CN104470507A - Tablet comprising melissa officinalis folium extract for preventing or treating angiogenesis or mmp activity-mediated disease - Google Patents
Tablet comprising melissa officinalis folium extract for preventing or treating angiogenesis or mmp activity-mediated disease Download PDFInfo
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Abstract
The present invention relates to a tablet for preventing or treating angiogenesis or matrix metalloproteinase (MMP) activity-mediated disease, the tablet comprising Melissa (Melissa officinalis) folium extract having rosmarinic acid, caffeic acid, and rutin as major active ingredients, and a pharmaceutically acceptable disintegrator. The tablet in which the dissolution rates of the rosmarinic acid or the caffeic acid are 80% or more within 30 minutes has an excellent release rate and is stable under accelerated conditions, and thus the tablet may be used effectively for the prevention or the treatment of angiogenesis or MMP activity-mediated disease, in particular, obesity.
Description
Technical field
The present invention relates to for prevention or treat angiogenesis (angiogenesis) or matrix metalloproteinase (matrix metalloproteinase, MMP) tablet of the disease of active mediation, this tablet comprises Herba Melissae officinalis (Melissa officinalis), and leaf extract (wherein, rosmarinic acid, caffeic acid and rutin (rutin, rutin) they are main active component) and pharmaceutically acceptable disintegrating agent.
Background technology
Herba Melissae officinalis (Melissa, Melissa officinalis), the herbaceos perennial of Labiatae family, is also referred to as Herba melissae axillaris (lemon balm).
Herba Melissae officinalis leaf extract comprises flavonoid (flavonoids), terpene acids (terpene acids), the glycosides of volatile oil, alcohol and phenolic compound and caffeic acid derivative.Especially, the flavonoid comprised in a large number in Herba Melissae officinalis blade comprises luteoloside, cosmosin (cosmosin), rhamnocitrin (rhamnocitrin) and isoquercitrin; And comprise ursolic acid as terpene acid.In these non-volatile compositions, comprise rosmarinic acid, and comprise caffeic acid derivative with the amount of about 4.7%.Volatile oil comprises geraniol, neral, citronellal and acetaminol.In addition, comprise coumaric acid, Polyphenols in Herba Melissae officinalis leaf extract and there is the cinnamic acid etc. of weak armaticity.
The effect of the main pharmaceutical compositions in Herba Melissae officinalis leaf extract is as described below:
Rosmarinic acid has strong anti-inflammatory and antipyretic effect, and the quintessence oil be included in leaf is used for the treatment of disease, particularly depression, nervous headache, the loss of memory, neuralgia, heating etc.In addition, also known rosmarinic acid has calmness, antibacterial, antiviral and hormone antagonist effect.Current, (anhydrous, dry) the Herba Melissae officinalis leaf extract known packets being contained the drying of a large amount of rosmarinic acid is used as blood circulation enhancer component.
Caffeic acid is included in the plant such as coffee and such as fruit, vegetable, herbaceous plant.Known it be as cancer chemopreventive agent and as in body and the antioxidant of external excellence work.When its chlorogenic acid form is esterified be quininic acid time, caffeinic absorption is limited, and the oral caffeic acid giving high dose causes stomach papilloma (stomach papillomas) in rats, and think that caffeic acid is carcinogen in these rats.The growth giving to show with the caffeic acid of the high dose of antioxidant combination colon tumor declines.
Rutin is flavonol glycosides material, and is distributed widely in nature.Its main physiologically active is capillary tube contraction, and is used as hemorrhage; But this effect is not very strong and is temporary transient.It also has blood capillary invigoration effect, and may be used for prevention and therapy cerebral hemorrhage, radioemesis (radiation sickness), hemorrhage etc.
Meanwhile, angiogenesis refers to the process from the new blood capillary of the vascularization of preexist.Under normal circumstances, during angiogenesis occurs in the cyclically-varying of fetal development, tissue regeneration and wound healing and corpus luteum development, female reproductive system, and strict adjustment is subject in these processes.
For adult, vascular endothelial cell growth slowly, and compared with the cell of other types, relative meaning divides not be fine.But, if desired, by hormone signal response, from the angiogenic factors of inflammatory cell release, the Angiogensis regulon (mediator) be separated is released into the stimulation induction adult angiogenesis of the activation of the hydrolytic enzyme of extracellular matrix or angiogenesis factor (factor).The process of angiogenesis is made up of following usually: the degraded of the basement membrane on the blood vessel of being induced by protease, the migration of vascular endothelial cell, to be formed by propagation inner chamber and vascular endothelial cell differentiation to reconstruct blood vessel and new being formed of blood capillary.In angiogenesis, one of most important event is the enzymatic degradation around the basement membrane on the blood vessel of vascular endothelial cell.The enzyme playing important effect is wherein the enzyme belonging to matrix metalloproteinase (MMP).
Known when angiogenesis be not the MMP that plays an important role in main regulation or angiogenesis by overactivity time, blood vessel grows abnormally, and therefore gives rise to diseases, as growth and the transfer of cancer, cardiovascular disease is as hemangioma, fibrohemangioma, vascular malformation, atherosclerosis, angiostenosis, idiopathic sclerosis (edemic sclerosis) and restenosis, ophthalmic diseases is as diabetic retinopathy, degeneration of macula (comprises old and feeble relevant degeneration of macula, as the degeneration of macula that the age is relevant), pterygium, retinal degeneration, the angiogenesis relevant to corneal transplantation, neovascular glaucoma, angiogenic corneal disease becomes, (retrolental) proliferation of fibrous tissue after crystalline lens, granular conjunctivitis, corneal ulcer, proliferative vitreoretinopathy, immaturity retinopathy (immature retinopathy), inflammatory eye, keratoconus, house Glenn Cotard (Sjogren's syndrome), myopia, eye neoplasms, repulsion in corneal transplantation, obesity etc. (see Polverini PJ, Critical Reviews in Oral Biology, 6 (3), 1995,230-247, ArupDas, et al., Progress in Retinal and Eye Research, 22,2003,721-748, Nick DiGirolamo, et al., IOVS, Vol.42, No.9, August 2001,1963-1968, Patricia Lee, et al., Survey of ophthalmology, vol 43, No.3, Nov-Dec 1998,245-269, D.B.Holland, et al., British Journal of Dermatology, 150,2004,72-81, Anthony H Vagnucci Jr, et al., The Lancet, vol 361, Feb.15,2003,605-608, Berislav V.Zlokovic, Trends in Neuroscience, Vol.28, No.4, April 2005,202-208, Jaap G.Neels, et al., The FASEB Journal express article10.1096/fj.03-1101fje.2004 Web publishing on April 14, D.L.Crandall, et al., Microcirculation, 4,1997,211-232, G.Voros, et al., Endocrinology, 146,2005,4545-4554, M.A.Rupnick, et al., PNAS, 99,2002,10730-10735, E.Brakenhielm, et al., Circ.Res., 94,2004,1579-1588, H.R.Lijnen, et al., Arterioscler Thromb Vasc Biol., 22,2002,374-379, and D.Demeulemeester, etal., Biochem.Biophys.Res.Commun., 329,2005,105-110).
Therefore, the exploitation of angiogenesis inhibitor or MMP activity inhibitor can obtain the treatment of these diseases.
About this, No. 10-550298th, Korean Patent passes through the experiment that end user's huve cell (HUVEC) suppresses blood vessel (tube) (as blood capillary) to be formed and the in vivo test using the allantocherion (chorioallantoic membrane) of mice Matrigel (matrigel) model and Embryo Gallus domesticus to test, and discloses Herba Melissae officinalis leaf extract and has blood vessel formation against function.
No. 10-473688th, Korean Patent further discloses Herba Melissae officinalis leaf extract and has inhibitory action to MMP (matrix metalloproteinase), and MMP (significant process of angiogenesis) in the degraded of the basement membrane around vascular endothelial cell plays an important role.
No. 10-903030th, Korean Patent discloses the method for the effect for increasing Herba Melissae officinalis leaf extract, and it comprises the following steps: (i) is with 50% to 100% ethanol or methanol extraction Herba Melissae officinalis, dry subsequently; (ii) suspend alcohol extract in water, uses ethyl acetate fractional distillation, then dry; And (iii) resuspended ethyl acetate fraction in water, dry to obtain the ethyl acetate fraction of Herba Melissae officinalis blade subsequently.In addition, it is disclosed that the example of the hard capsule comprising Herba Melissae officinalis leaf extract; But, when Herba Melissae officinalis leaf extract be prepare with capsule preparations time, due to capsule basic compound, active component is also not easy release, and owing to luming with capsule basic compound, the release of medicine is disadvantageous.When under the condition that the capsule preparations comprising Herba Melissae officinalis leaf extract is placed in high temperature and high humility, the rate of release of active component becomes slow, and therefore, the medicinal effects capsule comprising Herba Melissae officinalis leaf extract being shown to expectation is unaccommodated.
But above-mentioned prior art does not take into full account the active component showing medicinal effects showing and be derived from Herba Melissae officinalis leaf extract and the suitable preparation given to human body.
Therefore, the present inventor have studied the effect of the drug metabolism of the rate of release depending on the main active being derived from Herba Melissae officinalis leaf extract, and observe the effect change of the preparation of the pharmaceutical composition depending on stripping curve and comprise Herba Melissae officinalis leaf extract, thus complete the present invention.
Summary of the invention
Therefore, the object of this invention is to provide the pharmaceutical preparation comprising Herba Melissae officinalis leaf extract, wherein, rosmarinic acid, caffeic acid and rutin are main active, and it has Agiogenesis inhibition and abdominal obesity therapeutic effect, and show excellent drug metabolism.
In order to realize object above, the invention provides the tablet of the disease for preventing or treat angiogenesis or the mediation of MMP activity, wherein, tablet comprises Herba Melissae officinalis leaf extract, wherein, rosmarinic acid, caffeic acid and rutin are main active component and pharmaceutically acceptable disintegrating agent, and rosmarinic acid or caffeic acid dissolution are in 30 minutes 80% or more.
Even if be also the rate of release of stable, that there is active component excellence due to tablet according to the present invention under (accelerated) condition accelerated and show the solubility curve that it can maximize the effect of the disease for the treatment of or prevention angiogenesis or the mediation of MMP activity, therefore, tablet can be effectively used to be used for prevention or to treat above disease.
Accompanying drawing explanation
When combining the accompanying drawing of enclosing, by following explanation of the present invention, the object of above and other of the present invention and feature will become obvious, and accompanying drawing illustrates respectively:
Fig. 1 and Fig. 2 respectively illustrates the result of the test of rosmarinic acid and caffeic acid stripping from preparation in embodiment 2 and embodiment 3 and comparative example 1 respectively.
Fig. 3 to Fig. 5 respectively illustrates according to storage life under acceleration conditions, for the result that the stable content from rosmarinic acid, caffeic acid and the rutin in embodiment 2 and embodiment 3 and comparative example 1 preparation is tested;
Respectively illustrate according to storage life under acceleration conditions in Fig. 6 and Fig. 7, for the result of the steady dissolution qualitative test of rosmarinic acid, caffeic acid and the rutin in the preparation from embodiment 2 and embodiment 3 and comparative example 1; And
Fig. 8 shows in comparative example 2 and 3 and embodiment 4, by giving the change of the rat body weight of preparation.
Detailed description of the invention
The invention provides the tablet of the disease for preventing or treat angiogenesis or the mediation of MMP activity, wherein, this tablet comprises and has rosmarinic acid, caffeic acid and rutin as the Herba Melissae officinalis leaf extract of main active and pharmaceutically acceptable disintegrating agent, and rosmarinic acid or caffeinic dissolution are in 30 minutes 80% or more.
In the present invention, " dissolution (dissolution rate; rate of dissolution; dissolution rate) " refers to the following value measured: use the pure water of 900 milliliters as dissolution test liquid, and according to the method 2 in the ordinary test method of Pharmacopoeia Coreana, pulpboard method (Paddle method), at 37 ± 0.5 DEG C, the rotating speed of 50rpm carries out dissolution test.After the concrete time, with the metre filter dissolution fluid of 0.45 μm.Use liquid chromatograph (HPLC) analytic process in the ordinary test method of Pharmacopoeia Coreana, according to the Concentraton gradient condition of mobile phase A described below (5% aqueous formic acid) and Mobile phase B (methanol), with the speed operation mobile phase of 1ml/ minute.The sample of 10 μ L is injected analytical column, such as Zorbax Eclipse Plus C18 post (150x 4.6 millimeters) post, and under the wavelength of 285nm, analyzes effective ingredient to measure.
Concentraton gradient > in < mobile phase
According to one aspect of the present invention, be 80% or more (see Fig. 6 and Fig. 7) in 15 minutes according to rosmarinic acid in tablet of the present invention or caffeinic dissolution.
In addition, based on the gross weight of tablet, the tablet in the present invention with by weight 10% to 90% amount comprise Herba Melissae officinalis leaf extract.In an embodiment of the invention, based on the gross weight of tablet, tablet of the present invention with by weight 50% to by weight 90% amount comprise Herba Melissae officinalis leaf extract.
The tablet comprising Herba Melissae officinalis leaf extract of the present invention can make the release of active component become easy, thus the active component of 80% or more can be discharged, rosmarinic acid or caffeic acid is discharged in 30 minutes, and, even under the acceleration environment of high temperature and high humility, the rate of release of its composition changes hardly and is stable, and thus it can show excellent medicinal effects.Be with drug characteristic prepared by natural extracts, active component is blended in wherein, and therefore, the preparation with disintegrate ability is fast favourable, makes effective ingredient can play its drug effect simultaneously.Therefore, be similar to the present invention, the pharmaceutical composition comprising Herba Melissae officinalis leaf extract can be the form of tablet.
In the present invention, the general extraction methods of employing ethanol can be used to prepare Herba Melissae officinalis leaf extract according to following steps.First, with 10 to 40 times of the amount of Herba Melissae officinalis blade by weight, the ethanol of 50% to 100%, be preferably the ethanol of 70% to 80%, be more preferably the alcohol reflux extraction Herba Melissae officinalis leaf of 75%, the first concentration step then filtered.Then, the step of the extract used for twice above mixture (such as ethyl acetate: water=1:1 (the v/v)) fractional distillation (fractionation) of ethyl acetate and water is repeated.The ethyl acetate layer that collection obtains from above process, secondary (secondarily) are concentrated, dry also pulverizes to prepare according to Herba Melissae officinalis leaf extract of the present invention.The extract prepared above of use is as the ethyl acetate extract of the drying of the Herba Melissae officinalis blade in the present invention.
Herba Melissae officinalis blade or their mixture of dry Herba Melissae officinalis blade, non-dry can be used.In order to effective extraction, can be cut into small pieces Herba Melissae officinalis blade use.
According to the present invention, based on the gross weight of this extract, Herba Melissae officinalis leaf extract comprise by weight 5% or more rosmarinic acid, by weight 0.5% or more caffeic acid and by weight 1% or more rutin, and can comprise preferably by weight 5% to 10% rosmarinic acid, by weight 0.5% to 1% caffeic acid and by weight 1% to 2% rutin.An aspect according to an illustrative embodiment of the invention, according to the ethyl acetate extract of the drying of Herba Melissae officinalis leaf of the present invention contain by weight about 5.5% rosmarinic acid, by weight about 0.65% caffeic acid and by weight about 1.42% rutin (see table 2).
Herba Melissae officinalis leaf extract also can comprise the rosmarinic acid and caffeic acid that weight ratio is 1:0.1 to 1:0.2, caffeic acid and the rutin of weight ratio to be 1:1 to 1:4, more specifically weight ratio be 1:1 to 1:3, and weight ratio is rosmarinic acid and the rutin of 1:0.1 to 1:0.3.
In addition, tablet according to the present invention comprises pharmaceutically acceptable disintegrating agent to reach aforesaid dissolution, namely rosmarinic acid or caffeic acid in 15 minutes 80% or more dissolution.Disintegrating agent can be selected from by the following group formed: sodium starch glycollate (Sodium Starch Glycolate, sodium starchglycolate, SSG), crospovidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and their mixture, and based on the total weight of tablet, can with by weight 1% to 10% amount comprise disintegrating agent.
Pharmaceutically acceptable additive can be comprised further according to tablet of the present invention, additive is selected from by the following group formed: excipient, lubricant, binding agent and their mixture, and can be conventionally, by ethyl acetate extract and the mixing of pharmaceutically acceptable additive of the drying by Herba Melissae officinalis blade, then directly compress, or with the preparation of dry or moist mode tabletting.
Excipient can be selected from by the following group formed: microcrystalline Cellulose (MCC), light anhydrous silicic acid, mannitol, lactose, dalcium biphosphate, starch, low-substituted hydroxypropyl cellulose and their mixture, and based on the gross weight of tablet, can with by weight 7 to 87% amount comprise excipient.
Lubricant can be selected from by the following group formed: stearic acid, stearic slaine are as magnesium stearate and calcium stearate, Talcum, fatty acid cane sugar ester, hydrogenated vegetable oil, high melting-point wax, fatty glyceride, two Glyceryl Behenates and their mixture, and based on the total weight of tablet, can being that the amount of 0.2% to 5% comprises lubricant by weight.
Binding agent can be selected from by the following group formed: hydroxypropyl cellulose (HPC-L), hydroxypropyl emthylcellulose, polyvinylpyrrolidone, copolyvidone and their mixture, and based on the gross weight of tablet, can with by weight 1 to 10% amount comprise binding agent.
Tablet according to the present invention can be used for the disease of the disease of preventing or treating angiogenesis and being correlated with or MMP mediation, such as, be selected from the disease in the group of following composition: the growth of cancer and transfer, cardiovascular disease is as hemangioma, fibrohemangioma, vascular malformation, atherosclerosis, angiostenosis, idiopathic sclerosis and restenosis, ophthalmic diseases is as diabetic retinopathy, degeneration of macula (comprising the degeneration of macula that old and feeble relevant degeneration of macula is as relevant in the age), pterygium, retinal degeneration, the angiogenesis relevant to corneal transplantation, neovascular glaucoma, angiogenic corneal disease becomes, Terry's sign, granular conjunctivitis, corneal ulcer, proliferative vitreoretinopathy, immature retinopathy, inflammatory eye, keratoconus, house Glenn Cotard, myopia, repulsion in eye neoplasms and corneal transplantation, and obesity, and preferred obesity.
Therefore, the invention provides the method for the disease of angiogenesis for preventing or treat in experimenter or the mediation of matrix metalloproteinase (MMP) activity, comprising: aforesaid tablet is given to its experimenter of needs, such as, mammal, comprises people.
Embodiment
Next, the present invention is illustrated in greater detail with reference to following examples.But the following example provided is only for illustration of object, and scope of the present invention should not be limited to this by any way.
Embodiment 1: the composition in the ethyl acetate extract of the drying of Herba Melissae officinalis blade and the analysis of ratio
In order to effective component extracting from raw material Herba Melissae officinalis blade, prepare extract as follows and for component analysis.
Particularly, extract the Herba Melissae officinalis blade 4 hours of the drying of 200 kilograms with 75% alcohol reflux of the total 20 times of the Herba Melissae officinalis leaf weight of drying, and filtered by cartridge filter, and under reduced pressure first time concentrated.With the concentrate (amount: 50 kilograms) that mixture (1:1 (v/v)) (amount: the 50 kilograms) fractional distillation of ethyl acetate and water obtains thus, repeated twice.Then, collect ethyl acetate layer, the lower second time that reduces pressure is concentrated, dry also to be pulverized with the ethyl acetate extract obtaining Herba Melissae officinalis blade (amount: 8.2 kilograms).Carry out said process in triplicate to determine the repeatability for extracting, and following analysis package is contained in the ratio (ratio) of component in Herba Melissae officinalis leaf extract and component.
Herba Melissae officinalis leaf extract is analyzed by high performance liquid chromatography (HPLC).The ethyl acetate extract of the Herba Melissae officinalis blade prepared above of 10 μ l is injected Zorbax Eclipse Plus C18 post (150 × 4.6mm), and subsequently according in following table 1 record ratio with the speed elution flow phase A (5% aqueous formic acid) of 1mL/ minute and Mobile phase B (methanol), carry out at 285nm place analyzing the effective ingredient eluted.
[table 1]
| Time (minute) | Mobile phase A | Mobile phase B |
| 0 | 100 | 0 |
| 5 | 100 | 0 |
| 25 | 0 | 100 |
| 35 | 0 | 100 |
| 35.1 | 100 | 0 |
| 45 | 100 | 0 |
As the result of the effective ingredient analyzed in Herba Melissae officinalis leaf extract, Herba Melissae officinalis leaf extract on average containing by weight about 5.5% rosmarinic acid, by weight about 0.65% caffeic acid and by weight about 1.42% rutin, as shown in table 2 below.Based on analysis result, confirm that rosmarinic acid and caffeic acid can exist with the weight ratio of 1:0.1 to 1:0.2, caffeic acid and rutin can exist with the weight ratio of 1:1 to 1:3, and rosmarinic acid and rutin can be present in Herba Melissae officinalis leaf extract with the weight ratio of 1:0.1 to 1:0.3.
Think when rosmarinic acid, caffeic acid and rutin weight ratio appropriate balance and keep constant time, the acetic acid ethyl ester extract of Herba Melissae officinalis blade can show the medicinal effects of expectation.
Also think gross weight based on Herba Melissae officinalis leaf extract, comprise the rosmarinic acid of by weight 5.0% or more, by weight 0.5% or more caffeic acid and by weight 1.0% or more rutin be preferable for the reproducibility of medicinal effects, and it be very important for this to represent constantly and repeatedly can manage inclusions to maintain the repeatability of medicinal effects.
[table 2]
Embodiment 2: preparation comprises tablet-(1) of Herba Melissae officinalis leaf extract
According to the amount (unit: mg) recorded in following table 3, by using the microcrystalline Cellulose (MCC as excipient, Avicel PH101, FMC biopolymer) and light anhydrous silicic acid (Aerosil 200, Degussa), as the sodium starch glycolate (SSG of disintegrating agent, YUNG ZIP Chem) and as the magnesium stearate (S-Mg of lubricant, NOF Corporation) mix with the ethyl acetate extract of the drying of the Herba Melissae officinalis blade prepared in embodiment 1, and then carry out directly compressing preparing tablet.
Embodiment 3: preparation comprises tablet-(2) of Herba Melissae officinalis leaf extract
According to the amount (unit: mg) recorded in following table 3, by the ethyl acetate of the drying of the Herba Melissae officinalis leaf extract of preparation in embodiment 1 is mixed with MCC and SSG, mixture and binder liquid (are dissolved in the hydroxypropyl cellulose (HPC-L in water, Shin-Etsu)) Homogeneous phase mixing, then prepares granule by the granulating mixture obtained.By the granule of preparation 50 DEG C of dryings 2 hours, through 20 mesh sieves, mix with the light anhydrous silicic acid as excipient and the S-Mg as lubricant, then compress to prepare tablet.
Comparative example 1: preparation comprises the capsule of Herba Melissae officinalis leaf extract
According to amount (unit: mg) described in following table 3, by using the ethyl acetate extract of the drying of preparation in embodiment 1 with as excipient MCC and light anhydrous silicic acid and mix as the S-Mg of lubricant, and subsequently mixture is filled in the capsule of No. 0 size and prepares capsule.
[table 3]
Comparative example 2: the tablet not comprising Herba Melissae officinalis leaf extract given for the preparation of rat
In embodiment 2 and embodiment 3, the tablet of preparation has the dosage and size that are applicable to real human body (about 60 kilograms).For the measured body weight experiment given by rat, the tablet not comprising Herba Melissae officinalis leaf extract given for the preparation of rat with almost proportional with the ratio of the body weight of rat body weight and people ratio.
According to the compositions recorded in following table 4, the tablet given for the preparation of rat by the method identical with embodiment 3, except not adding dry Herba Melissae officinalis leaves ethyl acetate extract.
[table 4]
| Component | Comparative example 2 |
| Microcrystalline Cellulose | 6.0 |
| SSG | 1.8 |
| HPC-L | 0.2 |
| (purifying waste water) | (3.0) |
| SiO 2 | 0.5 |
| S-Mg | 0.2 |
| Gross weight | 8.7 |
Comparative example 3: the capsule comprising Herba Melissae officinalis leaf extract given for the preparation of rat
According to the amount (unit: mg) recorded in following table 5, by using the Herba Melissae officinalis leaves ethyl acetate extract of the drying prepared in embodiment 1 with as excipient MCC and light anhydrous silicic acid and mix as the S-Mg of lubricant, and subsequently, mixture is filled in the capsule of No. 5 sizes for the preparation of the capsule that rat gives.
Embodiment 4: the tablet comprising Herba Melissae officinalis leaf extract given for the preparation of rat
According to the amount (unit: mg) recorded in following table 5, the tablet given for the preparation of rat by the mode identical with embodiment 3.
[table 5]
| Component | Comparative example 3 | Embodiment 4 |
| Dry Herba Melissae officinalis leaves ethyl acetate extract | 10.0 | 10.0 |
| Microcrystalline Cellulose | 5.5 | 6.0 |
| SSG | - | 1.8 |
| HPC-L | - | 0.2 |
| (purifying waste water) | - | (3.0) |
| SiO2 | 0.2 | 0.5 |
| S-Mg | 0.2 | 0.2 |
| Capsule | 10.0 | - |
| Gross weight | 25.9 | 18.7 |
Test case 1: rosmarinic acid and the fragrant dissolution test of coffee
In the capsule of comparative example 1 and the tablet of embodiment 2 and embodiment 3, dissolution test is carried out to rosmarinic acid and caffeic acid (main active of Herba Melissae officinalis leaf extract).
For dissolution test, use the water of 900mL as dissolution test liquid, and according to the method 2 in the ordinary test method of Pharmacopoeia Coreana, paddle board method, 37 ± 0.5 DEG C, carry out with the rotary speed of 50rpm.From dissolution test after 5,10,15,30,45,60,90 and 120 minutes, get dissolution medium and filter through 0.45 μm of filter, and subsequently, measure rosmarinic acid and caffeinic dissolution by the method identical with the HPLC (high performance liquid chromatography) described in embodiment 1.Result is shown in Fig. 1 and Fig. 2.
As depicted in figs. 1 and 2, compared with the capsule prepared in comparative example 1, in the tablet of preparation in embodiment 2 and embodiment 3 rate of release of often kind of active component and final dissolution higher.Find in addition, these the two kinds of tablets prepared by the convection drying pressed disc method (direct dry-tableting process) in embodiment 2 and discharged in 30 minutes by tablet prepared by wet granulation method in embodiment 3 80% or more rosmarinic acid and caffeic acid.
Test case 2: the amount of testing effective ingredient under acceleration environment
The tablet of preparation in the capsule of preparation in comparative example 1 and embodiment 2 and embodiment 3 is packaged in HDPE bottle, and (40 DEG C and 75% relative humidity) preserves 6 months under acceleration conditions, and subsequently, the stability confirming preparation is measured to the main active of Herba Melissae officinalis leaf extract and the amount of rosmarinic acid, caffeic acid and rutin.Store 1,3 and after 6 months under acceleration environment, measure the amount of rosmarinic acid, caffeic acid and rutin, result is shown in Fig. 3 to Fig. 5.
As a result, between the capsule preparations prepared by convection drying tabletting and wet granulation and tablet formulation, there is not significant difference, and the amount of each composition does not significantly change.Particularly, tablet according to the present invention meets standard: by weight 5.0% or more rosmarinic acid, by weight 0.5% or more caffeic acid and by weight 1.0% or more rutin, and therefore, confirm that they are also stable under accelerating storage condition.
Test case 3: the change of dissolubility under mensuration acceleration environment
The tablet of 3 preparations in the capsule of preparation in comparative example 1 and embodiment 2 and embodiment is packaged in HDPE bottle, and (40 DEG C under acceleration conditions, 75% relative humidity) preserve 6 months, and subsequently, measure rosmarinic acid and caffeinic dissolution by the method identical with test example 1.After solubility test starts 15,30 and 60 minutes, trapping medium sample and evaluate dissolution, then by its compared with initial value to determine the degree changed, and result is shown in Fig. 6 and Fig. 7.
As shown in Figure 6 and Figure 7, in comparative example 1, the capsule of preparation demonstrates initial release rate slowly, and when they are kept under acceleration conditions, the rate of release illustrated continues to slow down in time.Think that capsule affects the rate of release of Herba Melissae officinalis leaf extract.Slowing down along with dissolving the probability that medicinal effects may change because exist, thinking that capsule is pharmaceutically less desirable preparation.All tablets of the present invention do not show significant change and are stable in rate of release.
Test case 4: give to animal and measure body weight change
In order to check Herba Melissae officinalis leaf extract to effect in the body of the obesity that high fat diet is induced, carry out following experiment.After the laundering period in one week, the rat in 7 week age is divided into the group often organizing 3 animals.With the high fat diet raising rat 8 weeks of 45kcal%, meanwhile, use subregion, give tablet every day 1 time (daily dose of Herba Melissae officinalis leaf extract: 10mg) of comparative example 2 and comparative example 3 and embodiment 4.Subsequently, measure the body weight of rat, and result is shown in Fig. 8.The comparison of individual average weight and analysis show that each result is significant (P<0.05) in each case.
As shown in Figure 8, the body weight not comprising the group of the tablet of Herba Melissae officinalis leaf extract giving in comparative example 2 preparation increased sharply along with the time.Meanwhile, compared with the group of the tablet giving to prepare in example 4, the group comprising the capsule of Herba Melissae officinalis leaf extract giving preparation in comparative example 3 shows the body weight increase of relatively high amount.This result is considered to relevant to the dissolution results in experimental example 1, and shows that the rate of release of rosmarinic acid and caffeic acid (effective ingredient of Herba Melissae officinalis leaf extract) plays an important role in the medicinal efficacy playing Herba Melissae officinalis leaf extract.In other words, if Herba Melissae officinalis leaf extract is prepared as capsule preparations as prepared in comparative example 3, and active constituents of medicine does not discharge well, and so the amount of each component of body absorption will be little, and therefore, can not show medicinal effects.
Therefore, find for the most suitable preparation of Herba Melissae officinalis leaf extract it is tablet formulation, rosmarinic acid and caffeic acid (main component of Herba Melissae officinalis leaf extract) in 30 minutes from wherein discharging 80% or more, thus show medicinal effects rapidly, and in storage process, it is little that it shows stripping change.
Claims (14)
1. the tablet of disease for prevention or treatment angiogenesis or the mediation of matrix metalloproteinase (MMP) activity, wherein, described tablet comprises and has rosmarinic acid, caffeic acid and rutin as Herba Melissae officinalis (Melissa officinalis) leaf extract of main active and pharmaceutically acceptable disintegrating agent, and the rosmarinic acid of described tablet or caffeinic dissolution are in 30 minutes 80% or more.
2. tablet according to claim 1, wherein, described rosmarinic acid or described caffeinic dissolution are in 15 minutes 80% or more.
3. tablet according to claim 1, wherein, by the described Herba Melissae officinalis leaf extract of following preparation: with the alcohol reflux Herba Melissae officinalis blade of 50% to 100%, filter subsequently and concentrate; Collect the ethyl acetate layer step of the concentrate heating up in a steamer acquisition with ethyl acetate and moisture being repeated twice generation; And it is subsequently, concentrated, dry and pulverize described ethyl acetate layer.
4. tablet according to claim 1, wherein, based on the gross weight of described Herba Melissae officinalis leaf extract, described Herba Melissae officinalis leaf extract comprise by weight 5% to 10% described rosmarinic acid, by weight 0.5% to 1% described caffeic acid and by weight 1% to 2% described rutin.
5. tablet according to claim 1, wherein, described Herba Melissae officinalis leaf extract comprises the described rosmarinic acid and described caffeic acid that weight ratio is 1:0.1 to 1:0.2.
6. tablet according to claim 1, wherein, described Herba Melissae officinalis leaf extract comprises the described caffeic acid and described rutin that weight ratio is 1:1 to 1:4.
7. tablet according to claim 1, wherein, described Herba Melissae officinalis leaf extract comprises the described rosmarinic acid and described rutin that weight ratio is 1:0.1 to 1:0.3.
8. tablet according to claim 1, wherein, described pharmaceutically acceptable disintegrating agent is selected from by the following group formed: sodium starch glycollate, crospovidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and their mixture.
9. tablet according to claim 1, wherein, based on the gross weight of described tablet, with by weight 1% to 10% amount comprise described pharmaceutically acceptable disintegrating agent.
10. tablet according to claim 1, described tablet comprises the pharmaceutically acceptable additive be selected from by the following group formed further: excipient, lubricant, binding agent and their mixture.
11. tablets according to claim 10, based on the gross weight of described tablet, described tablet comprise by weight 10% to 90% described Herba Melissae officinalis leaf extract, by weight 1% to 10% described disintegrating agent, by weight 7% to 87% described excipient, by weight 0.2 to 5% described lubricant and by weight 1% to 10% described binding agent.
12. tablets according to claim 1, wherein, the disease of described angiogenesis or the mediation of MMP activity is selected from the disease by the following group formed: the growth of cancer and transfer; The sclerosis of hemangioma, fibrohemangioma, vascular malformation, atherosclerosis, angiostenosis, idiopathic and restenosis; Repulsion in diabetic retinopathy, degeneration of macula, pterygium, retinal degeneration, the angiogenesis relevant to corneal transplantation, neovascular glaucoma, angiogenic corneal disease change, Terry's sign, granular conjunctivitis, corneal ulcer, proliferative vitreoretinopathy, immaturity retinopathy, inflammatory eye, keratoconus, house Glenn Cotard, myopia, eye neoplasms and corneal transplantation; And obesity.
13. tablets according to claim 12, wherein, the disease of described angiogenesis or the mediation of MMP activity is obesity.
14. 1 kinds to generate for prevention and therapy experimenter medium vessels or the method for diseases of matrix metalloproteinase (MMP) activity mediation, comprise and to be given by tablet according to claim 1 to its experimenter of needs.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020120078349A KR20140011209A (en) | 2012-07-18 | 2012-07-18 | Tablet comprising melissa officinalis extracts for preventing or treating angiogenesis or mmp activity mediated disease |
| KR10-2012-0078349 | 2012-07-18 | ||
| PCT/KR2013/006393 WO2014014271A1 (en) | 2012-07-18 | 2013-07-17 | Tablet comprising melissa officinalis folium extract for preventing or treating angiogenesis or mmp activity-mediated disease |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104470507A true CN104470507A (en) | 2015-03-25 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201380037668.7A Pending CN104470507A (en) | 2012-07-18 | 2013-07-17 | Tablet comprising melissa officinalis folium extract for preventing or treating angiogenesis or mmp activity-mediated disease |
Country Status (3)
| Country | Link |
|---|---|
| KR (1) | KR20140011209A (en) |
| CN (1) | CN104470507A (en) |
| WO (1) | WO2014014271A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105012261A (en) * | 2015-08-21 | 2015-11-04 | 德州德药制药有限公司 | Caffeic acid tablets and preparation method thereof |
| CN106176701A (en) * | 2016-08-11 | 2016-12-07 | 成都中医药大学 | Caffeic acid and the new application of derivant thereof |
| CN107889501A (en) * | 2015-03-30 | 2018-04-06 | 特拉维蒂斯创新有限责任公司 | A kind of method for preparing plant biomass water-soluble extractive |
| CN115397449A (en) * | 2020-04-08 | 2022-11-25 | 血管实验室公司 | Fractional extract of Melissa leaf and novel pharmaceutical composition comprising the same |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10898423B2 (en) | 2019-02-20 | 2021-01-26 | Rodan & Fields, Llc | Synergistic antioxidant compositions |
| KR102121969B1 (en) * | 2019-05-22 | 2020-06-11 | 주식회사 안지오랩 | Pharmaceutical Composition Comprising Fraction of Melissa Leaf Extract |
| KR102229760B1 (en) * | 2020-04-08 | 2021-03-22 | 주식회사 안지오랩 | Fraction of Melissa Leaf Extract and Novel Pharmaceutical Composition Comprising the Same |
| KR20230039352A (en) | 2021-09-14 | 2023-03-21 | 경상국립대학교산학협력단 | Composition for preventing or treating cardiovascular disease comprising rosmarinic acid as an active ingredient |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100500298B1 (en) * | 2000-12-12 | 2005-07-11 | 주식회사 안지오랩 | Composition containing melissa extract for the use of angiogenesis inhibitor |
| KR100903030B1 (en) * | 2007-08-23 | 2009-06-18 | 주식회사 안지오랩 | A fraction of Melissa leaf extract and a composition comprising the same |
| KR101217710B1 (en) * | 2010-04-29 | 2013-01-02 | 한림대학교 산학협력단 | Composition comprising the extract of Melissa officinalis for the improvement of age-related decrease in neurogenesis |
-
2012
- 2012-07-18 KR KR1020120078349A patent/KR20140011209A/en not_active Application Discontinuation
-
2013
- 2013-07-17 WO PCT/KR2013/006393 patent/WO2014014271A1/en active Application Filing
- 2013-07-17 CN CN201380037668.7A patent/CN104470507A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107889501A (en) * | 2015-03-30 | 2018-04-06 | 特拉维蒂斯创新有限责任公司 | A kind of method for preparing plant biomass water-soluble extractive |
| CN105012261A (en) * | 2015-08-21 | 2015-11-04 | 德州德药制药有限公司 | Caffeic acid tablets and preparation method thereof |
| CN105012261B (en) * | 2015-08-21 | 2018-03-06 | 德州德药制药有限公司 | A kind of caffeic acid piece and preparation method thereof |
| CN106176701A (en) * | 2016-08-11 | 2016-12-07 | 成都中医药大学 | Caffeic acid and the new application of derivant thereof |
| CN115397449A (en) * | 2020-04-08 | 2022-11-25 | 血管实验室公司 | Fractional extract of Melissa leaf and novel pharmaceutical composition comprising the same |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2014014271A1 (en) | 2014-01-23 |
| KR20140011209A (en) | 2014-01-28 |
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