CN107899005B - Composition containing fucoidan, tablet and application thereof - Google Patents
Composition containing fucoidan, tablet and application thereof Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/41—Porphyrin- or corrin-ring-containing peptides
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/02—Algae
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/02—Algae
- A61K36/03—Phaeophycota or phaeophyta (brown algae), e.g. Fucus
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/02—Algae
- A61K36/04—Rhodophycota or rhodophyta (red algae), e.g. Porphyra
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
Abstract
The invention relates to a composition containing fucoidan polysaccharide sulfate, a tablet and application thereof in treating mesangial proliferative glomerulonephritis. The composition is prepared from the following raw materials in parts by weight: 10-25 parts of phycocyanin, 5-25 parts of fucoidan, 30-60 parts of seaweed powder and 10-30 parts of excipient. The tablet prepared by the method is green to dark green, complete, smooth, uniform in color and luster, small in weight difference, free of splintering, moderate in disintegration time limit and stable in dosage form quality.
Description
Technical Field
The invention relates to a composition containing fucoidan polysaccharide sulfate, a tablet and application thereof, belonging to the technical field of medicine preparation.
Background
Some algae growing in fresh water, salt water lake and sea water, including blue algae, red algae, microalgae, etc., contain about 10% phycobiliprotein bodies, accounting for about 60% -70% of dry weight. Phycobiliprotein mainly comprises phycocyanin and allophycocyanin, and phycoerythrin and phycoerythrocyanin. The phycocyanin has the relative molecular mass of about 246KDa and consists of alpha-subunit (peptide bond) with the relative molecular mass of 18.5KDa and beta-subunit (beta-peptide bond) with the relative molecular mass of about 40KDa, the alpha-subunit in the phycocyanin is known to consist of 162 amino acids, the beta-subunit consists of 172 amino acids, and 1-4 phycocyanin chromophores are arranged on each alpha-subunit and beta-subunit, namely the phycocyanin is a combination of phycocyanin and water-soluble protein in a covalent bond form. Phycocyanin has effects of resisting oxidation, delaying aging, promoting growth and development, inhibiting liver tumor cells, protecting liver, increasing lymphocyte activity, improving immunity via lymphatic system, and enhancing disease resistance, phycocyanin in phycocyanin has structure similar to heme, can form soluble compound with iron, and can improve iron absorption, and stimulate hemopoiesis function of bone marrow.
Kelp is a large, long-banded, leathery marine brown algae plant, a substance rich in polysaccharides, and it is currently believed that the generalized laminarin includes 3 major polysaccharides, i.e., algin, fucoidan, and kelp starch. Algin is also called alginic acid or alginic acid, and is a general name for sodium salt, potassium salt, calcium salt, magnesium salt and other products of alginic acid extracted from brown algae such as kelp and gulfweed; alginic acid has significant pharmacological effects and can be used for the prevention and treatment of obesity, hypercholesterolemia and diabetes, because alginic acid inhibits the absorption of glucose and cholesterol by the small intestine. The fucoidan has good effect on treating cardiovascular and cerebrovascular diseases and early and medium chronic renal failure, has no toxic or side effect, has particularly obvious effects on improving renal function and increasing the clearance rate of the kidney to creatinine, and also has anticoagulant, antioxidant, antiviral, antitumor and immunoregulatory activities. The thallus Porphyrae has effects of enhancing immunity, reducing blood lipid, resisting aging, resisting oxidation, resisting blood coagulation, resisting tumor and protecting liver.
However, at present, there is no preparation of phycocyanin, fucoidan and seaweed powder, a preparation with stable quality, a preparation method thereof and application thereof in improving immunity, so that research on the preparation of phycocyanin, fucoidan and seaweed powder, the preparation with stable quality, the preparation method thereof and application thereof in improving immunity and the like have practical significance.
Disclosure of Invention
In order to overcome the technical defects, the invention particularly provides a composition containing phycocyanin, fucoidan and seaweed powder and application thereof in improving immunity.
The invention adopts the following technical scheme to realize the purpose:
a composition containing fucoidan is prepared from the following raw materials in parts by weight: 10-25 parts of phycocyanin, 5-25 parts of fucoidan, 30-60 parts of seaweed powder and 10-30 parts of excipient; preferably, 15-18 parts of phycocyanin, 16-20 parts of fucoidan, 44-49 parts of seaweed powder and 18-20 parts of excipient.
The molecular weight of the fucoidan sulfate is 15KDa-150KDa, preferably 30KDa-120KDa, further preferably 40KDa-110KDa, and more preferably 40KDa-60 KDa.
The fucoidin sulfate has a fucose content of 20% -35%, preferably 25% -32%, more preferably 30% -32%.
The sulfate radical content of the fucoidan sulfate is 25-35%, preferably 28-33%, and more preferably 30-33%.
The fucoidan sulfate is preferably prepared by the method described in application No. 201610572971.2. The high molecular weight coarse fucoidan is degraded into low molecular weight fucoidan by adopting an electro-Fenton method, wherein the low molecular weight fucoidan with the average molecular weight of 19.2KDa-36.1KDa, the fucose content of 29.9% -30.7% and the sulfate content of 30.4% -31.8% has better activity on lupus nephritis model mice. Alginic acid and fucosterol contained in mucilage of Undaria Pinnatifida have effects of reducing cholesterol in blood, facilitating discharge of excessive sodium ions in vivo, preventing cerebral thrombosis, improving and strengthening blood vessel, preventing arteriosclerosis and lowering hypertension.
The seaweed powder is one or more edible marine algae such as Asparagus (Asparagus schoberioides Kunth), carrageen (Chondrus ocellatus Holmes.), Enteromorpha (Enteromorpha prolifera), kelp (Thallius Laminarum), Undaria pinnatifida (Undaria pinnattifolia Suringar), laver (Porphyra umbellicis), Sargassum fusiforme (Harv.) Setch.
The excipient is selected from one or a combination of a plurality of diluents, disintegrants, glidants or lubricants; preferably, the excipient is prepared from the following raw materials in parts by weight: 6-12 parts of diluent, 5-18 parts of disintegrant and 0.1-1 part of glidant; 0.1-1 part of lubricant; further preferably 10 parts of diluent, 7-9 parts of disintegrant and 0.5 part of glidant; 0.5 part of lubricant.
Wherein the diluent is selected from one or more of microcrystalline cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and methyl cellulose;
the disintegrating agent is selected from one or more of starch, crospovidone, microcrystalline cellulose, sodium carboxymethyl starch and sodium alginate; wherein the starch is one or more of corn starch, potato starch or pregelatinized starch;
the glidant is selected from colloidal silicon dioxide and/or magnesium silicate;
the lubricant is selected from magnesium stearate and/or calcium stearate.
In some embodiments of the invention, the excipient consists of, by weight: 5-16 parts of sodium carboxymethyl starch, 6-10 parts of microcrystalline cellulose, 0.5-2 parts of sodium alginate, 0.5-1 part of magnesium stearate and 0.1-1 part of colloidal silicon dioxide.
In some embodiments of the invention, the excipient consists of, by weight: 5-16 parts of corn starch, 6-10 parts of microcrystalline cellulose, 0.5-2 parts of sodium alginate, 0.5-1 part of calcium stearate and 0.1-1 part of magnesium silicate.
The composition containing fucoidan can also contain 0.01-2 parts of flavoring agent; the flavoring agent is one or more of sorbitol, mannitol, and aspartame.
The composition can be further prepared into dosage forms commonly used in the field, preferably tablets, granules, capsules, pills and the like.
The invention also provides a tablet containing fucoidan polysaccharide sulfate, which is prepared from the following raw materials in parts by weight: 10-25 parts of phycocyanin, 5-25 parts of fucoidan, 30-60 parts of seaweed powder and 10-30 parts of excipient;
the molecular weight of the fucoidan sulfate is 15KDa-150KDa, preferably 30KDa-120KDa, and further preferably 40KDa-110 KDa;
the fucose content in the fucoidan is 20% -35%, preferably 25% -32%, more preferably 30% -32%;
the sulfate radical content of the fucoidan sulfate is 25-35%, preferably 28-33%, and more preferably 30-33%;
the excipient is prepared from the following raw materials in parts by weight: 6-12 parts of diluent, 5-18 parts of disintegrant and 0.1-1 part of glidant; 0.1-1 part of lubricant;
wherein the diluent is selected from one or more of microcrystalline cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and methyl cellulose;
the disintegrating agent is selected from one or more of starch, crospovidone, microcrystalline cellulose, sodium carboxymethyl starch and sodium alginate; wherein the starch is one or more of corn starch, potato starch or pregelatinized starch;
the glidant is selected from colloidal silicon dioxide and/or magnesium silicate;
the lubricant is selected from magnesium stearate and/or calcium stearate.
The tablet can also contain 0.01-2 parts of flavoring agent.
The invention also provides a preparation method of the tablet containing fucoidan, which comprises the following steps:
(1) uniformly mixing the dried fucoidin sulfate, phycocyanin and diluent to obtain a component A;
(2) uniformly mixing the disintegrating agent and the seaweed meal in a dry state to obtain a component B;
(3) a, B mixing the two groups of granules, adding water as binder, making soft mass, sieving, granulating, drying at 50 deg.C, and sieving with 12-18 mesh sieve;
(4) continuously adding lubricant and glidant, mixing uniformly at 4.0-5.0Kg/cm2The tablets containing the fucoidan sulfate are prepared by pressure tabletting.
The invention relates to an application of a composition containing fucoidan or a tablet containing fucoidan in preparing a medicament for treating mesangial proliferative glomerulonephritis.
The invention has the following beneficial effects: the tablet obtained by the invention is green to dark green, has a complete and smooth surface, uniform color, small weight difference, no splintering, moderate disintegration time limit and stable dosage form quality, and has the function of improving immunity.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Example 1A composition containing fucoidan
This example provides a tablet containing fucoidan, which is prepared by the following steps:
(1) 996g of fucoidin sulfate (with average molecular weight of 40KDa), 900g of phycocyanin, 2904g of kelp powder, 60g of sodium alginate, 480g of sodium carboxymethyl starch and 600g of microcrystalline cellulose are respectively taken, dried for 4 hours at 60 ℃ and sieved by 120 meshes for later use.
(2) Mixing dried fucoidan (average molecular weight 40KDa), phycocyanin and microcrystalline cellulose uniformly. Mixing sodium carboxymethyl starch with sodium alginate, and mixing with herba Zosterae Marinae powder under dry state. Mixing the two groups of granules, adding 1200g water as binder, making soft mass, sieving, granulating, drying wet granules at 50 deg.C, sieving with 18 mesh sieve, adding 30g magnesium stearate and 30g colloidal silicon dioxide, mixing at 5.0Kg/cm2The weight of each tablet is 0.6g, and the total weight of the tablets is 10000.
Example 2A composition containing fucoidan
This example provides a tablet containing fucoidan, which is prepared by the following steps:
(1) 1200g of fucoidan (with average molecular weight of 60KDa), 1080g of phycocyanin, 2640g of Undaria pinnatifida powder, 60g of sodium alginate, 360g of corn starch and 600g of microcrystalline cellulose are respectively taken, dried at 60 ℃ for 4 hours and sieved with 120-mesh particles for later use.
(2) Mixing the dried fucoidan (average molecular weight is 60KDa), phycocyanin and microcrystalline cellulose uniformly. Mixing corn starch and sodium alginate, and mixing with Undaria Pinnatifida powder under dry state. Mixing the two groups of granules, adding 1200g water as binder, making soft mass, sieving, granulating, drying wet granules at 50 deg.C, sieving with 18 mesh sieve, adding 30g calcium stearate and 30g magnesium silicate, mixing at 4.0Kg/cm2The weight of each tablet is 0.6g, and the total weight of the tablets is 10000.
Example 3A composition containing fucoidan
This embodiment provides a chewable tablet containing fucoidan, which is prepared by the following steps:
(1) 996g of fucoidin sulfate (with average molecular weight of 40KDa), 900g of phycocyanin, 2874g of kelp powder, 60g of sodium alginate, 480g of sodium carboxymethyl starch and 600g of microcrystalline cellulose are respectively taken, dried for 4 hours at 60 ℃ and sieved by 120 meshes for later use.
(2) Mixing dried fucoidan (average molecular weight 40KDa), phycocyanin and microcrystalline cellulose uniformly. After sodium carboxymethyl starch and sodium alginate are mixed uniformly, the sodium carboxymethyl starch, kelp powder and 30g of mannitol are mixed uniformly in a dry state. Mixing the two groups of granules, adding 1200g water as binder, making soft mass, sieving, granulating, drying wet granules at 50 deg.C, sieving with 18 mesh sieve, adding 30g magnesium stearate and 30g colloidal silicon dioxide, mixing at 5.0Kg/cm2The weight of each tablet is 0.6g, and the total weight of the tablets is 10000.
Comparative example 1
A preparation comprises fucoidan 300g, phycocyanin 3300g, herba Zosterae Marinae powder 1200g, sodium alginate 60g, carboxymethyl starch sodium 480g, microcrystalline cellulose 600g, magnesium stearate 30g, and colloidal silicon dioxide 30g, and its preparation method is the same as example 1.
Comparative example 2
A preparation is prepared from 60g of fucoidan, 1020g of phycocyanin, 3600g of kelp powder, 60g of sodium alginate, 480g of sodium carboxymethyl starch, 600g of microcrystalline cellulose, 30g of magnesium stearate and 30g of colloidal silicon dioxide by the same method as example 1.
Comparative example 3
A preparation is prepared from 60g of fucoidan, 0g of phycocyanin, 4500g of kelp powder, 60g of sodium alginate, 480g of sodium carboxymethyl starch, 600g of microcrystalline cellulose, 30g of magnesium stearate and 30g of colloidal silicon dioxide, and the preparation method is the same as that of example 1.
Comparative example 4
A preparation is prepared from 300g of fucoidan, 900g of phycocyanin, 3600g of kelp powder, 60g of sodium alginate, 0g of sodium carboxymethyl starch, 1080g of microcrystalline cellulose, 30g of magnesium stearate and 30g of colloidal silicon dioxide by the same method as in example 1.
Comparative example 5
A preparation is prepared from 300g of fucoidan, 900g of phycocyanin, 3600g of kelp powder, 60g of sodium alginate, 1080g of sodium carboxymethyl starch, 0g of microcrystalline cellulose, 30g of magnesium stearate and 30g of colloidal silicon dioxide by the same method as in example 1.
Comparative example 6
A preparation is prepared from fucoidan 300g, phycocyanin 900g, herba Zosterae Marinae powder 3600g, sodium alginate 300g, sodium carboxymethyl starch 360g, microcrystalline cellulose 480g, magnesium stearate 30g, and colloidal silicon dioxide 30g, and its preparation method is the same as example 1.
Comparative example 7
A preparation is prepared from 300g of fucoidan, 900g of phycocyanin, 3600g of kelp powder, 60g of sodium alginate, 420g of sodium carboxymethyl starch, 600g of microcrystalline cellulose, 120g of magnesium stearate and 0g of colloidal silicon dioxide by the same method as example 1.
Comparative example 8
A preparation is prepared from 300g of fucoidan, 900g of phycocyanin, 3600g of kelp powder, 60g of sodium alginate, 420g of sodium carboxymethyl starch, 600g of microcrystalline cellulose, 0g of magnesium stearate and 120g of colloidal silicon dioxide, and is prepared by the same method as in example 1.
Comparative example 9
(1) 996g of fucoidin sulfate (with average molecular weight of 40KDa), 900g of phycocyanin, 2904g of kelp powder, 60g of sodium alginate, 480g of sodium carboxymethyl starch and 600g of microcrystalline cellulose are respectively taken, dried for 4 hours at 60 ℃ and sieved by 120 meshes for later use.
(2) Mixing dried fucoidan, phycocyanin, microcrystalline cellulose, herba Zosterae Marinae powder, carboxymethyl starch sodium, and sodium alginate, adding 1200g water as binder, making into soft material, sieving, granulating, drying at 50 deg.C, sieving with 18 mesh sieve, adding 30g magnesium stearate and 30g colloidal silicon dioxide, mixing, and adding 4.0Kg/cm2The weight of each tablet is 0.6g, and the total weight of the tablets is 10000.
Detection method
1. Visual inspection
Each of 100 tablets obtained in examples 1 to 2 and comparative examples 1 to 9 was taken out, laid on a white plate, placed 60cm under a 75W light source, and observed with the naked eye for 30 seconds at a distance of 30cm from the tablet.
2. Check for weight difference
After 20 tablets obtained in examples 1 to 2 and comparative examples 1 to 9 were each taken out and the total weight was precisely determined to obtain an average tablet weight, the weight of each tablet was precisely determined and the weight of each tablet was precisely determined to be not more than 2 tablets exceeding the limit of the weight difference and not more than 1 tablet exceeding the limit by 1 time as specified in Table 1 (0.6 g).
3. Friability detection
The friability of the tablets obtained in examples 1-2, comparative examples 1-9 was tested according to general rule 0923.
4. Disintegration time limit detection
The tablets obtained in examples 1 to 2 and comparative examples 1 to 9 were examined for disintegration time according to general rule 0921.
TABLE 1 quality inspection of tablets obtained in examples 1-2, comparative examples 1-9
"-" indicates no measurement result.
As is clear from the results in Table 1, when sodium carboxymethyl starch or microcrystalline cellulose was not added, the disintegration time was long although the weight difference and the friability were within the specifications; when too much sodium alginate is added, the disintegration time is also prolonged; when the colloidal silicon dioxide is not added, the surface of the tablet is uneven in color, has color spots, has large weight difference and has splinters; when magnesium stearate is not added, the molding cannot be performed due to adhesion with a die; when the adding sequence of the fucoidan, the phycocyanin, the microcrystalline cellulose, the kelp powder, the sodium carboxymethyl starch and the sodium alginate is changed, the disintegration time limit is prolonged. The preparation obtained in example 1/2 showed remarkable overall effects in terms of weight difference, friability, disintegration time and appearance.
Experimental study of immune function
1. Animal experiments
360 clean-grade Kunming mice, 6-8 weeks old, 20 + -0.2 g weight, male, were subjected to the following 6 experiments: the experiment comprises an organ/body weight ratio experiment, a carbon clearance experiment, a delayed allergy (DTH) experiment, a serum hemolysis number experiment, an antibody generating cell experiment, a mouse abdominal cavity macrophage phagocytosis chicken erythrocyte experiment, a ConA induction mouse spleen lymphocyte transformation experiment and a mouse NK cell activity experiment, wherein 60 experiments are divided into 6 groups, namely a blank control group, an example 1 group, an example 2 group, a comparative example 1 group, a comparative example 2 group and a comparative example 3 group, and each group comprises 10 experiments.
Dose per group: example 1 group intake 765mg/Kg, bw, 30 days; example 2 group intake 765mg/Kg, bw, 30 days; comparative example 1 group intake 765mg/Kg, bw, 30 days; comparative example 2 group intake 765mg/Kg, bw, 30 days; comparative example 3 group intake 765mg/Kg, bw, 30 days.
2. Index measurement
2.1 organ/body weight ratio test and carbon clearance test
After the mice were gavaged for 30 days, diluted India ink (100ml/Kg) was injected from the mouse tail vein according to the body weight of the mice, and 20. mu.L of blood was taken from the internal venous plexus 2 minutes and 10 minutes after the injection of the ink, respectively, and immediately added to 2 mL0.1% sodium carbonate solution. The Optical Density (OD) values were measured with a spectrophotometer at a wavelength of 600nm, with a sodium carbonate solution as a blank. Respectively using OD1And OD2The optical density values of the blood samples taken at 2 minutes and 10 minutes are shown.
Mice were sacrificed and liver, spleen and thymus were taken, blotted dry with filter paper for surface blood contamination of the viscera and weighed separately.
The ability of the mouse to clear carbon is expressed as phagocytosis index (a) and is calculated as follows.
K＝(lgOD1-lgOD2)/(t2-t1)
a is body weight × K1/3(liver weight + spleen weight)
TABLE 2 organ/body weight ratio test results
Remarking: "-" indicates P < 0.05.
As can be seen from the results in Table 2, after the tablets obtained in example 1 and example 2 are fed to the mice for 30 days, the thymus/body weight ratio and the spleen/body weight ratio are both obviously increased (P <0.05), and have significant difference, which indicates that the tablets obtained in example 1 and example 2 can increase the mass of the spleen and the thymus of the mice and promote the mice to produce immune cells. After the tablets obtained in comparative example 1, comparative example 2 and comparative example 3 were fed to mice for 30 days, the thymus/body weight ratio and the spleen/body weight ratio were not obvious (P >0.05), and were not statistically significant.
TABLE 3 mouse carbon clearance test results
Remarking: "-" indicates P < 0.05.
As can be seen from the results in table 3, after the tablets obtained in examples 1 and 2 were fed to the mice for 30 days, the phagocytic function of the mouse mononuclear-macrophages was evaluated by the carbon clearance test, and the phagocytic index was increased with significant difference (P <0.05), indicating that the tablets obtained in examples 1 and 2 significantly enhance the phagocytic function of the mouse mononuclear-macrophages. The tablets obtained in comparative example 1, comparative example 2 and comparative example 3 were fed to mice for 30 days, and the effect of enhancing the phagocytic function of mouse mononuclear-macrophages was less pronounced.
2.2 delayed allergic response (DTH) test
After the mice were gavaged for 30 days, the abdominal skin of each mouse was depilated with barium sulfide in a range of about 3cm × 3cm, sensitized with 50 μ L of DNFB solution, challenged with 10 μ L of DNFB solution after 5 days, the mice were sacrificed by dislocation of the cervical vertebrae after 24 hours of challenge, the left and right ear shells were cut off, the ear piece with a diameter of 8mm was removed with a punch, and weighed, and the difference between the left and right ears was indicated by the degree of DTH and the swelling ratio.
Swelling ratio (%) [ (right ear weight-left ear weight)/right ear weight ] × 100%
TABLE 4 mouse delayed allergic response (DTH) test results
Remarking: "-" indicates P < 0.05.
As can be seen from the results in table 4, after the tablets obtained in examples 1 and 2 were fed to the mice for 30 days, the delayed allergy (DTH) test results of the mice showed that the ear swelling rate of the mice was significantly higher than that of the blank control group (P <0.05), and the test results were positive. After feeding the tablets obtained in comparative example 1, comparative example 2 and comparative example 3 for 30 days, the results of the delayed allergy (DTH) test in mice were not significantly different from those of the blank control group (P > 0.05).
2.3 serum hemolysis number test and antibody-producing cell test
30 days after gastric administration, the mice were immunized by injecting 0.2ml of cell suspension of 2% (v/v) SRBC into the abdominal cavity of each mouse, and 5 days after the immunization, half of the hemolysis value (HC) was obtained from the blood and spleen of each mouse50) And detecting antibody-producing cells.
Half maximal hemolysis value (HC)50) Measurement of (2)
After the mice are subjected to intragastric administration for 30 days, 0.2ml of cell suspension of 2% (v/v) SRBC is injected into the abdominal cavity of each mouse for immunization, after 5 days, the eyeballs are removed, blood is taken, the mixture is placed for 1 hour to separate out serum, the mixture is centrifuged at 2000 rpm for 10 minutes, and the serum is collected. Diluting serum (300 times) by using normal saline, placing 1ml of diluted serum into a test tube, sequentially adding 0.5ml of cell suspension of 10% (v/v) SRBC and 1ml of complement (diluted by using normal saline according to a ratio of 1: 10), additionally arranging a control tube (replaced by normal saline) without adding serum, preserving the temperature in a constant-temperature water bath at 37 ℃ for 15-30 minutes, and stopping the reaction by using an ice bath. Centrifuging at 2000 rpm, collecting supernatant 1ml, adding Du's reagent, simultaneously collecting 10% (v/v) SRBC cell suspension 0.25ml, adding Du's reagent to 4ml, mixing well, standing for 10 min, blank at 540nm with a control tube, and measuring optical density value of each tube respectively.
Half maximal hemolysis value (HC)50) (optical Density of sample/optical Density at half-maximal hemolysis of SRBC) × dilution factor
Antibody-producing cell assay
Taking spleen of the mouse immunized by the SRBC for 5 days, placing the spleen in a small plate containing Hank's solution, slightly grinding the spleen to prepare cell suspension, filtering the cell suspension by a 200-mesh screen, centrifuging the cell suspension for 10 minutes at 1000 rpm, washing the cell suspension twice by the Hank's solution, finally suspending the cell in 5mLRPMI1640 culture solution, counting the cells, and performing cell countingAdjusting the cell concentration to 5X 106one/mL. Heating and dissolving surface layer culture medium (1g agarose added with double distilled water to 100mL), placing in 45-50 deg.C water bath for heat preservation, mixing with Hank's solution with equal amount of pH7.2-7.4 and 2 times concentration, subpackaging into small tubes with 0.5mL per tube, adding 50 μ L10% SRBC (v/v, prepared with SA buffer solution), and 20 μ L spleen cell suspension (5 × 106And each/mL), quickly mixing, pouring the mixture on a slide with an agarose thin layer, making parallel sheets, after agar is solidified, horizontally buckling the slide on a sheet frame, putting the slide in a carbon dioxide incubator for incubation for 1-1.5 hours, adding a patch (1:8) of SA buffer solution into a groove of the slide frame, continuing the incubation for 1-1.5 hours, and counting the number of hemolytic plaques.
TABLE 5 results of mouse serum hemolysis number experiment and antibody-producing cell experiment
Remarking: "-" indicates P < 0.05.
As is clear from the results in Table 5, the half hemolysis value (HC50) and the number of hemolytic plaques/10 of the tablets obtained in example 1 and example 2 were observed after feeding the mice for 30 days6Splenocyte results were significantly higher than blank control (P)<0.05), the result of the experiment is positive. Half hemolysis value (HC50), number of hemolytic plaques/10 of tablets obtained in comparative example 1, comparative example 2 and comparative example 3 after feeding mice for 30 days6Splenocyte results were not significantly different from the placebo group (P)>0.05)。
2.4 experiment of phagocytosis of chicken red blood cells by macrophages in abdominal cavity of mouse
After the mice are subjected to gastric lavage for 30 days, 1mL of 2% chicken erythrocyte suspension is injected into the abdominal cavity of each mouse, after 30 minutes, the mice are killed by cervical dislocation, the mice are fixed on a wax plate in an inverted position, the abdominal wall skin is cut off in the middle, 2mL of physiological saline is injected into the abdominal cavity, the mouse plate is rotated for 1 minute, 1mL of abdominal cavity washing liquid is sucked out, the mouse washing liquid is evenly dripped on 2 glass slides and is placed into an enamel box filled with wet gauze, the incubation is carried out for 30 minutes at 37 ℃, and then the mice are rinsed in the physiological saline to remove cells which are not pasted. Air-drying, fixing with 1:1(v/v) acetone methanol solution for 20 min, staining with 4% (v/v) Giemsa-phosphate buffer solution for 15 min, rinsing with distilled water, air-drying, and counting macrophages with a 40X microscope.
Phagocytosis ratio (%) × 100 (number of macrophages engulping chicken red blood cells/number of macrophages counted) × 100
Phagocytosis index-number of phagocytosed chicken red blood cells/counted number of macrophages
TABLE 6 results of experiment on phagocytosis of chicken red blood cells by mouse abdominal macrophages
Remarking: "-" indicates P < 0.05.
As can be seen from the results in table 6, the results of phagocytosis rate and phagocytosis index were significantly higher than those of the blank control (P <0.05) after feeding the tablets obtained in examples 1 and 2 for 30 days, and the results were positive. After feeding the tablets obtained in comparative example 1, comparative example 2 and comparative example 3 for 30 days, the results of phagocytosis rate and phagocytosis index were not significantly different from those of the blank control group (P > 0.05).
2.5 ConA-induced splenic lymphocyte transformation experiment in mice
After the mice had been gavaged for 30 days, the mice were sacrificed by cervical dislocation, the spleens were aseptically taken out and placed in a dish containing an appropriate amount of sterile Hank's solution, and the spleens were gently ground with forceps to prepare single cell suspensions. Filtering with 200 mesh screen, washing with Hank's solution for 2 times, centrifuging at 1000 rpm for 10 min, suspending the cells in 1mL complete culture solution, staining with talofen blue to count viable cells (more than 95%), and adjusting cell concentration to 3 × 106one/mL.
Each spleen cell suspension was added to a 24-well plate in two wells, 1mL of each well, 75. mu.L of LCoA solution (equivalent to 7.5. mu.g/mL) was added to one well, and the other well was used as a control, and incubated in a 5% carbon dioxide incubator at 37 ℃ for 72 hours, 4 hours before the end of the incubation, 0.7mL of supernatant was gently aspirated from each well, 0.7mL of serum-free RP1640 MI medium was added, and 50. mu.L of MTT (5mg/mL) was added to each well, and the incubation was continued for 4 hours. After the culture is finished, 1mL of acidic isopropanol is added into each hole, and the mixture is uniformly blown and beaten to ensure that the purple crystals are completely dissolved. Then, the cells were divided into 96-well culture plates, each of which was prepared as 3 parallel wells, and the optical density (OD value) was measured at a wavelength of 570nm using a microplate reader. The proliferation capacity of lymphocytes was expressed by subtracting the optical density of the wells without ConA from the optical density of the wells with ConA.
TABLE 7 results of ConA-induced splenic lymphocyte transformation experiments in mice
Remarking: "-" indicates P < 0.05.
As can be seen from the results in table 7, after the tablets obtained in examples 1 and 2 were fed to the mice for 30 days, the result of ConA-induced lymphocyte proliferation (OD difference) was significantly higher than that of the blank control group (P <0.05), and the experimental result was positive. After feeding the tablets obtained in comparative example 1, comparative example 2 and comparative example 3 for 30 days, there was no significant difference in the results of ConA-induced lymphocyte proliferation (OD difference) compared with the blank control group (P > 0.05).
2.6 mouse NK cell Activity test
After the mice had been gavaged for 30 days, the mice were sacrificed by cervical dislocation, the spleens were aseptically taken out and placed in a dish containing an appropriate amount of sterile Hank's solution, and the spleens were gently ground with forceps to prepare single cell suspensions. Filtered through a 200 mesh screen and washed 2 times with Hank's solution, centrifuged at 1000 rpm for 10 minutes each time. Discarding supernatant to bounce the cell pulp, adding 0.5mL of sterilized water for 20 seconds, lysing erythrocytes, adding 0.5mL of 2 times of Hank's solution and 8 mLHank's solution, centrifuging at 1000 rpm for 10 minutes, resuspending with 1mL of RPMI1640 complete culture solution containing 10% calf serum, diluting with 1% glacial acetic acid, counting (viable cell number should be above 95%), staining with talophen blue, and countingThe number of viable cells should be more than 95%, and the final cell concentration is adjusted to 2X 10 by using RPMI1640 complete culture medium7one/mL.
100 mul each of target cells and effector cells (effective target ratio 50:1) were taken and added to a U-shaped 96-well plate, 100 mul each of target cells and culture solution were added to natural target cell release holes, and 100 mul each of target cells and 1% NP40 were added to maximum target cell release holes, each of which was provided with three parallel wells, and cultured at 37 ℃ in a 5% carbon dioxide incubator for 4 hours, then the 96-well plate was centrifuged at 1500 rpm for 5 minutes, 100 mul of supernatant was aspirated from each well and placed in a 96-well plate, and 100 mul of LDH was added to the substrate solution at the same time, reacted for 3 minutes, 130 mul of 1mol/L HCl was added to each well, and Optical Density (OD) was measured at 490nm using a microplate reader.
NK cell activity was calculated as follows:
NK cell activity (%) - (reflecting pore OD value-natural release pore OD value)/(maximum release pore OD value-natural release pore OD value) ] × 100%
TABLE 8 mouse NK cell Activity test results
Remarking: "-" indicates P < 0.05.
As is clear from the results in Table 8, the results of the NK cell activity (%) of mice were significantly higher than those of the blank control group (P <0.05) after feeding the tablets obtained in examples 1 and 2 to the mice for 30 days, and the results were positive. After feeding the tablets obtained in comparative example 1, comparative example 2 and comparative example 3 to mice for 30 days, there was no significant difference in the results of the mouse NK cell activity (%) as compared with the blank control group (P > 0.05).
According to the judgment regulation of the immunity enhancing function in the health food functional test method, the results of any two aspects of cellular immunity function, humoral immunity function, single macrophage function and NK cell activity are positive, and the tested sample can be judged to have the function of enhancing the immunity. According to the measurement and the results of each index of 2.1 to 2.6, the results of the tablets obtained in the example 1 and the example 2 are positive after the tablets are fed for 30 days, so that the tablets obtained by the method have the function of enhancing the immunity of the mice.
Application example (Effect on mesangial proliferative glomerulonephritis (MspGN))
40 clean male SD rats with the body weight of 180-200 g are selected and randomly divided into a blank control group, a pathological group, an example 1 group, an example 2 group and 10 rats in each group.
Blank control group: feeding for 8 weeks normally, and performing intragastric gavage with normal saline to obtain blank control group;
pathology group (MsPGN model): gavage 20mg every other day from the first day of experiment for 8 weeks, and injecting staphylococcal enterotoxin B from tail vein for 1 time respectively on the 8 th day and the 15 th day of experiment, wherein the dosage of staphylococcal enterotoxin B is 0.4mg/Kg body weight; 0.2mL of complete Freund's adjuvant (containing 2mg of bovine serum albumin) was injected subcutaneously at the sub-point on the 1 st day of the experiment, and 0.2mL of incomplete Freund's adjuvant (containing 2mg of bovine serum albumin) was injected subcutaneously at the sub-point on the 8 th day of the experiment.
Example 1 group: the pathological model was established by the same method as the pathological group, and the tablets obtained in example 1 were gavaged from day 15, and the dose was 765mg/Kg body weight.
Example 2 group: the pathological model was established by the same method as the pathological group, and the tablets obtained in example 2 were used for intragastric administration from day 15, and the dose was 765mg/Kg body weight.
Detection indexes are as follows: urine red blood cells, 24h urine protein, urea nitrogen and blood creatinine.
TABLE 9 test results of application examples
Remarking: "+" indicates P <0.01 compared to the case group.
The results in table 8 show that the tablets obtained in examples 1 and 2 can reduce red blood cells of the MsPGN rat, significantly reduce 24h urine protein, urea nitrogen and blood creatinine, and have a certain protective effect on the kidney function of the MsPGN rat.
In addition, the glomerular ultrastructure of each group of rats is observed by a light microscope, and the glomerulus of the rats in the blank control group is not obviously changed, and the renal tubules and the renal interstitium are normal; the glomerulus of a rat in a pathological group is obviously enlarged, the number of mesangial cells is increased, mesangial matrixes are proliferated to different degrees, part of saccules are adhered, the lumen of a capillary vessel is narrowed, collapsed and blocked, and the renal tubule and a basement membrane are normal; the membrane cells of the example 1 group and the example 2 group were slightly proliferated, without balloon adhesion, without pressure deformation of the capillary lumen, and the renal tubules and basement membrane were normal. Observing the glomerular ultrastructure of each group of rats by using an electron microscope to find that the rats in the blank control group have no obvious change and have normal renal tubules and renal interstitium; pathological rat glomerular mesangial cells and mesangial stroma are proliferated, dense sediments are deposited at the base part to form a cord shape, and the foot process shape and the renal tubule shape of epithelial cells are normal; the mesangial cells and mesangial matrix of rats in the example 1 group and the example 2 group were slightly hyperplastic, no dense precipitate was observed, and the morphology of the foot process and the renal tubule of the epithelial cells were normal.
Typical cases
Zhangqi, male, age 26, 3.7g of 24h urine protein, 121 mu mol/L of serum creatinine, 11mmol/L of urea nitrogen, renal puncture examination, renal puncture tissue with 12 glomeruli, diffuse mild mesangial hyperplasia, moderate focal stage exacerbation, 1 glomeruli bulbar sclerosis, and thick basement membrane; the glomerular epithelial cells show water denaturation, the renal interstitium shows infiltration of small focal inflammatory cells, the glomerular blood vessels do not have lesions, and the mild mesangial proliferative glomerulonephritis. The tablets obtained in example 1 were taken 2 tablets at a time, 3 times a day, and the results were reviewed after 3 months: 1.1g of urine protein after 24 hours, 91.2 mu mol/L of blood creatinine and 4.3mmol/L of urea nitrogen, and has remarkable curative effect.
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (3)
1. The tablet containing fucoidan is characterized by being prepared from the following raw materials in parts by weight: 10-25 parts of phycocyanin, 5-25 parts of fucoidan, 30-60 parts of seaweed powder and 10-30 parts of excipient;
the molecular weight of the fucoidan polysaccharide sulfate is 40KDa-60 KDa;
the excipient comprises the following components in parts by weight: 5-16 parts of sodium carboxymethyl starch, 6-10 parts of microcrystalline cellulose, 0.5-2 parts of sodium alginate, 0.5-1 part of magnesium stearate and 0.1-1 part of colloidal silicon dioxide;
or, the excipient consists of the following components in parts by weight: 5-16 parts of corn starch, 6-10 parts of microcrystalline cellulose, 0.5-2 parts of sodium alginate, 0.5-1 part of calcium stearate and 0.1-1 part of magnesium silicate;
the seaweed powder is kelp powder or undaria pinnatifida powder.
2. The method for preparing fucoidan-containing tablet according to claim 1, comprising:
(1) uniformly mixing the dried fucoidin sulfate, phycocyanin and diluent to obtain a component A;
(2) uniformly mixing the disintegrating agent and the seaweed meal in a dry state to obtain a component B;
(3) a, B mixing the two groups of granules, adding water as binder, making soft mass, sieving, granulating, drying at 50 deg.C, and sieving with 12-18 mesh sieve;
(4) continuously adding lubricant and glidant, mixing uniformly at 4.0-5.0Kg/cm2The tablets containing the fucoidan polysaccharide sulfate are prepared by pressure tabletting;
wherein the diluent is sodium carboxymethyl starch and microcrystalline cellulose, the disintegrant is microcrystalline cellulose, sodium carboxymethyl starch and sodium alginate, the lubricant is magnesium stearate, and the glidant is colloidal silicon dioxide;
or the diluent is microcrystalline cellulose, the disintegrating agent is corn starch, microcrystalline cellulose and sodium alginate, the lubricant is calcium stearate, and the glidant is magnesium silicate.
3. The use of the fucoidan-containing tablet according to claim 1 for the preparation of a medicament for the treatment of mesangial proliferative glomerulonephritis.
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| CN102151284A (en) * | 2011-02-24 | 2011-08-17 | 楼岩 | Composition containing fucoidin sulfate and application thereof |
| CN106084085A (en) * | 2016-07-19 | 2016-11-09 | 北京颐方生物科技有限公司 | A kind of preparation method and application of low-molecular-weight algal polysaccharide sulfate |
| CN106176799A (en) * | 2016-07-21 | 2016-12-07 | 中国科学院海洋研究所 | A kind of sulfated fucan is as the application of immunostimulant |
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| CN101028282A (en) * | 2007-03-12 | 2007-09-05 | 北京世纪博康医药科技有限公司 | Use of low-molecular weight phaeophytin polyose sulfate in preparation of medicine for treating kidney disease |
| CN102151284A (en) * | 2011-02-24 | 2011-08-17 | 楼岩 | Composition containing fucoidin sulfate and application thereof |
| CN106084085A (en) * | 2016-07-19 | 2016-11-09 | 北京颐方生物科技有限公司 | A kind of preparation method and application of low-molecular-weight algal polysaccharide sulfate |
| CN106176799A (en) * | 2016-07-21 | 2016-12-07 | 中国科学院海洋研究所 | A kind of sulfated fucan is as the application of immunostimulant |
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