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WO2004067016A1 - Utilisation d'une poudre de nano-cuivre dans la preparation de medicaments de prevention et de traitement de l'osteoporose et de fractures - Google Patents

Utilisation d'une poudre de nano-cuivre dans la preparation de medicaments de prevention et de traitement de l'osteoporose et de fractures Download PDF

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Publication number
WO2004067016A1
WO2004067016A1 PCT/CN2003/000099 CN0300099W WO2004067016A1 WO 2004067016 A1 WO2004067016 A1 WO 2004067016A1 CN 0300099 W CN0300099 W CN 0300099W WO 2004067016 A1 WO2004067016 A1 WO 2004067016A1
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WO
WIPO (PCT)
Prior art keywords
copper powder
nano
osteoporosis
group
control group
Prior art date
Application number
PCT/CN2003/000099
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English (en)
Chinese (zh)
Inventor
Si Ma
Yan Li
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Si Ma
Yan Li
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.)
Filing date
Publication date
Application filed by Si Ma, Yan Li filed Critical Si Ma
Priority to AU2003221272A priority Critical patent/AU2003221272A1/en
Publication of WO2004067016A1 publication Critical patent/WO2004067016A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/34—Copper; Compounds thereof
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis

Definitions

  • the present invention is a kind of nano-copper powder used as a preparation for preventive treatment; the application of t osteoporosis and fracture medicine. ⁇ Background technique ⁇
  • osteoporosis is a systemic skeletal disease characterized by a decrease in bone mass and degradation of the microstructure of the bone, leading to increased bone fragility and prone to fracture. With the increase of the elderly population, osteoporosis may become the enemy of most people's health in the future. Therefore, this kind of high incidence and metabolic bone disease is one of the problems that the medical profession is currently studying. Osteoporosis is mainly divided into two major categories: primary and secondary.
  • Primary osteoporosis is a physiological change that occurs due to aging or women's postmenopausal bone tissue. Due to certain diseases (such as endocrine disorders, chronic diseases such as kidney, liver and gastrointestinal calcium absorption disorders), malnutrition and drug-induced osteoporosis are called secondary osteoporosis.
  • Osteoporosis is usually treated with calcium or estrogen replacement therapy at home and abroad.
  • most current calcium supplement drugs are not well absorbed or calcium and phosphorus cannot be deposited in the bone after absorption.
  • Estrogen replacement therapy can directly improve bone metabolism in postmenopausal women and effectively prevent the progressive loss of bone in the first few years after menopause.
  • its short-term effect can hardly last.
  • the long-term use can easily lead to various complications, such as breast Cancer, endometrial cancer and other serious complications.
  • the purpose of the present invention is to provide an application of nano-copper powder as a medicine for the prevention and treatment of osteoporosis and fracture, that is, to fully utilize the anti-osteoporosis and accelerate fracture healing effects of nano-copper powder, which can effectively overcome the problems existing in the prior art.
  • As an ideal medicine for the prevention and treatment of osteoporosis it is effective for primary and secondary osteoporosis and fractures caused by osteoporosis, with little toxic and side effects.
  • the purpose of the present invention is achieved as follows:
  • nano-copper powder as a medicine can be made into dosage forms such as tablets, capsules, granules and the like.
  • the nano-copper powder of the present invention is used for preparing osteoporosis and fracture prevention medicines. Its main component is nano-copper powder, which is commercially available.
  • nano-copper powder can be laser, chemical, physical and low temperature. Prepared by freezing and other methods. However, there have been no reports on the preparation of medicines for the prevention and treatment of osteoporosis and fractures. .
  • nano-copper powder The pharmacodynamics of nano-copper powder was used to determine the preventive and therapeutic effects of nano-copper powder on experimental osteoporosis caused by dexamethasone, and the preventive and therapeutic effect of nano-copper powder on experimental osteoporosis induced by retinoic acid.
  • the test showed that the nano copper powder can promote the formation and cross-linking of bone collagen, collagen and elastin, maintain and restore connective tissue, and can be used to prevent and treat osteoporosis and fractures. It opens up new uses for the clinical preparation of nano-copper powder-containing pharmaceutical preparations as a medicine for the prevention and treatment of osteoporosis and fractures. In this test method:
  • Test drug Nano-copper powder, black powder, provided by Shenyang 21st Century Nanotechnology Co., Ltd., when needed, 0.5% CMC: Na solution is used to prepare a suspension with the required concentration.
  • mice Wistar rats, Kunming mice, male and female, provided by the Animal Center of Shenyang Pharmaceutical University, certificate number: 033.
  • Rats were 250-300 g, half male and 48 female. Randomly divided into 6 groups: normal control group, model Type control group, Gushukang group (1.8g / kg). Nano-copper powder was divided into three dose groups of 0.842 g / kg and 2.5272 mg / kg and 7.5816 mg / kg. In addition to the normal control group, the other groups were intramuscularly injected with dexamethasone 2.5 mg / kg twice a week for 6 consecutive weeks. At the same time, the model was administered by intragastric administration at a dose of 1 ml / 100 g once a day, which was normal. The control group was given the same amount of vehicle. On the next day after the last administration, blood was collected from the eyes of the rats.
  • the serum was separated by centrifugation at 2500 rpm for 10 minutes, and the serum calcium, phosphorus, copper, zinc, magnesium and other inorganic ions and various biochemical indicators were measured.
  • rats were sacrificed by cervical spine removal, left and right femurs were removed and the attached soft tissues were removed. Bone mineral density was measured with a dual-energy X-ray bone densitometer on the right femur, and then a three-point bending test using a universal material machine was performed to record the fracture load.
  • Rats were 250-300 g, half male and 48 female. Randomly divided into 6 groups: normal control group, model control group, Gushukang group (1.8g / kg), nano-copper powder 0.842 g / kg, 2.5272mg / kg, 7.5816mg / kg three dose groups. Except the normal control group, the other groups were intramuscularly injected with dexamethasone 2.5 mg / kg twice a week for 6 consecutive weeks. It was caused by an experimental osteoporosis rat model. After the successful modeling, each administration group was administered with 1 ml / 100 g orally according to the set dose, once a day, and the normal control group was given the same amount of vehicle for 4 weeks.
  • mice Female rats were weighed, weighing 300--350 g, for a total of 48 rats. Randomly divided into 6: groups: 'sham operation group, model control group, Gushukang group (1.8g / kg), nano copper powder 0.842.g / kg, 2.5272mg / kg, 7.5816mg / kg three dose groups. Except for the sham operation group, the rats were anesthetized intraperitoneally with 4 pentobarbital sodium, fixed, opened on the back, bilaterally removed the ovary, 'ligated fallopian tubes, sutured the wound, and disinfected. In the sham operation group, the ovaries were not removed after laparotomy. The rest of the steps were the same as those in the operation group.
  • each administration group was administrated with l ml / 100 g once a day according to the set dose, once a day, the sham operation group was given the same amount of vehicle, and the model control group was fed normally for three consecutive months.
  • blood was collected from the veins of the rats' eyes, and the serum was separated by centrifugation at 2500 rpm for 10 minutes, and the serum estradiol, calcitonin, and osteocalcin were measured.
  • rats were sacrificed by cervical spine removal, left and right femurs were removed, and the attached soft tissue was removed.
  • the right femur was measured for bone mineral density using a dual-energy X-ray bone densitometer, and then a three-point bending test using a universal material machine was performed to record the fracture load.
  • a three-point bending test using a universal material machine was performed to record the fracture load.
  • Uterine weight and calculate uterine index The experimental results were statistically processed and tested for significance by t test.
  • Rats were 180-260g, half male and half male, a total of 48 rats. Randomly divided into 6 groups: normal control group, model control group, Gushukang group (1.8.g / kg), nano copper powder 0.842 g / kg, 2.5272mg / kg, 7.5816mg / kg three dose groups. Except for the normal control group, all the other groups were given retinoic acid 70mg / kg once a day for 2 weeks. At the same time of modeling, each administration group was intragastrically administered with 1ml / 100g according to the set dose, once a day, and the empty control group was given the same amount of vehicle, and the model control group was raised normally for 4 weeks.
  • Rats were 180-260g, half male and half male, a total of 48 rats. Randomly divided into 6 groups: normal control group, model control group, Gushukang group (1.8g / kg), nano copper powder 0.842 / kg, 2.5272mg / kg, 7.5816mg / kg three dose groups. Except for the normal control group, all the other groups were given retinoic acid 70mg / kg once a day for 2 weeks. After the successful modeling, each administration group started to administer lml / 100g intragastrically according to the set dose, once a day. The blank control group was given the same amount of vehicle, and the model control group was raised normally for 4 weeks.
  • Kunming mice weighing 18-22 g, 50 males and 50 females, fasted for 12 hours before the test, randomly divided into 5 groups according to body weight, 10 mice in each group, and administered orally at different dose groups.
  • the dose interval was 1: 0.8
  • the dosing volume was 0.2ml / 10g of the body weight of the mice, and the animals were continuously observed for 14 days after the administration.
  • the reaction and death of the animals were recorded, and the LD 5 was calculated by the Bliss method. And 95% confidence limit.
  • the copper powder medium and high-dose groups and Gushukang group can significantly reduce the serum ALP levels of model rats PO.05 or P ⁇ 0.01, the results are shown in Table 7; compared with the normal control group, the serum hydroxyproline levels of model rats Significantly increased P ⁇ 0.05, significantly reduced creatinine level P ⁇ 0.01, significantly increased ratio of hydroxyproline to creatinine P ⁇ 0.01, nano-copper powder can significantly reduce serum HOP levels P ⁇ 0.05, and increased creatinine level P ⁇ 0.01 Correspondingly, the ratio of hydroxyproline to creatinine was reduced by PO.05 or P ⁇ 0.01, and its effect was better than that of the osteoclast group. The results are shown in Table 8.
  • nano copper powder has a good preventive effect on dexamethasone-induced osteoporosis and can reduce Long-term high-dose glucocorticoid-induced bone loss and a certain dose-dependent effect of nano-copper powder on bone mineral density of right femur in osteoporotic rats induced by dexamethasone
  • the wet weight of iliac bone is significantly lower than that of the blank control group P ⁇ 0.01, and the high-dose nano-copper powder group can significantly increase the femoral wet weight of model rats P ⁇ 0.05, which is better than osteoporosis.
  • the results are shown in Table 12-13.
  • the serum alkaline phosphatase level in the model control group was significantly higher.
  • P ⁇ 0.05 the nano copper powder and Gushukang had no significant effect on serum ALP.
  • the results are shown in Table 14.
  • the serum hydroxyproline level in the model group significantly increased P ⁇ 0.01.
  • Creatinine level was significantly reduced by P ⁇ 0.05, and the ratio of hydroxyproline to creatinine was increased by P ⁇ 0.01.
  • Nano-copper powder can significantly reduce the serum HOP level in model rats, PO.05 or P ⁇ 0.01, and reduce the ratio of hydroxyproline to creatinine.
  • the experimental results show that compared with the normal control group, the bone density of the model control group is significantly reduced (PO.01), and the nano-copper powder can significantly increase the bone mineral density of osteoporotic rats.
  • PO.05 and P ⁇ 0.01 there is no significant difference compared with Gushukang group.
  • the results are shown in Table 16.
  • the fracture load of the model control group was significantly lower than that of the blank control group (P ⁇ 0.01).
  • the results are shown in Table 17; the femoral wet weight of each administration group has an increasing trend compared with the model group, but the difference is not significant.
  • the length was significantly reduced by P ⁇ 0.01.
  • the osteoporosis group and the nano-copper high-dose group could significantly increase the femoral volume and length of model rats P ⁇ 0.05.
  • the femoral diameter of each administration group was compared with the model group. There are no significant differences.
  • the results are shown in Tables 18-19.
  • the effect of nano-copper powder on the uterine weight of ovariectomized rats is shown in Table 20.
  • Gushukang and nano-copper powder can significantly increase uterine weight and uterine index PO.05 in rats.
  • Alcohol, calcitonin levels were significantly reduced? ⁇ 0.05 or? ⁇ 0.01, osteocalcin The levels were significantly increased P ⁇ 0.05, and there was no significant difference in serum estradiol levels between the administration groups.
  • nano-copper powder has a significant preventive effect on osteoporosis caused by ovarian removal, can reduce bone loss caused by ovariectomy, increase bone thickness, and the effect is dose-dependent. '
  • the preventive effect of nano-copper powder on experimental osteoporosis caused by retinoic acid shows that the bone density of the model control group is significantly lower than that of the normal control group (P ⁇ 0.01), and the nano-copper powder can significantly increase bone.
  • the bone mineral density of osteoporotic rats is PO.05 and P ⁇ 0.01 compared with the model control group, and there is no significant difference compared with the osteoporosis group.
  • Control group (P ⁇ 0.01), Gushukang group and nano-copper powder dose groups can significantly increase the breaking load of model rats PO.05 and P ⁇ 0.01, the results are shown in Table 23; Nano-copper powder caused bone damage to retinoic acid Quality
  • the effects of wet, dry, and gray weights of the left femur in pine rats are shown in Table 24.
  • the femoral wet, dry, and gray weights of the model control group were significantly lower than those of the blank control group P ⁇ 0.01, the osteoporosis group and nano-copper powder. Can all significantly increase the femoral wet, dry and grey weights in model rats? ⁇ 0.05 or?
  • the model The level of serum hydroxyproline in the group rats significantly increased PO.01, the creatinine level significantly decreased PO.01, the ratio of hydroxyproline to creatinine significantly increased PO.01, and the nano-copper powder could significantly reduce the serum HOP level P ⁇ 0.05 Raising creatinine levels PO.05 and P ⁇ 0.01, correspondingly lowering the ratio of hydroxyproline to creatinine P ⁇ 0.01, the effect is better than that of the osteoclast group.
  • the results are shown in Table 29. The above experimental results show that nano-copper powder has a good preventive effect on retinoic acid-induced osteoporosis, can reduce bone loss caused by long-term high-dose retinoic acid, and the effect is dose-dependent.
  • the experimental results show that the bone density of the model control group is significantly lower than that of the normal control group (P ⁇ 0.01), and the nano copper powder can significantly increase the bone mineral density of osteoporotic rats.
  • the results are shown in Table 30; the effect of nano copper powder on the wet and dry left femoral weight of retinoic acid-induced osteoporotic rats is shown in Table 31, and the femoral wetness of model control group The weight and dry weight were significantly lower than those in the blank control group P ⁇ 0.05 or!> ⁇ 0.01.
  • the nano-copper powder high-dose group could significantly increase the femoral wet and dry weight of model rats PO.05; the femoral volume and length of the model group rats And diameter and normal pair Compared with the control group, P ⁇ 0.05 or P ⁇ 0.01 was significantly reduced.
  • the osteoporosis group and the nano-copper powder dose groups can significantly increase the femoral volume and diameter of model rats P ⁇ 0.05 or P ⁇ 0.01, and the nano-copper powder high dose group Can significantly increase the femur length in model rats.
  • the results are shown in Table 32. The above experimental results show that: nano-copper powder has a good therapeutic effect on retinoic acid-induced osteoporosis, which is consistent with the results of preventive administration.
  • Embodiment 1 Preparation of tablets
  • Dosage Orally, one tablet at a time, twice daily.
  • Dosage Orally, one capsule at a time, twice daily.
  • Embodiment 3 Preparation of Granules

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

L'invention concerne l'utilisation d'une poudre de nano-cuivre dans la préparation de médicaments, pour prévenir et traiter l'ostéoporose ainsi que les fractures, ses caractéristiques sont les suivantes : la matière est une poudre de nano-cuivre d'un diamètre particulaire de 0,1-1 000 nm, le rapport entre la poudre de nano-cuivre et la préparation est de 0,00025-0,0125 :1 dans les médicaments obtenus. Elle tire suffisamment avantage des fonctions de la poudre de nano-cuivre comme anti-ostéoporose et pour favoriser un hénosis d'une fraction et elle résout efficacement le problème de l'art. Elle constitue un médicament idéal dans la prévention et le traitement de l'ostéoporose, de l'ostéoporose primaire et secondaire, et des fractures résultant de l'ostéoporose, son effet curatif est certain et elle présente peu de toxicité et d'effets secondaires.
PCT/CN2003/000099 2003-01-28 2003-01-29 Utilisation d'une poudre de nano-cuivre dans la preparation de medicaments de prevention et de traitement de l'osteoporose et de fractures WO2004067016A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003221272A AU2003221272A1 (en) 2003-01-28 2003-01-29 Use of a nano-copper powder in preparation of the medicaments in preventing and treating of osteoporosis and fracture

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNB031109551A CN1234371C (zh) 2003-01-28 2003-01-28 纳米铜粉作为制备预防治疗骨质疏松、骨折药物的应用
CN03110955.1 2003-01-28

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050053673A1 (en) * 2003-09-05 2005-03-10 Shrirang Netke Composition and method for facilitating bone healing
CN112999433B (zh) * 2021-02-23 2022-07-05 吴江永元生物科技有限公司 一种Cu-Zn复合材料宫内节育器及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988009347A1 (fr) * 1987-05-29 1988-12-01 Kabivitrum Ab Nouveaux derives d'heparine
WO1992002235A1 (fr) * 1990-08-06 1992-02-20 The Procter & Gamble Company Complements de calcium et de traces de mineraux
CN1127070A (zh) * 1995-06-18 1996-07-24 侯润安 新型保健营养奶粉及其生产方法
CN1299678A (zh) * 1999-12-15 2001-06-20 李全才 中药神农精骨灵

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988009347A1 (fr) * 1987-05-29 1988-12-01 Kabivitrum Ab Nouveaux derives d'heparine
WO1992002235A1 (fr) * 1990-08-06 1992-02-20 The Procter & Gamble Company Complements de calcium et de traces de mineraux
CN1127070A (zh) * 1995-06-18 1996-07-24 侯润安 新型保健营养奶粉及其生产方法
CN1299678A (zh) * 1999-12-15 2001-06-20 李全才 中药神农精骨灵

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HAIBAO SHEN: "Tthe function of microelement copper in chinese traditional medicine", SICHUAN TRADITIONAL CHINESE MEDICINE, vol. 4, no. 10, 1986, pages 52 *

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CN1234371C (zh) 2006-01-04
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