CN115040541A - Chitosan sustained-release calcium preparation and preparation method thereof - Google Patents
Chitosan sustained-release calcium preparation and preparation method thereof Download PDFInfo
- Publication number
- CN115040541A CN115040541A CN202210809483.4A CN202210809483A CN115040541A CN 115040541 A CN115040541 A CN 115040541A CN 202210809483 A CN202210809483 A CN 202210809483A CN 115040541 A CN115040541 A CN 115040541A
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- calcium
- chitosan
- preparation
- powder
- release
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Images
Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/32—Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
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- A—HUMAN NECESSITIES
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Abstract
The invention discloses a chitosan slow-release calcium preparation and a preparation method thereof. The chitosan slow-release calcium preparation comprises the following components in parts by weight: 0.1-30 parts of yak bone strengthening powder, 10-60 parts of calcium gluconate, 1-20 parts of glucosamine hydrochloride, 10-60 parts of chondroitin, 1-20 parts of lysine hydrochloride, 10-90 parts of calcium chitosan sustained release microspheres and 0.1-100 parts of auxiliary materials; wherein, the chitosan calcium sustained release microspheres are prepared from chitosan, vanillin, sodium alginate and calcium gluconate. The preparation method comprises the following steps: sieving; weighing and mixing to obtain powder A; preparing calcium chitosan sustained-release microspheres to obtain powder B; and preparing the obtained powder A and powder B into corresponding dosage forms. The invention uses calcium gluconate and yak bone strengthening powder as calcium source, uses chitosan calcium slow release microspheres as slow release carrier to realize the sustained slow release of calcium ions, and treats and prevents calcium deficiency and enhances the calcium supplement effect by combining various means such as directly supplementing calcium, promoting calcium absorption, reducing calcium loss, improving bone metabolism and bone nutrition and the like.
Description
Technical Field
The invention belongs to the technical field of health-care food, relates to a calcium supplement preparation for treating and preventing calcium deficiency, and particularly relates to a chitosan sustained-release calcium preparation capable of supplementing calcium for a long time and increasing bone density and a preparation method thereof.
Background
Osteoporosis is a systemic disease characterized by low bone mass and microstructural destruction of bone tissue, leading to increased bone fragility and susceptibility to fracture, and is a common disease in the elderly. Osteoporosis endangers approximately one third of women over the age of 50 and one fifth of men over the age of 50 worldwide. With the increase of the average life span of the population, bone diseases are increasingly threatening the health of people.
The medical circles at home and abroad agree that the main reason for osteoporosis and hyperosteogeny is caused by long-term calcium deficiency of human bodies, and for the disease, a calcium supplement method is mainly adopted for prevention and treatment at present.
In the domestic market, a plurality of calcium supplement products are available, but inorganic calcium supplement preparations are mainly used, and the inorganic calcium supplement preparations are used for treating osteoporosis and hyperplasia and have the problem of difficult absorption by human bodies. For example, oyster shell and clam shell are used as raw materials, and are calcined at high temperature to prepare a calcium mixture, the main components of the calcium mixture are calcium oxide, calcium hydroxide and a small amount of calcium carbonate, and the inorganic calcium salts are basically slightly soluble or insoluble in water, are not easy to be absorbed by human bodies and have certain toxicity.
The existing calcium supplement products also have some organic calcium supplement preparations, and the organic calcium supplement preparations contain calcium deposition elements which can accelerate the deposition of calcium on bones, but most of the organic calcium supplement preparations have low calcium content, such as 9 percent of calcium gluconate and 12 percent of calcium lactate, so that the calcified soft tissues are difficult to restore. In addition, acidic components such as phosphorus, sulfur, chlorine and the like contained in the body can be combined with organic calcium, and the general organic calcium supplement components enter the body seriously and suddenly released, so that the concentration of calcium in the body can not be maintained at a continuous high level, and the calcium supplement effect is not obvious.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a chitosan sustained-release calcium preparation and a preparation method thereof.
The chitosan slow-release calcium preparation mainly comprises the following components in parts by weight:
0.1-30 parts of yak bone strengthening powder, 10-60 parts of calcium gluconate, 1-20 parts of glucosamine hydrochloride, 10-60 parts of chondroitin, 1-20 parts of lysine hydrochloride, 10-90 parts of calcium chitosan sustained release microspheres and 0.1-100 parts of auxiliary materials;
wherein, the calcium chitosan sustained-release microspheres are prepared by mixing 1-30 parts of chitosan and absolute ethyl alcohol according to a certain weight ratio, adding 0.1-10 parts of vanillin, stirring uniformly, then adding 2 wt% acetic acid aqueous solution containing 0.1-15 parts of acetic acid, and reacting completely to obtain vanillin modified chitosan; mixing 10-60 parts of calcium gluconate and an absolute ethanol solution to obtain a calcium gluconate ethanol solution, uniformly mixing the calcium gluconate ethanol solution with vanillin-modified chitosan, heating the mixture to 60 ℃ for reaction for 2 hours to obtain a vanillin chitosan calcium sustained-release microsphere suspension, mixing the vanillin chitosan calcium sustained-release microsphere suspension with a 2 wt% sodium alginate aqueous solution containing 1-10 parts of sodium alginate, adding a 2 wt% calcium chloride aqueous solution containing 0.1-10 parts of calcium chloride, uniformly mixing, removing a solvent after the reaction is finished, forming a precipitate, and performing suction filtration and drying to obtain the calcium gluconate sustained-release microsphere suspension.
The preparation provided by the invention is a tablet, a coated tablet, a hard capsule, a soft capsule, a granule or an oral liquid.
The efficacy of the chitosan sustained-release calcium preparation of the invention is illustrated as follows:
the calcium gluconate, the chitosan calcium sustained-release microspheres and the yak bone strengthening powder in the chitosan sustained-release calcium preparation are used as calcium supplements for treating and preventing calcium deficiency. Compared with similar organic calcium supplement products, the calcium gluconate has relatively high calcium content, best water solubility and stable chemical property, is in an ionic state in gastrointestinal tracts, is nearly neutral in aqueous solution, does not stimulate intestines and stomach, and can be quickly absorbed by a human body, so that the bone mineral density can be increased. The calcium chitosan sustained-release microspheres are a carrier loaded with calcium gluconate which is water-soluble calcium, and realize the effect of slowly releasing calcium ions. The yak bone strengthening powder is used as an auxiliary calcium source of organic calcium, is prepared by processing bovine bone marrow serving as a raw material, and can supplement substances such as chondroitin, vitamins, lecithin and the like required in vivo, thereby achieving the effects of strengthening bones, conditioning intestines and stomach and improving immunity.
The invention selects the chitosan calcium slow release microspheres as the slow release carrier of the calcium gluconate, and is based on the following points: chitosan is the only basic polysaccharide existing in nature, and has the effects of resisting cancer and improving immunity. In addition, on one hand, the chitosan molecular chain contains amino groups which can form a cross-linked network structure with aldehyde groups on vanillin used as edible essence, and water-soluble calcium gluconate is wrapped to delay the release of the water-soluble calcium gluconate; on the other hand, the chitosan has positive charge amino groups and negative charge carboxyl groups carried by the sodium alginate, and complex coacervate is formed through electrostatic interaction, so that the water-soluble calcium gluconate is embedded in network gaps of the coacervate. The calcium chitosan sustained-release microspheres can form an excellent sustained-release effect on calcium ions under the superposition effect of the two crosslinked networks.
The glucosamine hydrochloride in the chitosan sustained-release calcium preparation can promote the synthesis of human mucopolysaccharide, improve the viscosity of joint synovial fluid and improve the metabolism of joint cartilage; by stimulating the biochemical synthesis of mucopolysaccharide and increasing the intake of bone calcium, the metabolism function and nutrition of cartilage tissue are improved, the viscosity of synovial fluid can be improved and enhanced, the synthesis of the synovial fluid is increased, the joint lubrication function is enhanced, and the osteoarthropathy caused by rheumatic arthritis can be treated.
The chondroitin in the chitosan sustained-release calcium preparation is a glycosaminoglycan connected to protein to form proteoglycan, has certain effects of relieving pain and promoting cartilage regeneration by matching with glucosamine hydrochloride, can reduce pain of osteoarthritis patients, improve joint function, reduce joint swelling and hydrops, and absorb water into molecules of proteoglycan, so that the cartilage is thickened and the synthesis amount of synovial fluid in the joint is increased, thereby protecting the cartilage and reducing the abrasion and degeneration of the cartilage.
Lysine hydrochloride in the chitosan sustained-release calcium preparation is used as essential amino acid for human bodies, can promote the synthesis of protein and the absorption and utilization of calcium, and has the effects of improving intelligence, promoting growth, increasing weight, helping to generate antibodies and improving immunity.
And the in-vitro calcium ion slow release experiment, the bone density experiment, the acute toxicity experiment and the 30-day feeding experiment show that the chitosan slow release calcium preparation has definite efficacy, is safe and nontoxic, can be taken for a long time, and can be used for supplementing calcium for a long time.
In conclusion, the chitosan sustained-release calcium preparation is a product which is prepared by taking yak bone strengthening powder, calcium gluconate, glucosamine hydrochloride, chondroitin sulfate or hydrochloride, lysine hydrochloride and chitosan calcium sustained-release microspheres as main raw materials and has the functions of treating and preventing calcium deficiency. Wherein, the calcium gluconate is a commonly used calcium supplement and can directly supplement calcium; the calcium chitosan sustained-release microspheres are compatible with calcium gluconate, and the sustained high-level calcium concentration in the body is maintained by sustained and sustained release of calcium ions, so that calcium absorption is promoted, calcium loss is reduced, and the calcium supplement effect is effectively improved; the yak bone strengthening powder is used for synergistically supplementing calcium; glucosamine hydrochloride can improve bone metabolism and bone nutrition; chondroitin sulfate or hydrochloride has an important role in transporting or supporting materials to form bones; lysine hydrochloride can improve calcium absorption and accumulation in vivo, and increase bone density. Therefore, the invention realizes the effects of treating and preventing calcium deficiency and enhancing the calcium supplement effect by combining various means of directly supplementing calcium, persistently and slowly releasing calcium ions to promote calcium absorption, reduce calcium loss, improve bone metabolism, bone nutrition and the like.
The preparation method of the chitosan sustained-release calcium preparation comprises the following steps:
sieving: sieving yak bone strengthening powder, calcium gluconate, glucosamine hydrochloride, chondroitin, lysine hydrochloride and adjuvants with mesh number designed at normal temperature and pressure;
weighing and mixing, namely weighing the screened yak bone strengthening powder, calcium gluconate, glucosamine hydrochloride, chondroitin and lysine hydrochloride according to the designed weight and uniformly mixing to obtain powder A;
preparing calcium chitosan sustained-release microspheres: mixing chitosan and absolute ethyl alcohol according to a certain weight ratio, adding vanillin according to a designed weight portion, uniformly stirring, adding acetic acid aqueous solution according to a designed weight portion, and completely reacting to obtain vanillin modified chitosan; mixing the designed weight part of calcium gluconate with an absolute ethanol solution to obtain a calcium gluconate ethanol solution, uniformly mixing the calcium gluconate ethanol solution with vanillin modified chitosan, heating the mixture to 60 ℃ for reaction for 2 hours to obtain vanillin calcium chitosan sustained-release microsphere suspension, mixing the vanillin calcium chitosan sustained-release microsphere suspension with the designed weight part of sodium alginate aqueous solution, adding the designed weight part of calcium chloride aqueous solution, uniformly mixing, removing the solvent after the reaction is finished to form a precipitate, and performing suction filtration and drying to obtain chitosan calcium sustained-release microsphere B powder;
and preparing the obtained powder A and powder B into corresponding dosage forms.
The preparation process of the chitosan sustained-release calcium preparation is simple and easy to implement, the preparation procedures of products with different dosage forms are basically the same, and the batch production of products with various dosage forms is conveniently and simultaneously carried out.
Drawings
Fig. 1 is a schematic diagram of a slow release curve of calcium ions in simulated artificial intestinal fluid provided by the invention.
Detailed Description
The present invention is further described below with reference to specific examples so that those skilled in the art can better understand the present invention and can practice the present invention, but the examples are not intended to limit the present invention.
In the present specification, unless otherwise specified, all technical terms used are terms commonly used by those of ordinary skill in the art; the experimental method without specific conditions noted in the specification is a conventional experimental method; the test materials used in the present specification were all commercially available products unless otherwise specified.
Example 1 granules
The preparation method comprises the following steps: 1) sieving: sieving yak bone strengthening powder, calcium gluconate, glucosamine hydrochloride, chondroitin, lysine hydrochloride, acesulfame potassium and starch with 100 mesh sieve respectively at normal temperature and normal pressure; 2) weighing and mixing: weighing the screened yak bone strengthening powder, calcium gluconate, glucosamine hydrochloride, chondroitin and lysine hydrochloride according to the formula, putting the weighed yak bone strengthening powder, calcium gluconate, glucosamine hydrochloride, chondroitin and lysine hydrochloride into a three-dimensional motion mixer, mixing for more than 30 minutes, and uniformly mixing to obtain powder A; 3) preparing calcium chitosan sustained-release microspheres: mixing 80.0g of chitosan and absolute ethyl alcohol according to a certain weight ratio, adding 10.0g of vanillin, uniformly stirring, adding a 2 wt% acetic acid aqueous solution containing 15.0g of acetic acid, and completely reacting to obtain vanillin-modified chitosan; mixing 200.0g of calcium gluconate with an absolute ethanol solution to obtain a calcium gluconate ethanol solution, uniformly mixing the calcium gluconate ethanol solution with vanillin-modified chitosan, heating the mixture to 60 ℃ for reaction for 2 hours to obtain vanillin calcium chitosan sustained-release microsphere suspension, mixing the vanillin calcium chitosan sustained-release microsphere suspension with a 2 wt% sodium alginate aqueous solution containing 15.0g of sodium alginate, adding a 2 wt% calcium chloride aqueous solution containing 10.0g of calcium chloride, uniformly mixing, removing a solvent after the reaction is finished, forming a precipitate, and performing suction filtration and drying to obtain chitosan calcium sustained-release microsphere B powder; 4) preparing granules: mixing 8.0g of acesulfame potassium with powder A and powder B; adding 10 wt% starch slurry to make soft mass, making wet granule, drying at 80 + -l 0 deg.C, grading, and packaging to obtain granule.
The using method comprises the following steps: it is administered orally 3 times a day, 0.9g each time, after meals.
The method is suitable for people: middle-aged and elderly people and people for preventing calcium deficiency.
EXAMPLE 2 tablets
The preparation method comprises the following steps: 1) sieving: sieving yak bone strengthening powder, calcium gluconate, glucosamine hydrochloride, chondroitin, lysine hydrochloride, magnesium stearate and starch with 100 mesh sieve respectively at normal temperature and normal pressure; 2) weighing and mixing: weighing the screened yak bone strengthening powder, calcium gluconate, glucosamine hydrochloride, chondroitin and lysine hydrochloride according to the formula, putting the weighed yak bone strengthening powder, calcium gluconate, glucosamine hydrochloride, chondroitin and lysine hydrochloride into a three-dimensional motion mixer, mixing for more than 30 minutes, and uniformly mixing to obtain powder A; 3) preparing calcium chitosan sustained-release microspheres: mixing 170.0g of chitosan and absolute ethyl alcohol according to a certain weight ratio, adding 10.0g of vanillin, uniformly stirring, adding a 2 wt% acetic acid aqueous solution containing 30.0g of acetic acid, and completely reacting to obtain vanillin-modified chitosan; mixing 200.0g of calcium gluconate with an absolute ethanol solution to obtain a calcium gluconate ethanol solution, uniformly mixing the calcium gluconate ethanol solution with vanillin-modified chitosan, heating the mixture to 60 ℃ for reaction for 2 hours to obtain vanillin calcium chitosan sustained-release microsphere suspension, mixing the vanillin calcium chitosan sustained-release microsphere suspension with a 2 wt% sodium alginate aqueous solution containing 20.0g of sodium alginate, adding a 2 wt% calcium chloride aqueous solution containing 10.0g of calcium chloride, uniformly mixing, removing a solvent after the reaction is finished, forming a precipitate, and performing suction filtration and drying to obtain chitosan calcium sustained-release microsphere B powder; 4) preparation of tablets: mixing the powder A and the powder B in a three-dimensional motion mixer for 30 minutes to obtain total mixed powder C; preparing 10 wt% starch slurry with 8.0g starch as wetting agent to obtain soft material, sieving the soft material, wet granulating to obtain wet granule, oven drying at 80 + -l 0 deg.C, and grading to obtain granule D; 102.0g of magnesium stearate is added and mixed, and then the mixture is tabletted by a rotary tablet machine to obtain tablets.
The using method comprises the following steps: it is administered orally 3 times a day, 2.1g each time, after meals.
The method is suitable for people: middle-aged and elderly people and people for preventing calcium deficiency.
Example 3 Soft capsules
The preparation method comprises the following steps: 1) sieving: sieving yak bone strengthening powder, calcium gluconate, glucosamine hydrochloride, chondroitin and lysine hydrochloride with 100 mesh sieve at normal temperature and pressure; 2) weighing and mixing: weighing the screened yak bone strengthening powder, calcium gluconate, glucosamine hydrochloride, chondroitin and lysine hydrochloride according to the formula, putting the weighed yak bone strengthening powder, calcium gluconate, glucosamine hydrochloride, chondroitin and lysine hydrochloride into a three-dimensional motion mixer, mixing for more than 30 minutes, and uniformly mixing to obtain powder A; 3) preparing calcium chitosan sustained-release microspheres: mixing 120.0g of chitosan and absolute ethyl alcohol according to a certain weight ratio, adding 20.0g of vanillin, uniformly stirring, adding a 2 wt% acetic acid aqueous solution containing 30.0g of acetic acid, and completely reacting to obtain vanillin-modified chitosan; mixing 500.0g of calcium gluconate with an absolute ethanol solution to obtain a calcium gluconate ethanol solution, uniformly mixing the calcium gluconate ethanol solution with vanillin-modified chitosan, heating the mixture to 60 ℃ for reaction for 2 hours to obtain vanillin calcium chitosan sustained-release microsphere suspension, mixing the vanillin calcium chitosan sustained-release microsphere suspension with a 2 wt% sodium alginate aqueous solution containing 20.0g of sodium alginate, adding a 2 wt% calcium chloride aqueous solution containing 10.0g of calcium chloride, uniformly mixing, removing a solvent after the reaction is finished, forming a precipitate, and performing suction filtration and drying to obtain chitosan calcium sustained-release microsphere B powder; 4) preparation of soft capsules: and (3) fully mixing the powder A, the powder B and the like in a three-dimensional motion mixer for 30 minutes, then stirring and mixing the powder A and the powder B with 500.0g of PEG400 in a pulping pot for 20 minutes, then adding 8.0g of ethylparaben, uniformly mixing to obtain a soft capsule content C liquid, dripping the C liquid into a suspension of gelatin, glycerol and water by adopting a dripping method, cooling to obtain capsules, and drying to obtain the soft capsules.
The using method comprises the following steps: it is administered orally 3 times a day, 2.0g each time, after meals.
The method is suitable for people: middle-aged and elderly people and people for preventing calcium deficiency.
EXAMPLE 4 coated tablet
The preparation method comprises the following steps: 1) sieving: sieving yak bone strengthening powder, calcium gluconate, glucosamine hydrochloride, chondroitin, lysine hydrochloride, microcrystalline cellulose and magnesium stearate with 100 mesh sieve respectively at normal temperature and normal pressure; and 2) weighing and mixing: weighing the screened yak bone strengthening powder, calcium gluconate, glucosamine hydrochloride, chondroitin and lysine hydrochloride according to the formula, putting the weighed yak bone strengthening powder, calcium gluconate, glucosamine hydrochloride, chondroitin and lysine hydrochloride into a three-dimensional motion mixer, mixing for more than 30 minutes, and uniformly mixing to obtain powder A; 3) preparing calcium chitosan sustained-release microspheres: mixing 80.0g of chitosan and absolute ethyl alcohol according to a certain weight ratio, adding 30.0g of vanillin, stirring uniformly, adding a 2 wt% acetic acid aqueous solution containing 20.0g of acetic acid, and completely reacting to obtain vanillin-modified chitosan; mixing 300.0g of calcium gluconate with an absolute ethanol solution to obtain a calcium gluconate ethanol solution, uniformly mixing the calcium gluconate ethanol solution with vanillin-modified chitosan, heating the mixture to 60 ℃ for reaction for 2 hours to obtain vanillin calcium chitosan sustained-release microsphere suspension, mixing the vanillin calcium chitosan sustained-release microsphere suspension with a 2 wt% sodium alginate aqueous solution containing 20.0g of sodium alginate, adding a 2 wt% calcium chloride aqueous solution containing 10.0g of calcium chloride, uniformly mixing, removing a solvent after the reaction is finished, forming a precipitate, and performing suction filtration and drying to obtain chitosan calcium sustained-release microsphere B powder; 4) preparation of coated tablets: fully mixing the powder A and the powder B; adding microcrystalline cellulose, mixing uniformly, and performing dry granulation; adding magnesium stearate, mixing, and tabletting with rotary tabletting machine to obtain plain tablet; preparing coating solution with concentration of 8 wt% from 10.0g polyvidone K30 with 65% ethanol, controlling temperature at 65 deg.C, spraying the coating solution on plain tablet in coating pan for more than 3 times, and air drying to obtain coated tablet.
The using method comprises the following steps: it is administered orally 3 times a day, 1.5g each time, after meals.
The method is suitable for people: middle-aged and elderly people and people for preventing calcium deficiency.
Example 5 hard capsules
The preparation method comprises the following steps: 1) sieving: sieving yak bone strengthening powder, calcium gluconate, glucosamine hydrochloride, chondroitin, lysine hydrochloride and microcrystalline cellulose with 100 mesh sieve respectively at normal temperature and normal pressure; 2) weighing and mixing: weighing the screened yak bone strengthening powder, calcium gluconate, glucosamine hydrochloride, chondroitin and lysine hydrochloride according to the formula, putting the weighed yak bone strengthening powder, calcium gluconate, glucosamine hydrochloride, chondroitin and lysine hydrochloride into a three-dimensional motion mixer, mixing for more than 30 minutes, and uniformly mixing to obtain powder A; 3) preparing calcium chitosan sustained-release microspheres: mixing 80.0g of chitosan and absolute ethyl alcohol according to a certain weight ratio, adding 40.0g of vanillin, uniformly stirring, adding a 2 wt% acetic acid aqueous solution containing 10.0g of acetic acid, and completely reacting to obtain vanillin-modified chitosan; mixing 380.0g of calcium gluconate with an absolute ethanol solution to obtain a calcium gluconate ethanol solution, uniformly mixing the calcium gluconate ethanol solution with vanillin-modified chitosan, heating the mixture to 60 ℃ for reaction for 2 hours to obtain vanillin calcium chitosan sustained-release microsphere suspension, mixing the vanillin calcium chitosan sustained-release microsphere suspension with a 2 wt% sodium alginate aqueous solution containing 20.0g of sodium alginate, adding a 2 wt% calcium chloride aqueous solution containing 10.0g of calcium chloride, uniformly mixing, removing a solvent after the reaction is finished, forming a precipitate, and performing suction filtration and drying to obtain chitosan calcium sustained-release microsphere B powder; 4) preparation of hard capsules: and fully mixing the powder A and the powder B with 30.0g of microcrystalline cellulose, performing dry granulation, and filling the obtained granules into a capsule shell to obtain the hard capsule.
The using method comprises the following steps: it is administered orally 3 times a day, 1.0g each time, after meals.
The method is suitable for people: middle-aged and elderly people and people for preventing calcium deficiency.
EXAMPLE 6 oral liquid preparation
The preparation method comprises the following steps: 1) sieving: sieving yak bone strengthening powder, calcium gluconate, glucosamine hydrochloride, chondroitin and lysine hydrochloride with 100 mesh sieve at normal temperature and pressure; 2) weighing and mixing: weighing the screened yak bone strengthening powder, calcium gluconate, glucosamine hydrochloride, chondroitin sulfate and lysine hydrochloride according to the formula, putting the weighed materials into a three-dimensional motion mixer, mixing for more than 30 minutes, and uniformly mixing to obtain powder A; 3) preparing calcium chitosan sustained-release microspheres: mixing 70.0g of chitosan and absolute ethyl alcohol according to a certain weight ratio, adding 10.0g of vanillin, uniformly stirring, adding a 2 wt% acetic acid aqueous solution containing 10.0g of acetic acid, and completely reacting to obtain vanillin-modified chitosan; mixing 300.0g of calcium gluconate with an absolute ethanol solution to obtain a calcium gluconate ethanol solution, uniformly mixing with vanillin-modified chitosan, heating to 60 ℃ for reaction for 2 hours to obtain a vanillin calcium chitosan sustained-release microsphere suspension, mixing with a 2 wt% sodium alginate aqueous solution containing 10.0g of sodium alginate, adding a 2 wt% calcium chloride aqueous solution containing 10.0g of calcium chloride, uniformly mixing, removing the solvent after the reaction is finished, forming a precipitate, and performing suction filtration and drying to obtain chitosan calcium sustained-release microsphere B powder; 4) preparation of oral liquid: dissolving the powder A, honey and mannitol in 10000mL of purified water, filtering with a 0.45 micron microporous membrane to obtain a solution A, uniformly mixing the solution A with a 2 wt% povidone aqueous solution containing 10.0g of povidone, adding the chitosan calcium slow-release microsphere B powder, fully stirring to obtain a viscous suspension, filling into a bottle, and sterilizing to obtain the oral liquid.
The using method comprises the following steps: it is administered orally 3 times a day, 10mL each time, after meals.
The method is suitable for people: middle-aged and elderly people and people for preventing calcium deficiency.
In vitro calcium ion sustained release test
1. Sample preparation: samples prepared according to the formulation and procedure described in example 1.
2. In vitro calcium ion sustained release test
And (3) preparing NH3-NH4 buffer solution with the pH value of 9.5, wherein under the weak alkaline environment, calcium ions and azoarsine III form 1: 2, drawing a calcium ion standard curve at the wavelength of maximum absorption 650nm by adopting an ultraviolet spectrophotometry. According to the beer's law and the standard curve, the concentration of the dissolved calcium ions in the artificial intestinal juice is deduced reversely, and a graph 1 is drawn, wherein the graph 1 is a schematic diagram of the slow release curve for simulating the calcium ions in the artificial intestinal juice provided by the invention.
3. In vitro calcium ion slow release test result
As can be seen from fig. 1, in the initial stage, the calcium-chitosan sustained-release microsphere is in the swelling stage, the calcium ion release speed is slow, but after 2 hours, the calcium-chitosan sustained-release microsphere network structure is corroded, and the calcium ion release speed becomes fast. But the linear relation of the in vitro calcium ion accumulation release degree is better in the whole release process, and the intestinal slow release drug delivery characteristic is excellent. The granules have slow release speed of calcium ions due to the existence of the calcium chitosan sustained-release microspheres, which is that amino groups on a chitosan molecular chain react with aldehyde groups in vanillin molecules to generate a schiff base structure, so that the calcium ions are prevented from being released outwards from the interior of the microspheres, and the sustained-release effect is further realized.
The chitosan sustained-release calcium preparation of the present invention was tested for its edible safety and bone density increasing function in accordance with the "health food inspection and evaluation technical criteria" of the ministry of health (2003 edition).
Acute toxicity test
1. Sample preparation: samples prepared according to the formulation and procedure described in example 1.
2. Animal experiments: ICR mice were used for the experiments.
3. Oral acute toxicity test (MTD) in mice: 20 mice (20-22 g) with half each of male and female were selected for the test, and the test was performed by oral gavage twice at a dose of 20.0 g/kg. BW, and the administration was followed by continuous observation for 14 days. The signs of intoxication and death were recorded.
4. As a result: mice of both sexes were gavaged at a dose of 20.0 g/kg. BW, and observed for 14 days continuously after administration. No obvious toxic manifestation is seen during the experiment period, and no death is caused during the observation period. The test substance has acute oral toxicity (MTD) of more than 20.0g/kg & BW for mice of both sexes, and belongs to non-toxic grade according to the acute toxicity grading of food safety toxicology evaluation program and method (2003 edition).
TABLE 1 mouse acute toxicity test results
Feeding test for 30 days
1. Sample preparation: samples were prepared according to the recipe and procedure described in example 1. The amount is 15g/60kg BW day.
2. Experimental animals: selecting 80 rats with body weight of 55-80g and SPF Wistar, each half of male and female,
3. the test method comprises the following steps: the dose design is as follows: 5.00, 10.00, 15.00g/kg & BW (corresponding to 25 times, 50 times, 100 times of the amount to be used artificially, respectively). Rats were randomly divided into three test subject groups and control groups, 20 per group, each half male and female. The control group was fed normal basal diet and the test group was fed spiked with different doses of the samples. Animals were fed in a single cage, and were fed ad libitum for 30 days.
4. Observation of indices and results
4.1 biochemical index determination:
serum alanine Aminotransferase (ALT), aspartate transferase (AST), urea nitrogen (BUN), Cholesterol (CHO), Triglycerides (TG), blood Glucose (GLU), Total Protein (TP), Albumin (ALB), Creatinine (CRE) were measured. All biochemical indexes of the experimental animals at the end of the experiment are normal, and the biochemical indexes of the animals in each group are not statistically different from those of the animals in the control group (P is more than 0.05).
4.2 gross observations and pathological tissue examinations:
at the end of the experiment, the animals were sacrificed by cervical dislocation and the gross pathological changes of the major organs, the chest and the abdominal cavity were observed. The liver, kidney, spleen and testis of all animals were removed, weighed and the organ coefficients calculated. No significant pathological changes were observed in all major organs.
The toxicological test result shows that the product is non-toxic and can be taken for a long time.
Bone mineral density test
1. Sample preparation: samples were prepared according to the formulation and procedure described in example 1
2. Test animals: 4-week weaning SD male rats, 60-80g in weight, 10 per group. Feeding animals with cholesterol-containing feed results in animal models of disorders of lipid metabolism.
3. Selecting the dosage: the test design is low, medium and high (500, 1000, 1500mg/kg & BW) three dose groups, a low calcium control group (100mg/kg & BW) and a standard inorganic calcium carbonate control group (1500mg/kg & BW). Three-month control trials were given and the following criteria were observed.
4. As a result:
TABLE 2 Effect on bone Density and bone calcium content in rats
| Group of | Bone density at midpoint | Distal bone density | Osteoporosis spot bone density |
| Low calcium control group | 0.02±0.01 | 0.04±0.01 | 0.02±0.01 |
| Calcium carbonate control group | 0.18±0.01 | 0.20±0.01 | 0.09±0.01 |
| Low dose group | 0.08±0.01 | 0.18±0.01 | 0.03±0.01 |
| Middle dose group | 0.10±0.01 | 0.17±0.01 | 0.05±0.01 |
| High dose group | 0.20±0.01 | 0.27±0.01 | 0.10±0.01 |
As can be seen from Table 2, when the low, medium and high dose groups were compared with the low calcium control group, the midpoint bone density and the distal bone density were significantly different, and the osteoporosis point bone density in the high dose group was significantly different from that in the low calcium control group (P ≦ 0.01). The osteoporosis point bone density of the medium dose group is significantly different from that of the low calcium control group (P ≦ 0.05). Comparing the low, medium and high dose groups with the calcium carbonate control group, the high dose group was found to have a higher bone density increasing effect than calcium carbonate.
The functional experiment results judge that the bone calcium content and the bone density are both obviously higher than those of a low-calcium control group, so that the product can be judged to have the function of increasing the bone density.
The above-described embodiments are merely relatively good examples to fully illustrate the present invention, and are not intended to limit the present invention. Various modifications and alterations to this invention will become apparent to those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the scope of the claims of the present invention.
Claims (10)
1. A chitosan slow-release calcium preparation is characterized by comprising the following components in parts by weight:
0.1-30 parts of yak bone strengthening powder, 10-60 parts of calcium gluconate, 1-20 parts of glucosamine hydrochloride, 10-60 parts of chondroitin, 1-20 parts of lysine hydrochloride, 10-90 parts of calcium chitosan sustained release microspheres and 0.1-100 parts of auxiliary materials;
wherein, the calcium chitosan sustained-release microspheres are prepared by mixing 1-30 parts of chitosan and absolute ethyl alcohol according to a certain weight ratio, adding 0.1-10 parts of vanillin, stirring uniformly, then adding 2 wt% acetic acid aqueous solution containing 0.1-15 parts of acetic acid, and reacting completely to obtain vanillin modified chitosan; mixing 10-60 parts of calcium gluconate and an absolute ethanol solution to obtain a calcium gluconate ethanol solution, uniformly mixing the calcium gluconate ethanol solution with vanillin-modified chitosan, heating the mixture to 60 ℃ for reaction for 2 hours to obtain a vanillin chitosan calcium sustained-release microsphere suspension, mixing the vanillin chitosan calcium sustained-release microsphere suspension with a 2 wt% sodium alginate aqueous solution containing 1-10 parts of sodium alginate, adding a 2 wt% calcium chloride aqueous solution containing 0.1-10 parts of calcium chloride, uniformly mixing, removing a solvent after the reaction is finished, forming a precipitate, and performing suction filtration and drying to obtain the calcium gluconate sustained-release microsphere suspension.
2. The chitosan sustained-release calcium preparation according to claim 1, wherein the preparation is a tablet, a coated tablet, a hard capsule, a soft capsule, a granule or an oral liquid.
3. The chitosan sustained-release calcium preparation according to claim 2, wherein when the preparation is a tablet, the auxiliary material comprises one or more of microcrystalline cellulose, povidone K30, magnesium stearate, hypromellose, acesulfame potassium and starch.
4. The chitosan sustained-release calcium preparation according to claim 2, wherein when the preparation is a coated tablet, the auxiliary material comprises one or more of hypromellose, povidone K30, magnesium stearate and acrylic resin.
5. The chitosan sustained-release calcium preparation according to claim 2, wherein when the preparation is a hard capsule, the adjuvant comprises one or more of starch, microcrystalline cellulose, sodium carboxymethyl starch, and magnesium stearate.
6. The chitosan sustained-release calcium preparation according to claim 2, wherein when the preparation is a granule, the auxiliary material comprises one or more of starch, microcrystalline cellulose, sugar powder, dextrin, acesulfame potassium and mannitol.
7. The chitosan sustained-release calcium preparation according to claim 2, wherein when the preparation is an oral liquid, the auxiliary material comprises one or more of povidone, honey, sugar powder, mannitol, sorbitol and acesulfame potassium.
8. The chitosan sustained-release calcium preparation according to claim 2, wherein when the preparation is a soft capsule, the auxiliary material is one or more of gelatin, glycerin, PEG400, ethylparaben and simple syrup.
9. A preparation method of a chitosan sustained-release calcium preparation is characterized by comprising the following steps:
sieving: sieving yak bone strengthening powder, calcium gluconate, glucosamine hydrochloride, chondroitin, lysine hydrochloride and adjuvants with mesh number designed at normal temperature and pressure;
weighing and mixing, namely weighing the screened yak bone strengthening powder, calcium gluconate, glucosamine hydrochloride, chondroitin and lysine hydrochloride according to the designed weight and uniformly mixing to obtain powder A;
preparing calcium chitosan sustained-release microspheres: mixing chitosan and absolute ethyl alcohol according to a certain weight ratio, adding vanillin according to a designed weight portion, uniformly stirring, adding acetic acid aqueous solution according to a designed weight portion, and completely reacting to obtain vanillin modified chitosan; mixing the designed weight part of calcium gluconate with an absolute ethanol solution to obtain a calcium gluconate ethanol solution, uniformly mixing the calcium gluconate ethanol solution with vanillin modified chitosan, heating the mixture to 60 ℃ for reaction for 2 hours to obtain vanillin calcium chitosan sustained-release microsphere suspension, mixing the vanillin calcium chitosan sustained-release microsphere suspension with the designed weight part of sodium alginate aqueous solution, adding the designed weight part of calcium chloride aqueous solution, uniformly mixing, removing the solvent after the reaction is finished to form a precipitate, and performing suction filtration and drying to obtain chitosan calcium sustained-release microsphere B powder;
and preparing the obtained powder A and powder B into corresponding dosage forms.
10. The method for preparing the chitosan sustained-release calcium preparation according to claim 9, wherein the preparation of the obtained powder A and powder B into corresponding dosage forms comprises the following steps:
preparation of granules: fully mixing the obtained powder A and the powder B to obtain total mixed powder C; mixing the starch slurry and the total mixed powder C in a designed weight ratio to prepare a soft material, sieving the soft material, performing wet granulation, drying, and finishing granules to obtain granules D; subpackaging the granules D in packaging bags to obtain granules E;
preparation of hard capsules: fully mixing the microcrystalline cellulose in the designed weight part with the obtained powder A and powder B, granulating by a dry method, and filling the obtained granules into a plant capsule shell to obtain a hard capsule F;
preparation of tablets: mixing the obtained powder A and B to obtain total mixed powder C; mixing the starch slurry and the total mixed powder C in a designed weight ratio to prepare a soft material, sieving the soft material, performing wet granulation, drying, and finishing granules to obtain granules D; adding the granules D into magnesium stearate in the designed weight part, mixing, and tabletting by using a rotary tablet machine to obtain tablets G;
preparation of coated tablets: taking povidone K30 in the designed weight part, preparing coating liquid with the concentration of 8 wt% by using ethanol with the volume concentration of 65%, controlling the temperature at 65 ℃, putting the tablet G in a coating pan, spraying the coating liquid for more than 3 times, enabling the appearance to be uniform, enabling a coating film to be formed completely, and airing to obtain a coated tablet H;
preparation of soft capsules: mixing the obtained powder A and B with PEG400 and ethylparaben in a certain weight ratio by a dripping method to obtain soft capsule content, dripping into suspension of gelatin, glycerol and water, cooling, drying, and making into soft capsule I;
preparation of oral liquid: dissolving the obtained powder A in purified water, filtering with 0.45 micrometer microporous membrane to obtain solution A, mixing solution A and polyvidone water solution, adding the obtained powder B, stirring to obtain viscous suspension, bottling, and sterilizing to obtain oral liquid J.
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