CN101439030A - Pharmaceutical composition containing lycopene and preparation method thereof - Google Patents
Pharmaceutical composition containing lycopene and preparation method thereof Download PDFInfo
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- CN101439030A CN101439030A CNA2008102447940A CN200810244794A CN101439030A CN 101439030 A CN101439030 A CN 101439030A CN A2008102447940 A CNA2008102447940 A CN A2008102447940A CN 200810244794 A CN200810244794 A CN 200810244794A CN 101439030 A CN101439030 A CN 101439030A
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Abstract
The invention relates to the pharmaceutical preparation field, in particular to a pharmaceutical composition with lycopene. The pharmaceutical composition is characterized in that poloxamer 188 is added so as to greatly improve the water solubility of the lycopene; in particular, after the lycopene and the poloxamer 188 are prepared into solid dispersion or, together with cyclodextrin, are prepared into a cyclodextrin iclusion complex, bioavailability of the lycopene is remarkably improved.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to a kind of pharmaceutical composition that contains lycopene and preparation method thereof.
Background technology
Lycopene (lycopene), molecular formula C
40H
36, molecular weight 536.85 is a kind of of carotenoid, and in all carotenoid, it has the function of the strongest elimination singlet oxygen and eliminates the function of free radical, and its elimination ability to singlet oxygen is 2 times of carotene, 100 times of vitamin E; It can slow down the oxidation of low density lipoprotein, LDL, reduces the cholesterol in the blood plasma, prevents the cardiovascular diseases; Its effectively anticancer breeding has the anti-cancer and cancer-preventing effect, especially carcinoma of prostate is had good therapeutical effect, and it has the activating immune cell function in addition, but enhancing human body immunity power and defying age.Lycopene has effect so widely, unrivaled superiority like this is arranged in the body-care field, ought to be widely used, but because the dissolubility of lycopene in water is extremely low, has only about 0.002 μ g/ml, make it in vivo can not stripping and be absorbed, influence its bioavailability.It is a kind of and unsettled material under normal conditions in addition, and this is because have unique two bond distance's chains in its molecular structure, very easily oxidized degraded and isomerization in air, thus its function is reduced or inefficacy.
It is good that this just need be prepared into lycopene dissolubility, and the fast and stable formulation of stripping just helps the application of lycopene.At present, yet there are no lycopene is prepared into the dissolubility height, fast and the stable formulation report of stripping, CN200610037859.5 discloses a kind of " composition and method of making the same of beta-schardinger dextrin-and HP-mixed inclusion lycopene ", this method is by being prepared into cyclodextrin clathrate with lycopene, improved the dissolubility of lycopene to a certain extent, be 14 μ g/ml to the maximum, and increased stability, remained unchanged very little but should invent the degree that increases the lycopene dissolubility.For existing commercial preparation lycopene oil capsule, it only is lycopene suspendible in oil in addition, and external stripping is poor, and intravital bioavailability is low.
Summary of the invention
The invention discloses a kind of pharmaceutical composition of lycopene, the dissolubility of pharmaceutical composition of the present invention in water is increased to 150-460 μ g/ml, and dissolution improves greatly, and stripping was more than 75% in 45 minutes.
The inventor finds in to Study of Lycopene, on adding medicament during solubilizing agent commonly used, can increase the dissolubility of lycopene, but solubilizing effect is limited, but when in lycopene, adding poloxamer 188, the water solublity of lycopene obviously strengthens, and therefore formed technical scheme of the present invention: the solid pharmaceutical preparation of lycopene of the present invention contains lycopene and poloxamer 188.
Further discover, when lycopene and poloxamer 188 are prepared into solid dispersion, best results.The water solublity and the stability of lycopene have greatly been improved.
When preparation lycopene solid dispersion, use respectively different preparing carriers (lycopene: vehicle weight than=1:5), partial results sees Table 1:
Table 1 different carriers prepares the dissolubility of lycopene solid dispersion
| Bearer type | Polyvinylpyrrolidone k30 | Poloxamer 188 | Polyethylene Glycol | Beta-schardinger dextrin- |
| C(μg/ml) | 74.4 | 285.1 | 122.6 | 10.9 |
By table 1 as seen, poloxamer 188 effects are best, are preferably the carrier of solid dispersion.The inventor has also investigated when preparation lycopene and poloxamer 188 solid dispersion ratio to the influence of dissolubility.See Table 2.
Table 2 lycopene and poloxamer 188 solid dispersion ratios are to the influence of dissolubility
| Lycopene: poloxamer 188 | 1∶0.5 | 1:1 | 1:3 | 1:5 | 1:7 | 1:10 | 1:12 |
| C(μg/ml) | 64.4 | 140.5 | 205 | 285.1 | 284.3 | 282.9 | 286.8 |
Table 2 as seen, in lycopene and poloxamer 188 solid dispersion, the ratio of lycopene and poloxamer 188 solid dispersion is after 1:5, changes in solubility is very little, consider that from cost and solubilising angle the preferable range of both weight ratios is at 1:1～1:10, more preferably 1:3～1:5.
Preparation method by general solid dispersion, commonly used have three kinds of polishing, solvent method and fusion methods, but because lycopene is to the unstability of heat, can not prepare with fusion method, can only use polishing, solvent method preparation, the preferred solvent method, the lycopene solid dispersion dissolubility up 460 μ g/ml of this method preparation
Lycopene and poloxamer 188 solid dispersion can be with the preparations of following method: lycopene and poloxamer 188 added organic solvents are ultrasonic to make dissolving, on Rotary Evaporators, boil off most of organic solvent, and vacuum drying, dry thing grinding is promptly.The preferred oxolane of described organic solvent, chloroform or ethyl acetate are considered from the toxicity of solvent with to lycopene dissolubility two aspects, more preferably oxolane.
Find if add the third material, cyclodextrin clathrate is had certain influence in the research that lycopene is prepared into cyclodextrin clathrate, table 3 is to add the solubility test data of the third different materials when being prepared into the ternary clathrate:
Table 3 different additive is to the influence of ternary clathrate
| Type | Macrogol 4000 | Polyethylene glycol 6000 | Poloxamer 188 | PVP | HPMC |
| C(μg/ml) | 17.4 | 23.6 | 74.8 | 24.8 | 21.7 |
(lycopene: the third material: beta cyclodextrin=1:0.5:9, weight ratio)
By table 3 as seen, lycopene and poloxamer 188 are prepared into cyclodextrin clathrate together, and promptly during the ternary clathrate, the water solublity of lycopene is greatly improved, be better than other additives, improve more than 7 times than common lycopene cyclodextrin clathrate water solublity.
Further the addition of poloxamer 188 is discovered: different amounts also has certain influence to clathrate.Three kinds of material proportions are meant the total amount proportioning of lycopene, poloxamer 188 and beta cyclodextrin in the table 4.
Table 4 Different Weight proportioning is to the influence of clathrate
| Three kinds of |
1∶0∶9 | 1∶0.5∶9 | 1∶1∶9 | 1∶2∶9 | 1∶3∶9 |
| C(μg/ml) | 25.5 | 74.8 | 105.2 | 86.3 | 90.3 |
Table 4 as seen, three's total amount ratio is better at 1:0.5-2:3-9, that best is 1:1:9.
Lycopene ternary clathrate of the present invention can prepare with following method: earlier lycopene is dissolved in the organic solvent, add again in the mixture of poloxamer 188 and beta-schardinger dextrin-, grind, vacuum drying, dry thing grinds promptly, milling time reached more than 1 hour, and the dissolubility maximum can reach 150 μ g/ml.The preferred oxolane of described organic solvent, chloroform or ethyl acetate.More preferably oxolane.
Preferred hydroxypropyl-the beta-schardinger dextrin-of beta cyclodextrin.
Above-mentioned ternary clathrate wants high with respect to the dissolubility (27 μ g/ml) of the binary clathrate of reporting in the document, has the advantage that increases substantially dissolubility.Though the increase degree of ternary clathrate dissolubility is big less than solid dispersion, it also has special advantages, makes its flowability and compressibility all very good behind the beta-cyclodextrin inclusion compound.In addition, the ternary clathrate is also better to the stability of heat.
The solid dispersion of above-mentioned lycopene or cyclodextrin clathrate can further add pharmaceutic adjuvant and be prepared into various dosage forms on the pharmaceutics.Described dosage form preferred tablet, capsule, micropill etc.Described pharmaceutic adjuvant can be diluent, disintegrating agent, lubricant, slow-release material etc.Diluent can be one or more compositions that increase tablet or capsules weight and volume, as lactose, alpha lactose, starch, pregelatinized Starch, microcrystalline Cellulose, sorbitol, mannitol, inorganic calcium salt etc., can be wherein a kind of, page or leaf can be wherein several mixture.In the preferred crospolyvinylpyrrolidone of disintegrating agent, cross-linking sodium carboxymethyl cellulose, the low-substituted hydroxypropyl cellulose one or more.One or more mixture in the preferred magnesium stearate of lubricant, Pulvis Talci, the Polyethylene Glycol hydrogenated vegetable oil.
The inventor finds in research lycopene solid dispersion or ternary clathrate tablet and capsular preparation process, lycopene can be adsorbed on the insoluble adjuvant very securely, on the adjuvant of especially high adsorption capacity own, so tablet and capsule prescription should be controlled the consumption of the strong adjuvant of adsorptivity under the prerequisite that satisfies tablet and capsule preparation requirement as far as possible.
The inventor finds in research lycopene solid dispersion or ternary clathrate tablet and capsular preparation process, the equal incompatibility wet granulation of the solid dispersion of lycopene or ternary clathrate, this may be relevant with the unstability of the water solublity of solid dispersion or ternary clathrate and lycopene, so tablet and capsular preparation all require direct compression or dry granulation.
Lycopene solid dispersion that the present invention is prepared or ternary clathrate water or in 0.5%SLS 45 minutes accumulation dissolution be significantly increased than its physical mixture, improved the dissolution rate and the degree of lycopene greatly.Stripping data and curve are seen accompanying drawing 1.
The present invention investigates the lycopene solid dispersion of preparation or the stability of ternary clathrate, the factor of investigating is respectively light, air and heat (60 ℃), the result shows, in lycopene solid dispersion and the lycopene ternary clathrate, lycopene is to light, the stability of air and heat all has very big improvement than lycopene, and utmost point significant difference (p＜0.01) is all arranged, and stability data is seen accompanying drawing 2,3.
Bioavailability description of test lycopene solid dispersion of the present invention and ternary clathrate show better effectiveness and practicality.Be the rat bioavailability experiment of lycopene solid dispersion of the present invention and ternary clathrate below:
Healthy male Sprangue-Dawley (SD) rat behind the fasting 12h, is taked gastric infusion, and normal feeding behind the 15min is got blood in certain hour point anesthesia posterior orbit venous plexus.Adopt binary system of the present invention and ternary system administration group respectively, lycopene oil formulation matched group, with reference to the relative bioavailability experimental technique, calculates relative bioavailability by AUC by 6 every group.Dosage is as the criterion with lycopene contained in the preparation, is 40mg/kg.
Handle the AUC that obtains lycopene oil formulation (the lycopene raw material of 10mg is suspended in the olive oil of 1mL), solid dispersion and ternary clathrate with non-compartment model method
0 → 60hBe respectively 422.3 ± 43.6 (ng/ml) h, 1135.8 ± 409.4 (ng/ml) h and 1063.2 ± 149.3 (ng/ml) h.The result shows, lycopene solid dispersion or ternary clathrate that the present invention makes are compared with oil formulation, can significantly improve the bioavailability of lycopene, the AUC of solid dispersion and ternary clathrate is respectively 2.69 ± 0.969 and 2.56 ± 0.359 times of oil formulation.Curve and pharmacokinetic parameters figure see accompanying drawing 4, table 5 during medicine.
Table 5 lycopene oil suspension, solid dispersion and the ternary clathrate pharmacokinetic parameters behind rat oral administration (40mg/kg).
| Parameter | Oil suspension | Solid dispersion | The ternary clathrate |
| C max(ng/ml) | 29.7±11.7 | 43.3±6.2 | 46.1 |
| T max(h) | 10±5.3 | 13.3±9.5 | 14.7±8.3 |
| AUC 0-60h(ng/ml)h | 422.3±43.6 | 1135.8±409.4 * | 1063.2±149.3 * |
| AUMC(ng/ml)h 2 | 6464.3±1534.7 | 26352.3±19109.6 | 26822.8±7950.8 * |
| MRT(h) | 38±12.7 | 32±5.0 | 57.9±19.6 |
| F relative 0-60h(％) | 100±10.3 | 269.0±96.9 * | 255.5±35.9 * |
*P＜0.05vs oil prepare (is that reference preparation carries out statistical test with the LP oil suspension)
Fig. 1 is lycopene solid dispersion and ternary clathrate and its physical mixture accumulation dissolution
Fig. 2 is lycopene solid dispersion and lycopene raw material stability study
Fig. 3 is lycopene ternary clathrate and lycopene raw material stability study
Fig. 4 be lycopene oil suspension, solid dispersion and ternary clathrate through the blood drug level behind the rat oral administration (40mg/kg) through the time curve.
Specific embodiments
The preparation of lycopene solid dispersion and tablet thereof
Get lycopene 5g and poloxamer 1885g, add and ultrasonicly in the 600ml oxolane to make dissolving, boil off most of solvent on Rotary Evaporators, 40 ℃ of bath temperatures are inserted vacuum drying 24h, and dry thing grinds and promptly gets solid dispersion.
With lactose 256g elder generation and solid dispersion mixing, add differential silica gel 5.6g, crospolyvinylpyrrolidone 2.8g, magnesium stearate 5.6g again, mix homogeneously is pressed 1000.
45 minutes leachable 75% (n=6) in water of tablet.
Embodiment 2
The preparation of lycopene solid dispersion and tablet thereof
Get lycopene 5g and poloxamer 18815g, add and ultrasonicly in the 600ml oxolane to make dissolving, boil off most of solvent on Rotary Evaporators, 40 ℃ of bath temperatures are inserted vacuum drying 24h, and dry thing grinds and promptly gets solid dispersion.
With lactose 251.6g elder generation and solid dispersion mixing, crospolyvinylpyrrolidone 2.8g, magnesium stearate 5.6g, mix homogeneously is pressed 1000.
45 minutes leachable 76% (n=6) in water of tablet.
Embodiment 3
The preparation of lycopene solid dispersion and tablet thereof
Get lycopene 5g and poloxamer 18825g, add and ultrasonicly in the 600ml oxolane to make dissolving, boil off most of solvent on Rotary Evaporators, 40 ℃ of bath temperatures are inserted vacuum drying 24h, and dry thing grinds and promptly gets solid dispersion.
With lactose 241.6g elder generation and solid dispersion mixing, dry granulation mechanism grain adds crospolyvinylpyrrolidone 2.8g, magnesium stearate 5.6g, and mix homogeneously is pressed 1000.
45 minutes leachable 83% (n=6) in water of tablet.
Embodiment 4
The preparation of lycopene solid dispersion and capsule thereof
Get lycopene 5g and poloxamer 18845g, add and ultrasonicly in the 600ml oxolane to make dissolving, boil off most of solvent on Rotary Evaporators, 40 ℃ of bath temperatures are inserted vacuum drying 24h, and dry thing grinds and promptly gets solid dispersion.
With lactose 219.8g elder generation and solid dispersion mixing, add differential silica gel 5.6g, magnesium stearate 5.6g again, mix homogeneously, 1000 in encapsulating capsule.
45 minutes leachable 81% (n=6) in water of tablet.
Embodiment 5
The preparation of lycopene ternary clathrate and capsule thereof
Get lycopene 5g, poloxamer 1885g and HP-15g, earlier lycopene is dissolved in the oxolane, join again in poloxamer 188 and the HP-, insert beveller or grinding in ball grinder 1h, insert vacuum drying 24h, dry thing grinds and promptly gets the ternary clathrate.
With lactose 243.8g elder generation and ternary clathrate mixing, add differential silica gel 5.6, magnesium stearate 5.6 again, mix homogeneously, 1000 in encapsulating capsule.
45 minutes leachable 82% (n=6) in 0.5%SLS of tablet
Embodiment 6
The preparation of lycopene ternary clathrate and tablet thereof
Get lycopene 5g, poloxamer 18810g and hydroxypropyl 25g, earlier lycopene is dissolved in the oxolane, join again in poloxamer 188 and the HP-, insert beveller or grinding in ball grinder 1h, insert vacuum drying 24h, dry thing grinds and promptly gets the ternary clathrate.
With starch 226g elder generation and ternary clathrate mixing, add differential silica gel 5.6g, crospolyvinylpyrrolidone 2.8g, magnesium stearate 5.6g again, mix homogeneously is pressed 1000.
45 minutes leachable 79% (n=6) in 0.5%SLS of tablet
Embodiment 7
The preparation of lycopene ternary clathrate and capsule thereof
Get lycopene 5g, poloxamer 1885g and HP-45g, earlier lycopene is dissolved in the oxolane, join again in poloxamer 188 and the HP-, insert beveller or grinding in ball grinder 1h, insert vacuum drying 48h, dry thing grinds and promptly gets the ternary clathrate.
With lactose 223.8g elder generation and ternary clathrate mixing, add differential silica gel 5.6g, magnesium stearate 5.6g again, mix homogeneously, 1000 in encapsulating capsule.
45 minutes leachable 87% (n=6) in 0.5%SLS of tablet.
Claims (10)
1, a kind of solid pharmaceutical preparation that contains lycopene is characterized in that containing lycopene and poloxamer 188.
2, the solid pharmaceutical preparation of claim 1, wherein lycopene and poloxamer 188 weight ratios are 1:1～1:10.
3, the solid pharmaceutical preparation of claim 1 is characterized in that lycopene and poloxamer 188 are that form with solid dispersion exists.
4, the solid pharmaceutical preparation of claim 1 wherein also contains beta-schardinger dextrin-.
5, the solid pharmaceutical preparation of claim 4, wherein beta-schardinger dextrin-and lycopene and poloxamer 188 exist with the form of cyclodextrin clathrate.
6, the solid pharmaceutical preparation of claim 5, wherein the weight ratio of lycopene, poloxamer 188, beta-schardinger dextrin-is 1:0.5-2:3-9.
7, the solid pharmaceutical preparation of claim 4, wherein beta-schardinger dextrin-is hydroxypropyl-beta-schardinger dextrin-.
8, the solid pharmaceutical preparation of claim 1 adds also that adjuvant is prepared into tablet, capsule or micropill on the pharmaceutics.
9, the preparation method of the solid pharmaceutical preparation of claim 3 comprises: lycopene and poloxamer 188 added organic solvents are ultrasonic to make dissolving, on Rotary Evaporators, boils off most of solvent, and vacuum drying, dry thing grinds promptly.
10, the preparation method of the solid pharmaceutical preparation of claim 5 comprises: lycopene is dissolved in the organic solvent, joins again in the mixture of poloxamer 188 and beta-schardinger dextrin-, grind, and vacuum drying, dry thing grinds promptly.
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| CN102451179A (en) * | 2010-10-27 | 2012-05-16 | 香港双健现代药物技术有限公司 | Enteric solid preparation containing lycopene, resveratrol or melatonin and preparation method thereof |
| CN103919751A (en) * | 2014-04-23 | 2014-07-16 | 甘肃靖远鸿泰番茄制品有限公司 | Lycopene-SOD (Superoxide Dismutase) enteric capsule and preparation method thereof |
| CN104799301A (en) * | 2014-01-28 | 2015-07-29 | 南京生矶坊生物工程有限公司 | Lycopene tablet for spot removal, and preparation method thereof |
| CN104800182A (en) * | 2014-01-28 | 2015-07-29 | 南京生矶坊生物工程有限公司 | Lycopene tablet for protecting liver and relieving alcohol effect, and preparation method thereof |
| CN104800181A (en) * | 2014-01-28 | 2015-07-29 | 南京生矶坊生物工程有限公司 | Lycopene tablet for enhancing functions of prostate, and preparation method thereof |
| CN107441504A (en) * | 2017-09-06 | 2017-12-08 | 广州中医药大学 | Lycopene inclusion compound and preparation method thereof and lycopene inclusion compound tablet, capsule and particle |
| CN108210360A (en) * | 2018-02-06 | 2018-06-29 | 德之馨（上海）有限公司 | A kind of water solubility whitening formula and its preparation method and application |
| CN109419775A (en) * | 2017-08-25 | 2019-03-05 | 南京生矶坊生物工程有限公司 | A kind of water-soluble lycopene and its preparation method and application |
| CN109674767A (en) * | 2019-01-18 | 2019-04-26 | 安徽瑞达健康产业有限公司 | A kind of pellet and preparation method thereof containing lycopene |
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2008
- 2008-12-18 CN CNA2008102447940A patent/CN101439030A/en active Pending
Cited By (11)
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| CN102451179A (en) * | 2010-10-27 | 2012-05-16 | 香港双健现代药物技术有限公司 | Enteric solid preparation containing lycopene, resveratrol or melatonin and preparation method thereof |
| CN104799301A (en) * | 2014-01-28 | 2015-07-29 | 南京生矶坊生物工程有限公司 | Lycopene tablet for spot removal, and preparation method thereof |
| CN104800182A (en) * | 2014-01-28 | 2015-07-29 | 南京生矶坊生物工程有限公司 | Lycopene tablet for protecting liver and relieving alcohol effect, and preparation method thereof |
| CN104800181A (en) * | 2014-01-28 | 2015-07-29 | 南京生矶坊生物工程有限公司 | Lycopene tablet for enhancing functions of prostate, and preparation method thereof |
| CN103919751A (en) * | 2014-04-23 | 2014-07-16 | 甘肃靖远鸿泰番茄制品有限公司 | Lycopene-SOD (Superoxide Dismutase) enteric capsule and preparation method thereof |
| CN109419775A (en) * | 2017-08-25 | 2019-03-05 | 南京生矶坊生物工程有限公司 | A kind of water-soluble lycopene and its preparation method and application |
| CN109419775B (en) * | 2017-08-25 | 2021-02-09 | 南京生矶坊生物工程有限公司 | Water-soluble lycopene and preparation method and application thereof |
| CN107441504A (en) * | 2017-09-06 | 2017-12-08 | 广州中医药大学 | Lycopene inclusion compound and preparation method thereof and lycopene inclusion compound tablet, capsule and particle |
| CN108210360A (en) * | 2018-02-06 | 2018-06-29 | 德之馨（上海）有限公司 | A kind of water solubility whitening formula and its preparation method and application |
| CN108210360B (en) * | 2018-02-06 | 2021-02-12 | 德之馨（上海）有限公司 | Water-soluble whitening formula and preparation method and application thereof |
| CN109674767A (en) * | 2019-01-18 | 2019-04-26 | 安徽瑞达健康产业有限公司 | A kind of pellet and preparation method thereof containing lycopene |
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Open date: 20090527 |