Calcium-magnesium-zinc oral liquid and preparation method thereof

Abstract

The invention provides a calcium-magnesium-zinc oral liquid and a preparation method thereof. According to the invention, different supplementation amounts of different age groups are achieved through the optimal proportion of three elements of calcium, magnesium and zinc, and the key technology is that calcium ions and magnesium ions are in a supersaturated state in an aqueous solution and are not separated out through a gradient constant-temperature control process. Compared with a traditional formula, the beverage contains 0 preservative, 0 pigment and 0 cane sugar, is suitable for diabetics to use, and is more easily accepted by vast consumers. And after an acceleration test, each index of the product meets the quality standard regulation, so that the stability is effectively improved.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to a calcium-magnesium-zinc oral solution and a preparation method thereof. Background Art

[0002] Childhood is a critical period for bone development. It is a stage in a person's life when bone development and height grow rapidly. The body's bones and teeth develop rapidly, and the body needs a lot of calcium. However, influenced by my country's eating habits, children in the growing period cannot get all the calcium needed for body growth from food. Adolescence is the second peak period of human growth and development. In order to meet the needs of growth and development, adolescents need more calcium. Secondly, the human body's bone density generally reaches its peak (bone peak) at the age of 30. The higher the bone peak, the lower the risk of osteoporosis in old age. The height of the bone peak mainly depends on whether the calcium intake during adolescence is rich. Calcium plays an extremely important physiological function in the human body, so it is necessary to maintain a good calcium nutrition status. For children in special physiological stages, pregnant women, the elderly, and patients in the recovery period or during illness, the rational use of calcium supplements is an important means to meet the body's calcium intake needs.

[0003] Calcium deficiency is one of the important factors that cause human aging and various diseases. (1) Causes bone relocation. Long-term calcium deficiency causes a decrease in blood calcium, which will produce serious pathological reactions, such as increased neuromuscular excitability, a state of obvious irritation, convulsions, coma, seizures and even death. Long-term calcium deficiency and continuous compensation by bone calcium will cause the amount of bone calcium to continue to decrease. If a person has a calcium deficit of 30 to 50 mg per day, it will be compensated by the bone calcium store. In the long run, the total amount of human bones will be lost at a rate of 1% per year, and by the age of 60, the bone mass will be lost by 30%. By the age of 70, it will be reduced by 50%. Long-term stimulation of parathyroid receptors by calcium deficiency will produce hyperfunction, resulting in increased blood calcium and soft tissue calcium, causing abnormal relocation of bone calcium. In addition, due to excessive secretion of parathyroid hormone (PTH), the level of calcitonin (CT) is also increased. The increase in PTH level promotes the formation of osteoclasts (OC) and accelerates the bone resorption process. The increase in CT level promotes the formation of osteoblasts (OB). It accelerates the bone formation process, which is the pathological basis for the coexistence of bone resorption and bone hyperplasia. Long-term calcium deficiency will eventually lead to osteoporosis (OP) and bone hyperplasia. (2) Insufficient calcium intake causes rickets due to incomplete development in early childhood. Bone formation is slow in childhood, and poor bone peak quality affects height, weight, and overall development. In adulthood, bone mineral and BMD decrease significantly. The first part of the human body to age is bone tissue. In old age, especially in women after menopause, bone loss accelerates, the bone cortex becomes thinner, toughness and strength decrease, bone brittleness increases, the risk of fracture increases, and fracture healing is difficult. In terms of body shape, hunchbacks, bent waists, shorter height, tooth loss, slow movements, and old looks appear. Calcium deficiency accelerates the aging process. (3) Calcium deficiency will lead to an imbalance in the proportion of body fluid ions, causing endocrine disorders and increasing the incidence of cardiovascular and cerebrovascular diseases (CVD) and hyperthyroidism, and increasing the risk of calcification of blood vessels and organs.

[0004] Magnesium is one of the essential elements involved in life activities and metabolism. It is a component of bones and plays an important role in promoting bone growth and maintaining normal bone function. If the intake of magnesium is too low for a long time, it will cause chronic magnesium deficiency, which will inevitably cause harm to human health. Magnesium deficiency is mainly manifested clinically as emotional anxiety, irritability, hand and foot cramps, hyperreflexia, etc. Diseases related to magnesium deficiency include hypertension, ischemic heart disease, arrhythmia, diabetes, arthritis and chronic renal failure; in addition, insufficient magnesium intake can also cause digestive disorders and miscarriage, premature birth, fetal development abnormalities, etc. For preschool children who are in the growth and development period, children with insufficient magnesium intake may have skin injuries that are difficult to heal, taste retardation, poor appetite or even anorexia, and symptoms such as abnormal digestion and absorption, which seriously affect the growth and development of the body.

[0005] Zinc is a very important trace element in the human body and is the key to promoting the normal development of children. Years of practice have confirmed that zinc deficiency will inevitably affect the development and growth of the human body. . Zinc improves the sense of taste. When zinc is deficient, the taste and smell will be poor, the person will have anorexia, and the growth and intellectual development will be lower than normal. Zinc also has the functions of spermatogenesis, anti-ulcer, and improving immunity. Once a man is zinc deficient, it will lead to a decrease in sperm count, decreased vitality, poor semen liquefaction, and ultimately male infertility. Zinc deficiency can also cause adolescents to have no secondary sexual characteristics and cannot have normal reproductive development. Zinc intake can shrink the ulcer surface and accelerate the healing of ulcers. Zinc supplementation can adjust the distribution of trace element zinc in the body, while regulating the body's immunity, enhancing the body's defense capabilities and reducing the recurrence of ulcers.

[0006] Calcium magnesium zinc oral solution is an oral solution made from organic substances with high bioavailability and high food safety, such as calcium gluconate, L-calcium lactate, magnesium gluconate and zinc gluconate, with purified water, sweetener, lactic acid and flavors as auxiliary materials. It can supplement the three elements of calcium, magnesium and zinc at the same time, and has the functions of promoting bone growth and maintaining normal human metabolism. The simultaneous intake of calcium, magnesium and zinc can promote each other's absorption and synergistically enhance the effect, which can also reduce the cost of taking and improve patient compliance. It is suitable for people aged 4-17, adults, pregnant women and nursing mothers.

[0007] At present, most of the products on the market that supplement calcium, magnesium and zinc at the same time are oral solid dosage forms or liquid suspension products made from raw materials in a non-dissolved state. The prescription contains a large amount of excipients, and there are problems such as slow release, irritation, poor taste, low compliance, and inconvenience for children and people with dysphagia to take. In addition, it needs to consume gastric acid to convert into an ion state before it can be absorbed and utilized by the human body, which increases the irritation to the gastrointestinal tract. This product is an oral solution dosage form, all elements are completely dissolved into calcium, magnesium, and zinc ion states, and there is no disintegration and release process of solid preparations. The content of calcium, magnesium, and zinc is moderate, which can be directly and quickly absorbed and utilized by the human body, is not easily interfered by other ingredients or substances, and has high bioavailability.

[0008] The calcium magnesium zinc oral liquid and its preparation method are characterized in that each 1000mL calcium magnesium zinc oral liquid is highly bioavailable and safe for oral administration, and is mainly composed of the following raw materials: 20-60g L-calcium lactate, 20-60g calcium gluconate, 90-110g magnesium gluconate, 1-1.6g zinc gluconate, 0.2-1.0g sweetener, 5-10g lactic acid, 0.1-0.5ml essence, etc., and is prepared through a series of strict production processes, and is an effective product for supplementing multiple minerals. The L-calcium lactate, calcium gluconate, ferrous gluconate, and zinc gluconate selected in this product can be used for people aged 4-17, adults, pregnant women, nursing mothers, and other suitable people who lack multiple minerals. This product is an oral solution dosage form, does not have the disintegration and release process of a solid oral dosage form, has high bioavailability, can be quickly absorbed and utilized by the human body, and is more suitable for people with dysphagia and weak digestive function. Summary of the invention

[0009] In order to ensure that the three elements can meet the needs of all kinds of people, and at the same time ensure that high-concentration solutions basically do not produce crystallization or can be redissolved after a small amount of precipitation, the sources and quality of calcium, magnesium and zinc raw materials are controlled, indicators higher than national standards are established, and the possibility of crystallization in the solution is controlled from the source. Through the gradient constant temperature control process, the optimal formula ratio of two calcium sources and magnesium raw materials is selected to improve the solubility and product stability of calcium gluconate; the process optimizes the temperature parameters and the influence of high impurity conversion in the preparation process, effectively reducing the phenomenon of crystallization due to temperature changes that affects product stability, and overcoming the difficulty of preparing supersaturated solutions and formulating them into highly stable and industrializable oral liquid dosage forms.

[0010] In view of the deficiencies in the prior art, the technical problem to be solved by the present invention is: a calcium-magnesium-zinc oral liquid for solving health problems caused by calcium, magnesium and zinc deficiency and a preparation method thereof. A calcium-magnesium-zinc oral liquid is composed of the following raw materials: calcium gluconate, L-calcium lactate, magnesium gluconate, zinc gluconate, lactic acid, a sweetener, an essence and purified water. The sweetener is at least one of sucralose, steviol glycoside, sodium cyclamate and disodium glycyrrhizinate.

[0011] A calcium magnesium zinc oral solution and a preparation method thereof, wherein the formula comprises: L-Calcium lactate 20~60g Calcium gluconate 20-60g Magnesium gluconate 90-110g Zinc gluconate 1-1.6g Sweetener 0.2~1.0g Lactic acid 5~10ml Essence 0.1~0.5ml Add purified water to 1000ml

[0012] The present invention also provides a method for preparing calcium magnesium zinc oral solution, comprising the following steps:

[0013] 1. Take 20% to 70% of the volume of purified water in the preparation tank, heat and boil, add calcium gluconate, L-calcium lactate, zinc gluconate, and magnesium gluconate, stir until completely dissolved, heat and boil for 20 to 60 minutes, add sweetener, and after dissolution, cool to 60 to 70°C with stirring to obtain active calcium magnesium zinc solution, and filter it with titanium rod into the preparation tank, and control the temperature of the filtered solution to 55 to 65°C;

[0014] 2. Add lactic acid to the liquid preparation tank, add purified water to almost the full amount, stir evenly, adjust the pH value to 3.0-7.0 with lactic acid, add essence after passing the test, add purified water to the full amount, stir evenly, and filter through titanium rods, ceramic membranes, and folded membranes. The temperature of the liquid is controlled at 40-50°C by constant temperature filtration, and the temperature of the liquid is controlled at 30-50°C by constant temperature during filling. Lock the mouth, sterilize at 100-120°C for 20-40 minutes, inspect by light, package, and put into storage.

[0015] The stability of the product is closely related to the quality of the raw materials. If the calcium gluconate raw material is impure, the solution will easily produce insoluble calcium oxalate, which will cause the solution to crystallize out. In terms of raw material control, calcium gluconate of higher standards was selected, and phosphate, oxalate, organic impurities and boric acid items were controlled. The calcium gluconate used in the product formula is higher than the Chinese Pharmacopoeia 2020 Supplement, United States Pharmacopoeia 43, European Pharmacopoeia 10.5 and British Pharmacopoeia 2020 standards.

[0016] Phosphates and oxalates exist in the solution in the form of ions. Phosphates and oxalates can form precipitation with free calcium ions in their free state. Therefore, controlling the content of phosphates and oxalates can effectively reduce the risk of calcium precipitation and improve product stability.

[0017]

[0018] Lactic acid and calcium L-lactate are used in the prescription to form ion pairs and control the pH environment during the preparation process, which helps to improve the solubility of calcium gluconate at low temperatures and reduce the risk of precipitation. Compared with the Chinese Pharmacopoeia 2020 Supplement and the United States Pharmacopoeia 43, organic impurities and boric acid are internally controlled to reduce the impact of impurity conversion.

[0019] The calcium-magnesium-zinc oral solution prepared in the present application promotes the absorption of calcium, magnesium and zinc ions by enhancing the permeability of the preparation and improving cell membrane fluidity. Compared with other oral dosage forms, it is absorbed more rapidly and the dosage is more accurate. It is suitable for all kinds of people, and is more suitable for children, the elderly, those with dysphagia and those with weak digestive function.

[0020] The calcium magnesium zinc oral liquid prepared by the present application has 0 preservatives, 0 pigments, and 0 sucrose, which improves the product safety and is conducive to the use of consumers. The added sweetener is one or two of sucralose, stevioside, and disodium glycyrrhizinate, all of which are sugar-free sweeteners and are suitable for use by diabetic patients.

[0021] The filter materials used are titanium rods (1-20µm), folded membranes (0.10um-0.45um), and ceramic membrane filtration. The number of ceramic membrane channels is 10-60, the length of the membrane element is 200-2000mm, and the flow rate on the membrane surface is 1-8m / s. The purpose is to use several filter materials at the same time to improve the clarity of the product.

[0022] In the preparation method of the present application, calcium gluconate and calcium lactate are appropriately mixed, which solves the problem of easy precipitation of calcium gluconate, increases the calcium content in the solution, and improves product stability.

[0023] Lactic acid and L-calcium lactate solution are used as the pH stabilizing buffer system, which can not only provide a stable pH environment for the solution and improve the stability of the product, but also play a role in dissolution and prevention of precipitation at low temperatures.

[0024] High-standard calcium gluconate raw materials are used, and phosphate, oxalate, organic impurities and boric acid items are internally controlled to reduce the possibility of calcium precipitation.

[0025] The invention adopts a composite formula of L-calcium lactate, calcium gluconate, magnesium gluconate, zinc gluconate and sweetener, which improves the stability of calcium-magnesium-zinc oral liquid and can improve the utilization rate of calcium, magnesium and zinc ions in the oral liquid by human body. The product has good taste, is easy to absorb, is convenient to take and has no side effects, and is favored by consumers after being put on the market. DETAILED DESCRIPTION

[0027] The present invention is described in more detail below by way of examples, but the present invention is not limited to the scope of the embodiments described.

[0028] Example 1

[0029]

[0030] 1. Take 400 ml of purified water, heat and boil, add calcium gluconate to dissolve while stirring constantly, add L-calcium lactate, zinc gluconate, and magnesium gluconate, stir until completely dissolved, heat and boil for 20 minutes, add sweetener, and after dissolution, cool to 60°C while stirring to obtain active calcium magnesium zinc solution, filter it with titanium rod into the liquid preparation tank, and control the temperature of the filtered solution to 55-60°C.

[0031] 2. Add lactic acid to the liquid preparation tank, add purified water to almost the full amount, stir evenly, adjust the pH value to 3.5 with lactic acid, add essence after passing the test, add purified water to the full amount, stir evenly, and filter through titanium rods, ceramic membranes, and folded membranes. The temperature of the liquid is controlled at 40-45°C by fine filtration, and the temperature of the liquid is controlled at 30-40°C by filling. Lock the mouth, sterilize at 100°C for 40 minutes, inspect by light, package, and put into storage.

[0032] Example 2

[0033]

[0034] 1. Take 450 ml of purified water, heat and boil, add calcium gluconate, L-calcium lactate, zinc gluconate, and magnesium gluconate, stir until completely dissolved, heat and boil for 30 minutes, add sweetener, and after dissolution, cool to 65°C with stirring to obtain active calcium magnesium zinc solution, filter it into the preparation tank with titanium rod, and control the temperature of the filtered solution to 60-65°C.

[0035] 2. Add lactic acid to the liquid preparation tank, add purified water to almost the full amount, stir evenly, adjust the pH value to 5.0 with lactic acid, add essence after passing the test, add purified water to the full amount, stir evenly, and filter through titanium rods, ceramic membranes, and folded membranes. The temperature of the liquid is controlled at 40-50°C by fine filtration, and the temperature of the liquid is controlled at 35-45°C by filling. Lock the mouth, sterilize at 110°C for 30 minutes, inspect by light, package, and put into storage.

[0036] Example 3

[0037]

[0038] 1. Take 600 ml of purified water, heat and boil, add calcium gluconate, L-calcium lactate, zinc gluconate, and magnesium gluconate, stir until completely dissolved, heat and boil for 40 minutes, add sweetener, and after dissolution, cool to 70°C with stirring to obtain active calcium magnesium zinc solution, filter with titanium rod into the liquid preparation tank, and control the temperature of the filtered solution to 60-65°C.

[0039] 2. Add lactic acid to the liquid preparation tank, add purified water to nearly the full amount, stir evenly, adjust the pH value to 5.0 with lactic acid, add essence after passing the test, add purified water to the full amount, stir evenly, filter through titanium rods, ceramic membranes, and folded membranes, control the liquid temperature at 50-55°C with constant temperature, control the liquid temperature at 40-50°C with constant temperature during filling, lock the mouth, sterilize at 120°C for 20 minutes, inspect with lights, package, and put into storage

[0040] Data on accelerated stability study of calcium magnesium zinc oral solution

[0041]

[0042] Test Example 1

[0043] Male rats (SPF level) weighing 60-75g were fed for one week for test adaptation and then used for testing. Specifically: at 9:00 pm on the day before the test, the mice were fasted but not watered. At 8:00 am on the next day, the rats were randomly divided into five groups, each with 10 rats. One group was gavaged with saline as the control group, one group was gavaged with calcium carbonate as the control group, and the remaining three groups were gavaged with the calcium magnesium zinc oral solution prepared in Example 1-3 (dosage was 10 mL / kg bw). After continuous gavage for 3 months, various indicators were tested.

[0044] Determination of bone calcium content: The animals were killed after feeding for 3 months, and the right femur was stripped out. The whole femur that was baked to constant weight was accurately weighed and placed in a 150ml conical flask that was dried and cleaned after being treated with hydrochloric acid. 15-20ml of nitric acid + perchloric acid (4:1) was added and heated on a hot plate until white smoke appeared and the mixture was transparent and colorless. A few milliliters of deionized water were added and boiled to drive out the remaining acid. Repeat twice, and after constant volume, the mixture was determined using an atomic absorption spectrophotometer.

[0045] Calcium absorption experiment: After 3 weeks of administration of the sample, the rats were placed in stainless steel metabolic cages for a 3-day calcium metabolism experiment. The food intake for 3 days was recorded, and feces were collected for 72 hours to determine the calcium content in the feed samples and feces. The feed was evenly mixed and dried after passing through a 20-mesh sieve; the rat feces samples were evenly mixed and dried in an oven at 80 degrees Celsius, cooled in a dryer, and ground. 0.300-1.000g of feed or feces was accurately weighed and digested with a mixed acid of nitric acid and perchloric acid, and the calcium content in the feed and feces was determined by atomic absorption spectrometry to calculate the calcium absorption rate. The apparent absorption rate of calcium (%) = (calcium intake - fecal calcium) / calcium intake x 100%.

[0046] Blood was collected from mice in each group 0 hour before and 1 hour after oral administration, and serum was obtained by centrifugation to measure the calcium ion concentration in the serum. After administration, mice in each group were fasted but not watered.

[0047] Table 1 Test results of bone calcium content

[0048]

[0049] Note: SPSS analysis showed that compared with the control group, * is P < 0.05, which is statistically significant.

[0050] Table 2 Test results for promoting calcium absorption

[0051]

[0052] Note: SPSS analysis showed that compared with the control group, * is P < 0.05, which is statistically significant.

[0053] Test Example 2

[0054] Effect evaluation: 150 subjects who needed calcium supplementation were randomly divided into 3 groups, 50 in each group, for clinical evaluation. The subjects took calcium magnesium zinc oral solution 3 times a day, 1 bottle each time, for a total of 3 months.

[0055] Table 3 Taking effect evaluation test results

[0056]

[0057] It can be seen from the test results that the calcium magnesium zinc oral solution of the present invention is not only easily absorbed and utilized by the human body, but also has higher bioavailability, and is mild in nature and has little irritation to the gastrointestinal tract. It has the effects of promoting bone growth, improving osteoporosis and arthritis, and maintaining normal metabolism of the human body, and has the characteristics of good product properties, good stability, short production cycle, low equipment investment cost, good absorption, etc., and is therefore more suitable for large-scale production and application.

[0058] Conclusion: The above stability investigation results show that the calcium magnesium zinc oral solution prepared by the formula process of the present invention has the characteristics of good product properties, good stability, short production cycle, low equipment investment cost, etc., and is therefore more suitable for large-scale production applications.

Claims

1. A calcium magnesium zinc oral solution and a preparation method thereof, characterized in that: Each 1000mL of calcium magnesium zinc oral solution is mainly composed of the following raw materials: 20-60g of L-calcium lactate, 20-60g of calcium gluconate, 90-110g of magnesium gluconate, 1-1.6g of zinc gluconate, 0.2-1.0g of sweetener, 5-10ml of lactic acid, and 0.1-0.5ml of flavor.

2. The method for preparing calcium magnesium zinc oral solution by gradient constant temperature control process according to claim 1, characterized in that: The method comprises the following steps: a. Take 20% to 70% of the volume of purified water in the preparation tank, heat and boil, add calcium gluconate, L-calcium lactate, zinc gluconate, magnesium gluconate, stir until completely dissolved, heat and boil for 20 to 60 minutes, add sweetener, after dissolution, cool to 60 to 70°C with stirring to obtain active calcium magnesium zinc solution, filter with titanium rod into the preparation tank, and control the temperature of the filtered solution to 55 to 65°C; b. Add lactic acid to the liquid preparation tank, add purified water to almost the full amount, stir evenly, adjust the pH value to 3.0-7.0 with lactic acid, add essence after passing the test, add purified water to the full amount, stir evenly, and filter through titanium rods, ceramic membranes, and folded membranes. The temperature of the liquid is controlled at 40-50℃ by fine filtration, and the temperature of the liquid is controlled at 30-50℃ by filling. Lock the mouth, sterilize at 100-120℃ for 20-40 minutes, inspect by light, package, and put into storage.

3. The calcium magnesium zinc oral solution as claimed in claim 1, characterized in that: The sweetener is one or two of sucralose, steviol glycoside, cyclamate and disodium glycyrrhizinate.

4. The method for preparing calcium magnesium zinc oral solution according to claim 2, characterized in that: The sterilization process has a temperature control range of 100-120°C and a sterilization method of moist heat sterilization.

5. The method for preparing a multi-mineral oral liquid according to claim 2, characterized in that: The filter material is a combination of titanium rod (1-20µm), folded membrane (0.1um-0.45um), and ceramic membrane filtration, wherein the number of channels of the ceramic membrane is 10-60, the length of the membrane element is 200-2000mm, and the flow rate on the membrane surface is 1-8m / s.

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