CN101229225A - Salvia miltiorrhiza total phenolic acid gastric stasis preparation - Google Patents
Salvia miltiorrhiza total phenolic acid gastric stasis preparation Download PDFInfo
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Abstract
The invention belongs to the medicine technical field, in particular to a gastric retention preparation containing total salvianolic acid. The invention adopts the effective position of the Chinese medicine of total salvianolic acid as the main component, and the stomach retention preparation is made with acceptable auxiliary materials in pharmacy. The preparation of the invention is gastric floating preparation or stomach mucoadhesive preparation; the invention can significantly prolong the retention time of the total salvianolic acid on the stomach and the upper part of small intestine, enhance stability of medicine, and prolong effective absorption time and improve the utilizing degree of salvianolic acid biology through the double effect of enhancing the medicine stability and prolonging the effective absorption time. The invention can not only improve gastrointestinal absorption, but also have better efficacy in treating gastric ulcer and some other diseases; the invention also has simple production technique and is easy for industrialization; the invention is easy for the patients to take with good compliance.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of Gastroretentive formulations that contains Radix Salviae Miltiorrhizae total phenolic acids.
Background technology
Radix Salviae Miltiorrhizae is the dry root and rhizome of Labiatae salvia Radix Salviae Miltiorrhizae (Salvia miltiorrhiza Bunge), is one of medical material the most frequently used in China's traditional medicine.Modern chemistry and pharmacological research show; mainly contain fat-soluble tanshinone and water miscible salvianolic acid composition in the Radix Salviae Miltiorrhizae; wherein salvianolic acid is the main effective site of Radix Salviae Miltiorrhizae; has the significant protection cardiovascular system brain injury of unifying; anti-hepatic fibrosis; the treatment gastric ulcer; effects such as cell death inducing and control neurodegenerative diseases; its effective ingredient comprises salviol acid A (salvianolic acid A); B (salvianolic acid B); C; D; E; F; G; danshensu (danshensu); protocatechualdehyde (protocatechuicaldehyde); salviol (salviol); rosmarinic acid (rosmarinic acid); alkannic acid (lithospermic acid) etc.; wherein the content with salvianolic acid B is the highest; activity is the strongest; studies show that the activity of Radix Salviae Miltiorrhizae total phenolic acids is better than the effect of single salvianolic acid.
Clinical the most frequently used administering mode is an oral administration, this administering mode good patient compliance.But the absorption of the gastrointestinal of salvianolic acid composition is very poor in the clinical studies show Radix Salviae Miltiorrhizae oral formulations, and bioavailability is low, and salvianolic acid A has only 20.5% in the average absorption rate of small intestinal; Salvianolic acid B behind the oral Radix Salviae Miltiorrhizae water extract of rat is eliminated the half-life and is had only 19.16min; The elimination half-life of danshensu is 0.94h ± 0.21h behind volunteer oral's Radix Salviae Miltiorrhizae water decoction.There is the research experiment result to show, behind the oral salvianolic acid solution of Beagle dog, has only 1.21% in the absolute bioavailability of salvianolic acid B.Therefore, be necessary to adopt modern preparation technique, research salvianolic acid new oral drug-supplying system is with bioavailability and the curative effect after the raising oral preparation drug administration.Known in this field, if will make drug absorption enter body circulation, reach action target spot, just must overcome the water solublity, stability, permeable membrane etc. of medicine obstruction to the absorption process generation.Salvianolic acid belongs to the medicine of medicine biopharmaceutics categorizing system III class, and promptly dissolubility height, permeable membrane are poor.There are some researches show that the stability of salvianolic acid is subject to pH influence, in pH＞6 o'clock, easily degrade, thus salvianolic acid instability under small intestinal pH condition, and very low at small intestinal posterior segment absorbance, this is the low main cause of salvianolic acid oral administration bioavailability.But research also shows, but its kept stable in gastric juice, and absorb better relatively at stomach and small intestinal epimere.
The Entogastric lingering preparation was meant by the holdup time of prolong drug at gastric, improved the absorption of medicine and/or reduced untoward reaction, adjusted rate of releasing drug as required simultaneously, to obtain the oral administration system of more satisfactory controlled-release effect.The Entogastric lingering system has some advantages, is particularly suitable for following several situation: 1. mainly in the medicine of stomach and the absorption of small intestinal epimere; 2. almost insoluble or unsettled medicine in intestinal juice; 3. stomach medicine.Therefore, relevant extremely personnel's the concern of novel formulation that contains salvianolic acid of development.
Summary of the invention
The Gastroretentive formulations that contains Radix Salviae Miltiorrhizae total phenolic acids that the purpose of this invention is to provide a kind of high bioavailability.
Gastroretentive formulations energy significant prolongation Radix Salviae Miltiorrhizae total phenolic acids of the present invention is in the time of staying of stomach and upper part of small intestine, thereby increase medicine stability and prolong effective soak time, the gastrointestinal that not only increases Radix Salviae Miltiorrhizae total phenolic acids absorbs, improve oral administration biaavailability, and can bring into play better therapeutic aspect the diseases such as treatment gastric ulcer.
It is principal agent that the present invention adopts the effective ingredient in Chinese Radix Salviae Miltiorrhizae total phenolic acids, makes Gastroretentive formulations with acceptable accessories.Wherein, the mass ratio of Radix Salviae Miltiorrhizae total phenolic acids and adjuvant is 1: 1～4.
Radix Salviae Miltiorrhizae total phenolic acids of the present invention is meant that the dry root and rhizome with salviamiltiorrhizabung (Salvia miltiorrhiza Bunge) is a raw material, through extracting the water solubility extract (commercially available) that purification obtains, wherein adopt determined by ultraviolet spectrophotometry, be 50%～100% in the content of the Radix Salviae Miltiorrhizae total phenolic acids of salvianolic acid B, the content of salvianolic acid B that adopts high effective liquid chromatography for measuring is for being not less than 40%.
Gastroretentive formulations of the present invention is made stomach float type preparation or stomach adhesive type preparation, and its dosage form is that intra-gastric floating tablet, intra-gastric floating microsphere, gastric mucoadhesive tablet, stomach adhesive pellet or stomach adhere to microsphere.Wherein intra-gastric floating microsphere, stomach adhesive pellet or stomach adhere to microsphere and can further make capsule, tablet or oral liquid administration.
The adjuvant of Radix Salviae Miltiorrhizae total phenolic acids stomach float type preparation of the present invention comprises tablet framework material, microballoon skeleton material, bleach activator, foaming agent, drug release rate regulator etc.Framework material accounts for 20%～70% of total formulation weight in the wherein said stomach floating preparation.
Framework material is selected from density less than 1 hydroxypropyl emthylcellulose (HPMC), methylcellulose (MC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), hydroxyethyl-cellulose (HEC), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA) or carbomer in the described Radix Salviae Miltiorrhizae total phenolic acids gastric floating tablet, or in the above-mentioned material two or more mixes and use.Preferred viscosities is the hydroxypropyl emthylcellulose of 4000～100000cpas; Two or more mixing that the framework material of described stomach float type microsphere is selected from chitosan, hydroxypropyl emthylcellulose (HPMC), methylcellulose (MC), hydroxypropyl cellulose (HPC), sodium carboxymethyl cellulose (CMC-Na), sodium alginate, acrylic resin, Merlon or ethyl cellulose (EC) or the above-mentioned material is used.
Bleach activator is selected from hydrophobicity and little aliphatic alcohols, esters or the fatty acid of relative density in the described floating preparation, as glyceryl monostearate, octadecanol, hexadecanol, spermol, stearic acid or Cera Flava etc.
Foaming agent in the described stomach floating preparation is selected from sodium bicarbonate or calcium carbonate or magnesium carbonate, or unites use with acidic materials such as citric acid, tartaric acid with certain proportion, preferred sodium bicarbonate.
Drug release rate regulator in the described stomach floating preparation is selected from lactose, mannitol, microcrystalline Cellulose, polyvinylpyrrolidone or acrylic resin, preferred lactose.
The adjuvant of Radix Salviae Miltiorrhizae total phenolic acids stomach adhesive type preparation of the present invention comprises tablet, micropill or microsphere supported material and bioadhesive material.
Tablet carrier material in the described stomach adhesive type preparation is selected from lactose, starch, amylum pregelatinisatum, microcrystalline Cellulose or pregelatinized Starch.
Micropill carrier material in the described stomach adhesive type preparation is selected from microcrystalline Cellulose, lactose, starch, sucrose or ethyl cellulose except that celphere.
Microsphere supported material in the described stomach adhesive type preparation is selected from ethyl cellulose (EC), polylactic acid (PLA), polylactic acid-glycolic guanidine-acetic acid copolymer (PLGA), polyglycolic acid (PGA) or methyl acrylate copolymer (MA).
Bioadhesive material accounts for 2%～30% of total formulation weight in the described stomach adhesive type preparation; One or both or the two or more material mixing that are selected from carbomer, polyacrylic polymer and derivant thereof, Polycarbophil, chitin and chitosan, alginic acid and sodium salt thereof, hyaluronic acid and sodium salt thereof, hydroxypropyl cellulose, carboxylic third methylcellulose and sodium salt, carboxymethyl cellulose and sodium salt thereof and polyisobutylene blend, polyvinyl alcohol and copolymer thereof, polyvidone and copolymer thereof, phytohemagglutinin or the melon glue are used.
Flotation property to the Radix Salviae Miltiorrhizae total phenolic acids stomach floating preparation of the present invention preparation adopts following in vitro method to investigate,
Get 0.1mol/L HCl solution 1000ml, under 37.0 ± 0.5 ℃ of conditions of steady temperature, get floating tablets and place the commentaries on classics basket, the 75r/min constant speed is rotated, and the rotation basket has been put into and observed rising the time of floating and lasting flotation time of Radix Salviae Miltiorrhizae total phenolic acids intra-gastric floating tablet.
Take by weighing the 100mg microsphere, be scattered in the hydrochloric acid solution surface of 250mL 0.1mol/L, after room temperature is placed 4h, collect the microsphere that swims on the liquid level, drying is weighed, and calculates its floatability of Radix Salviae Miltiorrhizae total phenolic acids intra-gastric floating microsphere.
The result shows that Radix Salviae Miltiorrhizae total phenolic acids intra-gastric floating tablet of the present invention has good flotation property in simulated gastric fluid, can satisfy the preparation design object of Entogastric lingering; The Radix Salviae Miltiorrhizae total phenolic acids intra-gastric floating microsphere has good flotation property in simulated gastric fluid, can realize the preparation design object of Entogastric lingering.
Table 1 is the present invention's three factors three horizontal quadrature experimental design tables.
Table 2 is Radix Salviae Miltiorrhizae total phenolic acids intra-gastric floating tablet flotation property result of the tests.
Table 3 be the Radix Salviae Miltiorrhizae total phenolic acids intra-gastric floating microsphere its floatability (
N=3).
Table 1
| Level | HPMC(％) | Octadecanol (%) | Sodium bicarbonate (%) |
| 1 2 3 | 20 40 60 | 10 20 30 | 2 5 8 |
Table 2
| Sequence number | Supplementary product consumption (%) | Flotation property | ||||
| HPMC | Octadecanol | Sodium bicarbonate | Lactose | Rise and float the time | Hold the time of floating | |
| 1 2 3 4 5 6 7 8 9 | 20(1) 20(1) 20(1) 40(2) 40(2) 40(2) 60(3) 60(3) 60(3) | 10(1) 20(2) 30(3) 10(1) 20(2) 30(3) 10(1) 20(2) 30(3) | 2(1) 5(2) 8(3) 5(2) 8(3) 2(1) 8(3) 2(1) 5(2) | 68 55 42 45 32 28 22 18 5 | 1.5min the floating immediately 1.0min of 0.5min is floating immediately floating immediately floating immediately floating immediately floating immediately | 3.5h 4h 6h ＞8h ＞8h ＞8h ＞8h ＞8h ＞8h |
Table 3
| Ethyl cellulose: principal agent (rate of charge) | Its floatability (%) |
| 10∶1 5∶1 2∶1 1∶1 1∶2 | 94.5±3.5 91.8±6.1 73.5±3.7 60.7±9.8 48.3±6.6 |
The present invention adopts following in vitro method that the adhesiveness of the Radix Salviae Miltiorrhizae total phenolic acids gastric mucoadhesive tablet of preparation is investigated, and adopt in the body method Radix Salviae Miltiorrhizae total phenolic acids stomach adhesive pellet of preparation and the adhesiveness of microsphere are investigated,
Exsomatize gastric tissue for sticking object with rabbit,, measure the adhesion of the adhesion tablet that adheres to the composition different content respectively with self-control adhesive force determinator.
About SD rat 200g, female, fasting is supplied water and is raised 24h, and micropill or 100 water 1ml of microsphere are poured in the rat stomach, puts to death behind the 3h and gets its stomach, and the place cuts off along lesser gastric curvature, micropill or the microsphere number of naked eyes counting on gastric mucosa of rat.
But experimental result shows adhesiveness of the present invention prescription significant prolongation tablet, micropill, the microsphere holdup time at gastric, and along with the increase of adhesiveness composition carbomer in the prescription, the adhesion of tablet and gastric mucosa and micropill or the microsphere retention rate in rat stomach obviously increases.
Table 4 is to adhere to the adhesion tablet of composition different content and the adhesion of rabbit gastric tissue.
Table 5 be adhere to the micropill of composition different content or microsphere the retention rate of gastric mucosa of rat (
N=5).
Table 4
Table 5
| Carbomer content (%) | Be detained percentage rate (%) | |
| Micropill (particle diameter 0.5～2mm) | Microsphere (particle diameter 500～1000 μ m) | |
| 0 5 10 15 20 | 6.2±5.3 10.4±6.1 28.8±18.3 49.7±25.2 68.5±22.9 | 8.1±5.9 18.3±11.2 36.5±14.6 55.7±20.4 69.8±12.3 |
Through experiment confirm, the above-mentioned salvia miltiorrhiza total phenolic acid gastric stasis preparation of the present invention can the significant prolongation Radix Salviae Miltiorrhizae total phenolic acids in the time of staying of stomach and upper part of small intestine, thereby increase medicine stability and prolong effective soak time.
The present invention makes the Entogastric lingering preparation with salvianolic acid, can prolong drug in the time of staying of stomach and upper part of small intestine, by increasing medicine stability and prolonging the dual function of effective soak time, improve the salvianolic acid bioavailability.The gastrointestinal that the present invention not only improves salvianolic acid absorbs, and can bring into play better therapeutic aspect the diseases such as treatment gastric ulcer, and production technology is simple simultaneously, easily industrialization.Patient's taking convenience, compliance is good.
The specific embodiment
Further specify technical scheme of the present invention by the following example, but protection scope of the present invention is not limited to this.
Embodiment 1 Radix Salviae Miltiorrhizae total phenolic acids floating in stomach sheet 1
Radix Salviae Miltiorrhizae total phenolic acids 25%
Hydroxypropyl emthylcellulose 40%
Octadecanol 20%
Lactose 9%
Sodium bicarbonate 5%
Magnesium stearate 1%
With principal agent and adjuvant porphyrize, it is standby to cross 80 mesh sieves.Take by weighing the principal agent and the adjuvant of recipe quantity, after sieve, the direct powder compression tabletting gets the bright and clean intra-gastric floating tablet of outward appearance behind the mix homogeneously, and hardness is 3～5kg.In vitro method is observed flotation property, and tablet is floating immediately, continues flotation time＞8h.
Embodiment 2: Radix Salviae Miltiorrhizae total phenolic acids floating in stomach sheet 2
Radix Salviae Miltiorrhizae total phenolic acids 25%
Hydroxypropyl emthylcellulose 25%
Octadecanol 10%
Lactose 35%
Sodium bicarbonate 4%
Magnesium stearate 1%
With principal agent and adjuvant porphyrize, it is standby to cross 80 mesh sieves.Take by weighing the principal agent and the adjuvant of recipe quantity, after sieve, the direct powder compression tabletting gets the bright and clean intra-gastric floating tablet of outward appearance behind the mix homogeneously, and hardness is 3～5kg.In vitro method is observed flotation property, and 1.2min rises and floats, and continues flotation time 5h.
Embodiment 3: Radix Salviae Miltiorrhizae total phenolic acids floating in stomach sheet 3
Radix Salviae Miltiorrhizae total phenolic acids 25%
Hydroxypropyl emthylcellulose 60%
Octadecanol 10%
Sodium bicarbonate 4%
Magnesium stearate 1%
With principal agent and adjuvant porphyrize, it is standby to cross 80 mesh sieves.Take by weighing the principal agent and the adjuvant of recipe quantity, after sieve, the direct powder compression tabletting gets the bright and clean intra-gastric floating tablet of outward appearance behind the mix homogeneously, and hardness is 3～5kg.In vitro method is observed flotation property, and 0.2min rises and floats, and continues flotation time＞8h.
Embodiment 4: Radix Salviae Miltiorrhizae total phenolic acids floating in stomach microsphere 1
Radix Salviae Miltiorrhizae total phenolic acids 500mg
Ethyl cellulose 500mg
Polyvinyl alcohol 500mg
Take by weighing ethyl cellulose and be dissolved in right amount in the mixed solvent of 20mL dichloromethane-ethanol (volume ratio 1: 1), Radix Salviae Miltiorrhizae total phenolic acids is dissolved in wherein makes organic facies.Other gets a certain amount of polyvinyl alcohol (PVA) and is dissolved in the water of 100mL, and organic facies is added water, stirs 1h under certain speed.The microsphere sucking filtration that makes, washing, 40 ℃ are drying to obtain.Drug loading is 18.4%, and envelop rate is 45.2%, and its floatability in the simulated gastric fluid behind the 4h is 69.7 ± 9.8%.
Embodiment 5: Radix Salviae Miltiorrhizae total phenolic acids floating in stomach microsphere 2
Radix Salviae Miltiorrhizae total phenolic acids 250mg
Ethyl cellulose 500mg
Polyvinyl alcohol 500mg
Take by weighing ethyl cellulose and be dissolved in right amount in the mixed solvent of 20mL dichloromethane-ethanol (volume ratio 1: 1), Radix Salviae Miltiorrhizae total phenolic acids is dissolved in wherein makes organic facies.Other gets a certain amount of polyvinyl alcohol (PVA) and is dissolved in the water of 100mL, and organic facies is added water, stirs 1h under certain speed.The microsphere sucking filtration that makes, washing, 40 ℃ are drying to obtain.Drug loading is 13.1%, and envelop rate is 60.4%, and its floatability in the simulated gastric fluid behind the 4h is 67.2 ± 5.7%.
Embodiment 6: Radix Salviae Miltiorrhizae total phenolic acids floating in stomach microsphere 3
Radix Salviae Miltiorrhizae total phenolic acids 1000mg
Ethyl cellulose 500mg
Polyvinyl alcohol 500mg
Take by weighing ethyl cellulose and be dissolved in right amount in the mixed solvent of 20mL dichloromethane-ethanol (volume ratio 1: 1), Radix Salviae Miltiorrhizae total phenolic acids is dissolved in wherein makes organic facies.Other gets a certain amount of polyvinyl alcohol (PVA) and is dissolved in the water of 100mL, and organic facies is added water, stirs 1h under certain speed.The microsphere sucking filtration that makes, washing, 40 ℃ are drying to obtain.Drug loading is 19.0%, and envelop rate is 23.5%, and its floatability in the simulated gastric fluid behind the 4h is 64.2 ± 8.7%.
Embodiment 7: Radix Salviae Miltiorrhizae total phenolic acids gastric mucoadhesive tablet 1
Radix Salviae Miltiorrhizae total phenolic acids 25%
HPMC 30％
Carbomer 15%
Lactose 29%
80% ethanol is an amount of
Magnesium stearate 1%
With principal agent and adjuvant porphyrize, it is standby to cross 80 mesh sieves.Take by weighing the principal agent and the adjuvant of recipe quantity, the equivalent mix homogeneously that progressively increases, add an amount of 80% alcoholic solution and make soft material, cross 20 mesh sieves and make wet granular, put dry 1h in 60 ℃ of baking ovens, dried granule is crossed 24 mesh sieve granulate, add magnesium stearate lubricant then, mixing, tabletting promptly get the bright and clean tablet of outward appearance, and hardness is 3～5kg.The adhesion that records with the rabbit gastric tissue is 16.3 ± 1.4g/cm
2
Embodiment 8: Radix Salviae Miltiorrhizae total phenolic acids gastric mucoadhesive tablet 2
Radix Salviae Miltiorrhizae total phenolic acids 25%
HPMC 25％
Carbomer 25%
Lactose 24%
80% ethanol is an amount of
Magnesium stearate 1%
With principal agent and adjuvant porphyrize, it is standby to cross 80 mesh sieves.Take by weighing the principal agent and the adjuvant of recipe quantity, the equivalent mix homogeneously that progressively increases, add an amount of 80% alcoholic solution and make soft material, cross 20 mesh sieves and make wet granular, put dry 1h in 60 ℃ of baking ovens, dried granule is crossed 24 mesh sieve granulate, add magnesium stearate lubricant then, mixing, tabletting promptly get the bright and clean tablet of outward appearance, and hardness is 3～5kg.The adhesion that records with the rabbit gastric tissue is 19.8 ± 2.6g/cm
2
Embodiment 9: Radix Salviae Miltiorrhizae total phenolic acids gastric mucoadhesive tablet 3
Radix Salviae Miltiorrhizae total phenolic acids 25%
HPMC 15％
Carbomer 30%
Lactose 29%
80% ethanol is an amount of
Magnesium stearate 1%
With principal agent and adjuvant porphyrize, it is standby to cross 80 mesh sieves.Take by weighing the principal agent and the adjuvant of recipe quantity, the equivalent mix homogeneously that progressively increases, add an amount of 80% alcoholic solution and make soft material, cross 20 mesh sieves and make wet granular, put dry 1h in 60 ℃ of baking ovens, dried granule is crossed 24 mesh sieve granulate, add magnesium stearate lubricant then, mixing, tabletting promptly get the bright and clean tablet of outward appearance, and hardness is 3～5kg.The adhesion that records with the rabbit gastric tissue is 21.9 ± 1.9g/cm
2
Embodiment 10: Radix Salviae Miltiorrhizae total phenolic acids gastric mucoadhesive tablet 4
Radix Salviae Miltiorrhizae total phenolic acids 25%
Carbomer 45%
Lactose 29%
80% ethanol is an amount of
Magnesium stearate 1%
With principal agent and adjuvant porphyrize, it is standby to cross 80 mesh sieves.Take by weighing the principal agent and the adjuvant of recipe quantity, the equivalent mix homogeneously that progressively increases, add an amount of 80% alcoholic solution and make soft material, cross 20 mesh sieves and make wet granular, put dry 1h in 60 ℃ of baking ovens, dried granule is crossed 24 mesh sieve granulate, add magnesium stearate lubricant then, mixing, tabletting promptly get the bright and clean tablet of outward appearance, and hardness is 3～5kg.The adhesion that records with the rabbit gastric tissue is 24.1 ± 3.8g/cm
2
Embodiment 11: Radix Salviae Miltiorrhizae total phenolic acids gastric mucoadhesive tablet 5
Radix Salviae Miltiorrhizae total phenolic acids 25%
HPMC 45％
Lactose 29%
80% ethanol is an amount of
Magnesium stearate 1%
With principal agent and adjuvant porphyrize, it is standby to cross 80 mesh sieves.Take by weighing the principal agent and the adjuvant of recipe quantity, the equivalent mix homogeneously that progressively increases, add an amount of 80% alcoholic solution and make soft material, cross 20 mesh sieves and make wet granular, put dry 1h in 50 ℃ of baking ovens, dried granule is crossed 24 mesh sieve granulate, add magnesium stearate lubricant then, mixing, tabletting promptly get the bright and clean tablet of outward appearance, and hardness is 3～5kg.The adhesion that records with the rabbit gastric tissue is 9.7 ± 0.7g/cm
2
Embodiment 12: Radix Salviae Miltiorrhizae total phenolic acids stomach adhesive pellet 1
Radix Salviae Miltiorrhizae total phenolic acids 20%
HPMC 30％
Carbomer 20%
Microcrystalline Cellulose 30%
80% ethanol is an amount of
With principal agent and adjuvant porphyrize, it is standby to cross 80 mesh sieves.Take by weighing the principal agent and the adjuvant of recipe quantity, the equivalent mix homogeneously that progressively increases adds an amount of 80% alcoholic solution and makes soft material, (aperture 1.2mm) is extruded into fine strip shape through the extruder sieve plate, places spheronizator, regulates rotating speed and round as a ball time, make granule round as a ball fully, take out micropill in 50 ℃ of dry 4h.The retention rate that records at gastric mucosa of rat in the body method is 68.5 ± 22.9%.
Embodiment 13: Radix Salviae Miltiorrhizae total phenolic acids stomach adhesive pellet 2
Radix Salviae Miltiorrhizae total phenolic acids 20%
HPMC 30％
Carbomer 15%
Microcrystalline Cellulose 35%
80% ethanol is an amount of
With principal agent and adjuvant porphyrize, it is standby to cross 80 mesh sieves.Take by weighing the principal agent and the adjuvant of recipe quantity, the equivalent mix homogeneously that progressively increases adds an amount of 80% alcoholic solution and makes soft material, (aperture 1.2mm) is extruded into fine strip shape through the extruder sieve plate, places spheronizator, regulates rotating speed and round as a ball time, make granule round as a ball fully, take out micropill in 50 ℃ of dry 4h.The retention rate that records at gastric mucosa of rat in the body method is 49.7 ± 25.2%.
Embodiment 14: Radix Salviae Miltiorrhizae total phenolic acids stomach adhesive pellet 3
Radix Salviae Miltiorrhizae total phenolic acids 20%
HPMC 30％
Carbomer 10%
Microcrystalline Cellulose 40%
80% ethanol is an amount of
With principal agent and adjuvant porphyrize, it is standby to cross 80 mesh sieves.Take by weighing the principal agent and the adjuvant of recipe quantity, the equivalent mix homogeneously that progressively increases adds an amount of 80% alcoholic solution and makes soft material, (aperture 1.2mm) is extruded into fine strip shape through the extruder sieve plate, places spheronizator, regulates rotating speed and round as a ball time, make granule round as a ball fully, take out micropill in 50 ℃ of dry 4h.The retention rate that records at gastric mucosa of rat in the body method is 28.8 ± 18.3%.
Embodiment 15: Radix Salviae Miltiorrhizae total phenolic acids stomach adhesive pellet 4
Radix Salviae Miltiorrhizae total phenolic acids 20%
HPMC 30％
Carbomer 5%
Microcrystalline Cellulose 45%
80% ethanol is an amount of
With principal agent and adjuvant porphyrize, it is standby to cross 80 mesh sieves.Take by weighing the principal agent and the adjuvant of recipe quantity, the equivalent mix homogeneously that progressively increases adds an amount of 80% alcoholic solution and makes soft material, (aperture 1.2mm) is extruded into fine strip shape through the extruder sieve plate, places spheronizator, regulates rotating speed and round as a ball time, make granule round as a ball fully, take out micropill in 50 ℃ of dry 4h.The retention rate that records at gastric mucosa of rat in the body method is 10.4 ± 6.1%.
Embodiment 16: the Radix Salviae Miltiorrhizae total phenolic acids stomach adheres to microsphere 1
Radix Salviae Miltiorrhizae total phenolic acids 800mg
Ethyl cellulose 2400mg
Carbomer 600mg
The ethyl cellulose and the carbomer that take by weighing recipe quantity are dissolved in the 50ml dehydrated alcohol, add Radix Salviae Miltiorrhizae total phenolic acids, and stirring and dissolving joins in the 400ml lightweight paraffin oil that contains Span-80 10g, and under the room temperature condition, 600r/min stirs evaporation 16h.The sand core funnel sucking filtration is collected microsphere, petroleum ether (50ml * 3), and room temperature vacuum drying 24h is promptly.The retention rate that records at gastric mucosa of rat in the body method is 64.2 ± 8.7%.
Embodiment 17: the Radix Salviae Miltiorrhizae total phenolic acids stomach adheres to microsphere 2
Radix Salviae Miltiorrhizae total phenolic acids 800mg
Ethyl cellulose 2550mg
Carbomer 450mg
The ethyl cellulose and the carbomer that take by weighing recipe quantity are dissolved in the 50ml dehydrated alcohol, add Radix Salviae Miltiorrhizae total phenolic acids, and stirring and dissolving joins in the 400ml lightweight paraffin oil that contains Span-80 10g, and under the room temperature condition, 600r/min stirs evaporation 16h.The sand core funnel sucking filtration is collected microsphere, petroleum ether (50ml * 3), and room temperature vacuum drying 24h is promptly.The retention rate that records at gastric mucosa of rat in the body method is 55.7 ± 20.4%.
Embodiment 18: the Radix Salviae Miltiorrhizae total phenolic acids stomach adheres to microsphere 3
Radix Salviae Miltiorrhizae total phenolic acids 800mg
Ethyl cellulose 2700mg
Carbomer 300mg
The ethyl cellulose and the carbomer that take by weighing recipe quantity are dissolved in the 50ml dehydrated alcohol, add Radix Salviae Miltiorrhizae total phenolic acids, and stirring and dissolving joins in the 400ml lightweight paraffin oil that contains Span-80 10g, and under the room temperature condition, 600r/min stirs evaporation 16h.The sand core funnel sucking filtration is collected microsphere, petroleum ether (50ml * 3), and room temperature vacuum drying 24h is promptly.The retention rate that records at gastric mucosa of rat in the body method is 36.5 ± 14.6%.
Embodiment 19: the Radix Salviae Miltiorrhizae total phenolic acids stomach adheres to microsphere 4
Radix Salviae Miltiorrhizae total phenolic acids 800mg
Ethyl cellulose 2850mg
Carbomer 150mg
The ethyl cellulose and the carbomer that take by weighing recipe quantity are dissolved in the 50ml dehydrated alcohol, add Radix Salviae Miltiorrhizae total phenolic acids, and stirring and dissolving joins in the 400ml lightweight paraffin oil that contains Span-80 10g, and under the room temperature condition, 600r/min stirs evaporation 16h.The sand core funnel sucking filtration is collected microsphere, petroleum ether (50ml * 3), and room temperature vacuum drying 24h is promptly.The retention rate that records at gastric mucosa of rat in the body method is 18.3 ± 11.2%.
Claims (14)
1. salvia miltiorrhiza total phenolic acid gastric stasis preparation is characterized in that by Radix Salviae Miltiorrhizae total phenolic acids be principal agent, makes Gastroretentive formulations with acceptable accessories, and wherein, the mass ratio of Radix Salviae Miltiorrhizae total phenolic acids and adjuvant is 1: 1～4.
2. by the described salvia miltiorrhiza total phenolic acid gastric stasis preparation of claim 1, it is characterized in that described Radix Salviae Miltiorrhizae total phenolic acids is is raw material with the salviamiltiorrhizabung, through extracting the water solubility extract that purification obtains, with determined by ultraviolet spectrophotometry, wherein the content in the Radix Salviae Miltiorrhizae total phenolic acids of salvianolic acid B is 50%～100%; Measure the content of salvianolic acid B for being not less than 40% with high performance liquid chromatogram.
3. by the described salvia miltiorrhiza total phenolic acid gastric stasis preparation of claim 1, it is characterized in that described Gastroretentive formulations is stomach float type preparation or stomach adhesive type preparation, wherein said stomach float type preparation is intra-gastric floating tablet or intra-gastric floating microsphere; Described stomach adhesive type preparation is that gastric mucoadhesive tablet, stomach adhesive pellet or stomach adhere to microsphere.
4. by the described salvia miltiorrhiza total phenolic acid gastric stasis preparation of claim 3, it is characterized in that the adjuvant of described stomach float type preparation comprises tablet framework material, microballoon skeleton material, bleach activator, foaming agent or drug release rate regulator; Wherein said framework material accounts for 20%～70% of total formulation weight.
5. by the described salvia miltiorrhiza total phenolic acid gastric stasis preparation of claim 4, it is characterized in that described tablet framework material is selected from and refer to that density is less than 1 hydroxypropyl emthylcellulose, methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxyethyl-cellulose, polyvinylpyrrolidone, polyvinyl alcohol or carbomer or two or more mixing wherein.
6. by the described salvia miltiorrhiza total phenolic acid gastric stasis preparation of claim 4, it is characterized in that described microballoon skeleton material is selected from chitosan, hydroxypropyl emthylcellulose, methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, sodium alginate, acrylic resin, Merlon or ethyl cellulose or two or more mixing wherein.
7. by the described salvia miltiorrhiza total phenolic acid gastric stasis preparation of claim 4, it is characterized in that described bleach activator is a hydrophobicity and little aliphatic alcohols, esters or the fatty acid of relative density is selected from glyceryl monostearate, octadecanol, hexadecanol, spermol, stearic acid or Cera Flava.
8. by the described salvia miltiorrhiza total phenolic acid gastric stasis preparation of claim 4, it is characterized in that described foaming agent is selected from sodium bicarbonate, calcium carbonate or magnesium carbonate or unites use with citric acid or tartaric acid.
9. by the described salvia miltiorrhiza total phenolic acid gastric stasis preparation of claim 4, it is characterized in that described drug release rate regulator is selected from lactose, mannitol, microcrystalline Cellulose, polyvinylpyrrolidone or acrylic resin.
10. by the described salvia miltiorrhiza total phenolic acid gastric stasis preparation of claim 3, it is characterized in that the adjuvant of described stomach adhesive type preparation comprises tablet, micropill or microsphere supported material or bioadhesive material, described bioadhesive material accounts for 2%～30% of total formulation weight.
11., it is characterized in that described tablet carrier material is selected from lactose, starch, amylum pregelatinisatum, microcrystalline Cellulose or pregelatinized Starch by the described salvia miltiorrhiza total phenolic acid gastric stasis preparation of claim 10.
12., it is characterized in that described micropill carrier material except that celphere, is selected from microcrystalline Cellulose, lactose, starch, sucrose or ethyl cellulose by the described salvia miltiorrhiza total phenolic acid gastric stasis preparation of claim 10.
13., it is characterized in that described microsphere supported material is selected from ethyl cellulose, polylactic acid, polylactic acid-glycolic guanidine-acetic acid copolymer, polyglycolic acid or methyl acrylate copolymer by the described salvia miltiorrhiza total phenolic acid gastric stasis preparation of claim 10.
14. by the described salvia miltiorrhiza total phenolic acid gastric stasis preparation of claim 10, it is characterized in that described bioadhesive material is selected from wherein two or more of carbomer, polyacrylic polymer and derivant thereof, Polycarbophil, chitin and chitosan, alginic acid and sodium salt thereof, hyaluronic acid and sodium salt thereof, hydroxypropyl cellulose, carboxylic third methylcellulose and sodium salt, carboxymethyl cellulose and sodium salt thereof and polyisobutylene blend, polyvinyl alcohol and copolymer thereof, polyvidone and copolymer thereof, phytohemagglutinin or melon glue and mixes.
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2007101709481A CN101229225A (en) | 2007-11-23 | 2007-11-23 | Salvia miltiorrhiza total phenolic acid gastric stasis preparation |
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2007101709481A CN101229225A (en) | 2007-11-23 | 2007-11-23 | Salvia miltiorrhiza total phenolic acid gastric stasis preparation |
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| CN101229225A true CN101229225A (en) | 2008-07-30 |
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| CNA2007101709481A Pending CN101229225A (en) | 2007-11-23 | 2007-11-23 | Salvia miltiorrhiza total phenolic acid gastric stasis preparation |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101919817A (en) * | 2010-07-23 | 2010-12-22 | 山东齐都药业有限公司 | Lafutidine gastric-retention controlled-release composite |
| CN101940554A (en) * | 2010-09-03 | 2011-01-12 | 四川大学 | Multi-core adhesive microspheres for loading water soluble low molecular medicament and preparation method thereof |
| CN103479674A (en) * | 2013-09-18 | 2014-01-01 | 连云港中医药高等职业技术学校 | Intra-gastric floating type cuttlebone sustained release tablet for treating gastric ulcer and preparation method thereof |
| CN105287421A (en) * | 2015-12-01 | 2016-02-03 | 上海中医药大学 | Paeonol gastric floating tablet and preparation method thereof |
| CN107320440A (en) * | 2017-06-12 | 2017-11-07 | 深圳市老年医学研究所 | Composition of gastric retention containing sulforaphen and preparation method thereof |
| CN107468752A (en) * | 2017-07-25 | 2017-12-15 | 北京中医药大学 | A kind of compound Danshen Root sticks micropill and its preparation technology |
| CN108210476A (en) * | 2016-12-19 | 2018-06-29 | 湖南尔康制药股份有限公司 | Chloramphenicol starch capsule of gastric retention floating and preparation method thereof |
| CN108542889A (en) * | 2018-04-18 | 2018-09-18 | 中国药科大学 | Dexketoprofen trometamol stomach retention sustained-release piece |
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2007
- 2007-11-23 CN CNA2007101709481A patent/CN101229225A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101919817A (en) * | 2010-07-23 | 2010-12-22 | 山东齐都药业有限公司 | Lafutidine gastric-retention controlled-release composite |
| CN101919817B (en) * | 2010-07-23 | 2012-05-30 | 山东齐都药业有限公司 | Lafutidine gastric-retention controlled-release composition |
| CN101940554A (en) * | 2010-09-03 | 2011-01-12 | 四川大学 | Multi-core adhesive microspheres for loading water soluble low molecular medicament and preparation method thereof |
| CN103479674A (en) * | 2013-09-18 | 2014-01-01 | 连云港中医药高等职业技术学校 | Intra-gastric floating type cuttlebone sustained release tablet for treating gastric ulcer and preparation method thereof |
| CN105287421A (en) * | 2015-12-01 | 2016-02-03 | 上海中医药大学 | Paeonol gastric floating tablet and preparation method thereof |
| CN108210476A (en) * | 2016-12-19 | 2018-06-29 | 湖南尔康制药股份有限公司 | Chloramphenicol starch capsule of gastric retention floating and preparation method thereof |
| CN107320440A (en) * | 2017-06-12 | 2017-11-07 | 深圳市老年医学研究所 | Composition of gastric retention containing sulforaphen and preparation method thereof |
| CN107468752A (en) * | 2017-07-25 | 2017-12-15 | 北京中医药大学 | A kind of compound Danshen Root sticks micropill and its preparation technology |
| CN108542889A (en) * | 2018-04-18 | 2018-09-18 | 中国药科大学 | Dexketoprofen trometamol stomach retention sustained-release piece |
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