioctic acid has oxidized form (a-lipoic acid, LA) and reduced form (dihydrolipoic acid, DHLA), relative molecular mass is than water solublity ascorbic acid (ascorbate, AsA) large, but less than fat-soluble tocopherol, therefore it not only had water solublity but also tool fat-soluble
1).
Aging is that antioxidant system ability declines, and active oxygen accumulation causes cell DNA, lipid, protein oxidative damage and the inevitable physiological process that causes.Arivazhagan etc. have done relatively more comprehensive, systematic research to the senile-resistant efficacy of DL-LA.Serial experiment condition is: trophophase approximately 3～4, and 22 months, mouse was respectively mice, rat, by every 1kg body weight peritoneal injection DL-LA100mg/d, 7, sampling and testing after 14d.Contrast and experiment is: 1) GSH in rat plasma, AsA, VE content, activities of antioxidant enzymes reduce, and-OH concentration rises, and DL-LA can effectively control each changes of biochemical indexes; 2) DL-LA can improve the activity of the cyclophorase such as content and cytochrome C oxidase of GSH, AsA in rats'liver, kidney mitochondrion, VE, increases nucleic acid, the protein content of liver,kidney,spleen; 3) content of the neurotransmitters such as the GSH of rat brain different tissues, AsA, VE, nucleic acid, protein, dopamine declines, the activity of antioxidase improves, and supplementary DL-LA can effectively reverse the variation of above-mentioned biochemical parameter; 4) DL-LA can reduce lipid peroxidation (LPO) level of rat, and the LPO of itself and mice is on close level
2-5).
About the large quantity research of thioctic acid antioxidation application is still confined to external, zoopery at present.In Germany, thioctic acid extensively gos deep into for the clinical research of the diseases such as diabetic neuropathy, but because of differences such as individuality, administering mode, dosage, times, and is all individually dosed conventionally, and is difficult to the satisfied effect of reaching an agreement.But, consider the seriousness of diabetic neuropathy long oxidation damage and lack more effective treatment approach, the LA choice drug of still can yet be regarded as, long-term appropriate diet supplemented with lipoic acid perhaps more effectively prevent diabetes with and the generation of complication.Fewer for the research of the relevant disease of liver and other diseases impact about thioctic acid, need to be done further research.
BHT chemical name is 2,6-di-tert-butyl-4-methy phenol, and it is taking paracresol, isobutanol as raw material, and using concentrated sulphuric acid as catalyst, aluminium oxide is dehydrant, and reaction generates 2,6 ditertiary butyl p cresol.In food processing, be used as antioxidant.Antioxidant refers to that some can suppress or delay the organic compound of high polymer and the thermal oxide in air of other organic compound.Popular, be to prevent that polymeric material from causing rotten material because being oxidized.Mar í a A.Moyano
6)reported Deng people that thioctic acid and auxiliary material B HT had interaction.This produces many problems while causing thioctic acid and auxiliary material B HT coupling, how correctly to use BHT but main composition not to be exerted an influence and becomes the technology point of being badly in need of improvement with performance antioxidation.
Summary of the invention
Inventor's discovery, BHT consumption can improve the stability of thioctic acid within the specific limits.Further; the inventor also finds; when BHT is dissolved in concentration higher than 70% ethanol after; thioctic acid is carried out to wet granulation; BHT can be evenly distributed on lipoic acid particle surface; the protective effect of thioctic acid is significantly better than to the physical mixture of BHT and thioctic acid, thereby can further improves the stability of thioctic acid.Based on this, the object of this invention is to provide the thioctic acid composition and method of making the same of a kind of BHT of utilization.The thioctic acid compositions that the present invention develops is more stable than conventional thioctic acid preparation.
Particularly, on the one hand, the invention provides a kind of thioctic acid compositions, it comprises 2,6-di-tert-butyl-4-methy phenol (BHT) and active component thioctic acid, and wherein the weight ratio of BHT and active component thioctic acid is 0.1～0.3:100.
In one embodiment, in thioctic acid compositions, the weight ratio of antioxidant BHT and active component thioctic acid is 0.1:100,0.2:100 or 0.3:100.
In one embodiment, described thioctic acid compositions also comprises other adjuvants, and wherein, pregelatinized Starch is as filler, and the percentage ratio that accounts for gross weight is 5%～10%, and preferably 5%～8%; Colloidal silica is as fluidizer, and the percentage ratio that accounts for gross weight is 0.5%～2%.
In one embodiment, the percentage ratio that in thioctic acid compositions, antioxidant BHT accounts for composition total weight is 0.09%～0.27%.
In the present invention, described compositions can be capsule, granule, powder or tablet.
On the other hand, the present invention also provides the preparation method of thioctic acid compositions of the present invention, and the antioxidant BHT that it is 0.1～0.3:100 that described method comprises weight ratio mixes with active component thioctic acid.
In one embodiment, described in, be mixed into physical mixed.
In one embodiment, described mixing comprises antioxidant BHT is dissolved in to the ethanol that concentration is greater than 70%.
In embodiments of the present invention, the concentration of ethanol used can be: 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%.
In one embodiment, described preparation method is wet granulation.
Described " wet granulation " is the method being most widely used in medical industry.In the present invention, described " wet granulation " has implication well known in the art.Particularly, described " wet granulation " refer to and in drug powder, add binding agent, powder coalesced together and prepare the method for granule by the crane span structure of binding agent or adhesive effect.In the art, described " wet granulation " can comprise that for example extruding is granulated, rotate granulation, fluidized granulation and stirring granulation etc.Those skilled in the art can select to carry out the actual conditions of wet granulation, such as temperature, rotating speed etc. according to actual needs.
Described " physical mixed " refers to that raw material to be mixed and/or adjuvant directly mix.
BHT can react with thioctic acid as antioxidant, but mixes with principal agent thioctic acid proper proportion, can significantly improve the stability of product.
Effect of the present invention
The part by weight of 1.BHT and thioctic acid, at 0.1～0.3:100, can significantly improve the stability of product.
2. BHT is dissolved in to more than 70% ethanol, with thioctic acid and other adjuvant wet granulations, can further improves the stability of product.Compare traditional physical mixed, its oxidation impurities has clear improvement.
Brief description of the drawings
Fig. 1: the present invention fill a prescription the oxidation impurities content of preparation and the curve of BHT content of 1-8.
Fig. 2 a: embodiment of the production technology of wet granulation of the present invention.
Fig. 3: dissolution when pH4.0 dissolution medium and the curve of time.
Fig. 4: dissolution when pH1.0 dissolution medium and the curve of time.
Fig. 5: dissolution when dissolution medium is water and the curve of time.
Fig. 6: dissolution when pH6.8 dissolution medium and the curve of time.
Detailed description of the invention
Embodiment 1: wet granulation
Pharmaceutical formulation for wet granulation is as shown in table 1 below.
Table 1: for the formula 1-4 of wet granulation
Method for making: colloidal silica mixed 26 mesh sieves with pregelatinized Starch, thioctic acid is crossed 26 mesh sieves.BHT is dissolved in 95% ethanol, carries out wet granulation, and the material after granulation is crossed 26 mesh sieves, and 35 DEG C are dried 2 hours.With 26 mesh sieve granulate, fill No. 2 capsule.
Embodiment 2: physical mixed
Pharmaceutical formulation for physical mixed is as shown in table 2 below.
Table 2: for the formula 5-8 of physical mixed
Method for making: colloidal silica mixed 26 mesh sieves with pregelatinized Starch, thioctic acid is crossed 26 mesh sieves.BHT pulverizes, and crosses 80 mesh sieves.By the mixing of materials after sieving, fill No. 2 capsule.
Embodiment 3: the mensuration of oxidation impurities content
EXPERIMENTAL DESIGN:
Under thioctic acid capsule preparations high temperature (40 DEG C) condition that the embodiment of the present invention 1 and 2 is made, investigate 30 days, the reference preparation of use is
(Jiangsu Wan He pharmaceutical Co. Ltd, product batch number: 110401).
Method for detecting impurities:
Chromatographic column: ZORBAX SB-C18(4.6mm × 250mm, 5 μ m)
Mobile phase: methanol-0.005M potassium dihydrogen phosphate-acetonitrile (116:92:18), phosphoric acid is adjusted pH to 3.0
Flow velocity: 1.0ml/min
Column temperature: 35 DEG C
Detector wavelength: UV215nm
Get fine powder appropriate (being capsule 's content), be placed in brown volumetric flask, add mobile phase and dissolves and make the solution of about lipoic acid 1.2mg in every 1ml, filtration, gets subsequent filtrate as need testing solution; It is appropriate that precision measures thioctic acid reference substance, adds mobile phase dilution and make the solution containing 0.012mg in every 1ml, product solution in contrast.Precision measures reference substance solution 20 μ l injection liquid chromatographies and regulates detection sensitivities, and the peak height that makes main constituent is full scale 10～25%.Precision measures need testing solution 20 μ l again, and injection liquid chromatography records 2.5 times to main constituent retention time of chromatogram.In need testing solution chromatogram, if any impurity peaks (except solvent peak), total impurities must not be greater than main peak area (1.0%) in reference substance solution, and single impurity peak area must not be greater than 0.5 times (0.5%) of contrast liquid main peak area.
Result as shown in Tables 3 and 4.
Table 3: 8 formulas of the present invention are investigated the oxidation impurities content after 30 days under 40 DEG C of environment
Result by table 3 can find out, compared with reference preparation, the ratio of BHT and thioctic acid is 0.2:100, and BHT is dissolved in 95% ethanol, and while carrying out physical mixed and wet granulation respectively, its oxidation impurities content all obviously reduces, and has effectively improved the stability of preparation.
Table 4: the oxidation impurities content (8 formulas of the present invention are investigated the oxidation impurities content after 30 days under 40 DEG C of environment) of contrast wet granulation and physical mixed method for making.
Meanwhile, according to BHT content (mg) and the mapping of oxidation impurities content.Result as shown in Figure 1, can find out that by the above results the ratio of BHT and thioctic acid is 0.2:100, and BHT is dissolved in 95% ethanol, and while carrying out wet granulation, its oxidation impurities content obviously reduces, and has effectively improved the stability of preparation.
Embodiment 4: influence factor's test
By in embodiment 1, the fill a prescription 2 thioctic acid capsule preparations that make and reference preparation (
jiangsu Wan He pharmaceutical Co. Ltd, product batch number: 110401) place 10 days with above-mentioned reference preparation under high temperature (40 DEG C, 60 DEG C), high humidity (92.5%RH), high light (Lx4500) condition, by the method for detecting impurities described in embodiment 3, the content that detects oxidation impurities, result is as shown in table 5.
Fill a prescription in table 5: the embodiment 12 thioctic acid capsule preparations that make and above-mentioned reference preparation placed the mensuration of 10 days rear oxidation impurity and total impurities under high temperature (40 DEG C, 60 DEG C), high humidity (92.5%RH), high light (Lx4500) condition
Result by table 5 can find out, the oxidation impurities of formula self-control preparation of the present invention under 4 conditions and total impurities are all significantly lower than reference preparation.Can find out that by the above results BHT is dissolved in after ethanol, be wrapped in principal agent surface, oxidation impurities content has obtained obvious improvement, has significantly improved the stability of preparation.
Embodiment 5: with the comparison of reference preparation in 4 kinds of dissolution mediums
Taking the formula of following table 6 as the production according to complete preparation by the technique of Fig. 2.
Table 6
Experimental technique: get by the above-mentioned preparation making and reference preparation (
jiangsu Wan He pharmaceutical Co. Ltd, product batch number: 110401), with reference to dissolution method (two annex X C the second methods of Chinese Pharmacopoeia version in 2010), respectively taking the acetate buffer of the 0.1M HCl solution of 900ml water, pH1.0, pH4.0, pH6.8 phosphate buffer as dissolution medium, rotating speed is per minute 100 to turn, and respectively at the different time points of stripping, gets solution appropriate, filter, get subsequent filtrate and measure according to high performance liquid chromatography (two annex V D of Chinese Pharmacopoeia version in 2000).With Cosmosil C18(4.6mm × 150mm, 5 μ are m) chromatographic column, and 0.025mol/L phosphoric acid-acetonitrile (60:40) is mobile phase, and flow velocity is 1.2ml/min, and detection wavelength is UV220nm, keep room temperature.Get 20 μ l injection liquid chromatographies, record chromatogram.
Separately get thioctic acid reference substance appropriate, accurately weighed, add stripping medium dissolves and make the solution product solution in contrast of respective concentration, be measured in the same method.The results are shown in following table 7-10.
Dissolution when table 7:pH4.0 dissolution medium
Dissolution when table 8:pH1.0 dissolution medium
Table 9: dissolution when water is dissolution medium
Dissolution when table 10:pH6.8 dissolution medium
Result by table 7-10 is made stripping curve (seeing Fig. 3-Fig. 6).Can be found out by result, compared with reference preparation, the stripping curve of preparation of the present invention under 4 kinds of dissolution mediums is slightly low before 10 minutes during except pH1.0, substantially close under the condition of other media.
Embodiment 6:BHT dosage optimization
The inventor finds, the ratio of BHT and thioctic acid is 0.2:100, and BHT is dissolved in 95% ethanol wet granulation, and gained sample oxidation impurities content obviously reduces.On this basis, inventor continues to screen the suitable amounts of BHT.
1. the preparation of sample
Table 11: sample preparation technique and formula
Method for making: colloidal silica mixed 26 mesh sieves with pregelatinized Starch, thioctic acid is crossed 26 mesh sieves.BHT is dissolved in 95% ethanol, carries out wet granulation, and the material after granulation is crossed 26 mesh sieves, and 35 DEG C are dried 2 hours.With 26 mesh sieve granulate, fill No. 2 capsule.
2. oxidation impurities assay
According to the assay method of embodiment 3, sample prepared by embodiment 6 is measured oxidation impurities content place 30 days under 40 DEG C of environment after.
Sample prepared by table 12: embodiment 6 is investigated the oxidation impurities content after 30 days under 40 DEG C of environment
Result shows, BHT and thioctic acid ratio are at 0.1～0.3:100, and it is more than 70% ethanol that BHT is dissolved in concentration, carries out wet granulation, can significantly improve the stability of preparation.
List of references
1) Tang Chunfang, Liu Yunguo.The research overview of thioctic acid.China's biochemical drug impurity.2005，26（1）：52-55.
2）Arivazhagan?P?et?al.Effect?of?DL-a-lipoic?acidon?the?status?of?lipid?peroxidation?and?antioxidants?in?aged?rats.Pharmacobgical?Research,2000,41(3):189-198.
3）Arivazhagan?P?et?al.Effect?of?DL-a-lipoic?acid?on?mitochondrial?enzymes?in?aged?rats.Chemico?Biological?Interations,2001,128:189-198.
4）Arivazhagan?P?et?al.Effect?of?DL-a-lipoic?acid?on?the?status?of?lipid?protein?oxidative?in?various?brain?regions?of?aged?rats.Nutritional?Biochemistry,2002,13:619-624.
5）Arivazhagan?P?et?al.Effect?of?DL-a-lipoic?acid?on?the?status?of?lipid?peroxidationg?and?to?antioxidant?enzymes?in?various?brain?regious?of?aged?rats.Expermental?Gerontology,2002,37:803-811.
6）Maria?A?et?al.Thermal?analysis?of?lipoic?acid?and?evaluation?of?the?compatibility?with?excipientes.J?Therm?Anal?Calorim,2010,99:631-637.
Claims (10)
1. thioctic acid compositions, it comprises 2,6-di-tert-butyl-4-methy phenol and active component thioctic acid, and wherein 2, the weight ratio of 6-di-tert-butyl-4-methy phenol and active component thioctic acid is 0.1～0.3:100.
2. thioctic acid compositions claimed in claim 1, wherein, the weight ratio of 2,6-di-tert-butyl-4-methy phenol and active component thioctic acid is 0.1:100,0.2:100 or 0.3:100.
3. the thioctic acid compositions described in claim 1 or 2, it also comprises other adjuvants, and wherein, pregelatinized Starch is as filler, and the percentage ratio that accounts for gross weight is 5%～10%, preferably 5%～8%; Colloidal silica is as fluidizer, and the percentage ratio that accounts for gross weight is 0.5%～2%.
4. the thioctic acid compositions described in aforementioned any one claim, wherein, the percentage ratio that 2,6-di-tert-butyl-4-methy phenol accounts for composition total weight is 0.09%～0.27%.
5. the thioctic acid compositions described in aforementioned any one claim, wherein, described compositions is capsule, granule, powder or tablet.
6. the preparation method of the thioctic acid compositions described in any one in claim 1-5, it is 0.1～0.3:100 2 that described method comprises weight ratio, 6-di-tert-butyl-4-methy phenol mixes with active component thioctic acid.
7. preparation method claimed in claim 6, described in be mixed into physical mixed.
8. preparation method claimed in claim 6, described mixing comprises that it is more than 70% ethanol that 2,6-di-tert-butyl-4-methy phenol is dissolved in to concentration, then mixes with active component thioctic acid.
9. preparation method claimed in claim 9, wherein, the concentration of described ethanol is 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%.
10. the preparation method described in claim 8 or 9, it is wet granulation.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114487144A (en) * | 2020-11-13 | 2022-05-13 | 北京四环制药有限公司 | Method for improving lipoic acid detection recovery rate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1868463A (en) * | 2006-06-15 | 2006-11-29 | 南方医科大学珠江医院 | Slow-release prepn. contg. alpha-lipoic acid or its derivatives, and preparing method therefor |
-
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1868463A (en) * | 2006-06-15 | 2006-11-29 | 南方医科大学珠江医院 | Slow-release prepn. contg. alpha-lipoic acid or its derivatives, and preparing method therefor |
Non-Patent Citations (2)
| Title |
|---|
| MARI´A A. MOYANO 等: "Thermal analysis of lipoic acid and evaluation of the compatibility with excipientes", 《JOURNAL OF THERMAL ANALYSIS AND CALORIMETRY》 * |
| 张金彦 等: "药物硫辛酸的研究进展", 《现代化工》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114487144A (en) * | 2020-11-13 | 2022-05-13 | 北京四环制药有限公司 | Method for improving lipoic acid detection recovery rate |
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