CN105363023A

CN105363023A - Composition with effects of protecting joints and increasing bone mineral density and preparation method of composition

Info

Publication number: CN105363023A
Application number: CN201510765569.1A
Authority: CN
Inventors: 常弘杰; 余孝云; 李志明; 陆宝宝
Original assignee: Health Pharmaceutical (china) Co Ltd; JIANKANGYUAN PHARMACEUTICAL GROUP CO Ltd; SHENZHEN TAITAI PHARMACEUTICAL INDUSTRY Co Ltd
Current assignee: Health Pharmaceutical (china) Co Ltd; JIANKANGYUAN PHARMACEUTICAL GROUP CO Ltd; SHENZHEN TAITAI PHARMACEUTICAL INDUSTRY Co Ltd
Priority date: 2015-11-11
Filing date: 2015-11-11
Publication date: 2016-03-02

Abstract

The invention provides a composition with effects of protecting joints and increasing bone mineral density. The composition is prepared from the following components in parts by weight: 250-400 parts of calcium citrate malate, 150-300 parts of N-Sulfo-glucosamine potassium salt, 100-200 parts of chondroitin sulfate, 50-150 parts of bone collagen peptide powder, and 10-50 parts of casein phosphopeptides. According to the composition provided by the invention, the active ingredients achieve the synergistic effect, the bioavailability is high, and the composition can be used for increasing the bone mineral density and restoring the bone functions. Through a preparation method provided by the invention, the composition can be prepared into a compound preparation, the curative effects are definite, the quality is controllable, no toxic or side effect exists, and the composition is suitable for large-scale popularization and application.

Description

A kind of composition and method of making the same that there is joint protection and increase bone density effect

Technical field

The present invention relates to a kind of compositions, be specifically related to a kind of compositions that there is joint protection and increase bone density effect.

Background technology

Osteoporosis (Osteoporosis, OP) be a kind ofly to reduce with bone amount, bone micro-structure destroys, bone fragility increases, the systemic skeletal disease that fracture is feature easily occurs.The data display of World Health Organization (WHO), osteoporotic sickness rate was 21% at 50 ~ 60 years old, and be 58% at 60 ~ 70 years old, be almost 100% at 70 ~ 80 years old, especially the sickness rate of postmenopausal women and elderly men is higher, and occurs the trend of rejuvenation.Particularly the dietary habit of Chinese residents is easy to cause calcareous intake deficiency and then cause developing osteoporosis rate to be on the rise.Therefore, osteoporotic prevention and therapy is imperative.

All be known as caused by " marrow of suffering from a deficiency of the kidney loses " the pathogen and pathology of tcm of primary osteoporosis at present, on the pathologic basis that marrow of suffering from a deficiency of the kidney loses, other various pathological changes concurrent, as weakness of the spleen and stomach, deficiency of qi and blood, stagnation of blood stasis etc.

Degenerative osteoarthritis (Osteoarthritis, OA) be a kind of chronic joint diseases being feature with the degeneration of articular cartilage, destruction and hyperosteogeny, also known as osteoarthritis, degenerative osteoarthritis, it is mainly in some specific joint, gets involved the most common with waist, knee joint.

Osteoarthritis sickness rate in middle-aged and elderly people is very high, be only second to heart disease, sickness rate also will rise with advancing age, and the disability rate of this disease is up to 53%, be called as " the No.1 disease that the mankind are disabled ", had a strong impact on the healthy of middle-aged and elderly people and quality of life.Many experts think that this disease earliest period pathologic basis is the change of metabolism of articular cartilage, and namely chondrocyte synthetic proteins polysaccharide reduces and causes proteoglycan content and proteoglycan in cartilage matrix to aggregate into the decline of macromolecular ability.Modern Chinese medicine scholar is inheriting TCM academic thought and is using for reference on the basis of doctor trained in Western medicine theory of medicine, more deep to the understanding of the cause of disease of degenerative osteoarthritis, pathogenesis, once the multiple pathology theory such as " suffering from a deficiency of the kidney ", " blood stasis is said ", " anemofrigid-damp arthralgia is said " is proposed.

Modern medicine thinks that degenerative osteoarthritis and osteoporosis are two kinds of diverse diseases, has different pathological changes separately.Wherein, based on articular cartilage damage, along with the prolongation of the course of disease, can there is the increase of periarticular osteophyte and local bone amount, i.e. so-called " hyperosteogeny " in the main pathological change of degenerative osteoarthritis at middle and advanced stage; And osteoporotic main pathological change is bone mineral content and bone mineral density decline, the micro structure of bone is disorderly and destroy.

Skeleton is made up of Organic substance and inorganic matter: Organic substance, and mainly protein (wherein 80% is collagen protein), can make skeleton have certain toughness; And inorganic matter, mainly calcareous and phosphorus matter, make skeleton have certain hardness, therefore, the existing toughness of skeleton has hardness again.People is different with the ratio of inorganic matter at the Organic substance of Different age group skeleton, the organic relative amount of skeleton of children and adolescent is high, so their skeleton suppleness and plasticity higher, and the inorganic matter relative amount of the skeleton of middle-aged and elderly people is high, so bone hardness is higher, easily fracture.

Saying popular at present comprises replenishing the calcium prevents and treats osteoporosis, but clinical research shows, most sufferers of osteoporosis face is not that calcium deficiency causes, and the inorganic matters such as simple supplementary calcium, can not be guaranteed on not only absorbing, also will make skeletogenous fragility to increase, the pernicious consequence such as osteodynia, fracture more easily occur, so the object of bone health fundamentally can not be solved.Therefore for numerous person in middle and old age's osteoporosis colony; be badly in need of one both supplement calcium; and promote that calcium absorbs and deposits in skeleton, make skeleton flexible, flexible, comprehensively there is joint and protect and increase bone density, prevent and treat osteoporotic skeleton health-care product.

Summary of the invention

For the problems referred to above, the invention provides a kind of compositions that there is joint protection and increase bone density effect.Mutually work in coordination with between effect component of compositions of the present invention, bioavailability is high, can for increasing bone density, recovery bone function.The preparation method of compositions of the present invention can be made into compound preparation, and determined curative effect is quality controllable, has no side effect, and is suitable for large-scale promotion application.

Technical scheme for realizing above-mentioned purpose is as follows:

The invention provides a kind of compositions having joint protection and increase bone density effect, described compositions comprises calcium cirate malate, Glucosamine sulfate potassium chloride, chondroitin sulfate, bone collagen Gly-His-Lys and phosphopeptide caseinate;

Wherein, count by weight, described compositions comprises calcium cirate malate 250 ~ 400 parts, Glucosamine sulfate potassium chloride 150 ~ 300 parts, chondroitin sulfate 100 ~ 200 parts, bone collagen Gly-His-Lys 50 ~ 150 parts, phosphopeptide caseinate 10 ~ 50 parts;

Preferably, count by weight, described compositions comprises calcium cirate malate 300 ~ 350 parts, Glucosamine sulfate potassium chloride 200 ~ 250 parts, chondroitin sulfate 140 ~ 180 parts, bone collagen Gly-His-Lys 80 ~ 120 parts, phosphopeptide caseinate 20 ~ 40 parts;

Preferably, count by weight, described compositions comprises calcium cirate malate 330 parts, Glucosamine sulfate potassium chloride 220 parts, chondroitin sulfate 160 parts, bone collagen Gly-His-Lys 100 parts, phosphopeptide caseinate 30 parts;

Preferably, described compositions also comprises curcumin; Preferably, count by weight, described curcumin is 10 ~ 50 parts, preferably 20 ~ 40 parts, more preferably 25 parts.

Compositions of the present invention also comprises pharmaceutically acceptable adjuvant, wherein said adjuvant be selected from filler, diluent, wetting agent, binding agent, disintegrating agent, lubricant, correctives or coating material one or more;

Preferably, described filler is selected from one or more in lactose, microcrystalline Cellulose, pregelatinized Starch, resistant dextrin, dextrin or starch; One or more in preferred lactose, microcrystalline Cellulose or resistant dextrin;

Preferably, described binding agent is selected from one or more in copolyvidone, polyvidone, hypromellose or hyprolose; Preferred copolyvidone;

Preferably, described lubricant is selected from one or more in magnesium stearate, silicon dioxide, Pulvis Talci, Polyethylene Glycol or magnesium laurylsulfate; One or both in preferred magnesium stearate, silicon dioxide;

Preferably, described coating material is selected from one or more of hydroxypropyl emthylcellulose, polyvinyl alcohol, Pulvis Talci, Polyethylene Glycol, polyvinylpyrrolidone, glyceryl triacetate, soybean phospholipid, Tween 80, PVP K30, dextrin, sodium carboxymethyl cellulose or titanium dioxide.

Compositions of the present invention can be tablet, capsule, granule, electuary, solid beverage, oral liquid or beverage, preferred capsule, tablet, granule or electuary, further preferred tablet and electuary, more preferably tablet;

Preferably, when described compositions is tablet, count by weight, described accessory package contains lactose 30 ~ 70 parts, copolyvidone 30 ~ 70 parts, microcrystalline Cellulose 20 ~ 60 parts, silicon dioxide 0 ~ 10 part, magnesium stearate 3 ~ 10 parts; Preferably, count by weight, described accessory package contains lactose 40 ~ 60 parts, copolyvidone 40 ~ 60 parts, microcrystalline Cellulose 30 ~ 50 parts, silicon dioxide 3 ~ 7 parts, magnesium stearate 5 ~ 8 parts; Preferably, count by weight, described accessory package contains lactose 50 parts, copolyvidone 50 parts, microcrystalline Cellulose 40 parts, silicon dioxide 5 parts, magnesium stearate 5 parts;

Preferably, when described compositions is electuary, count by weight, described accessory package is containing silicon dioxide 8 ~ 9 parts; Magnesium stearate 8 ~ 9 parts, resistant dextrin 785 ~ 810 parts; Preferably, count by weight, described accessory package contains silicon dioxide 8 parts, magnesium stearate 8 parts, resistant dextrin 810 parts.

Compositions of the present invention consists of when being tablet: in every 1000, calcium cirate malate 330g, Glucosamine sulfate potassium chloride 220g, chondroitin sulfate 160g, bone collagen Gly-His-Lys 100g, phosphopeptide caseinate 30g, lactose 50g, copolyvidone 50g, microcrystalline Cellulose 40g, silicon dioxide 5g, magnesium stearate 5g;

Preferably, consist of when described compositions is tablet: in every 1000, calcium cirate malate 330g, Glucosamine sulfate potassium chloride 220g, chondroitin sulfate 160g, bone collagen Gly-His-Lys 100g, phosphopeptide caseinate 30g, curcumin 25g, lactose 50g, copolyvidone 50g, microcrystalline Cellulose 40g, silicon dioxide 5g, magnesium stearate 5g.

Compositions of the present invention consists of when being electuary: in every 1000 bags, calcium cirate malate 1980g, Glucosamine sulfate potassium chloride 1320g, chondroitin sulfate 960g, bone collagen Gly-His-Lys 600g, phosphopeptide caseinate 180g, silicon dioxide 50g, magnesium stearate 50g, resistant dextrin 4860g.

The preparation method of compositions of the present invention comprises the steps: to control each supplementary material moisture≤5.0%, takes each supplementary material by described proportioning, mixing, and controlling moisture is≤5.0%;

Preferably, described preparation method comprises the steps: each supplementary material is crossed 60 ~ 80 mesh sieves and controls each supplementary material moisture≤5.0%, takes each supplementary material by described proportioning, mixes 30 ~ 75 minutes, and controlling moisture is≤5.0%;

Preferably, the preparation method of described compositions comprises the steps: each supplementary material is crossed 60 ~ 80 mesh sieves and controls each supplementary material moisture≤5.0%, takes each supplementary material by described proportioning, mixes 30 ~ 75 minutes, and controlling moisture is≤5.0%; Described adjuvant is added, mixing, obtained tablet, capsule, granule, electuary, solid beverage, oral liquid or beverage in said mixture.

When compositions of the present invention is tablet, its preparation method comprises the steps:

(1) each supplementary material is crossed 60 ~ 80 mesh sieves, control each supplementary material moisture≤5.0%, take each supplementary material by described proportioning;

(2) Glucosamine sulfate potassium chloride and silicon dioxide mixing are mixed 30 ~ 60 minutes with all the other supplementary materials after 5 ~ 30 minutes, control moisture≤5.0%; Preferably, after Glucosamine sulfate potassium chloride and silicon dioxide are mixed 5 ~ 30 minutes, remix 5 minutes after crossing 80 mesh sieves, mix 30 ~ 60 minutes with all the other supplementary materials afterwards, control moisture≤5.0%;

(3) by the mixture tabletting that described step (2) obtains, obtain tablet, the hardness of described tablet is 12 ~ 20kg;

Preferably, described preparation method is further comprising the steps of:

(4) water-soluble film coating pre-mixing agent and purified water is adopted to be mixed with coating solution; Preferably, according to weight percent meter, described film coating pre-mix dose is 5 ~ 15% of label weight, and coating solution solid content is 5 ~ 20%, preferably 7 ~ 15%;

(5) coating solution using step (4) to obtain carries out coating to the tablet that described step (3) obtains;

Preferably, the inlet temperature in described step (5) is 65 ~ 85 DEG C, and leaving air temp is 50 ~ 60 DEG C, and sheet bed tempertaure is 40 ~ 50 DEG C, and atomizing pressure is 0.1 ~ 0.3Mpa;

Preferably, the tablet weightening finish after coating described in described step (5) is 3%.

When compositions of the present invention is electuary, its preparation method comprises the steps:

A each supplementary material is crossed 60 ~ 80 mesh sieves by (), control each supplementary material moisture≤5.0%, take each supplementary material by described proportioning;

B Glucosamine sulfate potassium chloride and silicon dioxide are mixed 5 ~ 30 minutes by ();

C mixture that step (b) obtains by () mixes with all the other supplementary materials, controls moisture≤5.0%, to obtain final product;

Preferably, when described compositions is electuary, its preparation method comprises the steps:

B Glucosamine sulfate potassium chloride and silicon dioxide are mixed 5 ~ 15 minutes by ();

C mixture that step (b) obtains by () and all the other supplementary materials are placed in mixer and mix 30 ~ 60 minutes, and described mixer rotating speed is 10 ~ 15 revs/min, control moisture≤5.0%, to obtain final product.

Compositions of the present invention has joint protection in preparation and increases the purposes in the food of bone density effect, medicine or health food.

The preparation method of compositions of the present invention, comprises the steps:

Measure each supplementary material moisture, control moisture≤5.0%; Each supplementary material is crossed 60 ~ 80 mesh sieves, takes each supplementary material by formula; The Glucosamine sulfate potassium chloride of recipe quantity and silicon dioxide are mixed 5 ~ 15 minutes, mixing is carried out 30 ~ 60 minutes again with the above-mentioned unclassified stores automatic lifting hopper mixer sieved, material is released and loads in transfer container and weigh, sampling detects moisture on moisture test apparatus, controls moisture≤5.0%; Add pharmaceutically acceptable adjuvant, make capsule, tablet, electuary or granule.

As one preferred embodiment, the invention provides the preparation method of described compositions, wherein said compositions is direct compression tablet, and preparation method comprises the steps: to measure each supplementary material moisture, controls moisture≤5.0%; Calcium cirate malate, bone collagen Gly-His-Lys, phosphopeptide caseinate, lactose, copolyvidone, microcrystalline Cellulose are crossed 60 mesh sieves; Chondroitin sulfate, magnesium stearate cross 80 mesh sieves, take each supplementary material by formula; Glucosamine sulfate potassium chloride and silicon dioxide are mixed 5 minutes, crosses 80 mesh sieves, remix 5 minutes; Carry out mixing 30 ~ 60 minutes with the above-mentioned unclassified stores automatic lifting hopper mixer sieved again, material is released and loads in transfer container and weigh, sample and detect moisture on moisture test apparatus, control moisture≤5.0%; Tabletting machine, Hardness Control at 12 ~ 20kg, tabletting terminates rear moisture test apparatus and detects moisture, control moisture≤5.0%;

Preparation method of the present invention comprises the step of coating further:

Prepare coating solution by film coating pre-mix dose and purified water, control inlet temperature, sheet bed tempertaure, leaving air temp during coating, atomizing pressure, the label made to above-mentioned steps carries out coating; Preferably, in described coating solution, film coating pre-mix dose weight content is about 15%, increases weight about 3% after controlling every coating tablets; That is: required coating materials consumption (film coating pre-mix dose is 5 ~ 15% of label weight) is calculated according to the proportion of goods damageds on coating weight gain and seed-coating machine; Require to calculate purified water consumption according to coating solution solid content; Preferably, the inlet temperature in described coating steps is about 75 DEG C; Leaving air temp is about 55 DEG C; Sheet bed tempertaure is about 45 DEG C; Atomizing pressure is 0.1 ~ 0.3Mpa.

In compositions supplementary material of the present invention, calcium cirate malate with citric acid, malic acid and calcium carbonate for raw material is made through neutralization reaction, synthesis, precipitation, filtration, oven dry, disintegrating process.Calcium cirate malate is the basal nutrient maintaining bone density, is also the key factor affecting bone density, and supplementary calcium preparation can maintenance sclerotin, increases bone density, prevention of osteoporosis, makes sclerotin more closely knit.Because calcium carbonate cost is low, calcium content is high, what the health food major part thus increasing bone density at present adopted is calcium carbonate, but calcium carbonate poorly water-soluble, need during absorption to consume gastric acid, affect gastric sour environment, affect normal stool function, long-term taking can cause constipation, inappetence, have a stomach-ache.And the calcium cirate malate in compositions of the present invention be calcium, the organic-acid complex that fits in by a certain percentage of citric acid and malic acid, there is highly dissoluble, high biological absorption usability, reduce that ferrum resistance to suction hinders, excellent flavor and the feature of safety non-toxic.

In compositions supplementary material of the present invention, Glucosamine sulfate potassium chloride can expedite the emergence of and supplementary knuckle synovia in a large number, thus continuous lubricating joint cartilage surface, reduce wear, make joint part nimbly and freely.Glucosamine has glucosamine hydrochloride and sulfate etc., there are some researches show, sulfate is more conducive to absorption of human body than hydrochlorate, and its principle is that human body cartilage mainly mediates by sulfate radical the absorption of D-glucosamine, sulphuric acid D-glucosamine has this sulfate radical, and hydrochlorate does not then possess this advantage.Due to the glucosamine sulfate very easily moisture absorption and oxidation, and Glucosamine sulfate potassium chloride stable chemical nature, safe and reliable, therefore select Glucosamine sulfate potassium chloride to be formula material.

In compositions supplementary material of the present invention, chondroitin sulfate has lubrication osteoarthrosis function, effective alleviation dyskinesia, promote the micronutrients such as skeleton nutrition material absorbing calcium, potassium, magnesium, sodium, vitamin D, osteoblastic increment can be promoted in vivo, can the effective osteopathia such as prevention and therapy osteoporosis, arthralgia.

In compositions supplementary material of the present invention, bone collagen Gly-His-Lys is the collagen protein extracted from Os Bovis seu Bubali, and collagen protein is the major protein in articular cartilage, collagen protein forms network structure in bone, be responsible for clinging calcareous, maintain the toughness of bone, increase bone density.

In compositions supplementary material of the present invention, phosphopeptide caseinate is milk protein through enzymolysis, the powder polypeptide series products that goes the techniques such as bitterness, concentrated, spraying dry to make.Phosphopeptide caseinate has in or weakly alkaline environment neutral at small intestinal lower end pH can become soluble complex with calcium binding, stops phosphate anion to the precipitation of calcium ion, calcium ion concentration is increased thus promotes the Passive intake of calcium.

In compositions supplementary material of the present invention, curcumin is a kind of pigment extracted from zingiberaceous plant Rhizoma Curcumae Longae, also exists in other zingiberaceous plant.Modern study finds that curcumin can react by inflammation-inhibiting, and have the effect of antioxidation, resisting rheumatoid disease, curcumin can prevent arthroncus, arthritis, effective to cardiovascular disease, cancer etc.

Resistant dextrin of the present invention is a kind of soluble dietary material, and the anti-little intestinal digestion of major part, mainly at colon fermentation.Resistant dextrin can become balanced diet ingredient and can promotion health, as reduced blood glucose response and the health etc. improving intestinal, in addition, its digestion tolerance threshold is also very outstanding, and the amount making it digest is best suited for the optimum change of the intestinal ecosystem reaching expectation.Resistant dextrin also can be dissolved in cold water completely and viscosity can not be caused to increase, and the toleration taken is good, is a kind of desirable supplementary material improving F&B fiber content.

Modern medicine thinks that degenerative osteoarthritis and osteoporosis are two kinds of diverse diseases, has different pathological changes separately.Wherein, based on articular cartilage damage, along with the prolongation of the course of disease, can there is the increase of periarticular osteophyte and local bone amount, i.e. so-called " hyperosteogeny " in the main pathological change of degenerative osteoarthritis at middle and advanced stage; And osteoporotic main pathological change is bone mineral content and bone mineral density decline, the micro structure of bone is disorderly and destroy.The present inventor thinks, although the main pathological change property of there are differences of above-mentioned two kinds of diseases, degenerative osteoarthritis and osteoporosis are degenerative disease, and sickness rate becomes positive correlation with increasing age, finds that two kinds of diseases usually and deposit appearance clinically.Therefore, the angle research osteoporosis of the present invention from bone density and the relation of degenerative osteoarthritis, find through research, bone density and the flexible bone of Osteoarthritis obviously decline, with bone structure change, show that the generation of osteoarthritis and osteoporosis have substantial connection.

The present invention according to the pathological characteristic of osteoarthritis, provide a kind of increase bone density, protection and improve articular cartilage function, the technical scheme of composition and method of making the same of inflammation-inhibiting reaction is through the technical scheme that a large amount of screening test obtains.

Compositions of the present invention is mainly for osteoarthrosis sub-health population, from the osteoporotic angle of improvement, at supplementary calcium preparation with while promoting calcium absorption, add glucosamine and the chondroitin sulfate crude drug of human bone joint needs, realize Synergistic, improve osteoarticular sub-health status, increase bone density.

Each supplementary material of compositions of the present invention promotes the absorption of calcium and the deposition on skeleton from different perspectives, by different mechanism, suppresses dissolving and the loss of calcium, promote the formation of bone matrix, thus comprehensively make bone density increase, recover bone function.

Judge according to increasing the criterion of the bone substance density improving function method of inspection in " health food inspection and assessment technical specification " (version in 2003), it is positive that compositions of the present invention increases bone substance density improving function, and this given the test agent can use as calsium supplement.

The compositions that there is joint protection and increase bone density effect provided by the invention, can increase bone density, alleviate bone pain, recover bone function and suppress osteoarthritic inflammation reaction, its beneficial effect is:

Effective promotion calcium absorption; Repair osteoarthrosis cell, promote bone cell growth; Obvious increase bone density, prevents and treats osteoporosis; Effective promotion skeleton collagen metabolism, stabilization of bony collagen meshwork, activation muscles and bones, anti-curing arthritis and aching; Recover osteoarthrosis proper motion function; Reduce fracture occurrence risk; Suppress osteoarthritic inflammation reaction, improve the quality of living.

Compositions of the present invention can make tablet through direct compression, without wet granular or dry particle disposal, improves the stability of effective ingredient, and shortens operation, more economically and environmental protection.

Compositions of the present invention designs ingenious uniqueness, mutually works in coordination with between component, and bioavailability is high, for increasing bone density, can alleviate bone pain, recover bone function, obviously solve the symptoms such as osteoporosis, bone pain and osteoarthrosis afunction; The preparation method of compositions of the present invention, technique is simple, easy to operate, is applicable to commercial production, has no side effect, be suitable for large-scale promotion application.

Detailed description of the invention

Referring to specific embodiment, the present invention is described.It will be appreciated by those skilled in the art that these embodiments are only for illustration of the present invention, its scope do not limited the present invention in any way.

Experimental technique in following embodiment, if no special instructions, is conventional method.Supplementary material used in following embodiment, reagent material etc., if no special instructions, be commercially available purchase product.

embodiment 1: composition tablet preparation of the present invention

1, raw material composition:

Calcium cirate malate 330g, Glucosamine sulfate potassium chloride 220g, chondroitin sulfate 160g, bone collagen Gly-His-Lys 100g, phosphopeptide caseinate 30g.

2, adjuvant consists of:

Lactose 50g, copolyvidone 50g, microcrystalline Cellulose 40g, silicon dioxide 5g, magnesium stearate 5g.

3, preparation method:

(1) measure each supplementary material moisture, and control moisture≤5.0%;

(2) calcium cirate malate, bone collagen Gly-His-Lys, phosphopeptide caseinate, lactose, copolyvidone, microcrystalline Cellulose are crossed 60 mesh sieves; Chondroitin sulfate, magnesium stearate cross 80 mesh sieves, take each supplementary material by formula;

(3) Glucosamine sulfate potassium chloride and silicon dioxide are mixed 5 minutes, cross 80 mesh sieves, remix 5 minutes; Carry out mixing 30 minutes with above-mentioned other material automatic lifting hopper mixer sieved again, after material to be loaded in transfer container and weighs, sampling and detect moisture on moisture test apparatus, is≤5.0% by above-mentioned Material control moisture;

(4) by the material tabletting machine that step (3) obtains, make 1000, Hardness Control is at 12 ~ 20kg, and sheet heavily controls the scope at 0.99g ± 5%; Described tabletting terminates rear moisture test apparatus and detects moisture, controls moisture≤5.0%;

(5) film coating pre-mix dose 29.7g is weighed, add purified water 198g as coating solvent, preparation coating solution, control inlet temperature about 75 DEG C, sheet bed tempertaure about 45 DEG C, the leaving air temp about 55 DEG C during coating, atomizing pressure is at 0.1 ~ 0.3Mpa, the label made to step (4) carries out coating, every agreement that contracts a film or TV play to an actor or actress 1.02 ± 5% grams after coating.

embodiment 2: composition tablet preparation of the present invention

1, raw material composition:

Calcium cirate malate 400g, Glucosamine sulfate potassium chloride 150g, chondroitin sulfate 200g, bone collagen Gly-His-Lys 50g, phosphopeptide caseinate 40g.

2, adjuvant composition:

Lactose 70g, copolyvidone 50g, microcrystalline Cellulose 30g, silicon dioxide 5g, magnesium stearate 5g.

3, preparation method:

(1) measure each supplementary material moisture, control moisture≤5.0%;

(2) each supplementary material is crossed 60 mesh sieves, take each supplementary material by formula;

(3) Glucosamine sulfate potassium chloride and silicon dioxide are mixed 30 minutes, mixing is carried out 45 minutes again with above-mentioned other material automatic lifting hopper mixer sieved, after material to be loaded in transfer container and weighs, sampling detects moisture on moisture test apparatus, is≤5.0% by above-mentioned Material control moisture;

(4) by the material tabletting machine that step (3) obtains, make 1000, Hardness Control is at 12 ~ 20kg, and sheet heavily controls the scope at 1.00g ± 5%; Described tabletting terminates rear moisture test apparatus and detects moisture, controls moisture≤5.0%.

embodiment 3: composition tablet preparation of the present invention

1, raw material composition:

Calcium cirate malate 250g, Glucosamine sulfate potassium chloride 300g, chondroitin sulfate 100g, bone collagen Gly-His-Lys 150g, phosphopeptide caseinate 40g.

2, adjuvant composition:

Lactose 30g, copolyvidone 50g, microcrystalline Cellulose 55g, silicon dioxide 5g, magnesium stearate 10g.

3, preparation method:

(1) measure each supplementary material moisture, control moisture≤5.0%;

(2) each supplementary material is crossed 80 mesh sieves, take each supplementary material by formula;

(3) Glucosamine sulfate potassium chloride and silicon dioxide are mixed 10 minutes, mixing is carried out 75 minutes again with above-mentioned other material automatic lifting hopper mixer sieved, after material to be loaded in transfer container and weighs, sampling detects moisture on moisture test apparatus, is≤5.0% by above-mentioned Material control moisture;

(5) film coating pre-mix dose 29.7g is weighed, add purified water 168.3g as coating solvent, preparation coating solution, control inlet temperature about 75 DEG C, sheet bed tempertaure about 45 DEG C, the leaving air temp about 55 DEG C during coating, atomizing pressure is at 0.1 ~ 0.3Mpa, the label made to step (4) carries out coating, every agreement that contracts a film or TV play to an actor or actress 1.02 ± 5% grams after coating.

embodiment 4: composition tablet preparation of the present invention

1, raw material composition:

Calcium cirate malate 300g, Glucosamine sulfate potassium chloride 250g, chondroitin sulfate 180g, bone collagen Gly-His-Lys 60g, phosphopeptide caseinate 50g.

2, adjuvant composition:

Lactose 40g, copolyvidone 60g, microcrystalline Cellulose 48g, silicon dioxide 7g, magnesium stearate 5g.

3, preparation method:

(1) measure each supplementary material moisture, control moisture≤5.0%;

(3) Glucosamine sulfate potassium chloride and silicon dioxide are mixed 15 minutes, mixing is carried out 60 minutes again with above-mentioned other material automatic lifting hopper mixer sieved, after material to be loaded in transfer container and weighs, sampling detects moisture on moisture test apparatus, is≤5.0% by above-mentioned Material control moisture;

(4) by the material tabletting machine that step (3) obtains, make 1000, Hardness Control is at 12 ~ 20kg, and sheet heavily controls the scope at 0.99g ± 5%; Described tabletting terminates rear moisture test apparatus and detects moisture, controls moisture≤5.0%.

embodiment 5: composition tablet preparation of the present invention

1, raw material composition:

Calcium cirate malate 350g, Glucosamine sulfate potassium chloride 200g, chondroitin sulfate 140g, bone collagen Gly-His-Lys 120g, phosphopeptide caseinate 30g.

2, adjuvant composition:

Lactose 60g, copolyvidone 40g, microcrystalline Cellulose 40g, silicon dioxide 5g, magnesium stearate 3g.

3, preparation method:

(1) measure each supplementary material moisture, control moisture≤5.0%;

(3) Glucosamine sulfate potassium chloride and silicon dioxide are mixed 5 minutes, mixing is carried out 60 minutes again with above-mentioned other material automatic lifting hopper mixer sieved, after material to be loaded in transfer container and weighs, sampling detects moisture on moisture test apparatus, is≤5.0% by above-mentioned Material control moisture;

(5) film coating pre-mix dose 29.7g is weighed, add purified water 564.3g as coating solvent, preparation coating solution, control inlet temperature about 75 DEG C, sheet bed tempertaure about 45 DEG C, the leaving air temp about 55 DEG C during coating, atomizing pressure is at 0.1 ~ 0.3Mpa, the label made to step (4) carries out coating, every agreement that contracts a film or TV play to an actor or actress 1.02 ± 5% grams after coating.

embodiment 6: composition tablet preparation of the present invention

1, raw material composition:

Calcium cirate malate 320g, Glucosamine sulfate potassium chloride 250g, chondroitin sulfate 180g, bone collagen Gly-His-Lys 80g, phosphopeptide caseinate 10g.

2, adjuvant composition:

Lactose 40g, copolyvidone 50g, microcrystalline Cellulose 48g, silicon dioxide 7g, magnesium stearate 5g.

3, preparation method:

(1) measure each supplementary material moisture, control moisture≤5.0%;

(3) Glucosamine sulfate potassium chloride and silicon dioxide are mixed 5 minutes, cross 80 mesh sieves, remix 5 minutes, mixing is carried out 60 minutes again with above-mentioned other material automatic lifting hopper mixer sieved, after material to be loaded in transfer container and weighs, sampling detects moisture on moisture test apparatus, is≤5.0% by above-mentioned Material control moisture;

(5) film coating pre-mix dose 29.7g is weighed, coating solution solid content 15%, preparation coating solution, control inlet temperature about 75 DEG C, sheet bed tempertaure about 45 DEG C, the leaving air temp about 55 DEG C during coating, atomizing pressure is at 0.1 ~ 0.3Mpa, the label made to step (4) carries out coating, every agreement that contracts a film or TV play to an actor or actress 1.02 ± 5% grams after coating.

embodiment 7: composition tablet preparation of the present invention

1, raw material composition:

Calcium cirate malate 330g, Glucosamine sulfate potassium chloride 220g, chondroitin sulfate 160g, bone collagen Gly-His-Lys 100g, phosphopeptide caseinate 30g, curcumin 25g.

2, adjuvant composition:

Lactose 50g, copolyvidone 65g, microcrystalline Cellulose 40g, silicon dioxide 5g, magnesium stearate 5g.

3, preparation method:

(1) measure each supplementary material moisture, control moisture≤5.0%;

(2) calcium cirate malate, bone collagen Gly-His-Lys, phosphopeptide caseinate, curcumin, lactose, copolyvidone, microcrystalline Cellulose are crossed 60 mesh sieves; Chondroitin sulfate, magnesium stearate cross 80 mesh sieves, take each supplementary material by formula;

(3) Glucosamine sulfate potassium chloride and silicon dioxide are mixed 5 minutes, cross 80 mesh sieves, remix 5 minutes; Carry out mixing 60 minutes with above-mentioned other material automatic lifting hopper mixer sieved again, after material to be loaded in transfer container and weighs, sampling and detect moisture on moisture test apparatus, is≤5.0% by above-mentioned Material control moisture;

(4) by the material tabletting machine that step (3) obtains, make 1000, Hardness Control is at 12 ~ 20kg, and sheet heavily controls the scope at 1.03g ± 5%; Described tabletting terminates rear moisture test apparatus and detects moisture, controls moisture≤5.0%;

(5) film coating pre-mix dose 31g is weighed, add purified water 210g as coating solvent, preparation coating solution, control inlet temperature about 75 DEG C, sheet bed tempertaure about 45 DEG C, the leaving air temp about 55 DEG C during coating, atomizing pressure is at 0.1 ~ 0.3Mpa, the label made to step (4) carries out coating, every agreement that contracts a film or TV play to an actor or actress 1.06 ± 5% grams after coating.

embodiment 8: composition tablet preparation of the present invention

1, raw material composition:

Calcium cirate malate 330g, Glucosamine sulfate potassium chloride 220g, chondroitin sulfate 160g, bone collagen Gly-His-Lys 100g, phosphopeptide caseinate 30g, curcumin 10g.

2, adjuvant composition:

3, preparation method:

(1) measure each supplementary material moisture, control moisture≤5.0%;

(3) Glucosamine sulfate potassium chloride and silicon dioxide are mixed 15 minutes, cross 80 mesh sieves, mixing is carried out 45 minutes again with above-mentioned other material automatic lifting hopper mixer sieved, after material to be loaded in transfer container and weighs, sampling detects moisture on moisture test apparatus, is≤5.0% by above-mentioned Material control moisture;

(5) film coating pre-mix dose 30g is weighed, add purified water 170g as coating solvent, preparation coating solution, control inlet temperature about 75 DEG C, sheet bed tempertaure about 45 DEG C, the leaving air temp about 55 DEG C during coating, atomizing pressure is at 0.1 ~ 0.3Mpa, the label made to step (4) carries out coating, every agreement that contracts a film or TV play to an actor or actress 1.03 ± 5% grams after coating.

embodiment 9: composition tablet preparation of the present invention

1, raw material composition:

Calcium cirate malate 400g, Glucosamine sulfate potassium chloride 150g, chondroitin sulfate 200g, bone collagen Gly-His-Lys 50g, phosphopeptide caseinate 40g, curcumin 20g;

2, adjuvant composition:

Lactose 60g, copolyvidone 50g, microcrystalline Cellulose 20g, silicon dioxide 5g, magnesium stearate 5g.

3, preparation method:

(1) measure each supplementary material moisture, control moisture≤5.0%;

(3) Glucosamine sulfate potassium chloride and silicon dioxide are mixed 5 minutes, mixing is carried out 45 minutes again with the above-mentioned automatic lifting of screened material hopper mixer, after material to be loaded in transfer container and weighs, sampling detects moisture on moisture test apparatus, is≤5.0% by above-mentioned Material control moisture;

(5) film coating pre-mix dose 30g is weighed, add purified water 120g as coating solvent, preparation coating solution, control inlet temperature about 75 DEG C, sheet bed tempertaure about 45 DEG C, the leaving air temp about 55 DEG C during coating, atomizing pressure is at 0.1 ~ 0.3Mpa, the label made to step (4) carries out coating, every agreement that contracts a film or TV play to an actor or actress 1.03 ± 5% grams after coating.

embodiment 10: composition tablet preparation of the present invention

1, raw material composition:

Calcium cirate malate 250g, Glucosamine sulfate potassium chloride 300g, chondroitin sulfate 100g, bone collagen Gly-His-Lys 150g, phosphopeptide caseinate 40g, curcumin 50g;

2, adjuvant composition:

Lactose 50g, copolyvidone 70g, microcrystalline Cellulose 50g, silica 1 0g, magnesium stearate 5g;

3, preparation method:

(1) measure each supplementary material moisture, control moisture≤5.0%;

(3) Glucosamine sulfate potassium chloride and silicon dioxide are mixed 30 minutes, mixing is carried out 75 minutes again with above-mentioned other material automatic lifting hopper mixer sieved, after material to be loaded in transfer container and weighs, sampling detects moisture on moisture test apparatus, is≤5.0% by above-mentioned Material control moisture;

(4) by the material tabletting machine that step (3) obtains, make 1000, Hardness Control is at 12 ~ 20kg, and sheet heavily controls the scope at 1.08g ± 5%; Described tabletting terminates rear moisture test apparatus and detects moisture, controls moisture≤5.0%;

(5) film coating pre-mix dose 33g is weighed, add purified water 438g as coating solvent, preparation coating solution, control inlet temperature about 75 DEG C, sheet bed tempertaure about 45 DEG C, the leaving air temp about 55 DEG C during coating, atomizing pressure is at 0.1 ~ 0.3Mpa, the label made to step (4) carries out coating, every agreement that contracts a film or TV play to an actor or actress 1.10 ± 5% grams after coating.

embodiment 11: composition tablet preparation of the present invention

1, raw material composition:

Calcium cirate malate 300g, Glucosamine sulfate potassium chloride 250g, chondroitin sulfate 180g, bone collagen powder 60g, phosphopeptide caseinate 50g, curcumin 40g;

2, adjuvant composition:

Lactose 40g, copolyvidone 68g, microcrystalline Cellulose 50g, silicon dioxide 7g, magnesium stearate 5g;

3, preparation method:

(1) measure each supplementary material moisture, control moisture≤5.0%;

(4) by the material tabletting machine that step (3) obtains, make 1000, Hardness Control is at 12 ~ 20kg, and sheet heavily controls the scope at 1.01g ± 5%; Described tabletting terminates rear moisture test apparatus and detects moisture, controls moisture≤5.0%.

embodiment 12: compositions electuary preparation of the present invention

1, raw material composition:

Calcium cirate malate 1980g, Glucosamine sulfate potassium chloride 1320g, chondroitin sulfate 960g, bone collagen Gly-His-Lys 600g, phosphopeptide caseinate 180g;

2, adjuvant composition:

Silicon dioxide 50g, magnesium stearate 50g, resistant dextrin 4860g;

3, preparation method:

(1) measure each supplementary material moisture, control moisture≤5.0%; Calcium cirate malate, bone collagen Gly-His-Lys, phosphopeptide caseinate, resistant dextrin are crossed 60 mesh sieves; Glucosamine sulfate potassium chloride, chondroitin sulfate, magnesium stearate cross 80 mesh sieves, take each supplementary material by formula;

(2) Glucosamine sulfate potassium chloride and silicon dioxide are mixed 15 minutes;

(3) mixture step (2) obtained mixes 60 minutes with other supplementary material automatic lifting hopper mixers, and rotating speed is 15 revs/min, and to control moisture be≤5.0%;

(4) material that obtains of step (3), is distributed into 1000 bags with aluminum-plastic composite membrane, 10 grams every bag.

embodiment 13: compositions electuary preparation of the present invention

1, raw material composition:

2, adjuvant composition:

Silicon dioxide 50g, magnesium stearate 50g, resistant dextrin 4710g;

3, preparation method:

(1) each supplementary material is crossed 80 mesh sieves, control each supplementary material moisture≤5.0%, take each supplementary material by described proportioning;

(2) Glucosamine sulfate potassium chloride and silicon dioxide are mixed 5 minutes;

(3) mixture that step (2) obtains is mixed 30 minutes with all the other supplementary materials with the rotating speed of 10 revs/min, control moisture≤5.0%;

(4) material that obtains of step (3), makes 1000 bags with aluminum-plastic composite membrane subpackage, 10 grams every bag.

embodiment 14: compositions electuary preparation of the present invention

1, raw material composition:

Calcium cirate malate 400g, Glucosamine sulfate potassium chloride 150g, chondroitin sulfate 200g, bone collagen Gly-His-Lys 50g, phosphopeptide caseinate 40g;

2, preparation method:

(1) measure each raw material moisture, control moisture≤5.0%;

(2) calcium cirate malate, bone collagen Gly-His-Lys, phosphopeptide caseinate are crossed 60 mesh sieves; Glucosamine sulfate potassium chloride, chondroitin sulfate cross 80 mesh sieves, take each raw material by formula;

(3) step (2) Raw automatic lifting hopper mixer mixes 60 minutes, and to control moisture be≤5.0%;

(4) material that obtains of step (3), makes 1000 bags with aluminum-plastic composite membrane subpackage, 8.4 grams every bag.

embodiment 15: recipe optimization optimization experiment

1, the impact on mobility and tablet weight difference, friability of supplementary material hybrid technique is investigated

Method 1: according to embodiment 1 formula ratio and technological operation, that is: mix 5 minutes by Glucosamine sulfate potassium chloride and silicon dioxide, crosses 80 mesh sieves, remix 5 minutes; Add the mixing of other supplementary material again;

Method 2: according to embodiment 8 formula ratio and technological operation, that is: mix 15 minutes by Glucosamine sulfate potassium chloride and silicon dioxide, crosses 80 mesh sieves, then add the mixing of other supplementary material;

Method 3: according to embodiment 1 formula ratio, all supplementary materials directly mix after crossing 60 ~ 80 mesh sieves, and other techniques are identical;

Method 4: according to embodiment 1 formula (the few 5g of silicon dioxide), all supplementary materials directly mix after crossing 60 ~ 80 mesh sieves, and other techniques are identical;

Batch mixing angle of repose, tablet weight variation, hardness range and friability in assay method 1-4, the results are shown in Table 1:

Table 1: supplementary material hybrid technique is on the impact of mobility and tablet weight difference, friability

Mixed method	Method 1	Method 2	Method 3	Method 4
					Batch mixing angle of repose °	35.17	36.85	41.55	44.34
Tablet weight variation (g)	0.99±2.3％	1.00±3.6％	0.99±5.2％	0.99±6.1％
					Hardness range (kg)	160～180	150～170	110～150	100～160
Friability (%)	0.13	0.15	1.10	1.64

As can be seen from the table, the technique of method 1 and method 2 is more excellent, namely adopts Glucosamine sulfate potassium chloride and silicon dioxide premixing, add the hybrid technique of other supplementary material mixing again, material is low for angle of repose, and compressibility is good, obtained tablet weight difference is little, and friability is low.Otherwise do not add the formula of lubricant silicon dioxide, material is high for angle of repose, and mobility is bad, and compressibility is bad, obtained tablet weight difference is large, and friability is high.

2, investigation wet granulation and direct powder compression of the present invention are on the impact of product efficacy component content

1, raw material composition:

Calcium cirate malate 330g, Glucosamine sulfate potassium chloride 220g, chondroitin sulfate 160g, bone collagen Gly-His-Lys 100g, phosphopeptide caseinate 30g;

2, adjuvant composition:

Lactose 50g, copolymer fibre 50g, microcrystalline Cellulose 40g, silicon dioxide 5g, magnesium stearate 5g,

3, illustrate: raw material and the accessory formula of wet granulation and powder vertical compression of the present invention are consistent, and soft material prepared by wet granulation 60% ethanol, dry moisture extremely≤5.0% at 60 DEG C, tabletting; Powder vertical compression of the present invention is prepared according to the method for embodiment 1; Contrast the content of Glucosamine sulfate potassium chloride and chondroitin sulfate under two kinds of tabletting modes; The results are shown in Table 2:

Table 2: wet granulation and powder vertical compression sheet of the present invention are on the impact of functional component content

Test item	Wet granulation	Powder vertical compression
			Outward appearance	Light yellow	Off-white color
Moisture	3.40	3.52
			Glucosamine sulfate potassium chloride %	17.4	19.6
Chondroitin sulfate %	15.93	15.86

Conclusion: carry out contrast visible under two kinds of same materials and supplementary product consumption condition, after employing wet granule compression tablet, the appearance color of product is light yellow, the product colour obtained than powder vertical compression sheet mode of the present invention is dark, and its Glucosamine sulfate potassium chloride content reduces.Illustrate that wet granule compression tablet technique is not suitable for this Recipe, technique of direct powder compression of the present invention should be adopted.

embodiment 16: the label humidity effect factor of compositions gained tablet of the present invention

Example 1 prepare label sample several pieces, except unlap, put in surface plate, in the constant humidity hermetic container of relative humidity 90% ± 5% place 10 days, period control temperature be 25 DEG C.Content results is in table 3:

Table 3: humidity effect factorial experiments result

Conclusion: compositions of the present invention is under high humidity environment, its Glucosamine sulfate potassium chloride content is along with the prolongation of standing time, content continuous decrease, illustrate that humidity will affect the stability of the content of Glucosamine sulfate potassium chloride, therefore result of the test points out compositions of the present invention to consider moisture preventive measure.Compositions of the present invention adopts film coating and the excellent high-density polyethylene plastics bottle of humidity resistance to be that packaging material carry out protection against the tide.

embodiment 17: stability test

1, get 1#, 2#, 3# tri-groups of samples prepared by embodiment 1,7 and 8, be positioned over high-density polyethylene plastics bottle, included desiccant, with metal pad pasting in bottle cap, with the sealing of electromagnetic induction heat sealing machine, sealing is positioned in climatic chamber, carries out stability test;

2, stability test acceleration environment: temperature 37 ± 2 DEG C, relative humidity RH75 ± 5%, avoids light direct projection;

3, physical and chemical index:

Moisture: the method specified by GB50O9.3 measures; Ash: the method specified by GB5OO9.4 measures; Protein: the method specified by GB50O9.5 measures; Disintegration: measure by the method for Chinese Pharmacopoeia 2015 editions regulation; Plumbous: the method specified by GB5009.12 measures; Arsenic: the method specified by GB/T5009.11 measures;

Effective component index detection method:

Calcium: the method specified by GB5009.92 measures; The assay method of chondroitin sulfate and glucosamine hydrochloride content carries out with reference to GB20365 method.

The results are shown in Table 4 ~ table 7;

Table 4: the above-mentioned sample detection result of the present embodiment

Table 5: the testing result after 1 month deposited by the above-mentioned sample of the present embodiment

Table 6: the testing result after 2 months deposited by the above-mentioned sample of the present embodiment

Table 7: the testing result after 3 months deposited by the above-mentioned sample of the present embodiment

As can be seen from the present embodiment stability test assay, above-mentioned 1#, 2#, 3# tri-groups of samples are white tablet, temperature 37 DEG C ~ 40 DEG C, 1,2,3 month is deposited respectively under the condition of relative humidity 75%, the organoleptic indicators such as the color of three groups of samples, character, flavour, abnormal smells from the patient and quality are all normal, without significant change occurs.

embodiment 18: composition tablet its mouse oral acute toxicity test prepared by the present invention

1, materials and methods

1.1 samples: the composition tablet prepared according to the embodiment of the present invention 1 is white tablet, close, and put aeration-drying place and preserve; Instructions of taking is recommended to be 1.0g/ sheet, 3 times/day, 2 pieces/times; With 60kg adult body restatement, the day recommended amounts of this sample is 0.1g/kgBW; Take sample 20.0g pure water during test and be diluted to 40.0mL for examination;

1.2 laboratory animals: the Kunming kind SPF level healthy mice 20 that Guangdong Medical Lab Animal Center provides, male and female half and half, original body mass scope is 18g ~ 22g;

Animal productiong credit number: SCXK (Guangdong) 2013-0002;

The certification of fitness is numbered: NO.44007200015420;

This center laboratory animal occupancy permit number: SYXK (Guangdong) 2013-0011;

Feeding environment: temperature change scope (DEG C): 20 ~ 26; Humidity mobility scale (%): 40 ~ 70;

Feedstuff: provided by Guangdong Medical Lab Animal Center;

L.3 dosage choice: adopt maximum tolerated dose (MTD) method, can gavage concentration, gavage capacity and safety coefficient according to the maximum of this sample, if tested material dosage is 20.0g/kgBW;

1.4 key instruments and reagent: electronic balance;

1.5 test methods: animal fasting can't help water after 16 hours, per os gavage secondary, 4 hours, interval, each gavage amount is 0.2mL/10gBW, observes one week, record mice poisoning manifestations and death condition;

1.6 test data statistics: employing SPSS13.0 statistical software spouts to go and adds up;

1.7 results judge: according to MTD numerical value, judge the toxicity grading of tested material; Tentatively pointed out by poisoning manifestations and characterize toxic action feature;

2, test result: composition tablet its mouse oral the acute toxicity tests prepared by the present invention is in table 7,20.0g/kgBW dosage group is not observed animal and is occurred untoward reaction and death, obtain D-glucosamine chrondroitin collagen calcium tablet male and female mice MTD>20.0g/kgBW, be equivalent to 200 times of tested material day recommended amounts.

Table 8: composition tablet the acute toxicity tests prepared by the embodiment of the present invention 1

3, its mouse oral acute toxicity test brief summary:

Male and female its mouse oral acute toxicity maximum tolerated dose (MTD) >20.0g/kgBW, according to acute toxicity classification, compositions of the present invention belongs to nontoxic level material.

embodiment 19: compositions mouse marrow cell micro nuclear test prepared by the present invention

1, materials and methods

1.1 samples: prepare composition tablet according to the embodiment of the present invention 1 are white tablet; Close, put aeration-drying place and preserve.Take during test sample 10.0,5.00,2.50g is diluted to 20.0mL for examination with pure water respectively;

1.2 laboratory animals: the Kunming kind SPF level healthy mice 50 that Guangdong Medical Lab Animal Center provides, male and female half and half, original body mass scope is 25g ~ 30g;

Animal productiong credit number: SCXK (Guangdong) 2013-0002;

The certification of fitness is numbered: NO.44007200O15797;

Feedstuff is provided by Guangdong Medical Lab Animal Center.

1.3 dosage choice: laboratory animal is divided into 5 groups at random, often organize 10, male and female half and half.According to the acute toxicity tests, if tested material maximum dose level is 10.0g/kgBW, this dosage to divide into 5.00,2.50g/kgBW two dosage, negative control group gives the pure water of equivalent, and positive controls selects 40mg/kgBW cyclophosphamide (CP).

1.4 key instruments and reagent: electronic balance, biosystem microscope, calf serum, Ji's nurse Sa dye liquor.

1.5 test methods: adopt 30 hours give tested material method test, per os gavage, gavage amount is 0.2mL/10gBW, first time contamination carried out second time contamination with same dosage after 24 hours, after 6 hours, under execution mice gets the film-making of bone marrow of sternum material, dyeing, oily mirror, every mice counts 1000 polychromatic erythrocytes (PCE), observes the polychromatic erythrocyte number containing micronucleus; If there is two or more micronucleus in a polychromatic erythrocyte, still micronucleus cell is had to count by one; Calculate each group of microkernel incidence (‰).Count the cell (NCE) that just incarnadines seen when observing 200 PCE to count simultaneously, obtain the ratio (PCE/RBC, RBC=PCE+NCE) of polychromatic erythrocyte number and Erythrocytes.

1.6 test data statistics: take statistics by Poisson distribution method and learn process.

1.7 results judge: tested material each dosage group micronuclear rates, compared with negative control group, when difference has statistical significance and has obvious dose-response relationship, can confirm as positive findings.If significant difference has significance, but during without dose-response relationship, must carry out repeated trials, result energy repetition person is defined as the positive.

2, result: compositions mouse marrow cell micro nuclear test prepared by the present invention the results are shown in Table 8 and table 9, the micronuclear rates of each dosage group of compositions mice prepared by the present invention compares with negative control group, difference that there are no significant (p>0.05).

Table 9: compositions female mice Micronucleus test result prepared by the present invention

Note: * * compares P<0.01 with negative control group.

Table 10: compositions Male mouse bone marrow cell micronucleus test result prepared by the present invention

Note: * * compares P<0.01 with negative control group.

3, mouse marrow cell micro nuclear test brief summary:

The micronucleus test result of compositions 2.50 ~ 10.0g/kgBW dosage prepared by tested material the present invention is for negative.

embodiment 20: compositions ammonia mouse inbred strain prepared by the present invention

1, materials and methods

1.1 samples: the composition tablet prepared according to embodiment 1 is white tablet; Close, put aeration-drying place and preserve.Take during test sample 10.0,5.00,2.50g is diluted to 20.0mL for examination with pure water respectively.

1.2 laboratory animals: the healthy male white mouse 25 of the Kunming kind SPF level that Guangdong Medical Lab Animal Center provides, original body mass scope is 25g ~ 35g;

Animal productiong credit number: SCXK (Guangdong) 2013-0002, the certification of fitness is numbered: NO.44007200015606;

Feedstuff is provided by Guangdong Medical Lab Animal Center.

1.3 dosage choice: laboratory animal is divided into 5 groups at random, often organize 5, according to the acute toxicity tests, if tested material maximum dose level is 10.0g/kgBW, this dosage to divide into 5.00,2.50g/kgBW two dosage, negative control group gives the pure water of equivalent, and positive controls selects 40mg/kgBW cyclophosphamide (CP).

1.4 key instruments and reagent: electronic balance, biosystem microscope; Normal saline, eosin stains liquid.

1.5 test methods: adopt per os gavage mode to give tested material, every day gavage once, continuous gavage 5 days, gavage amount is 0.2mL/10gBW, within after contamination the 35th day first, put to death animal and get the film-making routinely of bilateral epididymis, dyeing, under high power lens, microscopy is observed, and every mice counts 1000 complete sperms, often organize and check 5O00 bar sperm altogether, obtain Sperm malformation rate (‰).

1.6 test data statistics: take statistics by Wilcoson rank test method and learn process.

1.7 results judge: each dosage component does not compare with corresponding negative control group, the standard confirming as the positive be abnormal rate be at least negative control group times amount or through adding up significance, and have dose-response relationship.

2, result: compositions mouse inbred strain prepared by the present invention the results are shown in Table 11, by analysis, difference (p>0.05) that the rate of teratosperm of each dosage group of compositions that prepared by the present invention compares with negative control group that there are no significant.

Table 11: compositions mouse inbred strain result prepared by the present invention

Note: * * compares P<0.01 with negative control group.

3, mouse inbred strain brief summary:

The sperm malformation test result of tested material D-glucosamine chrondroitin collagen calcium tablet 2.50 ~ 10.0g/kgBW dosage is negative.

embodiment 21: compositions Salmonella typhimurium prepared by the present invention/mammal microsomal enzyme test (Salmonella reversion test)

1, materials and methods

1.1 samples: prepare composition tablet of the present invention according to embodiment 1 are white tablet; Close, put aeration-drying place and preserve.Sample 5.00g is taken before experiment, take distilled water as solvent, after sample dissolution, adding distil water is to 100.0mL, be mixed with the mother solution of 5% as maximum dose level, then with distilled water, 5 times taken turns doing to mother solution and be diluted to required each dose of test thing solution, 0.103MPa20min sterilizing, jolting mixes, and is for experiment.

1.2 test strains: through satisfactory Salmonella typhimurium histidine deficient TA97, TA98, TA1OO, TA102 test strain of qualification.

1.3 metabolism activation systems: the rat liver homogenate S9 liquid (adding when metabolism activation) that Polychlorinated biphenyls (PCB) is induced.

1.4 dosage choice: according to tested material to the toxicity of antibacterial and dissolubility thereof, determine that tested material maximum dose level is 5000ug/ ware, by 5 times of intervals, establish five dosage groups altogether, be respectively 5000,1000,200,40,8ug/ ware, establish from beaming back change, solvent control and positive controls simultaneously.

1.5 key instruments and reagent: electronic balance low-temperature and high-speed centrifuge, liquid nitrogen container, Biohazard Safety Equipment, constant incubator, water bath with thermostatic control, pressure cooker, homogenizer.

1.6 test methods (dull and stereotyped incorporation methods): add 0.10mL test strain enrichment liquid in top layer culture medium, 0.10mL tested material solution and 0.50mLS9 mixed liquor (adding when metabolism activation), pour on bottom culture medium flat plate after mixing, every dose group is three wares.Cultivate after 48 hours at putting 37 DEG C, record the every ware of each dosage group and return change clump count.

1.7 test data is added up: adopt SPSS13.0 statistical software to add up.

1.8 results judge: when tested material group return become clump count double above (namely tested material group return become clump count be equal to or greater than 2 be multiplied by solvent control group return change clump count), and have dose-response relationship or at least a certain test point have repeatably and have the positive reaction of statistical significance, be namely judged to be that this tested material Salmonella reversion test is positive.

2., result

Compositions Salmonella reversion test prepared by the present invention the results are shown in Table 12 and table 13, the each dosage group of compositions prepared by the present invention is to Salmonella typhimurium TA97, TAg8, TA100, TA102 tetra-strain test strain, when adding and do not add S9, return and become clump count and all do not exceed solvent control group and return and become 2 times of clump count, also without repeatably and have the test point of the positive reaction of statistical significance.

Table 12: compositions prepared by the present invention becomes result (the 1st time) to returning of Salmonella typhimurium

Note: the unit of dosage is (μ g/ ware)

Table 13: compositions prepared by the present invention becomes result (the 2nd time) to returning of Salmonella typhimurium

Note: the unit of dosage is (μ g/ ware)

3, Salmonella reversion test conclusion:

Compositions prepared by tested material the present invention is carried out plate to Histidine auxotroph strain of Salmonella typhimurium TA97, TA98, TA100, TA102 and is mixed test, no matter when adding and do not add S9 mixed liquor, the each dosage group of 8 ~ 5000ug/ ware does not all cause the recovery mutation colony number of test strain significantly to increase, and Salmonella reversion test result is negative.

embodiment 22: increase bone substance density improving function test

1, material

1.1 given the test agent: prepare compositions according to the embodiment of the present invention 1,1.0g/ sheet × 180 slice/bottle, polyethylene is bottled, white tablet, and human body recommended daily dosage is 1.0g/ sheet, 3 times/day, 2 pieces/times, and in the body weight 60kg that is grown up, recommended amounts is 0.10g/kgBW.

1.2 dose design: basic, normal, high three dosage groups are established in this experiment, dosage is respectively 0.50,1.00,3.00g/kgBW, be equivalent to 5,10,30 times of human body recommended amounts, separately establish a low calcium matched group (150mg/100g feedstuff) and a calcium carbonate control group (setting up the calcium carbonate control group identical with high dose calcium level).

1.3 tested materials preparations: mixed by given the test agent to sample in feedstuff, daily take in the conversion of 8g feedstuff by rat 100g body weight, to be mixed in low calcium matched group feedstuff by sample respectively make basic, normal, high dosage group tested material by 0.63%, 1.25% and 3.75%.

1. 4 tested material approach is given: tested material is given respectively each dosage treated animal and freely ingest; Low calcium control animals gives low calcium feedstuff (150mg/100g feedstuff); After testing, given the test agent calcium content is 9.33%, be 40% by calcium content in calcium carbonate, then suitable with high dose calcium carbonate dosage is 0.70g/kgBW, therefore on the basis of low calcium feedstuff, mix the calcium carbonate 0.875% identical with high dose group calcium level, give calcium carbonate control group animal ingestion.

1.4 give tested material approach: tested material is given respectively each dosage treated animal and freely ingest.

1.5 animals: SPF level SD kind healthy rat, body weight 67 ~ 93g, is provided by Nanfang Medical Univ's Experimental Animal Center, animal productiong credit number: SCXK (Guangdong) 2011-0015, and the certification of fitness is numbered: NO44002100003823; Pellet is produced by Guangdong Medical Lab Animal Center and is provided.

1.6 Animal Lab. conditions: Animal Lab. is barrier environment, animal occupancy permit number: SYXK (Guangdong) 2013-0011.Room temperature 20 ~ 26 DEG C, humidity 40 ~ 70%.

2, method

2.1 test methods: after 50 rats adapt to three days in laboratory conditions, be divided into five groups at random, are respectively basic, normal, high three the dosage groups of tested material, low calcium matched group and calcium carbonate control group, often organize 10, sub-cage rearing.By its human body recommended amounts, given the test agent day take in Ca and reach 559.8mg, therefore adopt that to replenish the calcium be main increase bone density verification scheme.Tested material and calcium carbonate are added and freely ingest to sample every day in low calcium feedstuff, every Mus ensures sufficient drinking-water, drinks deionized water to avoid obtaining calcium, continuous 90 days from drinking-water.Experiment starts and experiment periods claims weekly a body weight, measures a height (0-4 week).

2.2 observation index

2.2.1 body weight, height measure

Fasting, after 12 hours, measures body weight, height (O-4 week), once in a week.

2.2.2 femur gravimetry

Animal feeding was put to death after 90 days, separated right side femur, baked to constant weight in 105 DEG C of baking boxs.

2.2.3 femoral bmd measures

The bone density of femur mid point and femur distal end is measured with single photon bone density machine.

2.2.4 calcium content of bone and feedstuff calcium content mensuration aas determination.

2.2.5 calcium absorption experiment

2.2.5.1 the ablactation rat of growth promoter birth surrounding is after 1 week laundering period, sub-cage rearing 90 days.Drink deionized water to avoid obtaining calcium from drinking-water.Measure weekly height, body weight once.

2.2.5.2 metabolism

Test after 3 weeks and carry out calcium metabolism experiment in 3 days.Record 3 days food-intakes, collect 72 hours feces, measure calcium content in feedstuff and feces.

Calcium catalyst method in feedstuff and feces: measure by atomic absorption spectrophotometry.

Treatments of the sample: with the digestion of bone calcium, measure and carry out according to the step of atomic absorption spectrophotometer instrument description, measures liquid, standard solution and blank and all uses lanthana solution dilution.

Calculate and take in calcium (mg/ days)=Calcium Content in Foodstuff (mg/g) × feed consumption (g/ days)

Calcium content (mg/g) in excrement calcium (mg/ days)=feces × stool output (g/ days)

Apparent digestibility (%)=(taking in calcium-excrement calcium)/absorption calcium × 100% of calcium

2.3 statistical dispositions: adopt variance analysis, first carry out homogeneity test of variance by the program of variance analysis, variance is neat, calculates F value, F value≤F0.05, no significant difference between each group mean; F value >F0.05, P<0.05, add up with the comparative approach between two of mean between multiple experimental group and a matched group; Suitable variable transitions is carried out to the data of abnormal or heterogeneity of variance, after meeting normal state or variance and requiring together, adds up by the data after conversion; If do not reach normal state or the neat object of variance after variable transitions yet, use rank test instead and add up.

2.4 results judge: calcium content of bone or bone density are significantly higher than low calcium matched group and are not less than corresponding dosage calcium carbonate control group, and the absorbance of calcium is not less than calcium carbonate control group, can judge that tested material has the effect increasing bone substance density improving function.

3, result

The change of 3.1 body weight and food utilization: as seen from Table 14, body weight there was no significant difference between each group rat, shows that compositions prepared by the present invention has no significant effect the weight of animals.

Table 14: compositions prepared by the present invention on the impact of rat body weight (n=10, )

The mensuration of 3.2 heights: as seen from Table 15, each all heights of each dosage treated animal and low calcium matched group ratio, difference there are no significant meaning (P>0.05).

Table 15: compositions prepared by the present invention on the impact of rat height (n=10, )

The mensuration of 3.3 femur weight, calcium content of bone and bone density: as seen from Table 16, dosage group right lateral thigh bone weight compares with low calcium matched group, difference there are no significant meaning (P>0.05).Basic, normal, high dosage treated animal right lateral thigh calcium content of bone compares increase with low calcium matched group, and difference is very significant (P<0.01); High dose group animal right lateral thigh calcium content of bone compares with phase same level calcium carbonate control group and has no significant difference (P>0.05), shows that this given the test agent calcium content of bone result is positive.The mid point bone density of each group and calcium carbonate control group compares with low calcium matched group, no significant difference (P>0.005); The distal bone density of middle and high dosage group and calcium carbonate control group compares increase with low calcium matched group, and difference has very significant to anticipate (P<0.01); High dose group mid point and distal bone density compare with phase same level calcium carbonate control group, no significant difference (P>0.05), show that this given the test agent bone density result is positive.

Table 16: compositions prepared by the present invention on the impact of femur weight, calcium content of bone and bone density (n=10, )

Note: * * represents that each dosage group compares P<0.01 with low calcium matched group.

3.4 calcium absorption experiments, the mensuration of calcium apparent absorptivity: as seen from Table 17, the apparent absorptivity of calcium carbonate control group compares with low calcium matched group, and difference is very significant (P<0.01); But the apparent absorptivity of each dosage group calcium compares with calcium carbonate control group, difference there are no significant meaning (P>0.05), shows that this given the test agent can as calsium supplement.

Table 17: compositions prepared by the present invention on the impact of calcium apparent absorptivity (n=10, )

Continued 17: compositions prepared by the present invention on the impact of calcium apparent absorptivity (n=10, )

Group	Dosage (g/kg bw)	Take in calcium (mg/d)	Excrement calcium (mg/d)	The apparent absorptivity (%) of calcium
					Low calcium matched group	0.00	112.22±9.13	7.18±1.54	93.58±1.34##
Calcium carbonate contrasts	0.70	2670.17±320.34	262.76±42.43	90.12±1.31
					Low dose group	0.50	439.98±43.28	47.72±21.37	88.96±5.38
Middle dosage group	1.00	809.53±271.23	59.97±30.82	90.47±8.09
					High dose group	3.00	2771.08±214.18	250.91±61.71	90.96±1.99

Note: 1.## represents and compares P<0.01 with calcium carbonate control group.

2. the apparent absorptivity of each dosage group compares with calcium carbonate control group, F=0.291, P>0.05.

Two, assay and evaluation:

SPF level SD kind healthy rat is given to the pellet of the compositions prepared containing the embodiment of the present invention 1 of 0.63%, 1.25%, 3.75% every day, dosage is 0.50,1.00,3.00g/kgBW, be equivalent to 5,10,30 times of human body recommended amounts, test period totally 90 days, final result:

1, body weight: respectively organize Body Mass Index there was no significant difference (P>0.05) between rat whole experimental period, shows that D-glucosamine chrondroitin collagen calcium tablet has no significant effect the weight of animals.

2, height: each dosage treated animal 4 weeks heights and low calcium matched group ratio, difference there are no significant meaning (P>0.05).

3, femur weight: each dosage treated animal right lateral thigh bone weight compares with low calcium matched group, no significant difference (P>0.05).

4, calcium content of bone: basic, normal, high dosage treated animal right lateral thigh calcium content of bone compares increase with low calcium matched group, and difference is very significant (P<0.01); High dose group animal right lateral thigh calcium content of bone compares with phase same level calcium carbonate control group, no significant difference (P>0.05), shows that this given the test agent calcium content of bone result is positive.

5, bone density: the distal bone density of middle and high dosage group and calcium carbonate control group compares increase with low calcium matched group, and difference is very significant (P<0.01); High dose group mid point and distal bone density compare with phase same level calcium carbonate control group, no significant difference (P>0.05), show that this given the test agent bone density result is positive.

6, the apparent absorptivity of calcium: the apparent absorptivity of each dosage group calcium compares with calcium carbonate control group, difference there are no significant meaning (P>0.05), shows that this given the test agent can as calsium supplement.

Judge according to increasing the criterion of the bone substance density improving function method of inspection in " health food inspection and assessment technical specification " (version in 2003), it is positive that compositions prepared by the present invention increases bone substance density improving function, and this given the test agent can use as calsium supplement.

embodiment 23 is protected and is improved function of joint test

1, prepared by matched group 1#:

By content 0.45g/ grain specification, make 1000 capsules, each component and consumption as follows: calcium carbonate 50g, calcium cirate malate 140g, D-Glucosamine Hydrochloride 120g, chondroitin sulfate 100g, phosphopeptide caseinate 20g, Catergen 0g.

Preparation method: it is for subsequent use that D-Glucosamine Hydrochloride, chondroitin sulfate, calcium carbonate, calcium cirate malate, phosphopeptide caseinate, vitamin C are crossed 80 mesh sieves by (1) respectively; (2) by formula, precise D-Glucosamine Hydrochloride, chondroitin sulfate, calcium carbonate, calcium cirate malate, phosphopeptide caseinate, vitamin C, always mix, and incorporation time is 30 minutes; (3) be filled into always mixing material in Capsules.

Prepared by matched group 2#:

Formula is: D-glucosamine sulphuric acid potassium salt 220g, chondroitin sulfate 180g, calcium carbonate 140g, bone collagen 50g, magnesium stearate 3g; Prepare according to the preparation method of CN201410221898.5.

2, laboratory sample: according to the embodiment of the present invention 1 and embodiment 7 method preparation experiment sample 1#, laboratory sample 2#.

Current country is not still about protection and the standard test and the evaluation methodology that improve function of joint test, and this experiment, according to the related symptoms of joint disease and untoward reaction, mainly carries out functional evaluation test from seven aspects such as knee joint rest pains:

Subject Population is totally 200 examples, each 50 examples of matched group 1#, matched group 2#, laboratory sample 1#, laboratory sample 2#.Matched group and laboratory sample group Subject Population are 50 ~ 70 years old at the age, and men and women half and half, and the course of disease is 2-5, and left and right knee joint has symptom.

3, eating method and amount are: every day three times, each two (grains); Time of Administration 60 days, experimenter is before taking and take in process the medicine of the improvement osteoarthritic inflammation not using other oral or externals.

4, MAIN OUTCOME MEASURES: protect and improve function of joint test;

5, Function Appraising: with following 7 for symptom integral:

A. knee joint rest pain: be normally 0 point; Mild pain, the work that do not affect are 1 point; Comparatively severe pain, not affect sleep be 2 points; Severe pain, to affect sleep be 3 points.

B. motion of knee joint pain: be normally 0 point; On have symptom downstairs, bend and stretch without impact be 1 point; On have symptom downstairs, impact of having squatted down is 2 points; During walking, pain is 3 points.

C. tenderness: be normally 0 point; During weight, pain is 1 point; During moderate pressure, pain is 2 points; During slight pressure, pain is 3 points.

4. swelling: be normally 0 point; Slightly swollen, Xiyan knows to be 1 point; Soft tissue swelling, Xiyan do not know to be 2 points; Unclear, floating kneecap experiment (+) of Xiyan is 3 points.

D. morning is stiff: be normally 0 point; Bend and stretch stiff but very soon recover (being less than 10 minutes) be 1 point; Stiff, the short time can recover (10 ~ 20 minutes) 2 points; Stiff, the long period just recovers, and (being greater than 20 minutes) is 3 points.

E. knee sprung: be normally 0 point; Knee articulation 0 ~ 125 °, it is 1 point that knee sprung can reach 90 ~ 119 °; Knee sprung only reaches, and (20 ~ 89 °) are 2 points; It is 3 points that knee sprung angle is less than 20 °.

F. locomotor activity: maximum walking distance is not restricted to 0 point; Limitedly 1 point is made as more than 1km; About 1km or walking 16 minutes is limited is made as 2 points; 500 ~ 900m or walking 8 ~ 15 minutes is limited is made as 3 points; 300 ~ 500m is limited is made as 4 points; 100 ~ 300m is limited is made as 5 points; Be less than that 100m is limited is made as 6 points.

6, follow up time: follow up time is 60 days, follows up a case by regular visits to 200 examples;

7, experimental result: 200 cases all enter interpretation of result, is shown in symptom integral change list 18 before and after experiment;

Table 18: symptom integral change before and after experiment

Before and after experiment, symptom integral change list is found out, after the experiment test-meal of 60 days, the symptom integral of above-mentioned four groups reduces degree difference.Laboratory sample 1# and laboratory sample 2# symptom integral reduce degree and are greater than matched group 1 and matched group 2, and before and after treatment, twice integration differential compares, significant difference; Untoward reaction and side effect is all there is not in all experimenters in the test-meal process of 60 days.

Shown by above result of the test; compositions prepared by the present invention contribute to joint disease crowd knee joint rest pain, motion of knee joint pain, tenderness, swelling, morning deadlock, knee sprung, be improved in the untoward reaction such as locomotor activity and improve; contribute to joint injury reparation, there is protection and improve function of joint effect.

In a word, above specific description of embodiments of the present invention does not limit the present invention, and those skilled in the art can make various change or distortion according to the present invention, only otherwise depart from spirit of the present invention, all should belong to the scope of claims of the present invention.

Claims

1. have a compositions for joint protection and the effect of increase bone density, described compositions comprises calcium cirate malate, Glucosamine sulfate potassium chloride, chondroitin sulfate, bone collagen Gly-His-Lys and phosphopeptide caseinate;

2. compositions according to claim 1, it is characterized in that, described compositions also comprises pharmaceutically acceptable adjuvant, wherein said adjuvant be selected from filler, diluent, wetting agent, binding agent disintegrating agent, lubricant, correctives or coating material one or more;

3. compositions according to claim 1 and 2, it is characterized in that, described compositions can be tablet, capsule, granule, electuary, solid beverage, oral liquid or beverage, preferred capsule, tablet, granule or electuary, further preferred tablet and electuary, more preferably tablet;

4. compositions according to any one of claim 1 to 3, is characterized in that, consists of when described compositions is tablet: in every 1000, calcium cirate malate 330g, Glucosamine sulfate potassium chloride 220g, chondroitin sulfate 160g, bone collagen Gly-His-Lys 100g, phosphopeptide caseinate 30g, lactose 50g, copolyvidone 50g, microcrystalline Cellulose 40g, silicon dioxide 5g, magnesium stearate 5g;

5. compositions according to any one of claim 1 to 3, it is characterized in that, described compositions consists of when being electuary: in every 1000 bags, calcium cirate malate 1980g, Glucosamine sulfate potassium chloride 1320g, chondroitin sulfate 960g, bone collagen Gly-His-Lys 600g, phosphopeptide caseinate 180g, silicon dioxide 50g, magnesium stearate 50g, resistant dextrin 4860g.

6. a preparation method for compositions according to any one of claim 1 to 5, described preparation method comprises the steps: to control each supplementary material moisture≤5.0%, takes each supplementary material by described proportioning, mixing, and controlling moisture is≤5.0%;

7. the preparation method of compositions according to claim 6, when described compositions is tablet, its preparation method comprises the steps:

Preferably, described preparation method is further comprising the steps of:

8. want the preparation method of the compositions described in 7 according to right, when described compositions is electuary, its preparation method comprises the steps:

9. the compositions according to any one of claim 1 to 5 has joint protection in preparation and increases the purposes in the food of bone density effect, medicine or health product.