CN106821998B - Method for preparing vitamin AD micro-pills and compound amino acid capsule composition thereof - Google Patents

Method for preparing vitamin AD micro-pills and compound amino acid capsule composition thereof Download PDF

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CN106821998B
CN106821998B CN201710194040.8A CN201710194040A CN106821998B CN 106821998 B CN106821998 B CN 106821998B CN 201710194040 A CN201710194040 A CN 201710194040A CN 106821998 B CN106821998 B CN 106821998B
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vitamin
pellet
pellets
parts
micro
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CN106821998A (en
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彭潇波
马俊
陈广进
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Shenzhen Wanhe Pharmaceutical Co Ltd
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Shenzhen Wanhe Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1658—Proteins, e.g. albumin, gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Abstract

The invention relates to a method for preparing vitamin AD pellets and a compound amino acid capsule composition thereof. In particular, in one aspect, the invention relates to a vitamin AD pellet comprising vitamin a and vitamin D2; each 1g of the pellet contains 2-20 ten thousand of I.U. vitamin A and 0.2-2 ten thousand of I.U. vitamin D2. The invention also relates to a preparation method of the vitamin AD micro-pill, and a capsule of the compound amino acid vitamin micro-pill containing the vitamin AD micro-pill. The vitamin AD micro-pill and the compound amino acid vitamin capsule prepared by using the same have the characteristics of being superior to the existing product.

Description

Method for preparing vitamin AD micro-pills and compound amino acid capsule composition thereof
Technical Field
The present invention relates to vitamin AD pellets having a small and concentrated particle size and being particularly suitable for use as a filling or filling component of a hard capsule. The invention also relates to a preparation method of the vitamin AD micro-pill. In addition, the invention also relates to a pellet capsule and a preparation method thereof, in particular to a capsule containing 8 amino acids and 11 vitamin pellets, which can also be called as a compound amino acid capsule (8-11), and also relates to a preparation method of the capsule.
Background
The protein is the material basis of human life activity, and various physiological functions of human body, especially the immune function, the repair function of cell injury and the growth and development function, have very close relation with the normality or the normality of the metabolism. Under normal conditions, the human body obtains various amino acids through proteins in food to ensure the normal protein metabolism of the body. Of the 20 amino acids required for human protein synthesis, 8 amino acids are essential amino acids for human body, and these 8 amino acids cannot be synthesized in vivo and must be supplied in vitro. They are isoleucine, leucine, lysine, phenylalanine, threonine, valine, methionine and tryptophan. For protein synthesis, the 8 amino acids are all absent, and the protein synthesis is affected when the content is insufficient or the mixture ratio is unbalanced.
During the onset, progression and recovery of the disease, disorders of protein metabolism often occur due to various pathologies and stress reactions, as well as improper diet or affected digestive tract function, and often are closely related to death, complications and duration of the disease. Thus, in clinical practice, the supply of nitrogen is an indispensable and effective therapeutic means.
Since world war ii, hydrolyzed protein was first introduced in the united states for nitrogen supply during the course of disease. In the fifty years, large-scale fermentation and purification preparation of amino acid is realized in Japan, and favorable technical guarantee is provided for the transfusion of crystalline amino acid. In the seventies and eighties, the amino acid infusion continuously provides powerful support for treating various emergency and severe diseases clinically, particularly for treating critically ill patients and patients who can not take food orally.
However, for the treatment of chronic diseases, particularly for patients who can be taken orally, the limitations of amino acid infusion are very obvious. From the characteristics of amino acid metabolism in vivo, amino acid transfusion may cause the mismatching of amino acid in vivo, the overhigh concentration of serum amino acid in the transfusion process, the rapid decrease of the concentration of serum amino acid after the transfusion is stopped, aggravate the nitrogen discharge burden of liver, and possibly cause adverse reactions such as transfusion reaction, phlebephragmitis and the like. More importantly, the amino acid infusion only has the function of promoting positive nitrogen balance in short-term treatment, and the treatment effect is not obvious after long-term use.
For this reason, while parenteral nutrition is developed, various enteral nutrition preparations composed of nitrogen sources such as crystalline amino acids, hydrolyzed proteins, complete proteins, and the like are developed and perfected abroad. The enteral nutrition preparation is mainly taken orally, provides necessary nutrients to meet the metabolic needs of human bodies, is favorable for keeping the integrity of the structure and the function of an intestinal tract compared with parenteral nutrition, prevents intestinal tract mucosa atrophy and bacterial displacement caused by long-term parenteral nutrition, and is favorable for improving the immunity of organisms.
At present, the treatment of enteral nutrition is very important in clinical practice at home and abroad, and particularly in the long-term treatment of chronic diseases, the proportion of enteral nutrition treatment greatly exceeds parenteral nutrition treatment. "enteral nutrition is used as much as possible as the gastrointestinal function permits" is the principle of clinical nutrition therapy. Therefore, there is an urgent need to solve the problem of medicines for enteral nutrition therapy. Because of the instability of amino acid, the stability of the amino acid oral preparation product is poor, and the application of the amino acid oral preparation product is restricted. The invention name of Chinese patent CN1781486 is: the compound amino acid and vitamin capsule preparation and the preparation method thereof are believed that the product prepared by the invention has poor stability, and the appearance of the product is obviously discolored and the content of the product is obviously reduced at 12 months. In addition, CN101773512A discloses a pellet capsule containing 8 amino acids and 11 vitamins and a preparation method thereof, wherein a capsule shell contains 7 pellets, and it is believed that the 7 pellets in the pellet capsule cause significant content unevenness of individual pellets during mixing and encapsulating the pellets due to different properties. In addition, the Vitamin AD microbeads used in CN101773512A were obtained directly from the Japan research company, or from the China Riken Vitamin Co., Ltd., RikenDry AD-B100/10P imported to China. However, the present inventors have found in their studies that vitamin AD microbeads using such a research tend to have a significantly reduced content of vitamin A, D after being mixed with vitamin pellets a comprising niacinamide, calcium pantothenate, etc., and it is highly desirable for those skilled in the art to overcome this drawback and thus provide clinically a compound amino acid and vitamin preparation having excellent quality.
Disclosure of Invention
The invention aims to provide a vitamin AD micro-pill. The invention also aims to provide a preparation method of the vitamin AD micro-pill. The invention aims to provide a capsule containing pellets of 8 amino acids and 11 vitamins. It is a further object of the present invention to provide a method for preparing such capsules. It has been surprisingly found that vitamin AD pellets prepared by the process of the invention, when mixed with pellets according to the invention containing 8 amino acids and 11 vitamins, give a mixed formulation with excellent chemical stability, in particular as demonstrated by vitamin a and vitamin D2. The present invention has been completed based on the above finding.
Specifically, the invention provides a vitamin AD pellet which comprises vitamin A and vitamin D2.
A vitamin AD pellet according to any embodiment of the first aspect of the invention comprises 2 to 20 million i.u. vitamin a per 1 gram of pellet, e.g. 5 to 15 million i.u. vitamin a per 1 gram of pellet, e.g. 8 to 12 million i.u. vitamin a per 1 gram of pellet, e.g. 10 million i.u. vitamin a per 1 gram of pellet.
The vitamin AD pellets according to any of the embodiments of the first aspect of the invention, wherein the vitamin a is added to the vitamin AD pellets in the form of vitamin a or vitamin a palmitate or vitamin a acetate or other esters of vitamin a.
Vitamin AD pellets according to any one of the embodiments of the first aspect of the invention, comprising 0.2-2 ten thousand i.u. vitamin D per 1 gram of pellets2(which may also be referred to as calciferol, etc.), for example, 0.5-1.5 ten thousand I.U. vitamin D per 1 gram pellet2E.g. it is contained in every 1g of pelletsContains 0.8-1.2 ten thousand I.U. vitamin D2For example, it contains 1 ten thousand i.u. vitamin D per 1 gram pellet2。
Vitamin AD pellets according to any of the embodiments of the first aspect of the invention further comprise edible vegetable oils such as corn oil, soybean oil, peanut oil, sunflower oil, etc.
The vitamin AD micro-pellets according to any embodiment of the first aspect of the present invention comprise 100-200 mg, such as 120-160 mg, such as 130-150 mg of edible vegetable oil per 1g of micro-pellets.
Vitamin AD pellets according to any of the embodiments of the first aspect of the invention further comprise fatty acid sorbitan esters, such as span20 (i.e. span-20), span40 (i.e. span-40), span60 (i.e. span-60), span65 (i.e. span-65), span80 (i.e. span-80), span85 (i.e. span-85).
The vitamin AD pellets according to any of the embodiments of the first aspect of the present invention comprise 2-20 mg, such as 2-15 mg, such as 2-12 mg, of sorbitan fatty acid ester per 1 gram of pellets.
The vitamin AD pellets according to any one of the embodiments of the first aspect of the present invention, further comprise gelatin.
The vitamin AD pellets according to any of the embodiments of the first aspect of the present invention, comprise 400-700 mg, such as 500-650 mg, such as 550-600 mg of gelatin per 1 gram of pellets.
According to one embodiment of the first aspect of the invention, the vitamin AD pellets further comprise sucrose.
Vitamin AD pellets according to any of the embodiments of the first aspect of the invention comprise 100-300 mg, such as 150-250 mg, such as 180-240 mg sucrose per 1 gram pellet.
The vitamin AD pellets according to any one of the embodiments of the first aspect of the invention, further comprising a preservative. In one embodiment, the preservative is selected from the group consisting of sodium benzoate, sodium dehydroacetate, sorbic acid, potassium sorbate, methylparaben, ethylparaben, propylparaben, and combinations thereof.
The vitamin AD pellets according to any of the embodiments of the first aspect of the present invention, comprise 1-5 mg, such as 1.5-3 mg, such as 2-3 mg of preservative per 1g of pellets.
The vitamin AD micro-pellets according to any embodiment of the first aspect of the present invention comprise sodium benzoate, wherein 0.2-2 mg, such as 0.5-1.5 mg, such as 0.75-1 mg of sodium benzoate is contained in 1g of micro-pellets.
The vitamin AD pellets according to any of the embodiments of the first aspect of the present invention, wherein sodium dehydroacetate is present in an amount of 0.5-5 mg, such as 1-3 mg, such as 1.2-2 mg per 1g of pellets.
According to one embodiment of the first aspect of the present invention, the vitamin AD pellets are prepared according to a method comprising the following steps:
(1) mixing and dissolving vitamin A, vitamin D2, edible vegetable oil and sorbitan fatty acid ester to obtain oily liquid; dissolving gelatin and sucrose in water, adding antiseptic, stirring to dissolve to obtain aqueous solution;
(2) adding the oily liquid obtained in the step (1) into the stirred aqueous liquid, and stirring and mixing to obtain an emulsion;
(3) and (3) spraying and drying the emulsion obtained in the step (2) to obtain the vitamin AD micro-pill.
According to one embodiment of the first aspect of the present invention, in the vitamin AD pellets, in the step (1), the oily liquid is prepared at a temperature of 35-100 ℃, for example, at a temperature of 35-80 ℃. It has been found that, for example in examples 1-5 below, effective dissolution of the entire mass cannot be achieved when this temperature is below 30 ℃.
According to one embodiment of the first aspect of the present invention, the vitamin AD micro-pellets, wherein in step (1), the aqueous liquid is prepared at a temperature of 40-100 ℃, for example at a temperature of 50-85 ℃. It has been found that, for example in examples 1-5 below, at the above treatment temperatures, an overall manufacturing process can be achieved using a relatively small amount of water, for example 2-6 times the amount of gelatin, for example 3-6 times the amount of gelatin. It has been found that, for example in examples 1-5 below, effective dissolution of the entire mass cannot be achieved when this temperature is below 40 ℃, or that the amount of water required is increased particularly significantly, for example significantly to over 9 times the amount of gelatin.
The vitamin AD pellets according to any one of the embodiments of the first aspect of the present invention, wherein the temperature of the oily liquid and the aqueous liquid mixed in the step (2) is 50 to 100 ℃, for example 60 to 80 ℃. It has been found that, for example, in examples 1-5 below, emulsions of uniform particle size can be effectively formed in this temperature range.
The vitamin AD pellets according to any one of the embodiments of the first aspect of the present invention, wherein the spray drying of step (3) is to spray the emulsion into an environment with a temperature below 70 ℃ and dry to form microparticles.
According to the vitamin AD micro-pill of any embodiment of the first aspect of the invention, the spray drying in step (3) is to spray the emulsion into an environment with the temperature of 20-70 ℃ and dry to form micro-particles.
According to the vitamin AD micropill in any one of the embodiments of the first aspect of the present invention, the spray drying in the step (3) is to spray the emulsion into the environment with the temperature of 20-70 ℃ and to form the particle by fluidized bed drying.
Vitamin AD pellets according to any of the embodiments of the first aspect of the invention, wherein the spray drying of step (3) is to spray the emulsion into an environment with a temperature below-20 ℃ followed by (optionally in a fluidized state) sublimation drying to form microparticles;
vitamin AD pellets according to any of the embodiments of the first aspect of the invention, wherein the spray drying of step (3) is to spray the emulsion into an environment with a temperature below-30 ℃ followed by (optionally in a fluidized state) sublimation drying to form microparticles;
vitamin AD pellets according to any of the embodiments of the first aspect of the invention, wherein the spray drying of step (3) is to spray the emulsion into an environment with a temperature below-40 ℃ followed by (optionally in a fluidized state) sublimation drying to form microparticles;
the vitamin AD pellets according to any one of the embodiments of the first aspect of the present invention, wherein the environment at a temperature below-20 ℃ in step (3) is obtained by cooling the space environment using liquid nitrogen.
The vitamin AD pellets according to any one of the embodiments of the first aspect of the present invention, further comprising a lubricant. In one embodiment, the lubricant is added before, during, or after the pellets are dried. In one embodiment, the lubricant is selected from magnesium stearate, stearic acid, calcium stearate, talc, silica, polyethylene glycol with a molecular weight of 4000-6000, and the like, and combinations thereof. In one embodiment, the lubricant comprises 0.005-1%, such as 0.1-0.5% by weight of the dried vitamin AD pellets.
The vitamin AD pellets according to any one of the embodiments of the first aspect of the invention, wherein the drying in step (3) is such that the moisture content in the pellets is less than 10%, such as less than 7% on a loss on drying basis. The loss on drying is determined by drying at 105 ℃ for 2 hours.
According to the vitamin AD micro-pill of any embodiment of the first aspect of the invention, the average particle size is in the range of 200-1200 μm, especially the average particle size is in the range of 300-900 μm. It has been found that, for example, in examples 1 to 5 below, a desired average particle diameter can be obtained by intensity adjustment of the emulsification operation in step (2), for example, pellets having a relatively small average particle diameter can be obtained when the emulsification intensity is high, and pellets having a relatively large average particle diameter can be obtained when the emulsification intensity is relatively low.
Vitamin AD pellets according to any of the embodiments of the first aspect of the invention, wherein the number of pellets in the range of the average particle size ± 50 μm is more than 60% of the total number of pellets, such as more than 70% of the total number of pellets, such as more than 80% of the total number of pellets. This property indicates that the pellets of the present invention have a very narrow particle size distribution range. It has been surprisingly found, for example, in examples 1-5 below, that when a suitable amount of sucrose is added to the pellets, the above-described pellets exhibiting a narrow particle size distribution range can be obtained; however, the number of pellets in the range of. + -. 50 μm of the average particle size was less than 35% of the total number of pellets when sucrose was not added (for example, sucrose was not added in examples 1 to 5 below) or when other saccharides having good water solubility were added, indicating that pellets having a narrow particle size distribution range could not be obtained without sucrose or by using other saccharides.
Further, according to a second aspect of the present invention, there is provided a method of preparing vitamin AD pellets, for example according to any one of the embodiments of the first aspect of the present invention, comprising the steps of:
(1) mixing and dissolving vitamin A, vitamin D2, edible vegetable oil and sorbitan fatty acid ester to obtain oily liquid; dissolving gelatin and sucrose in water, adding antiseptic, stirring to dissolve to obtain aqueous solution;
(2) adding the oily liquid obtained in the step (1) into the stirred aqueous liquid, and stirring and mixing to obtain an emulsion;
(3) and (3) spraying and drying the emulsion obtained in the step (2) to obtain the vitamin AD micro-pill.
According to the method of any embodiment of the second aspect of the invention, the vitamin AD pellets comprise 2 to 20 million i.u. vitamin a per 1 gram, e.g. 5 to 15 million i.u. vitamin a per 1 gram of pellets, e.g. 8 to 12 million i.u. vitamin a per 1 gram of pellets, e.g. 10 million i.u. vitamin a per 1 gram of pellets.
The method according to any embodiment of the second aspect of the invention, wherein the vitamin a is added to the vitamin AD pellets in the form of vitamin a or vitamin a palmitate or vitamin a acetate or other esters of vitamin a.
According to the method of any embodiment of the second aspect of the invention, the vitamin AD pellets comprise 0.2-2 ten thousand i.u. vitamin D per 1 gram2(which may also be referred to as calciferol, etc.), for example, 0.5-1.5 ten thousand I.U. vitamin D per 1 gram pellet2For example, each 1g of the pellet contains 0.8-1.2 ten thousand I.U. vitamin D2For example, it contains 1 ten thousand i.u. vitamin D per 1 gram pellet2。
According to the method of any embodiment of the second aspect of the present invention, the edible vegetable oil is, for example, corn oil, soybean oil, peanut oil, sunflower oil, or the like.
According to the method of any embodiment of the second aspect of the invention, the vitamin AD pellets comprise 100 to 200mg, such as 120 to 160mg, such as 130 to 150mg of edible vegetable oil per 1 g.
According to the method of any embodiment of the second aspect of the present invention, the fatty acid sorbitan ester is, for example, span20, span40, span60, span65, span80, span 85.
According to the method of any embodiment of the second aspect of the invention, the vitamin AD pellets comprise 2-20 mg, such as 2-15 mg, such as 2-12 mg, of sorbitan fatty acid ester per 1 g.
According to the method of any embodiment of the second aspect of the invention, the vitamin AD pellets comprise 400 to 700mg, such as 500 to 650mg, such as 550 to 600mg of gelatin per 1 gram.
According to the method of any embodiment of the second aspect of the invention, the vitamin AD pellets comprise sucrose in an amount of 100 to 300mg, such as 150 to 250mg, such as 180 to 240mg, per 1 gram.
According to the method of any embodiment of the second aspect of the invention, the preservative is selected from the group consisting of sodium benzoate, sodium dehydroacetate, sorbic acid, potassium sorbate, methylparaben, ethylparaben, propylparaben, and combinations thereof.
According to the method of any embodiment of the second aspect of the invention, the vitamin AD pellets comprise 1-5 mg, such as 1.5-3 mg, such as 2-3 mg, of preservative per 1 gram.
According to the method of any embodiment of the second aspect of the present invention, the vitamin AD micro-pellets comprise 0.2-2 mg, such as 0.5-1.5 mg, such as 0.75-1 mg, of sodium benzoate per 1 g.
According to the method of any embodiment of the second aspect of the invention, the vitamin AD pellets comprise 0.5-5 mg, such as 1-3 mg, such as 1.2-2 mg, of sodium dehydroacetate per 1 gram.
In the method according to any one of the second aspect of the present invention, in the step (1), the oily liquid is prepared at a temperature of 35 to 100 ℃, for example, at a temperature of 35 to 80 ℃. It has been found that effective dissolution of the entire mass cannot be achieved when this temperature is below 30 ℃.
The process according to any embodiment of the second aspect of the present invention, wherein in step (1), the aqueous liquid is prepared at a temperature of 40 to 100 ℃, for example, 50 to 85 ℃. It has been found that at the above treatment temperatures, an overall manufacturing process can be achieved using relatively small amounts of water, for example 2-6 times the amount of gelatin, for example 3-6 times the amount of gelatin. It has been found that effective dissolution of the entire mass cannot be achieved when this temperature is below 40 ℃, or that the amount of water required is increased particularly significantly, for example to significantly more than 9 times the amount of gelatin.
The process according to any one of the embodiments of the second aspect of the present invention, wherein the temperature of the mixing of the oily liquid and the aqueous liquid in the step (2) is 50 to 100 ℃, for example 60 to 80 ℃. It has been found that emulsions of uniform particle size can be effectively formed in this temperature range.
The method according to any embodiment of the second aspect of the present invention, wherein the spray drying in step (3) is to spray the emulsion into an environment with a temperature below 70 ℃ and dry to form microparticles.
The method according to any embodiment of the second aspect of the present invention, wherein the spray drying in step (3) is to spray the emulsion into an environment with a temperature of 20 to 70 ℃ and dry to form microparticles.
The method according to any embodiment of the second aspect of the present invention, wherein the spray drying in step (3) is to spray the emulsion into an environment with a temperature of 20 to 70 ℃ and to form the microparticles by fluidized bed drying.
The method according to any embodiment of the second aspect of the present invention, wherein the spray drying of step (3) is spraying the emulsion into an environment having a temperature below-20 ℃ followed by sublimation drying (optionally in a fluidized state) to form microparticles;
the method according to any embodiment of the second aspect of the present invention, wherein the spray drying of step (3) is spraying the emulsion into an environment having a temperature below-30 ℃ followed by sublimation drying (optionally in a fluidized state) to form microparticles;
the method according to any embodiment of the second aspect of the present invention, wherein the spray drying of step (3) is spraying the emulsion into an environment having a temperature below-40 ℃ followed by sublimation drying (optionally in a fluidized state) to form microparticles;
the process according to any one of the embodiments of the second aspect of the present invention, wherein the environment at a temperature of less than-20 ℃ in step (3) is obtained by cooling the space environment using liquid nitrogen.
The process according to any embodiment of the second aspect of the present invention, wherein the drying in step (3) is such that the moisture content in the pellets is less than 10%, such as less than 7% on a loss on drying basis. The loss on drying is determined by drying at 105 ℃ for 2 hours.
According to the method of any embodiment of the second aspect of the present invention, vitamin AD micro-pellets are obtained, wherein the average particle size of the vitamin AD micro-pellets is in the range of 200-1200 μm, especially the average particle size of the vitamin AD micro-pellets is in the range of 300-900 μm. It has been found that the desired average particle size can be obtained by intensity adjustment of the emulsification in step (2), for example, pellets having a relatively small average particle size can be obtained when the emulsification intensity is high, and pellets having a relatively large average particle size can be obtained when the emulsification intensity is relatively low.
According to a second embodiment of the present invention, there is provided vitamin AD pellets, wherein the number of pellets in the range of the average particle size ± 50 μm is more than 60% of the total number of pellets, such as more than 70% of the total number of pellets, such as more than 80% of the total number of pellets. This property indicates that the pellets of the present invention have a very narrow particle size distribution range. It has been surprisingly found that when a suitable amount of sucrose is added to the pellets, pellets with a narrow particle size distribution range can be obtained; however, the number of pellets in the range of. + -. 50 μm in average particle size when sucrose is not added or other saccharides having good water solubility are added was less than 35% based on the total number of pellets, indicating that pellets having a narrow particle size distribution range cannot be obtained without sucrose or with other saccharides.
It has been found that the vitamin AD pellets of the present invention can completely replace the vitamin AD microbeads imported from japan research and development company used in compound amino acid capsule compositions such as capsules containing 8 amino acids and 11 vitamin pellets.
To this end, the third aspect of the present invention provides a capsule, which includes 7 spherical or approximately spherical pellets and a capsule shell for enclosing these pellets, where the 7 pellets include 8 amino acids and 11 vitamins, and the 7 pellets and their weight ratio (in parts by weight) are:
Figure BDA0001256929690000061
Figure BDA0001256929690000071
the capsule according to any embodiment of the third aspect of the present invention, wherein the thiamine nitrate pellets, vitamin pellets a, vitamin pellets b, amino acid pellets b, each independently, may be known, for example, may be described in CN 101773512A.
A capsule according to any embodiment of the third aspect of the invention, wherein the vitamin AD pellets are as described in any embodiment of the first aspect of the invention or are obtainable as described in any embodiment of the second aspect of the invention.
The capsule according to any embodiment of the third aspect of the present invention, wherein the amino acid pellet a comprises the following components in parts by weight:
Figure BDA0001256929690000072
the capsule according to any embodiment of the third aspect of the present invention, wherein the amino acid pellet a comprises the following components in parts by weight:
Figure BDA0001256929690000073
a capsule according to any one of the embodiments of the third aspect of the present invention, wherein the vitamin C pellets comprise, in parts by weight:
Figure BDA0001256929690000074
Figure BDA0001256929690000081
a capsule according to any embodiment of the third aspect of the present invention, wherein the vitamin C pellets comprise the following parts by weight:
Figure BDA0001256929690000082
the capsule according to any embodiment of the third aspect of the present invention comprises 7 spherical or approximately spherical pellets and a capsule shell for covering the pellets, wherein the 7 pellets comprise 8 amino acids and 11 vitamins, and the 7 pellets and the weight ratio (in parts by weight) thereof are as follows:
Figure BDA0001256929690000083
wherein the thiamine nitrate pellet comprises the following components in parts by weight:
Figure BDA0001256929690000084
the vitamin pellet a comprises the following components in parts by weight:
Figure BDA0001256929690000085
the amino acid pellet a comprises the following components in parts by weight:
Figure BDA0001256929690000086
Figure BDA0001256929690000091
the vitamin pellet b comprises the following components in parts by weight:
Figure BDA0001256929690000092
the amino acid pellet b comprises the following components in parts by weight:
Figure BDA0001256929690000093
the vitamin C pellet comprises the following components in parts by weight:
Figure BDA0001256929690000094
the capsule according to any embodiment of the third aspect of the present invention, wherein the 7 kinds of pellets and their weight ratio (in parts by weight) are:
Figure BDA0001256929690000095
Figure BDA0001256929690000101
wherein the thiamine nitrate pellet comprises the following components in parts by weight:
Figure BDA0001256929690000102
the vitamin pellet a comprises the following components in parts by weight:
Figure BDA0001256929690000103
the amino acid pellet a comprises the following components in parts by weight:
Figure BDA0001256929690000104
the vitamin pellet b comprises the following components in parts by weight:
Figure BDA0001256929690000105
the amino acid pellet b comprises the following components in parts by weight:
Figure BDA0001256929690000111
the vitamin C pellet comprises the following components in parts by weight:
Figure BDA0001256929690000112
the capsule according to any embodiment of the third aspect of the present invention, wherein the 7 kinds of pellets and their weight ratio (in parts by weight) are:
thiamine nitrate micro-pills 6.88
Vitamin micro-pill a 17.1
Amino acid micro-pill a 36.8
Vitamin micro-pill b 12
Amino acid micro-pills b 7.56
Vitamin C micro-pill 13.4
Vitamin AD micro-pill 6.2
Wherein the thiamine nitrate micro-pill comprises the following components in parts by weight:
thiamine nitrate 25
Lactose 45
Starch 4.5
Calcium carboxymethylcellulose 7.5
Methyl cellulose 2.2
Hydroxypropyl cellulose 1.9
Titanium white powder 2.3
Microcrystalline cellulose 11.6
The vitamin pellet a comprises the following components in parts by weight:
nicotinamide 36
Calcium pantothenate 10
Vitamin B6 4.3
Lactose 7.7
Calcium carboxymethylcellulose 14
Hydroxypropyl cellulose 1.8
Microcrystalline cellulose 20
Starch 8.3
The amino acid pellet a comprises the following components in parts by weight:
l-isoleucine 4.6
L-leucine 14.2
L-lysine hydrochloride 19.3
L-phenylalanine 3.9
L-threonine 3.3
L-valine 5.2
L-methionine 14.3
Lactose 17.6
Starch 2.1
Methyl cellulose 2.0
Hydroxypropyl cellulose 1.2
Microcrystalline cellulose 9.7
Yellow pigment 0.16
Calcium carboxymethylcellulose 2.44
Sodium dodecyl sulfate 1.5
The vitamin pellet b comprises the following components in parts by weight:
5-Hydroxyphthalic acid hydrochloride 0.684
Vitamin B2 9.24
Folic acid 0.56
Vitamin B12 0.0028
Lactose 44.17
Microcrystalline cellulose 31.1
Polyethylene glycol 6000 0.57
Calcium carboxymethylcellulose 0.62
Starch 4.68
The amino acid pellet b comprises the following components in parts by weight:
l-tryptophan 21.18
Vitamin E 4.56
Lactose 25.25
Starch 19.55
Calcium carboxymethylcellulose 1.66
Methyl cellulose 1.785
Hydroxypropyl cellulose 1.15
Red pigment 0.425
Yellow pigment 0.0425
Aluminium silicate 15.39
The vitamin C pellet comprises the following components in parts by weight:
vitamin C 46.3
Lactose 27.1
Starch 6.03
Microcrystalline cellulose 7.56
Calcium carboxymethylcellulose 4.5
Polyethylene glycol 6000 3.8
Methyl cellulose 1.8
Chocolate pigment 0.29
Hydroxypropyl cellulose 2.62
Citric acid 3。
A capsule according to any embodiment of the third aspect of the present invention having the formulation proportions as described in any of the examples herein.
In a fourth aspect, the present invention provides a process for the preparation of a capsule according to any one of the embodiments of the third aspect of the invention: preparing thiamine nitrate micro-pills, vitamin micro-pills a, amino acid micro-pills a, vitamin micro-pills b, amino acid micro-pills b, vitamin C micro-pills and vitamin AD micro-pills respectively, mixing the seven micro-pills according to a proportion, and encapsulating;
wherein the content of the first and second substances,
the vitamin AD pellets are as described in any of the embodiments of the first aspect of the invention, or are prepared by the method as described in any of the embodiments of the second aspect of the invention;
the preparation method of the 6 kinds of round pellets respectively and independently comprises the following steps:
(1) weighing the raw materials in proportion, and mixing the raw materials;
(2) preparing a soft material by using water as a wetting agent, wherein the kneading time is 4-10 minutes;
(3) granulating round pills, wherein the aperture of a screen mesh is 0.9 mm, and the speed of the round pills is 40-60 Hz;
(4) and (3) carrying out fluidized drying at the air inlet temperature of 45-65 ℃ or carrying out vacuum drying at the temperature of 50-60 ℃.
The method according to any one of the embodiments of the fourth aspect of the present invention, wherein the thiamine nitrate pellets, the vitamin pellets a, the amino acid pellets a, the vitamin pellets b, the amino acid pellets b and the vitamin C pellets are prepared by the following steps:
(1) the preparation method of the thiamine nitrate pellet comprises the following steps: mixing thiamine nitrate and pharmaceutic adjuvants in proportion, preparing a soft material by using water as a wetting agent, and kneading for 4-6 minutes; granulating round pills at a granulation speed of 0.3pm, wherein the aperture of a screen mesh is 0.9 mm, and the speed of the round pills is 50-60 Hz; carrying out fluidized drying, wherein the air inlet temperature is 45-65 ℃; sieving to obtain thiamine nitrate white pellet;
(2) the preparation method of the vitamin pellet a comprises the following steps: mixing nicotinamide, calcium pantothenate, vitamin B6 and auxiliary materials, and preparing a soft material by using water as a wetting agent, wherein the kneading time is 4-8 minutes; granulating round pills at a granulation speed of 0.3pm, a sieve mesh aperture of 0.9 mm and a round pill speed of 50-60 Hz; fluidized drying is carried out, wherein the air inlet temperature is 45-65 ℃; sieving to obtain white vitamin pellet;
(3) the preparation method of the amino acid pellet a comprises the following steps: mixing L-isoleucine, L-leucine, L-lysine hydrochloride, L-phenylalanine, L-threonine, L-valine, L-methionine and auxiliary materials in proportion, preparing a soft material by using water as a wetting agent, kneading for 15-20 minutes, granulating round pills, wherein the granulation speed is 0.3pm, the aperture of a screen mesh is 0.9 mm, the round pill speed is 40-50 Hz, and carrying out vacuum drying at 50-60 ℃; sieving to obtain yellow amino acid pellet;
(4) the preparation method of the vitamin pellet b comprises the following steps: mixing 5-hydroxy o-aminobenzoic acid hydrochloride, vitamin B2, folic acid, vitamin B12 and auxiliary materials in proportion, preparing a soft material by using water as a wetting agent, and kneading for 4-6 minutes; granulating round pills, wherein the granulation speed is 0.2pm, the aperture of a screen mesh is 0.9 mm, and the round pill speed is 40-50 Hz; fluidized drying is carried out, wherein the air inlet temperature is 45-65 ℃; sieving to obtain orange yellow vitamin pellet;
(5) the preparation method of the amino acid pellet b comprises the following steps: mixing L-tryptophan, vitamin E and auxiliary materials in proportion to prepare a soft material, wherein the kneading time is 5-10 minutes; granulating round pills, wherein the granulation speed is 0.2pm, the aperture of a screen mesh is 0.9 mm, and the round pill speed is 40-50 Hz; vacuum drying at 50-60 deg.c; sieving to obtain red amino acid pellet;
(6) the preparation method of the vitamin C pellet comprises the following steps: mixing vitamin C and auxiliary materials in proportion, using water as a wetting agent to prepare a soft material, and kneading for 4-6 minutes; granulating round pills, wherein the granulation speed is 0.2pm, the aperture of a screen mesh is 0.9 mm, and the round pill speed is 50-60 Hz; fluidized drying is carried out, wherein the air inlet temperature is 45-65 ℃; sieving to obtain vitamin C brown pellet;
(7) vitamin AD micropills: prepared as described in any embodiment of the second aspect of the invention.
The method according to any one of the embodiments of the fourth aspect of the present invention, wherein the preparation method of 6 kinds of the thiamine nitrate pellets, the vitamin pellets a, the amino acid pellets a, the vitamin pellets b, the amino acid pellets b and the vitamin C pellets respectively comprises:
(1) the preparation method of the thiamine nitrate pellet comprises the following steps: mixing thiamine nitrate and pharmaceutic adjuvants in proportion, and preparing a soft material by using water as a wetting agent, wherein the kneading time is 4.5-5 minutes; granulating round pills, wherein the aperture of a screen mesh is 0.9 mm, and the speed of the round pills is 55-60 Hz; carrying out fluidized drying, wherein the air inlet temperature is 50-60 ℃; sieving to obtain thiamine nitrate white pellet;
(2) the preparation method of the vitamin pellet a comprises the following steps: mixing nicotinamide, calcium pantothenate, vitamin B6 and auxiliary materials, and preparing a soft material by using water as a wetting agent, wherein the kneading time is 5-7 minutes; granulating round pills, wherein the aperture of a screen mesh is 0.9 mm, and the speed of the round pills is 55-60 Hz; fluidized drying is carried out, wherein the air inlet temperature is 45-65 ℃; sieving to obtain white vitamin pellet;
(3) the preparation method of the amino acid pellet a comprises the following steps: mixing L-isoleucine, L-leucine, L-lysine hydrochloride, L-phenylalanine, L-threonine, L-valine, L-methionine and auxiliary materials in proportion, preparing a soft material by using water as a wetting agent, kneading for 18-20 minutes, granulating round pills, sieving with a sieve mesh of 0.9 mm, and drying at 50-60 ℃ in vacuum; sieving to obtain yellow amino acid pellet;
(4) the preparation method of the vitamin pellet b comprises the following steps: mixing 5-hydroxy o-aminobenzoic acid hydrochloride, vitamin B2, folic acid, vitamin B12 and auxiliary materials in proportion, preparing a soft material by using water as a wetting agent, and kneading for 5-6 minutes; granulating round pills, wherein the aperture of a screen mesh is 0.9 mm, and the speed of the round pills is 45-50 Hz; fluidized drying is carried out, wherein the air inlet temperature is 50-60 ℃; sieving to obtain orange yellow vitamin pellet;
(5) the preparation method of the amino acid pellet b comprises the following steps: mixing L-tryptophan, vitamin E and auxiliary materials in proportion, using water as a wetting agent to prepare a soft material, and kneading for 7-9 minutes; granulating round pills, wherein the aperture of a screen mesh is 0.9 mm, and the speed of the round pills is 45-50 Hz; vacuum drying at 50-60 deg.c; sieving to obtain red amino acid pellet;
(6) the preparation method of the vitamin C pellet comprises the following steps: mixing vitamin C and auxiliary materials in proportion, using water as a wetting agent to prepare a soft material, and kneading for 5-6 minutes; granulating round pills, wherein the aperture of a screen mesh is 0.9 mm, and the speed of the round pills is 55-60 Hz; fluidized drying is carried out, wherein the air inlet temperature is 50-65 ℃; sieving to obtain vitamin C brown pellet;
(7) vitamin AD micropills: prepared as described in any embodiment of the second aspect of the invention.
Further, in a fifth aspect, the present invention provides a use of the vitamin AD pellet according to any one of the embodiments of the first aspect of the present invention or the vitamin AD pellet prepared by the method according to any one of the embodiments of the second aspect of the present invention in preparing a compound amino acid capsule, wherein the compound amino acid capsule comprises the following components in parts by weight:
Figure BDA0001256929690000141
the vitamin A and vitamin D2 are present in the vitamin AD pellets.
Any technical features of any embodiment of the present invention may be combined with any embodiment of any aspect, as long as such a combination does not contradict.
In the present invention, the term pellet refers to a pellet having a diameter of between 0.05mm and 1.5mm, preferably between 0.1mm and 1.2 mm. Such pellets may be spherical or approximately spherical. In the present invention, the term "approximately spherical" means that the pellet has a minor axis/aspect ratio of (0.2 to 1):1, preferably (0.5 to 1): 1. In the following examples, the short diameter/length-diameter ratio of all 7 kinds of prepared pellets is determined to be in the range of (0.5-1): 1, for example, the short diameter/length-diameter ratio of the vitamin AD pellets prepared by the invention is determined to be easily controlled to be in the range of (0.9-1): 1, and pellets with the average long diameter in the range of 0.2-1.2 mm can be easily obtained by adjusting the process parameters as described above, for example, pellets with the short diameter/length-diameter ratio, the long diameter and other parameters basically the same as those of the commercially available vitamin AD microbeads can be easily obtained. For example, it is believed that the short diameter/length-to-diameter ratio of commercially available vitamin AD microbeads is measured to be 0.94:1, and the long diameters are all between 0.4 and 0.6 mm; such commercially available Vitamin AD microbeads (Vitamin-AD Beads) are available directly from the market, for example from the japanese physical research company or from Riken Vitamin co., ltd., for example, with the product registration number H20110103 (issued by the chinese national food and drug administration under the trade name Riken Dry AD-B100/10P) which contains 100000 units of Vitamin a and 210000 units of Vitamin D per 1 g. Vitamin AD microbeads from japan research also have the same properties as Riken Vitamin co.
The various pellets of the present invention may be prepared using methods well known to those skilled in the art. In the present invention, in addition to vitamin AD pellets, various other pellets may be prepared using an extrusion spheronization pelleting process. In the present invention, the pellets were prepared using an RE/SP series extrusion spheronizer (manufactured by Guangzhou Xirui mechanical equipments Co., Ltd.) as not otherwise specified.
The invention relates to an application of 8 amino acids and 11 vitamin pellet capsules in preparing medicines for treating chronic liver and kidney diseases and foods for relieving and eliminating physical fatigue of exercise training.
Under the condition of chronic liver diseases, the bioavailability of amino acids by cells can be effectively improved on the basis of not increasing the burden of nitrogen excretion of patients, 8 amino acids and 11 vitamin pellet capsules for promoting protein biosynthesis have unique process and advanced technology, and the effective period is more than three years.
The present invention is an enteral nutrition preparation for improving the composition of nitrogen source amino acids, and has an outstanding advantage in the treatment of chronic diseases. Firstly, the amino acid and protein metabolism of a patient can be greatly improved without changing the dietary structure and other treatment schemes of the patient; secondly, in the case of chronic liver diseases, it can effectively improve the bioavailability of amino acids from cells and promote protein biosynthesis without increasing the burden of nitrogen excretion of patients. Compared with the prior amino acid product technology, the invention has the following advantages:
1. reasonable and scientific proportioning and good biological effect. The preparation is different from a common amino acid preparation, the proportion of 8 essential amino acids is comprehensively considered and determined by combining various factors of dietary protein structure, amino acid composition and human body absorption in Asia-Pacific region, wherein the proportion of branched chain amino acid, lysine and methionine is larger, and 11 vitamins are added simultaneously, so that the synergistic effect of the amino acid and the vitamin is fully exerted, the amino acid is absorbed in the human body in a balanced way, and the bioavailability of the amino acid is ensured.
2. The process is unique and advanced, the production technology of extrusion granulation and round pills is adopted, the defects of other oral amino acid preparations are overcome, the seven kinds of micro pills are prepared by 8 kinds of essential amino acids and 11 kinds of vitamins according to different physicochemical properties, the chemical reaction and degradation among the components can not occur in the storage period, and the stability of various active components in the product is improved.
Most of the amino acids in the invention are relatively stable, wherein tryptophan is relatively easy to decompose in the preparation and storage processes, so that the content is reduced. Tryptophan has indole nucleus, changes color when meeting light, and has poor stability. Tryptophan is the least stable amino acid. In the 8 kinds of essential amino acids for human body, L-tryptophan is unstable in property and is not suitable for being mixed with other 7 kinds of amino acids, the L-tryptophan and vitamin E are prepared into separate red pellets, the stability of the L-tryptophan is effectively improved, and the other 7 kinds of amino acids are prepared into yellow pellets, so that the stability of the product prepared by the method is far higher than that of the like product. The product may have a shelf life of more than three years.
3. The oral administration is convenient. The oral amino acid preparation can make up some deficiencies of amino acid infusion in the treatment that patients with chronic diseases need the amino acid preparation for a long time. The invention is more suitable for chronic patients taking medicine for a long time, not only reduces the economic burden of the patients, but also improves the mental bearing capacity of the patients.
The capsules obtained in the embodiments 1 to 5 of the invention are respectively kept for a long time at room temperature, are respectively sampled at 0, 3, 6, 9, 12, 18, 24 and 36 months, and are used for measuring various indexes of samples at different times according to a method recorded in the national drug standard WS1- (X-307) -2004Z and a measuring method recorded in the 2010 version of Chinese pharmacopoeia; the results show that after the capsule samples in the embodiments of the invention are retained for 0 to 36 months, the disintegration time (measured by a pharmacopoeia method) is between 10 and 18min, the content of 8 amino acids is respectively kept within the range of 95 to 107 percent of the marked amount within the period of 3 years, and the content of 11 vitamins is respectively kept within the range of 95 to 105 percent of the marked amount within the period of 3 years, which shows that the capsule of the invention completely meets the requirements of the quality standards of the medicines.
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible. The following examples further illustrate the invention without limiting it. In each of the following experiments, vitamin AD pellets were prepared in batches of at least 2kg per batch based on the total weight of the pellets, and the remaining pellets were prepared in batches of at least 10kg per batch based on the total weight of the pellets.
Example 1
The formula of the pellet capsule containing 8 amino acids and 11 vitamins provided by the invention is as follows: wherein the weight ratio of seven pellet round pellets, namely the thiamine nitrate pellet, the vitamin pellet a, the amino acid pellet a, the vitamin pellet b, the amino acid pellet b, the vitamin C pellet and the vitamin AD pellet, is as follows:
thiamine nitrate micro-pills 6.88
Vitamin preparationPellets a 17.1
Amino acid micro-pill a 36.8
Vitamin micro-pill b 12
Amino acid micro-pills b 7.56
Vitamin C micro-pill 13.4
Vitamin AD micro-pill 6.2
1. The formula of the thiamine nitrate pellet is as follows:
thiamine nitrate 250g
Lactose 450g
Starch 45g
Calcium carboxymethylcellulose 75g
Methyl cellulose 22g
Hydroxypropyl cellulose 19g
Titanium white powder 23g
Microcrystalline cellulose 116g
2. The formula of the vitamin pellet a is as follows:
nicotinamide 360g
Calcium pantothenate 100g
Vitamin B6 43g
Lactose 77g
Calcium carboxymethylcellulose 140g
Hydroxypropyl cellulose 18g
Microcrystalline cellulose 200g
Starch 83g
3. The formula of the amino acid pellet a is
L-isoleucine 46g
L-leucine 142g
L-lysine hydrochloride 193g
L-phenylalanine 39g
L-threonine 33g
L-valine 52g
L-methionine 143g
Lactose 176g
Starch 21g
Methyl cellulose 20g
Hydroxypropyl cellulose 12g
Microcrystalline cellulose 97g
Yellow pigment 1.6g
Calcium carboxymethylcellulose 24.4g
Sodium dodecyl sulfate 15g
4. The formula of the vitamin pellet b is as follows:
5-Hydroxyphthalic acid hydrochloride 6.84g
Vitamin B2 92.4g
Folic acid 5.6g
Vitamin B12 0.028g
Lactose 441.7g
Microcrystalline cellulose 311g
Polyethylene glycol 6000 5.7g
Calcium carboxymethylcellulose 6.2g
Starch 46.8
5. The formula of the amino acid pellet b is as follows:
l-tryptophan 211.8g
Vitamin E 45.6g
Lactose 252.5g
Starch 195.5g
Calcium carboxymethylcellulose 16.6g
Methyl cellulose 17.85g
Hydroxypropyl cellulose 11.5g
Red pigment 4.25g
Yellow pigment 0.425g
Aluminium silicate 153.9g
6. The formula of the vitamin C pellet is as follows:
Figure BDA0001256929690000171
Figure BDA0001256929690000181
7. the formula proportion (per 1000mg) of the vitamin AD micropill is as follows:
vitamin A palmitate 58.8mg (10 Waniu vitamin A)
Corn oil 141.2mg
Calciferols 0.25mg (1 wan iu vitamin D2)
Span20 10mg
Gelatin 572mg
Sodium benzoate 0.87mg
Sodium dehydroacetate 1.45mg
Sucrose Adding appropriate amount of the pellet to make the total weight of the pellet 1000mg
Wherein, the preparation methods of the 7 kinds of pellets respectively comprise the following steps:
(1) preparing thiamine nitrate pellets: mixing thiamine nitrate, lactose, starch, calcium carboxymethylcellulose, methylcellulose, hydroxypropyl cellulose, titanium dioxide and microcrystalline cellulose according to a proportion to prepare a soft material, wherein the kneading time is 5 minutes; granulating round pill with sieve mesh aperture of 0.9 mm and round pill speed of 60 Hz; fluidized drying is carried out, the air inlet temperature is 60 ℃, and drying is carried out for 3 hours; sieving to obtain thiamine nitrate white pellet;
(2) preparing vitamin pellets a: mixing nicotinamide, calcium pantothenate, vitamin B6, lactose, carboxymethylcellulose calcium, hydroxypropyl cellulose, microcrystalline cellulose and starch to prepare a soft material, and kneading for 7 minutes; granulating round pill with sieve mesh aperture of 0.9 mm and round pill speed of 60 Hz; fluidized drying is carried out, the air inlet temperature is 65 ℃, and drying is carried out for 5 hours; sieving to obtain white vitamin pellet;
(3) preparing amino acid pellets a: mixing the materials in proportion, preparing soft material, kneading for 20 min, granulating into round pill with sieve pore diameter of 0.9 mm and round pill speed of 50 Hz, and vacuum drying at 60 deg.C for 15 hr; sieving to obtain yellow amino acid pellet;
(4) preparing vitamin pellets b: mixing 5-hydroxy o-aminobenzoic acid hydrochloride, vitamin B2, folic acid, vitamin B12, lactose, microcrystalline cellulose, polyethylene glycol 6000, calcium carboxymethylcellulose and starch in proportion to prepare a soft material, and kneading for 6 minutes; granulating round pill with sieve mesh aperture of 0.9 mm and round pill speed of 50 Hz; fluidized drying for 4 hours at 60 ℃; sieving to obtain orange yellow vitamin pellet;
(5) preparing amino acid pellets b: mixing L-tryptophan, vitamin E, lactose, starch, carboxymethylcellulose calcium, methylcellulose, hydroxypropyl cellulose, haematochrome, yellow pigment and aluminum silicate in proportion to prepare a soft material, and kneading for 7 minutes; granulating round pill with sieve mesh aperture of 0.9 mm and round pill speed of 50 Hz; vacuum drying at 60 deg.C for 20 hr; sieving to obtain red amino acid pellet;
(6) preparing vitamin C pellets: mixing the materials in proportion to prepare a soft material, wherein the kneading time is 5-6 minutes; granulating round pills, wherein the aperture of a screen mesh is 0.9 mm, and the speed of the round pills is 60 Hz; fluidized drying for 3 hours at 65 ℃; sieving to obtain vitamin C brown pellet;
(7) vitamin AD micropills:
(1) mixing vitamin A, vitamin D2, edible vegetable oil, and sorbitan fatty acid ester at 45 deg.C for dissolving to obtain oily liquid; dissolving gelatin and sucrose (75 deg.C) in water (water to gelatin weight ratio of 4: 1), adding antiseptic, and stirring to dissolve to obtain aqueous solution;
(2) adding the oily liquid obtained in the step (1) into the stirred aqueous liquid, stirring and mixing (65 ℃) to obtain emulsion;
(3) and (3) spraying the emulsion obtained in the step (2) (fluidizing at 65 ℃), and drying (until the drying weight loss is less than 7%) to obtain the vitamin AD micro-pill.
Finally, mixing the 7 prepared pellets according to a proportion and encapsulating.
Example 2
The formula of the pellet capsule containing 8 amino acids and 11 vitamins provided by the invention is as follows:
wherein the weight ratio of seven pellet round pellets, namely the thiamine nitrate pellet, the vitamin pellet a, the amino acid pellet a, the vitamin pellet b, the amino acid pellet b, the vitamin C pellet and the vitamin AD pellet, is as follows:
thiamine nitrate micro-pills 2.66
Vitamin micro-pill a 16.35
Amino acid micro-pill a 35.0
Vitamin micro-pill b 11.4
Amino acid micro-pills b 6.65
Vitamin C micro-pill 12.73
Vitamin AD micro-pill 5.7
1. The formula of the thiamine nitrate pellet is as follows:
thiamine nitrate 76g
Lactose 225g
Starch 9g
Calcium carboxymethylcellulose 15g
Methyl cellulose 4.4g
Hydroxypropyl cellulose 3.8g
Titanium white powder 4.6g
Microcrystalline cellulose 58g
2. The formula of the vitamin pellet a is as follows:
nicotinamide 245g
Calcium pantothenate 62g
Vitamin B6 31g
Lactose 19.4g
Calcium carboxymethylcellulose 56g
Hydroxypropyl cellulose 3.6g
Microcrystalline cellulose 93.5g
Starch 16.6g
3. The formula of the amino acid pellet a is as follows:
Figure BDA0001256929690000191
Figure BDA0001256929690000201
4. the formula of the vitamin pellet b is as follows:
5-Hydroxyphthalic acid hydrochloride 3.6g
Vitamin B2 44g
Folic acid 3.6g
Vitamin B12 0.018g
Lactose 255g
Microcrystalline cellulose 157.5g
Polyethylene glycol 6000 1.7g
Calcium carboxymethylcellulose 1.84g
Starch 13.97g
5. The formula of the amino acid pellet b is as follows:
l-tryptophan 151g
Vitamin E 31g
Lactose 148.5g
Starch 115g
Calcium carboxymethylcellulose 3.9g
Methyl cellulose 4.2g
Hydroxypropyl cellulose 2.6g
Red pigment 1g
Yellow pigment 0.1g
Aluminium silicate 38.2g
6. The formula of the vitamin C comprises the following components:
vitamin C 315g
Lactose 135.5g
Starch 12.06g
Microcrystalline cellulose 15.12g
Calcium carboxymethylcellulose 9g
Polyethylene glycol 6000 7.6g
Methyl cellulose 3.6g
Chocolate pigment 0.58g
Hydroxypropyl cellulose 10g
Citric acid 10g
7. The formula proportion (per 1000mg) of the vitamin AD micropill is as follows:
vitamin A acetate Foldable 15 WanVA
Soybean oil 120mg
Calciferols 1.5 ten thousand VD2
Span40 2mg
Gelatin 400mg
Nipagin methyl ester 0.75mg
Nipagin ethyl ester 0.5mg
Sucrose Adding appropriate amount of the pellet to make the total weight of the pellet 1000mg
Wherein, the preparation methods of the 7 kinds of pellets respectively comprise the following steps:
(1) preparing thiamine nitrate pellets: mixing thiamine nitrate and pharmaceutic adjuvants according to a proportion to prepare a soft material, wherein the kneading time is 4.5 minutes; granulating round pills, wherein the aperture of a screen mesh is 0.9 mm, and the speed of the round pills is 550 Hz; fluidized drying is carried out for 5 hours, and the air inlet temperature is 50-60 ℃; sieving to obtain thiamine nitrate white pellet;
(2) preparing vitamin pellets a: mixing nicotinamide, calcium pantothenate, vitamin B6 and adjuvants to obtain soft material, and kneading for 6 min; granulating round pills, wherein the aperture of a screen mesh is 0.9 mm, and the speed of the round pills is 55-60 Hz; fluidized drying for 4 hours at 60 ℃; sieving to obtain white vitamin pellet;
(3) preparing amino acid pellets a: mixing L-isoleucine, L-leucine, L-lysine hydrochloride, L-phenylalanine, L-threonine, L-valine, L-methionine and auxiliary materials in proportion to prepare a soft material, kneading for 18 minutes, granulating into round pills, sieving with a sieve mesh of 0.9 mm, and drying in vacuum at 60 ℃ for 20 hours, wherein the sieve mesh is 4 Hz; sieving to obtain yellow amino acid pellet;
(4) preparing vitamin pellets b: mixing 5-hydroxy o-aminobenzoic acid hydrochloride, vitamin B2, folic acid, vitamin B12 and auxiliary materials in proportion to prepare a soft material, and kneading for 6 minutes; granulating round pills, wherein the aperture of a screen mesh is 0.9 mm, and the speed of the round pills is 45 Hz; fluidized drying for 3 hours at the air inlet temperature of 50 ℃; sieving to obtain orange yellow vitamin pellet;
(5) preparing amino acid pellets b: mixing L-tryptophan, vitamin E and auxiliary materials in proportion to prepare a soft material, and kneading for 8 minutes; granulating round pill with sieve mesh aperture of 0.9 mm and round pill speed of 50 Hz; vacuum drying at 60 deg.C for 20 hr; sieving to obtain red amino acid pellet;
(6) preparing vitamin C pellets: mixing vitamin C and auxiliary materials in proportion to prepare a soft material, and kneading for 5 minutes; granulating round pills, wherein the aperture of a screen mesh is 0.9 mm, and the speed of the round pills is 60 Hz; fluidized drying for 5 hours at 60 ℃; sieving to obtain vitamin C brown pellet;
(7) vitamin AD micropills:
(1) mixing vitamin A, vitamin D2, edible vegetable oil, and sorbitan fatty acid ester at 35 deg.C for dissolving to obtain oily liquid; dissolving gelatin and sucrose (100 deg.C) in water (water to gelatin weight ratio of 2: 1), adding antiseptic, and stirring to dissolve to obtain aqueous solution;
(2) adding the oily liquid obtained in the step (1) into the stirred aqueous liquid, stirring and mixing (100 ℃) to obtain emulsion;
(3) and (3) spraying the emulsion obtained in the step (2) (fluidizing at 30 ℃), and drying (until the drying weight loss is less than 7%) to obtain the vitamin AD micro-pill.
Finally, mixing the 7 prepared pellets according to a proportion and encapsulating.
Example 3
The formula of the pellet capsule containing 8 amino acids and 11 vitamins is as follows:
the weight ratio of seven pellet round pellets, namely thiamine nitrate pellets, vitamin pellets a, amino acid pellets a, vitamin pellets b, amino acid pellets b, vitamin C pellets and vitamin AD pellets, is as follows:
thiamine nitrate micro-pills 9.9
Vitamin micro-pill a 20.5
Amino acid micro-pill a 44.1
Vitamin micro-pill b 14.4
Amino acid micro-pills b 10.5
Vitamin C micro-pill 16.0
Vitamin AD micro-pill 9.36
1. The formula of the thiamine nitrate pellet is as follows:
Figure BDA0001256929690000211
Figure BDA0001256929690000221
2. the formula of the vitamin pellet a is as follows:
nicotinamide 580g
Calcium pantothenate 145g
Vitamin B6 72g
Lactose 174.6g
Calcium carboxymethylcellulose 168g
Hydroxypropyl cellulose 32.4g
Microcrystalline cellulose 280.5g
Starch 149.4g
3. The formula of the amino acid pellet a is as follows:
l-isoleucine 80g
L-leucine 248g
L-lysine hydrochloride 338g
L-phenylalanine 67g
L-threonine 56g
L-valine 90g
L-methionine 245g
Lactose 264g
Starch 37.8g
Methyl cellulose 36g
Hydroxypropyl cellulose 21.6g
Microcrystalline cellulose 174.6g
Yellow pigment 2.88g
Calcium carboxymethylcellulose 43.92g
Sodium dodecyl sulfate 30g
4. The vitamin pellet b comprises the following formula:
5-Hydroxyphthalic acid hydrochloride 8.3g
Vitamin B2 124g
Folic acid 8.3g
Vitamin B12 0.04g
Lactose 765g
Microcrystalline cellulose 472.5g
Polyethylene glycol 6000 15.3g
Calcium carboxymethylcellulose 16.56g
Starch 125.77g
5. The amino acid pellet b comprises the following components in parts by weight:
l-tryptophan 284g
Vitamin E 56g
Lactose 445.5g
Starch 345g
Calcium carboxymethylcellulose 35.1g
Methyl cellulose 37.8g
Hydroxypropyl cellulose 23.4g
Red pigment 9g
Yellow pigment 0.9g
Aluminium silicate 271.5g
6. The formula of the vitamin C pellet is as follows:
vitamin C 745g
Lactose 406.5g
Starch 108.5g
Microcrystalline cellulose 136.08g
Calcium carboxymethylcellulose 81g
Polyethylene glycol 6000 68.4g
Methyl cellulose 32.4g
Chocolate pigment 5.22g
Hydroxypropyl cellulose 50g
Citric acid 50g
7. The formula proportion (per 1000mg) of the vitamin AD micropill is as follows:
vitamin A Folding 5 ten thousand VA
Peanut oil 160mg
Calciferols 0.5 ten thousand VD2
Span60 20mg
Gelatin 700mg
Sorbic acid 0.65mg
Potassium sorbate 1mg
Sucrose Adding appropriate amount of the pellet to make the total weight of the pellet 1000mg
Wherein, the preparation methods of the 7 kinds of pellets respectively comprise the following steps:
(1) preparing thiamine nitrate pellets: mixing thiamine nitrate and pharmaceutic adjuvants according to a proportion to prepare a soft material, and kneading for 6 minutes; granulating round pill with sieve mesh aperture of 0.9 mm and round pill speed of 60 Hz; fluidized drying for 4 hours at the air inlet temperature of 65 ℃; sieving to obtain thiamine nitrate white pellet;
(2) preparing vitamin pellets a: mixing nicotinamide, calcium pantothenate, vitamin B6 and adjuvants to obtain soft material, and kneading for 8 min; granulating round pills, wherein the aperture of a screen mesh is 0.9 mm, and the speed of the round pills is 560 Hz; fluidized drying for 3 hours at the air inlet temperature of 65 ℃; sieving to obtain white vitamin pellet;
(3) preparing amino acid pellets a: mixing L-isoleucine, L-leucine, L-lysine hydrochloride, L-phenylalanine, L-threonine, L-valine, L-methionine and auxiliary materials in proportion to prepare a soft material, kneading for 20 minutes, granulating into round pills, sieving with a sieve mesh of 0.9 mm, and drying in vacuum at 60 ℃ for 15 hours, wherein the sieve mesh is used for sieving; sieving to obtain yellow amino acid pellet;
(4) preparing vitamin pellets b: mixing 5-hydroxy o-aminobenzoic acid hydrochloride, vitamin B2, folic acid, vitamin B12 and auxiliary materials in proportion to prepare a soft material, and kneading for 6 minutes; granulating round pill with sieve mesh aperture of 0.9 mm and round pill speed of 50 Hz; fluidized drying for 5 hours at the air inlet temperature of 65 ℃; sieving to obtain orange yellow vitamin pellet;
(5) preparing amino acid pellets b: mixing L-tryptophan, vitamin E and auxiliary materials in proportion to prepare a soft material, and kneading for 10 minutes; granulating round pill with sieve mesh aperture of 0.9 mm and round pill speed of 50 Hz; vacuum drying at 60 deg.C for 15 hr; sieving to obtain red amino acid pellet;
(6) preparing vitamin C pellets: mixing vitamin C and auxiliary materials in proportion to prepare a soft material, and kneading for 6 minutes; granulating round pill with sieve mesh aperture of 0.9 mm and round pill speed of 60 Hz; fluidized drying for 4 hours at the air inlet temperature of 65 ℃; sieving to obtain vitamin C brown pellet;
(7) vitamin AD micropills:
(1) mixing vitamin A, vitamin D2, edible vegetable oil, and sorbitan fatty acid ester (100 deg.C) to dissolve to obtain oily liquid; dissolving gelatin and sucrose (40 deg.C) in water (weight ratio of water to gelatin is 6: 1), adding antiseptic, and stirring to dissolve to obtain aqueous solution;
(2) adding the oily liquid obtained in the step (1) into the stirred aqueous liquid, stirring and mixing (50 ℃) to obtain emulsion;
(3) and (3) spraying the emulsion obtained in the step (2) to (-25 ℃ liquid nitrogen atmosphere/fluidization/sublimation), adding talcum powder (accounting for 0.2 percent of the weight of the finally obtained vitamin AD micro-pill), and drying (until the drying weight loss is less than 7 percent) to obtain the vitamin AD micro-pill.
Finally, mixing the 7 prepared pellets according to a proportion and encapsulating.
Example 4
The formula of the pellet capsule containing 8 amino acids and 11 vitamins is as follows:
the weight ratio of seven pellet round pellets, namely thiamine nitrate pellets, vitamin pellets a, amino acid pellets a, vitamin pellets b, amino acid pellets b, vitamin C pellets and vitamin AD pellets, is as follows:
thiamine nitrate micro-pills 47.7
Vitamin micro-pill a 167.2
Amino acid micro-pill a 358.8
Vitamin micro-pill b 117
Amino acid micro-pills b 70.05
Vitamin C micro-pill 130.65
Vitamin AD micro-pill 60.9
1. The formula of the thiamine nitrate pellet is as follows: (Unit: kilogram)
Thiamine nitrate 16.3
Lactose 33.75
Starch 2.7
Calcium carboxymethylcellulose 4.5
Methyl cellulose 1.32
Hydroxypropyl cellulose 1.14
Titanium white powder 1.38
Microcrystalline cellulose 8.7
2. The formula of the vitamin pellet a is as follows: (Unit: kilogram)
Nicotinamide 30.25
Calcium pantothenate 8.1
Vitamin B6 3.7
Lactose 4.1
Calcium carboxymethylcellulose 11.8
Hydroxypropyl cellulose 0.76
Microcrystalline cellulose 19.73
Starch 3.5
3. The formula of the amino acid pellet a is as follows: (Unit: kilogram)
Figure BDA0001256929690000241
Figure BDA0001256929690000251
4. The formula of the vitamin pellet b is as follows: (Unit: kilogram)
5-Hydroxyphthalic acid hydrochloride 0.465
Vitamin B2 6.05
Folic acid 0.415
Vitamin B12 0.002
Lactose 38.25
Microcrystalline cellulose 23.625
Polyethylene glycol 6000 0.51
Calcium carboxymethylcellulose 0.552
Starch 4.19215
5. The formula of the amino acid pellet b is as follows: (Unit: kilogram)
L-tryptophan 17.1
Vitamin E 3.65
Lactose 22.275
Starch 17.25
Calcium carboxymethylcellulose 1.17
Methyl cellulose 1.26
Hydroxypropyl cellulose 0.78
Red pigment 0.3
Yellow pigment 0.03
Aluminium silicate 13.575
6. The formula of the vitamin C pellet is as follows: (Unit: kilogram)
Vitamin C 38.9
Lactose 20.325
Starch 3.618
Microcrystalline cellulose 4.536
Calcium carboxymethylcellulose 2.7
Polyethylene glycol 6000 2.28
Methyl cellulose 1.08
Chocolate pigment 0.174
Hydroxypropyl cellulose 1.572
Citric acid 2
7. The formula proportion (per 1000mg) of the vitamin AD micropill is as follows:
vitamin A palmitate Folding 2 ten thousand VA
Sunflower seed oil 100mg
Calciferols 2 ten thousand VD2
Span80 15mg
Gelatin 500mg
Sodium benzoate 1mg
Sucrose Adding appropriate amount of the pellet to make the total weight of the pellet 1000mg
Wherein, the preparation methods of the 7 kinds of pellets respectively comprise the following steps:
(1) preparing thiamine nitrate pellets: mixing thiamine nitrate and pharmaceutic adjuvants according to a proportion to prepare a soft material, and kneading for 4 minutes; granulating round pill with sieve mesh aperture of 0.9 mm and round pill speed of 50 Hz; fluidized drying for 3 hours at the air inlet temperature of 65 ℃; sieving to obtain thiamine nitrate white pellet;
(2) preparing vitamin pellets a: mixing nicotinamide, calcium pantothenate, vitamin B6 and adjuvants to obtain soft material, and kneading for 4 min; granulating round pills, wherein the aperture of a screen mesh is 0.9 mm, and the speed of the round pills is 50 Hz; fluidized drying for 3 hours at the air inlet temperature of 45 ℃; sieving to obtain white vitamin pellet;
(3) preparing amino acid pellets a: mixing L-isoleucine, L-leucine, L-lysine hydrochloride, L-phenylalanine, L-threonine, L-valine, L-methionine and auxiliary materials in proportion to prepare a soft material, kneading for 15 minutes, granulating into round pills, sieving with a sieve mesh of 0.9 mm, and drying at 50 ℃ for 17 hours in vacuum; sieving to obtain yellow amino acid pellet;
(4) preparing vitamin pellets b: mixing 5-hydroxy o-aminobenzoic acid hydrochloride, vitamin B2, folic acid, vitamin B12 and auxiliary materials in proportion to prepare a soft material, and kneading for 4 minutes; granulating round pill with sieve mesh aperture of 0.9 mm and round pill velocity of 40 Hz; fluidized drying for 5 hours at the air inlet temperature of 45 ℃; sieving to obtain orange yellow vitamin pellet;
(5) preparing amino acid pellets b: mixing L-tryptophan, vitamin E and auxiliary materials in proportion to prepare a soft material, and kneading for 5 minutes; granulating round pill with sieve mesh aperture of 0.9 mm and round pill velocity of 40 Hz; vacuum drying at 50 deg.C for 18 hr; sieving to obtain red amino acid pellet;
(6) preparing vitamin C pellets: mixing vitamin C and auxiliary materials in proportion to prepare a soft material, wherein the kneading time is 4-6 minutes; granulating round pill with sieve mesh aperture of 0.9 mm and round pill speed of 50 Hz; fluidized drying for 3 hours at the air inlet temperature of 45 ℃; sieving to obtain vitamin C brown pellet;
(7) vitamin AD micropills:
(1) mixing vitamin A, vitamin D2, edible vegetable oil, and sorbitan fatty acid ester (80 deg.C) for dissolving to obtain oily liquid; dissolving gelatin and sucrose (50 deg.C) in water (water to gelatin weight ratio of 3: 1), adding antiseptic, and stirring to dissolve to obtain aqueous solution;
(2) adding the oily liquid obtained in the step (1) into the stirred aqueous liquid, stirring and mixing (60 ℃) to obtain emulsion;
(3) and (3) spraying the emulsion obtained in the step (2) to (-35 ℃ liquid nitrogen atmosphere/fluidization/sublimation, and adding silicon dioxide (accounting for 0.1 percent of the weight of the finally obtained vitamin AD micro-pill) in the drying process (until the drying weight loss is less than 7 percent) to obtain the vitamin AD micro-pill.
Finally, mixing the 7 prepared pellets according to a proportion and encapsulating.
Example 5
The formula of the pellet capsule containing 8 amino acids and 11 vitamins is as follows:
the weight ratio of seven pellet round pellets, namely thiamine nitrate pellets, vitamin pellets a, amino acid pellets a, vitamin pellets b, amino acid pellets b, vitamin C pellets and vitamin AD pellets, is as follows:
thiamine nitrate micro-pills 8.4
Vitamin micro-pill a 18.83
Amino acid micro-pill a 40.48
Vitamin micro-pill b 13.2
Amino acid micro-pills b 8.96
Vitamin C micro-pill 14.74
Vitamin AD micro-pill 7.92
1. The formula of the thiamine nitrate pellet package is as follows: (Unit: kilogram)
Thiamine nitrate 27.5
Lactose 56.25
Starch 6.3
Calcium carboxymethylcellulose 10.5
Methyl cellulose 3.08
Hydroxypropyl cellulose 2.66
Titanium white powder 3.22
Microcrystalline cellulose 14.5
2. The formula of the vitamin pellet a is as follows: (Unit: kilogram)
Nicotinamide 47
Calcium pantothenate 12.25
Vitamin B6 5.75
Lactose 16.76
Calcium carboxymethylcellulose 16.1
Hydroxypropyl cellulose 3.0
Microcrystalline cellulose 25
Starch 14
3. The formula of the amino acid pellet a is as follows: (Unit: kilogram)
L-isoleucine 6.3
L-leucine 19.5
L-lysine hydrochloride 26.55
L-phenylalanine 5.3
L-threonine 4.45
L-valine 7.1
L-methionine 19.4
Lactose 22
Starch 2.94
Methyl cellulose 2.8
Hydroxypropyl cellulose 1.68
Microcrystalline cellulose 13.58
Yellow pigment 0.224
Calcium carboxymethylcellulose 3.416
Sodium dodecyl sulfate 2.5
4. The formula of the vitamin pellet b is as follows: (Unit: kilogram)
5-Hydroxyphthalic acid hydrochloride 0.7
Vitamin B2 10.05
Folic acid 0.65
Vitamin B12 0.003
Lactose 63.75
Microcrystalline cellulose 39.375
Polyethylene glycol 6000 1.19
Calcium carboxymethylcellulose 1.288
Starch 9.78215
5. The formula of the amino acid pellet b is as follows: (Unit: kilogram)
Figure BDA0001256929690000271
Figure BDA0001256929690000281
6. The formula of the vitamin C pellet is as follows: (Unit: kilogram)
Vitamin C 60.4
Lactose 33.875
Starch 8.44
Microcrystalline cellulose 10.584
Calcium carboxymethylcellulose 6.3
Polyethylene glycol 6000 5.32
Methyl cellulose 2.52
Chocolate pigment 0.406
Hydroxypropyl cellulose 3.668
Citric acid 4
7. The formula proportion (per 1000mg) of the vitamin AD micropill is as follows:
vitamin A acetate Foldable 20 ten thousand VA
Corn oil 200mg
Calciferols 0.2 ten thousand VD2
Span40 12mg
Gelatin 650mg
Sodium dehydroacetate 3mg
Sucrose Adding appropriate amount of the pellet to make the total weight of the pellet 1000mg
In the first 6 kinds of pellet preparation, see example 1, vitamin AD pellet preparation method is as follows:
(1) mixing vitamin A, vitamin D2, edible vegetable oil, and sorbitan fatty acid ester (55 deg.C) to dissolve to obtain oily liquid; dissolving gelatin and sucrose (85 deg.C) in water (5: 1 weight ratio of water to gelatin), adding antiseptic, and stirring to dissolve to obtain aqueous solution;
(2) adding the oily liquid obtained in the step (1) into the stirred aqueous liquid, stirring and mixing (80 ℃) to obtain emulsion;
(3) and (3) spraying the emulsion obtained in the step (2) to (-45 ℃ liquid nitrogen atmosphere/fluidization/sublimation), drying (until the drying weight loss is less than 7%), and adding magnesium stearate (accounting for 0.2% of the weight of the finally obtained vitamin AD micro-pill) after drying to obtain the vitamin AD micro-pill.
Finally, mixing the 7 prepared pellets according to a proportion and encapsulating.
Test example 1:
in the above embodiments, the vitamin a pellet a and the vitamin AD pellet obtained in the above embodiments are mixed according to the proportion of the two in the capsule formula, the mixture is placed at 40 ℃ for 6 months, the vitamin a content and the vitamin D content in the mixture at 0 month and 6 months are measured (measured according to the method carried in the vitamin AD soft capsule or drop of the second part of the chinese pharmacopoeia 2015 edition, respectively), and the percentage obtained by dividing the content at 6 months by the content at 0 months and multiplying by 100% is the residual percentage of the vitamin a or D in the batch of mixture after the treatment of 40-6 months; the results showed that for the mixture obtained by mixing vitamin pellet a and vitamin AD pellet prepared in examples 1-5 above, the residual percentages of vitamin A and vitamin D were in the range of 97.3-99.0% and 97.6-99.3%, respectively, indicating that both vitamin A and vitamin D in these mixtures have excellent stability; in addition, the pellet capsules containing 8 amino acids and 11 vitamins obtained in examples 1-5 are treated for 40-6 months and the residual percentage of vitamin A, D is determined, so that the residual percentage of vitamin A is 97.5-99.4% and the residual percentage of vitamin D is 97.6-99.2%; this shows that vitamin AD pellets alone, or in combination with the remaining 6 pellets, exhibited substantially the same results for vitamin A, D stability. Then, Vitamin AD micro beads (Riken Dry AD-B100/10P, imported from Riken Vitamin Co., Ltd. into China, containing 10 ten thousand International units of Vitamin A and 1 ten thousand International units of Vitamin D2 per 1g of micro beads) purchased from Riken research corporation were mixed with the Vitamin micro beads a obtained in examples 1 to 5 above according to the ratio of the two in the capsule formulation, and the mixture was left at 40 ℃ for 6 months to measure the Vitamin A content and the Vitamin D content in the mixture at 0 month and 6 months (measured by the method carried in Vitamin AD soft capsules or drops in the second division of the national pharmacopoeia 2015 edition, respectively), for each batch of mixed samples, the percentage of vitamin A or D obtained by dividing the content at 6 months by the content at 0 months and multiplying the percentage by 100 percent, the residual percentage of vitamin A or D in the batch of mixture after being treated for 40-6 months; the results showed that for the blends of vitamin pellets a prepared in examples 1-5 above and Riken Dry AD-B100/10P, the residual percentages of vitamin A and vitamin D were in the range of 86.6-89.4% and 83.6-88.7%, indicating that the vitamin A and D stability in these blends was not satisfactory; in addition, the RikenDry AD-B100/10P is respectively substituted for the equal weight of vitamin AD pellets in the examples 1-5 to prepare capsules, and the treatment is carried out for 40-6 months at the same time, and the residual percentage of the vitamin A, D is measured, so that the residual percentage of the vitamin A is in the range of 87.1-88.9%, and the residual percentage of the vitamin D is in the range of 84.6-89.3%; this indicates that the commercially available Riken Dry AD-B100/10P alone or in combination with the remaining 6 pellets had unsatisfactory stability of vitamin A, D. Then, the stability of the five vitamin AD pellets prepared in the examples 1 to 5 of the present invention and the stability of the commercially available Riken Dry AD-B100/10P were examined according to the above method of 40 to 6 months treatment, and the residual percentages of vitamin A and vitamin D were respectively determined, and the results showed that the residual percentages of vitamin A and vitamin D in the 6 batches of vitamin AD pellets/microbeads were both in the range of 97.7 to 99.4%. The residual percentage of vitamin A or vitamin D in this test has a different meaning from the "indicated amount" in the following test, both being referred to differently and not necessarily being related.
The pellet capsule containing 8 amino acids and 11 vitamins is loaded into national drug standard, the standard number is WS1- (X-307) -2004Z, the standard is suitable for the pellet capsule containing 8 amino acids and 11 vitamins in the invention, and the capsule is suitable for the capsule obtained by replacing the vitamin AD pellets in the capsule with Japanese research vitamin AD microbeads; the capsules obtained in examples 1-5 of the present invention above were tested against this standard and it was found that each of the criteria met the specifications of the standard.
Test example 2:
in the present invention, the term pellet refers to a pellet having a diameter of between 0.05mm and 1.5mm, preferably between 0.1mm and 1.2 mm. Such pellets may be spherical or approximately spherical. In the present invention, the term "approximately spherical" means that the pellet has a minor axis/aspect ratio of (0.2 to 1):1, preferably (0.5 to 1): 1. In examples 1-5, the short/length-to-diameter ratios of all 7 kinds of pellets prepared herein were determined to be in the range of (0.5-1): 1, for example, the short/length-to-diameter ratios of the vitamin AD pellets prepared according to the present invention were determined to be easily controllable in the range of (0.9-1): 1, and pellets with an average long diameter in the range of 0.2-1.2 mm can be easily obtained by adjusting the process parameters as described above, for example, pellets with substantially the same short/length-to-diameter ratio, long diameter and other parameters as those of commercially available vitamin AD microbeads can be easily obtained. For example, it is believed that commercially available vitamin AD microbeads have a short diameter/length to diameter ratio of 0.94:1 and a long diameter of 0.4 to 0.6 mm.
As mentioned above, when the vitamin AD micropill is prepared, the micropill with the average particle size of 200-1200 μm, especially the micropill with the average particle size of 300-900 μm can be easily obtained by adjusting the process parameters. For example, the desired average particle diameter can be obtained by intensity adjustment of the emulsification in step (2), for example, pellets having a relatively small average particle diameter can be obtained when the emulsification intensity is high, and pellets having a relatively large average particle diameter can be obtained when the emulsification intensity is relatively low. The percentage of the number of the pellets in the range of the average particle size of ± 50 μm in the total number of the pellets was used as an index to evaluate the width of the pellet size distribution, which shows that the percentage was more than 70%, especially more than 80% in most cases, in each process step of preparing the vitamin AD pellets in examples 1 to 5, after the process parameters thereof were properly adjusted to meet the specification of the present invention, which indicates that the pellets of the present invention have a very narrow particle size distribution range.
When vitamin AD pellets were prepared as in examples 1-5 above, the moisture content in the pellets (as a result of loss on drying at 105 ℃ for 2 hours) was less than 7% after drying in step (3). In addition, the vitamin AD micro-pill prepared by the method does not use an organic solvent and does not have the problem of organic solvent residue.

Claims (26)

1. A vitamin AD micro pill, wherein each 1g of micro pill contains 2-20 ten thousand I.U. vitamin A and 0.2-2 ten thousand I.U. vitamin D2100-200 mg of edible vegetable oil, 2-20 mg of sorbitan fatty acid ester, 400-700 mg of gelatin, 100-300 mg of cane sugar and 1-5 mg of preservative; the vitamin AD pellet is prepared by the following steps:
(1) mixing and dissolving vitamin A, vitamin D2, edible vegetable oil and sorbitan fatty acid ester at the temperature of 35-80 ℃ to obtain oily liquid; dissolving gelatin and sucrose in water at 50-85 ℃, adding a preservative, and stirring to dissolve to obtain an aqueous solution; the sorbitan fatty acid ester is selected from: span20, span40, span60, span65, span80, span 85;
(2) adding the oily liquid obtained in the step (1) into the stirred aqueous liquid at the temperature of 60-80 ℃, and stirring and mixing to obtain an emulsion;
(3) spraying the emulsion obtained in the step (2) into an environment with the temperature lower than 70 ℃ and drying to form micro-particles, or spraying the emulsion into an environment with the temperature lower than-20 ℃ and then carrying out sublimation drying to form micro-particles, thus obtaining the vitamin AD micro-pellets.
2. The vitamin AD pellet according to claim 1, comprising 5 to 15 million i.u. vitamin a per 1 gram pellet.
3. The vitamin AD pellet according to claim 1, comprising 10 million i.u. vitamin a per 1 gram pellet.
4. Vitamin AD pellets according to claim 1, comprising 0.5-1.5 ten thousand I.U. vitamin D per 1 gram pellet2。
5. Vitamin AD pellets according to claim 1, comprising 1 ten thousand i.u. vitamin D per 1 gram pellet2。
6. The vitamin AD pellets according to claim 1, wherein the vitamin a is added to the vitamin AD pellets in the form of vitamin a or vitamin a palmitate or vitamin a acetate.
7. The vitamin AD pellet according to claim 1, wherein the edible vegetable oil is selected from the group consisting of corn oil, soybean oil, peanut oil, sunflower oil.
8. The vitamin AD micro-pellet according to claim 1, wherein each 1 gram micro-pellet comprises 120-160 mg of edible vegetable oil.
9. The vitamin AD pellet according to claim 1, comprising 2-15 mg of the sorbitan fatty acid ester per 1 gram of the pellet.
10. The vitamin AD pellets according to claim 1, comprising 500-650 mg of gelatin per 1 gram of pellets.
11. The vitamin AD pellets according to claim 1, comprising sucrose in an amount of 150-250 mg per 1 gram of pellets.
12. The vitamin AD pellets according to claim 1, wherein the preservative is selected from the group consisting of sodium benzoate, sodium dehydroacetate, sorbic acid, potassium sorbate, methylparaben, ethylparaben, propylparaben, and combinations thereof.
13. The vitamin AD pellets according to claim 1, comprising 1.5-3 mg of preservative per 1 gram of pellets.
14. The vitamin AD micro-pill according to claim 1, wherein in the step (3), the emulsion is sprayed into an environment with the temperature of 20-70 ℃ and dried to form micro-particles.
15. The vitamin AD micro-pill according to claim 1, wherein in the step (3), the emulsion is sprayed to an environment with the temperature of 20-70 ℃ and fluidized bed drying is carried out to form micro-particles.
16. The vitamin AD pellets according to claim 1, wherein the emulsion is sprayed in step (3) to an environment at a temperature below-30 ℃ and then subjected to sublimation drying in a fluidized state to form microparticles.
17. The vitamin AD pellets according to claim 1, wherein the emulsion is sprayed in step (3) to an environment at a temperature below-40 ℃ and then subjected to sublimation drying in a fluidized state to form microparticles.
18. The vitamin AD pellets according to claim 1, wherein said environment at a temperature below-20 ℃ in step (3) is obtained by cooling the space environment with liquid nitrogen.
19. The vitamin AD pellets according to claim 1, further comprising a lubricant selected from the group consisting of magnesium stearate, stearic acid, calcium stearate, talc, silica, polyethylene glycol with a molecular weight of 4000-6000 and combinations thereof.
20. The vitamin AD pellet according to claim 19, wherein the lubricant is added before, during or after drying of the pellet.
21. The vitamin AD pellet according to claim 19, wherein the lubricant is 0.005-1% by weight of the dried vitamin AD pellet.
22. The vitamin AD pellets according to claim 1, having a moisture content of less than 10% on a loss on drying basis; the loss on drying is determined by drying at 105 ℃ for 2 hours.
23. The vitamin AD micro-pellets according to claim 1, wherein the average particle size is in the range of 200 to 1200 μm.
24. A process for preparing a vitamin AD pellet according to any one of claims 1 to 23, comprising the steps of:
(1) mixing and dissolving vitamin A, vitamin D2, edible vegetable oil and sorbitan fatty acid ester at the temperature of 35-80 ℃ to obtain oily liquid; dissolving gelatin and sucrose in water at 50-85 ℃, adding a preservative, and stirring to dissolve to obtain an aqueous solution;
(2) adding the oily liquid obtained in the step (1) into the stirred aqueous liquid at the temperature of 60-80 ℃, and stirring and mixing to obtain an emulsion;
(3) spraying the emulsion obtained in the step (2) into an environment with the temperature lower than 70 ℃ and drying to form micro-particles, or spraying the emulsion into an environment with the temperature lower than-20 ℃ and then carrying out sublimation drying to form micro-particles, thus obtaining the vitamin AD micro-pellets.
25. A capsule comprises 7 spherical or approximately spherical pellets and a capsule shell for wrapping the pellets, wherein the 7 pellets contain 8 amino acids and 11 vitamins, and the 7 pellets and the weight ratio thereof are as follows: thiamine nitrate pellets: 2.66-9.9, vitamin pellet a: 16.35-20.5, amino acid pellet a: 35.0-44.1, vitamin pellet b: 11.4-14.4, amino acid pellet b: 6.65-10.5, vitamin C micro-pills: 12.73-16.0, vitamin AD micropills: 5.7 to 9.36;
wherein:
the vitamin AD pellet is according to any one of claims 1-23, or is prepared according to the method of claim 24;
the thiamine nitrate pellet comprises the following components in parts by weight: 7.6 to 30 parts of thiamine nitrate, 22.5 to 67.5 parts of lactose, 0.9 to 8.1 parts of starch, 1.5 to 13.5 parts of carboxymethyl cellulose calcium, 0.44 to 3.96 parts of methyl cellulose, 0.38 to 3.42 parts of hydroxypropyl cellulose, 0.46 to 4.14 parts of titanium dioxide and 5.8 to 17.4 parts of microcrystalline cellulose,
the vitamin pellet a comprises the following components in parts by weight: 24.5-58 parts of nicotinamide, 6.2-14.5 parts of calcium pantothenate, and 6 parts of vitamin B: 3.1 to 7.2, 1.94 to 17.46 of lactose, 5.6 to 16.8 of calcium carboxymethyl cellulose, 0.36 to 3.24 of hydroxypropyl cellulose, 9.35 to 28.05 of microcrystalline cellulose, 1.66 to 14.94 of starch,
the amino acid pellet a comprises the following components in parts by weight: 3.4 to 8 parts of L-isoleucine, 10.5 to 24.8 parts of L-leucine, 14.4 to 33.8 parts of L-lysine hydrochloride, 2.9 to 6.7 parts of L-phenylalanine, 2.45 to 5.6 parts of L-threonine, 3.9 to 9 parts of L-valine, 10.6 to 24.5 parts of L-methionine, 8.7 to 26.4 parts of lactose, 0.42 to 3.78 parts of starch, 0.4 to 3.6 parts of methyl cellulose, 0.24 to 2.16 parts of hydroxypropyl cellulose, 1.94 to 17.46 parts of microcrystalline cellulose, 0.032 to 0.288 part of yellow pigment, 0.488 to 4.392 parts of calcium carboxymethyl cellulose, and 0.5 to 3 parts of sodium dodecyl sulfate,
the vitamin pellet b comprises the following components in parts by weight: 5-hydroxy-ortho-aminobenzoate: 0.36-0.83, vitamin B2: 4.4-12.4, folic acid: 0.36-0.83, vitamin B12: 0.0018-0.004, lactose: 25.5-76.5, microcrystalline cellulose: 15.75-47.25, polyethylene glycol 6000: 0.17-1.53, calcium carboxymethyl cellulose: 0.184-1.656, starch: 1.397 to 12.577, respectively,
the amino acid pellet b comprises the following components in parts by weight: 15.1-28.4 of L-tryptophan, and vitamin E: 3.1 to 5.6 percent of lactose, 14.85 to 44.55 percent of lactose, 11.5 to 34.5 percent of starch, 0.39 to 3.51 percent of carboxymethyl cellulose calcium, 0.42 to 3.78 percent of methyl cellulose, 0.26 to 2.34 percent of hydroxypropyl cellulose, 0.1 to 0.9 percent of red pigment, 0.01 to 0.09 percent of yellow pigment and 3.82 to 27.15 percent of aluminum silicate,
the vitamin C pellet comprises the following components in parts by weight: vitamin C: 31.5-74.5 parts of lactose, 13.55-40.65 parts of lactose, 1.206-10.85 parts of starch, 1.512-13.608 parts of microcrystalline cellulose, 0.9-8.1 parts of calcium carboxymethyl cellulose, and 6000 parts of polyethylene glycol: 0.76-6.84, 0.36-3.24 of methylcellulose, 0.058-0.522 of chocolate pigment, 1-5 of hydroxypropyl cellulose and 1-5 of citric acid.
26. Use of the vitamin AD pellet according to any one of claims 1-23 or the vitamin AD pellet prepared by the method according to claim 24 for preparing a compound amino acid capsule, wherein the compound amino acid capsule comprises the following components in parts by weight: l-leucine: 18.3mg, L-lysine hydrochloride: 25mg, L-threonine: 4.2mg, L-tryptophan: 5mg, vitamin A: 2000IU, thiamine nitrate: 5mg, nicotinamide: 20mg, folic acid: 0.2mg, vitamin B12: 1ug, vitamin E: 1mg, L-isoleucine: 5.9mg, L-phenylalanine: 5mg, L-valine: 6.7mg, L-methionine: 18.4mg, vitamin D2: 200IU, vitamin B2: 3mg, vitamin B6: 2.5mg, calcium pantothenate: 5mg, vitamin C: 20mg, 5-hydroxy-ortho-aminobenzoate: 0.2 mg;
the vitamin A and vitamin D2 are present in the vitamin AD pellets.
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