WO2020215238A1 - Préparation de carbonate de calcium d3 soluble dans l'eau - Google Patents

Préparation de carbonate de calcium d3 soluble dans l'eau Download PDF

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Publication number
WO2020215238A1
WO2020215238A1 PCT/CN2019/084054 CN2019084054W WO2020215238A1 WO 2020215238 A1 WO2020215238 A1 WO 2020215238A1 CN 2019084054 W CN2019084054 W CN 2019084054W WO 2020215238 A1 WO2020215238 A1 WO 2020215238A1
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WIPO (PCT)
Prior art keywords
calcium carbonate
water
soluble calcium
binder
preparation
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Application number
PCT/CN2019/084054
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English (en)
Chinese (zh)
Inventor
黄辉
Original Assignee
黄辉
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by 黄辉 filed Critical 黄辉
Priority to PCT/CN2019/084054 priority Critical patent/WO2020215238A1/fr
Publication of WO2020215238A1 publication Critical patent/WO2020215238A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/10—Carbonates; Bicarbonates
    • 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

Definitions

  • the invention relates to a water-soluble calcium carbonate D 3 preparation, which belongs to the field of pharmaceutical preparations.
  • calcium is an essential mineral for the human body, 99% is distributed in bones and teeth, and about 1% is distributed in blood and other tissues. It is mainly involved in the development of bones and teeth, maintaining the normal activities of muscle and nerve conduction, and participating in physiological functions such as blood coagulation.
  • Calcium carbonate is an inorganic compound, which is neutral and hardly soluble in water. According to the human physiology study of calcium, it is found that calcium carbonate can only be absorbed by the intestinal tract and play a physiological role after the calcium ions are separated after gastric acid dissolution.
  • Calcium carbonate is currently the most widely used calcium supplement material due to its high calcium content, low price and high safety.
  • products on the market such as ordinary tablets, chewable tablets, capsules, soft capsules, granules, effervescent Granules, effervescent tablets, etc.
  • DOP diabetic osteoporosis
  • DN diabetic neuropathy
  • the effervescent solution is acidic.
  • the amount of acidic foaming agent will be slightly more than that of calcium carbonate, and the presence of a small amount of carbonic acid (reaction product) in the solution makes the solution acidic with a pH of about 4 after effervescence.
  • reaction product carbonic acid
  • Hyperacidity can cause symptoms such as belching, upper abdominal discomfort, heartburn, etc. It can also cause organic diseases of the digestive tract, such as gastritis, duodenitis, and peptic ulcer.
  • the current calcium carbonate effervescents on the market can achieve some calcium supplementation effects for patients with gastric acid deficiency, especially infants, children or the elderly, but the resulting hyperacidity The consequences of this are obviously counterproductive and do more harm than good.
  • the present invention provides a water-soluble calcium carbonate D 3 preparation, wherein the water-soluble calcium carbonate D 3 preparation comprises a weight ratio of 1:0.1-0.8:0.5-3 :0.2-0.7 calcium carbonate, vitamin D 3 , acidic complexing agent and binder; wherein said vitamin D 3 is a vitamin D 3 - ⁇ -cyclodextrin inclusion compound, said acidic complexing agent It is selected from one or any combination of citric acid, malic acid and tartaric acid; the binder is povidone, hydroxypropyl methylcellulose or a combination thereof.
  • the dosage form of the water-soluble calcium carbonate D 3 preparation is preferably granules.
  • Vitamin D 3 can promote intestinal calcium absorption, reduce kidney calcium excretion, has the function of promoting bone formation and bone mineralization, and is an essential nutrient for healthy bones. Therefore, the present invention combines calcium carbonate with vitamin D 3 to achieve a better calcium supplement effect.
  • Vitamin D for the optical properties, such as heat labile the present invention is employed in form vitamin D 3 after ⁇ - cyclodextrin bonded form vitamin D 3 [beta cyclodextrin inclusion complex, the inclusion of form vitamin D 3
  • the stability and the accuracy of its content have been significantly improved, ensuring the corresponding product quality and reducing the strict requirements on storage conditions. According to the national standard, the content of vitamin D 3 is required to account for more than 85% of the labeled amount. In order to leave room for degradation, there is no regulation on the line, and there is a risk of vitamin D accumulation and poisoning. In the present invention, vitamin D 3 is included, and its stability is improved. Without excessive feeding, the content is accurate.
  • VD 3 - ⁇ -cyclodextrin inclusion compound is as follows:
  • the preparation method of VD 3 - ⁇ -cyclodextrin inclusion compound includes the following steps:
  • the molar ratio of ⁇ -cyclodextrin to VD 3 is about 6:1.
  • VD 3 - ⁇ -cyclodextrin inclusion complexes There are many methods for preparing VD 3 - ⁇ -cyclodextrin inclusion complexes, which are similar to each other.
  • the preparation process and preparation method of the VD 3 - ⁇ -cyclodextrin inclusion complexes of the present invention are similar to those that have been publicly disclosed.
  • the preparation process and preparation method of the VD- ⁇ -cyclodextrin inclusion compound have some differences in steps or process parameters and details.
  • the advantage of these differences to the present invention is that compared with the inclusion compound obtained by the prior art
  • the VD 3 - ⁇ -cyclodextrin inclusion compound of the present invention has the advantages of higher inclusion rate, better stability after the inclusion compound is placed, and longer holding time of the stable state.
  • VD 3 - ⁇ -cyclodextrin inclusion compound obtained according to the existing publicly disclosed conventional process has been tested and the inclusion rate is generally lower than 75%, even if the claimed inclusion rate reaches 80 % Or even more than 80% of VD 3 - ⁇ -cyclodextrin inclusion compound, its substantial inclusion rate is the highest and does not exceed 80%, especially, the several commercially available VD 3 - ⁇ -rings verified by the present invention
  • the inclusion rate of dextrin inclusion compound is 65%-78%; while the inclusion rate of VD 3 - ⁇ -cyclodextrin inclusion compound obtained by the above-mentioned preparation method of the present invention generally reaches more than 80%, and the vast majority of VD
  • the inclusion rate of 3 - ⁇ -cyclodextrin inclusion compound (also called encapsulation rate or encapsulation rate) has reached over 85%.
  • the inclusion rate of the VD 3 - ⁇ -cyclodextrin inclusion compound of the present invention has always been maintained at above 80% in six months, one year, two years, and three years; while the relevant commercially available inclusion compound products After half a year, the inclusion rate showed a slow downward trend.
  • the VD 3 - ⁇ -cyclodextrin inclusion compound can be prepared by using the conventionally disclosed VD 3 - ⁇ -cyclodextrin inclusion compound, but for the purpose
  • the physical and chemical properties of the product are more stable, preferably the VD 3 - ⁇ -cyclodextrin inclusion compound obtained by the above-mentioned preparation method of the present invention, especially the VD 3 - ⁇ -cyclodextrin inclusion compound obtained by the above-mentioned preparation method of the present invention .
  • the preferred dosage form is water-soluble calcium carbonate D 3 granules and contains sodium bicarbonate; based on the weight of said calcium carbonate as 1 part, The weight of the sodium bicarbonate is 0.3-0.5.
  • the preparation of the present invention is preferably granules, and the specific research is as follows:
  • acidic complexing agent such as citric acid
  • the pH value of the dissolved solution is related to the amount of calcium carbonate, acidic complexing agent and sodium bicarbonate, when the amount (weight) ratio of calcium carbonate, acidic complexing agent and sodium bicarbonate is 1:1
  • the pH of the solution is about 6, which is close to neutral.
  • sodium bicarbonate is not added, or sodium bicarbonate is added
  • the amount of sodium bicarbonate is too small or too much, that is, relative to the above-mentioned calcium carbonate weight of 1, the ratio of the weight of sodium bicarbonate exceeding 0.3-0.5 is the above-mentioned "the amount of sodium bicarbonate added is too little or too much” , It can not produce the expected effect that the pH of the solution is about 6, which is close to neutral, or it can significantly reduce the dissolution of calcium carbonate.
  • the inventor also found that the dissolution rate of the vitamin D 3 - ⁇ -cyclodextrin inclusion compound in this solution was significantly increased, which greatly improved the bioavailability of fat-soluble vitamin D 3 .
  • the calcium carbonate D 3 granules of the present invention also contain a filler and/or a flavoring agent;
  • the filler is lactose, powdered sugar, sorbitol, mannitol or microcrystalline cellulose or any combination thereof, and the calcium carbonate D 3
  • the weight of the granule is 100%, and the weight of the filler accounts for 15-40%;
  • the flavoring agent is protein sugar, aspartame, stevioside, sucrose, flavor or sorbitol or any combination thereof , Based on the weight of the calcium carbonate D 3 granules as 100%, the weight of the corrective agent accounts for 1-20%.
  • the present invention also provides a preparation method of the water-soluble calcium carbonate D 3 preparation, which comprises the following steps:
  • the above preparation method further includes the following steps:
  • the above steps (4) and (5) are followed by drying and granulation steps.
  • the drying adopts a conventional drying method, such as drying under reduced pressure, and the drying temperature is controlled at 55°C to 75°C, and the particles are dried until the water content of the particles is not higher than 2%.
  • the granulation is to sizing the dried acid group and alkali group particles through a 2.5mm stainless steel sieve respectively, and then sieve the sizing particles through a swirling sieve to remove coarse particles and energy that cannot pass through the No. 1 sieve. Fine powder passing through No. 5 sieve.
  • the above-mentioned filler of the present invention is lactose, powdered sugar, sorbitol, mannitol, microcrystalline cellulose or any combination thereof, preferably lactose;
  • the binder is povidone, hydroxypropyl methylcellulose or its
  • the combination is preferably povidone, more preferably povidone K30;
  • the correcting agent is meringue, aspartame, stevioside, sucrose, flavor, sorbitol or any combination thereof, preferably meringue.
  • the calcium carbonate D 3 granules prepared according to the above steps produce a violent reaction when contacting water, the calcium carbonate dissolves quickly and completely, is convenient to take, and has a sweet and sour taste.
  • the prescription is further optimized to make the product more stable and safer, especially the pH value of the solution after dissolution is significantly increased to about 6, so that it will not It has any effect on the normal digestion and absorption of the stomach of the user and the secretion of gastric acid, avoiding the problem of excess gastric acid caused by the existing calcium carbonate effervescent while solving the problem of common calcium carbonate (such as tablets) consuming gastric acid.
  • the present invention also provides the application of calcium carbonate D 3 granules in supplementing human calcium or preventing and treating osteoporosis and infantile rickets.
  • the Chinese generic name of the calcium carbonate D 3 granules in the present invention is compound calcium carbonate granules.
  • the invention and creativity are: vitamin D and calcium carbonate are combined to supplement calcium while paying attention to calcium absorption to achieve certainty The purpose of calcium supplementation.
  • the vitamin D 3 - ⁇ -cyclodextrin inclusion compound after the inclusion of vitamin D by ⁇ -cyclodextrin significantly improves the stability and safety of the final product.
  • a specific ratio and a specific amount of sodium bicarbonate is added to the alkali part of calcium carbonate D 3 granules.
  • the inventor further verified the beneficial effects of the present invention through specific experiments.
  • the calcium carbonate D 3 particles of the present invention provided by Wuhan Tongji Modern Medicine Co., Ltd., the Chinese generic name of the medicine is designated as compound calcium carbonate particles, batch number: 20101112;
  • Compound calcium carbonate effervescent particles Shandong Dyne Marine Biological Pharmaceutical Co., Ltd., batch number: 20100801;
  • Vitamin D 3 raw material Zhejiang Garden Pharmaceutical Co., Ltd., batch number: 20091201;
  • Vitamin D 3 - ⁇ -cyclodextrin inclusion compound self-made by Wuhan Tongji Modern Pharmaceutical Company, batch number: 20101110;
  • Tretinoin Homemade by the People's Liberation Army 81899 Dermatology Hospital
  • Calci D (600mg calcium, 125iu VD 3 /tablet): Sino-US joint venture Suzhou Lida Pharmaceutical Co., Ltd., batch number: 20100803;
  • Wistar rat weighing (150 ⁇ 20)g, male; juvenile rat, weighing 35-50g, both male and female; provided by Xinjiang Medical Animal Center (Certificate of Production, Xinyidongzi No. 0416001).
  • Fang 1 to Fang 6 are made into granules for use.
  • Calcium carbonate dissolution test method absorb 10ml solution, filter with 0.8 ⁇ m microporous membrane, accurately absorb 5ml filtrate, add 100% KOH 4ml and calpurine 0.15g, use 0.05mol/L ethylenediaminetetraacetic acid The sodium solution is titrated until the solution changes from purple-red to pure blue. Record the volume of the consumed titrant, and calculate the content based on the equivalent of 5.05mg calcium carbonate per 1ml disodium edetate.
  • VD 3 - ⁇ -cyclodextrin inclusion compound (vitamin D 3 80 units) under various conditions, add water-isopropanol (1 ⁇ 1) solution, ultrasonic for 15 minutes, place in a separatory funnel, and extract with ether Three times, 25ml each time, combine the ether solution, dry with cold air, and dissolve the residue with 1ml of absolute ethanol as the test solution.
  • the content of vitamin D 3 in the test solution was determined by high performance liquid chromatography. The results are shown in Table 4.
  • mice Seventy wistar rats were randomly divided into normal saline control group (NS 5.0ml ⁇ kg -1 ), model group (tretinoin 70mg ⁇ kg -1 , ig.qd ⁇ 2 weeks), and Calci Group D (0.18g/kg, containing 60mg calcium, 2.5iu D 3 ) and 3 different doses of the calcium carbonate D 3 particle group of the present invention (0.34, 0.68, 1.36g/kg, containing 30, 60, 120 mg calcium; 6.25 , 12.5, 25iu D 3 ⁇ kg -1 ), all except the model group were administered ig, and each test group and the model group were given ig tretinoin for 2 weeks at the same time.
  • the rats were anesthetized with pentobarbital sodium 24 hours after the last administration, and the bone condition of each group was observed by X-ray imaging.
  • the X-ray imaging conditions were 25mA, 50kV, 0.08s.
  • the rats were sacrificed, the femurs of the rats were dissected, and the bone density was measured on a bone densitometer (3 points: greater trochanter, cadre, and epiphysis). The results are shown in Table 6.
  • the appropriate amount of sodium bicarbonate contained in the calcium carbonate D 3 particles of the present invention not only increases the solubility of the vitamin D 3 - ⁇ -cyclodextrin inclusion compound in water, but also increases the pH value of the solution after dissolution To about 6, it is close to neutral. Compared with the calcium carbonate effervescent currently used in the market, it is significantly improved, effectively avoiding the shortcomings caused by ordinary effervescent acid.
  • ⁇ -cyclodextrin inclusion of vitamin D 3 is selected , which not only improves the stability of calcium carbonate D 3 granules, but also makes the intake of vitamin D 3 more accurate, effectively avoiding the intake of vitamin D Accumulative poisoning caused by overdose.
  • the above-mentioned pharmacological experiment is a representative experiment of calcium carbonate D 3 granules in supplementing human calcium, preventing and treating osteoporosis and rickets in children.
  • This experimental model has statistical significance and representative exemplary effect. Therefore, it can be considered that, calcium carbonate granules 3 D of the invention for osteoporosis and rickets disease have good effect in prevention and treatment.
  • the dried acid group particles and alkali group particles are sized, that is, the two groups of particles are respectively sized through a 2.5mm stainless steel sieve, and the sized particles are sieved through a cyclone sieve to remove the particles that cannot pass 1 Coarse particles from No. sieve and fine powder that can pass No. 5 sieve;
  • the present invention is not limited to the above-mentioned embodiments, and any other products identical or similar to the present invention derived by anyone under the enlightenment of the present invention are not excluded from the protection scope of the present invention.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
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Abstract

L'invention concerne une préparation de carbonate de calcium D3 soluble dans l'eau, la préparation de carbonate de calcium D3 contenant un carbonate de calcium, une vitamine D, un agent complexant acide et du bicarbonate de sodium dans un rapport pondéral de 1 : 0,1 à 0,8 : 0,5-3 : 0,2 à 0,7. L'invention concerne en outre un procédé de préparation de la préparation de carbonate de calcium D3 soluble dans l'eau. La formulation de carbonate de calcium D3 soluble dans l'eau est utilisée pour compléter le calcium humain ou prévenir l'ostéoporose et le rachitisme infantile.
PCT/CN2019/084054 2019-04-24 2019-04-24 Préparation de carbonate de calcium d3 soluble dans l'eau WO2020215238A1 (fr)

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PCT/CN2019/084054 WO2020215238A1 (fr) 2019-04-24 2019-04-24 Préparation de carbonate de calcium d3 soluble dans l'eau

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS52130904A (en) * 1976-04-26 1977-11-02 Teijin Ltd Stabilization of vitamin d#
JPS52136778A (en) * 1976-05-06 1977-11-15 Teijin Ltd Horse fodder
JPH08196285A (ja) * 1995-01-27 1996-08-06 Godo Shiyusei Kk １α−ヒドロキシビタミンＤ類の製造方法
CN102225070A (zh) * 2011-05-27 2011-10-26 黄辉 一种碳酸钙泡腾颗粒剂
CN103463126A (zh) * 2013-09-25 2013-12-25 贵州联盛药业有限公司 碳酸钙d3颗粒剂及其制法
CN103494836A (zh) * 2013-09-23 2014-01-08 尹庆锋 一种复合碳酸钙及维生素d3咀嚼片的制备方法及其应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS52130904A (en) * 1976-04-26 1977-11-02 Teijin Ltd Stabilization of vitamin d#
JPS52136778A (en) * 1976-05-06 1977-11-15 Teijin Ltd Horse fodder
JPH08196285A (ja) * 1995-01-27 1996-08-06 Godo Shiyusei Kk １α−ヒドロキシビタミンＤ類の製造方法
CN102225070A (zh) * 2011-05-27 2011-10-26 黄辉 一种碳酸钙泡腾颗粒剂
CN103494836A (zh) * 2013-09-23 2014-01-08 尹庆锋 一种复合碳酸钙及维生素d3咀嚼片的制备方法及其应用
CN103463126A (zh) * 2013-09-25 2013-12-25 贵州联盛药业有限公司 碳酸钙d3颗粒剂及其制法

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