CN102210697A - Medicine composition for treating metabolic bone diseases - Google Patents
Medicine composition for treating metabolic bone diseases Download PDFInfo
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- CN102210697A CN102210697A CN201010137896XA CN201010137896A CN102210697A CN 102210697 A CN102210697 A CN 102210697A CN 201010137896X A CN201010137896X A CN 201010137896XA CN 201010137896 A CN201010137896 A CN 201010137896A CN 102210697 A CN102210697 A CN 102210697A
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Abstract
The invention relates to a medicine composition for treating metabolic bone diseases and a preparing method thereof. The composition comprises minodronate, cholecalciferol compounds and a proper quantity of composite medicines of other additives. The composition comprises two active components, such as minodronate and the cholecalciferol compounds which can work cooperatively, and is added with the proper quantity of additives. The medicine composition disclosed by the invention can be used for inhibiting hypercalcemia caused by using cholecalciferol compounds only; due to the existence of the cholecalciferol compounds, inhibition to bone reconstruction activity caused by the minodronate can be compensated and compliance to side effects, and the like, of alimentary canal can be reduced.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition for the treatment of metabolic osteopathy and preparation method thereof, wherein said compositions is made into a kind of minodronic acid, cholecalciferol compounds and combination drug of other additives in right amount of containing, and belongs to medical technical field.
Background technology
(osteoporosis, OP) be is the disease of the whole body bone amount change of feature with minimizing of osseous tissue content and fracture risk rising to osteoporosis.Provide October nineteen ninety clearly in the 3rd international osteoporosis (OP) conference that hold in Copenhagen, Denmark capital definition: OP reduces a kind of illness that the osseous tissue microstructure is impaired and thing followed fracture risk increases with the bone amount.This disease more and more is subject to people's attention.About 200,000,000 people in the whole world suffer from osteoporosis at present, and its sickness rate has leapt to commonly encountered diseases, frequently-occurring disease the 7th.Existing 8,400 ten thousand people of China's patients with osteoporosis (comprising that the bone amount reduces) account for 6.6% of total population, expect 2010, and potential patients with osteoporosis will increase to 1.14 hundred million people; Reached 1.5 hundred million people in 2025.Because of osteoporotic influence, the incidence rate of old man's Hip Fracture is 11.26/10 ten thousand in the southern city, is 74.6/10 ten thousand at northern area more than 50 years old, the average age of onset of Hip Fracture is 67.2 years old, and the low and osteoporosis of bone amount is to cause senile fracture's principal element.
The present osteoporosis remedy thing that uses clinically mainly contains as estrogens, selective estrogen regulator, calcitonin and bisphosphonates and to be beneficial to the minimizing bone resorption; Also have some medicines, can increase the formation of bone as fluoride and parathyroid hormone.Anti-bone resorption therapy is very effective in the treatment osteoporosis, even if it can not induce the formation of new bone usually.Up to now, bisphosphonates is still the most widely used anti-bone resorption medicine, it is the synthetic analogues of endogenous mineral deposit inhibitor pyrophosphate, can suppress bone resorption, and increase bone mineral density (BMD), can effectively treat osteoporosis, Paget and cancer-related osteopathia.
Bisphosphonates treatment osteoporosis causes the minimizing of bone resorption in early days, and the bone formation that continues reduces.The early stage absorption that suppresses bone can make serum calcium reduce.Thisly cause that the reduction of serum calcium needs clinical intervention sometimes, all the more so in hypothyroid patient.In addition, diphosphonate inhibition bone resorption and half-life are very long, the conversion of the over-drastic inhibition bone of meeting, and life-time service should note influencing bone strength [OTT SM.J Clin Endocrinol-Metab, 2001,86 (4): 183521836].For alleviating the reduction to osteoblastic over-drastic inhibitory action and serum calcium, the doctor that 75-85% is arranged approximately in the U.S. recommends to use simultaneously calcium preparation or vitamin D when using diphosphonate to patient.But because this administering mode inconvenience, only there is 57% patient dependence good approximately.
Minot phosphoric acid be the 3rd generation azepine aryl diphosphonate derivant, it suppresses bone resorption activity is respectively Alendronic acid and pamidronic acid 10 times and 100 times.Chemical name: 1-hydroxyl-2-[imidazo (1,2-a) pyridin-3-yl] ethylidene) two phosphonic acids-hydrates, chemical structural formula:
Pharmaceutical research has compared the inhibitory action of some kinds of nitrogenous diphosphonates to mevalonate pathway, and the result shows: the FPP synthase is the main pharmacological target spot of minodronic acid and other diphosphonates; Concentration is 1nmolL
-1Or above minodronic acid can effectively suppress recombinant human FPP synthase (IC external
50=0.003 μ molL
-1).The activity of these diphosphonates and its inhibition of isoprenylization and to suppress the ability of bone resorption in the rat body closely related in the osteoclast of cell-free extract (rabbit reticulocyte lysate) and purification.
In a lot of animal models, show that all minodronic acid has potential activity.Minot phosphoric acid shows to have the minimizing serum Ca in the P of Rats IH model
2+The effect of concentration.In this model, the minimum effective dose of minodronic acid and other diphosphonate is respectively: minodronic acid 0.3mg/kg, pamidronic acid is 300mg/kg, and Alendronic acid is 30mg/kg, and this test shows that minodronic acid has littler biological activity and better oral administration biaavailability.
Calcitriol (1,1, 25-dihydroxycholecalciferol) can promote the absorption of intestinal to calcium, and regulates the calcification of sclerotin.For the severe renal nonfunction, particularly accept the patient of hemodialysis for a long time, the ossified triol of endogenous synthetic obviously reduces even stops fully.The shortage of calcitriol plays a part crucial for the formation of renal osteodystrophy.Alfacalcidol is converted into calcitriol through 25 hydroxylase effects in liver, osteoblast is also expressed 25 hydroxylase mRNA, also alfacalcidol can be converted into to have active calcitriol.Dimension., give birth to plain D and be converted into active calcitriol.
The situation that sufferers of osteoporosis face exists vitamin D to lack had been reported in American-European and many areas, the world in 2005.Discover that Beijing area postmenopausal women vitamin D deficiency person reaches 90%.For sufferers of osteoporosis face, because the vitamin D metabolism thing lacks and the increase of vitamin D resistance companion compensatory parathyroid hormone secretion is the osteoporotic important cause of disease, so vitamin D Can is necessary.Discover, gerontal patient, calcium Deficiency of Intake, the vitamin D person of lacking, vitamin D Can is to certain effect that has of prevention ilium portion's fracture and non-vertebral fracture, but be in a bad way, fracture history person was arranged in the past, calcium preparation and vitamin D are the medicines on basis, also will select stronger medicine for treating osteoporosis for use, as bisphosphonates.
Patent CN100577172C has announced the prescription patent of Allan sodium phosphate and calcitriol; Patent 20048-0043618.0 has announced the prescription patent of Diphosphonate and vitamin D3, this patent has comprised the prescription of minodronic acid and zoledronic acid and vitamin D3, but has got rid of the group patent that comprises minodronic acid and zoledronic acid and alfacalcidol and calcitriol.Patent 200710099341 has been announced compound alendronate sodium vitamine D 3 orally disintegrating tablets and preparation method thereof.Patent 200510037153 has been announced Alendronate sodium and vitamin D3 compound injection.Yet there are no relevant report about the compositions of minodronic acid and alfacalcidol/calcitriol.
Summary of the invention
The present invention in the treatment of metabolic osteopathy, reaching good therapeutic effect, and reduces untoward reaction with minodronic acid and cholecalciferol compounds use in conjunction, makes things convenient for medication simultaneously.
Technical scheme
A kind of pharmaceutical composition of medicine group treatment metabolic osteopathy, it comprises minodronic acid granule and the particulate mixture of cholecalciferol compounds, wherein, cholecalciferol compounds structural formula is as follows:
Formula I
R
1For-H or-OH; Wherein (1), described cholecalciferol compounds granule are by adding excipient in cholecalciferol compounds and alcoholic acid mixture, in above-mentioned mixture, add ethanol, antioxidant and binding agent then, said mixture is ground into granule and dry the acquisition; (2), described minodronic acid granule is by admixed excipients, absorption enhancer and minodronic acid, adds ethanol and binding agent then in above-mentioned mixture, and said mixture is ground into granule and dry the acquisition.
The cholecalciferol compounds 400-20 that comprises per 1 weight portion in the described compositions, the minodronic acid of 000 weight portion, induce laboratory animal to suffer from osteoporosis among the present invention, be placed in a large amount of experiments of mixture of the minodronic acid of variable concentrations and alfacalcidol/calcitriol, the mixture optimum mixture ratio example of these variable concentrations also can be controlled at the calcium concentration in the blood ratio of normal level for can prevent osteoporosis effectively.The result shows: the optimal proportion of two kinds of compositions is the alfacalcidol/calcitriol chemical compound 400-20 of per 1 weight portion in the medicine, the minodronic acid of 000 weight portion.The every dosage unit of proposed combination thing contains 0.1-3.0ug alfacalcidol/calcitriol and 1-30mg minodronic acid, and optimal dosage is minodronic acid 1mg, alfacalcidol 0.25ug or calcitriol 0.25ug.
Described metabolic osteopathy comprises: osteoporosis, osteomalacia, renal osteodystrophy, hypothyroidism and rickets.
Described compositions is prepared to tablet, granule and capsule.
The additive that uses as a kind of absorption enhancer is sodium lauryl sulphate, and it accounts for the 0.01-10% of pharmaceutical composition total amount.
Its preparation method comprises: (1), obtain the particulate method of cholecalciferol compounds by series of steps, this step is by add excipient in calcitriol and alcoholic acid mixture, in above-mentioned mixture, add ethanol, antioxidant and binding agent then, said mixture is ground into the granule and dry acquisition of 16-50 order size; (2), obtain the particulate method of minodronic acid by series of steps, this step is mixed by excipient, absorption enhancer and minodronic acid, in above-mentioned mixture, add ethanol and binding agent then, said mixture is ground into the granule and dry acquisition of 16-50 order size; (3), the cholecalciferol compounds granule that obtains from step (1) of a kind of mixture and step (2) obtain the minodronic acid granule, in said mixture, add disintegrating agent and lubricant then, last tabletting, the cholecalciferol compounds 400-20 that contains per 1 weight portion in the compositions, the minodronic acid of 000 weight portion, wherein said excipient are the 70-97wt% of total composition; Described antioxidant is to be selected from following one or more: Yoshinox BHT, Yoshinox BHT ether, a-tocopherol and lecithin, and the content of described antioxidant accounts for the 0.001-10wt% of total composition; Wherein said adhesive is selected from ketopyrrolidine, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, and described adhesive accounts for the 0.01-10wt% of total composition; Wherein said disintegrating agent is selected from cross-linking sodium carboxymethyl cellulose and carboxymethylcellulose calcium, and described disintegrating agent accounts for the 0.1-20wt% of total composition; Wherein said lubricant is selected from calcium stearate, hard magnesium and Talcum, and described lubricant accounts for the 0.1-20wt% of total composition.
Need to use excipient among the present invention, as xylitol, mannitol and sorbitol.The purpose that adds is to avoid its direct mixing, causes the stability decreases of alfacalcidol/calcitriol, and we dilute minodronic acid and alfacalcidol/calcitriol producing their granule respectively with excipient.
With the rat after the modeling, give composition sample respectively, observe rat osseous tissue, measure the concentration of calcium ion in blood and the urine, find: compare with matched group, the bone trabecula area that gives the rat of composition sample obviously increases, and illustrates that this medicine can treat the osteoporosis disease.Compound administration can remain on normal level with the blood calcium concentration of rat substantially, and when using minodronic acid separately, blood calcium concentration can obviously reduce.
The compositions of minodronic acid and alfacalcidol/calcitriol has synergism: minodronic acid improves bone volume and bone mass; Alfacalcidol/calcitriol improves osteoblast activity, the big intestinal absorption of calcium.Untoward reaction compensates mutually, and cushioning effect is arranged: minodronic acid reduces calcium content, and alfacalcidol/calcitriol improves calcium content, and the two is cancelled out each other.
Beneficial effect:
Pharmaceutical composition of the present invention can be given full play to the pharmacological action of each Main Ingredients and Appearance: the hypercalcemia that causes in the time of can suppressing to give the cholecalciferol compounds separately, the cholecalciferol compounds can be compensatory owing to the excessive inhibitory action of minodronic acid to bone, take the compound recipe of minodronic acid and cholecalciferol compounds simultaneously, can reduce compliances such as gastral side effect, reduce and take the inconvenience that brings separately, make things convenient for the patient, become a kind of ideal treatment medicine for treating osteoporosis.
Specific embodiment:
Embodiment 1 minodronic acid and alfacalcidol/calcitriol are to the influence of rat metabolic osteopathy
(1), medication
Get 110 of healthy clean maturation and individual roughly the same female rats, be divided into 11 groups, every group 10, stay 1 group to organize after normal one week of nursing as blank, implement ovarian resection for remaining 10 groups, oral administration is respectively: individually dosed minodronic acid, alfacalcidol, calcitriol and their composition of medicine, administration time was 8 weeks, 1 time weekly.Dosage such as table 1.
(2), assay method
Collect 24 hours urine sample of rat, centrifugal, low temperature storage.Get blood, centrifugal, collect serum, low temperature storage.Use calcium determinating reagent box (ARSENAZO III method) and measure the concentration of calcium (24h) in blood calcium concentration, the urine.
Separate rat tibia, formalin fixed with 4%.The tibia that above-mentioned processing is obtained carries out decalcification to be handled: placed 10% salpeter solution 8 hours, with the dehydration of Different concentrations of alcohol eluting, with dimethylbenzene and the embedding of stone sodium 2 times, section, thickness 3cm is with Lignum Sappan single-minded Yihong dyeing.Observe with magnifier, observe bone trabecular area (bone trabecular area is a kind of method accurately of weighing the bone health situation, and bone trabecular area area is big more, shows that sclerotin is healthy more).
Table 1 minodronic acid, alfacalcidol, calcitriol dosage
(3), measurement result
Tibial bone girder microscopic examination result shows: behind the surgical removal of ovaries, the area of the obviously normal rat of the bone trabecula area of rat (blank group) reduces; Find simultaneously: the bone trabecula area of minodronic acid group, minodronic acid and alfacalcidol group, minodronic acid and three groups of rats of calcitriol group obviously increases than the area of matched group, and does not increase at the alfacalcidol group of single usefulness, the bone trabecula area of calcitriol group rat.
The concentration determination result such as the table 2 of calcium in blood calcium concentration and the urine.By table 2 result as can be seen: (a), single significantly raise with calcium concentration in the serum in calcitriol and the alfacalcidol treatment group, and list obviously descends with the serum calcium cancentration in the minodronic acid group, this is because calcitriol and alfacalcidol have increased the absorption of calcium in intestinal, and minodronic acid has suppressed bone resorption by reducing parathyroid hormone, calcium is released in the blood flow in the prevention bone, has reduced the absorption of calcium in the intestinal; Compound administration can remain on normal level with the blood calcium concentration of rat substantially.(b), single concentration with calcium in calcitriol and the alfacalcidol treatment group urine significantly raises, and is and single with not significant change of calcium concentration in the minodronic acid group urine, the concentration of calcium during compound administration also can raise and urinate.
The concentration determination result of calcium in blood calcium concentration of table 2 rat and the urine
Above result of study shows: prescription of the present invention can stop the progress of osteoporosis effectively, and blood calcium concentration and UCaE can be remained on normal level.
The preparation of embodiment 2-3 minodronic acid and calcitriol tablet
Prepare nude film according to composition shown in the table 3 and content.
At first, the D-mannitol is added in the mixture of being made up of calcitriol and ethanol, add ethanol, antioxidant and adhesive then.Separate with the step of preparation calcitriol, other composition minodronic acid, mannitol, absorption enhancer are mixed; Then to wherein adding ethanol and adhesive.Then calcitriol and minodronic acid are mixed, add disintegrating agent and lubricant then, then tabletting.
The preparation of embodiment 4-5 minodronic acid and alfacalcidol capsule
According to preparing capsule shown in the table 4.
At first, xylitol is added in the mixture of being made up of alfacalcidol and ethanol, add ethanol, antioxidant and adhesive then, whole mixture is ground into 16-50 order size and dry down to obtain the alfacalcidol granule at 40 ℃ with conventional pulverizer.Separate with the step of preparation calcitriol, other composition minodronic acid, xylitol, absorption enhancer are mixed; In said mixture, add ethanol and adhesive then.Pulverizer with a kind of routine is ground into 16-50 order size and dry down to obtain the minodronic acid granule at 40 ℃ with whole mixture then.Then alfacalcidol and minodronic acid are mixed, add disintegrating agent and lubricant then, incapsulate then.
Table 3
Table 4
Claims (8)
1. pharmaceutical composition for the treatment of metabolic osteopathy, it comprises minodronic acid granule and the particulate mixture of cholecalciferol compounds, wherein, cholecalciferol compounds structural formula is as follows:
R
1For-H or-OH; Wherein
(1), described cholecalciferol compounds granule is by adding excipient in cholecalciferol compounds and alcoholic acid mixture, add ethanol, antioxidant and binding agent then in above-mentioned mixture, and said mixture is ground into granule and dry the acquisition; And
(2), described minodronic acid granule is by admixed excipients, absorption enhancer and minodronic acid, adds ethanol and binding agent then in above-mentioned mixture, and said mixture is ground into granule and dry the acquisition; The cholecalciferol compounds 400-20 that comprises per 1 weight portion in the wherein said compositions, the minodronic acid of 000 weight portion.
2. according to the pharmaceutical composition that is used for the treatment of metabolic osteopathy of claim 1, wherein said metabolic osteopathy comprises: osteoporosis, osteomalacia, renal osteodystrophy, hypothyroidism and rickets.
3. according to the pharmaceutical composition that is used for the treatment of metabolic osteopathy of claim 1, wherein said compositions is prepared to tablet, granule and capsule.
4. according to the pharmaceutical composition that is used for the treatment of metabolic osteopathy of claim 1, the cholecalciferol compounds is a kind of of calcitriol and alfacalcidol.
5. according to the pharmaceutical composition that is used for the treatment of metabolic osteopathy of claim 1, wherein said excipient is xylitol, mannitol and sorbitol.
6. according to the pharmaceutical composition that is used for the treatment of metabolic osteopathy of claim 1, the every dosage unit of wherein said compositions contains promising 0.1-3.0ug cholecalciferol compounds and 1-30mg minodronic acid.
7. according to the pharmaceutical composition that is used for the treatment of metabolic osteopathy of claim 1, wherein be sodium lauryl sulphate as the additive that a kind of absorption enhancer uses, it accounts for the 0.01-10% of pharmaceutical composition total amount.
8. according to the pharmaceutical composition that is used for the treatment of metabolic osteopathy of claim 1, its preparation method comprises:
(1), obtains the particulate method of cholecalciferol compounds by series of steps, this step is by add excipient in bone cholecalciferol compounds and alcoholic acid mixture, in said mixture, add ethanol, antioxidant and binding agent then, said mixture is ground into the granule and dry acquisition of 16-50 order size;
(2), obtain the particulate method of minodronic acid by series of steps, this step is mixed by excipient, absorption enhancer and minodronic acid, in above-mentioned mixture, add ethanol and binding agent then, said mixture is ground into the granule and dry acquisition of 16-50 order size;
(3), the cholecalciferol compounds granule that obtains from step (1) of a kind of mixture and step (2) obtain the minodronic acid granule, adds disintegrating agent and lubricant, the method for last tabletting then in said mixture;
Contain the cholecalciferol compounds 400-20 of per 1 weight portion in the wherein said compositions, the minodronic acid of 000 weight portion, wherein said excipient are the 70-97wt% of total composition;
Wherein said antioxidant is selected from following one or more: Yoshinox BHT, Yoshinox BHT ether, a-tocopherol and lecithin, and the content of described antioxidant accounts for the 0.001-10wt% of total composition;
Wherein said adhesive is selected from ketopyrrolidine, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, and described adhesive accounts for the 0.01-10wt% of total composition;
Wherein said disintegrating agent is selected from cross-linking sodium carboxymethyl cellulose and carboxymethylcellulose calcium, and described disintegrating agent accounts for the 0.1-20wt% of total composition;
Wherein said lubricant is selected from calcium stearate, hard magnesium and Talcum, and described lubricant accounts for the 0.1-20wt% of total composition.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1420777A (en) * | 1999-10-20 | 2003-05-28 | 柳柳产业株式会社 | Pharmaceutical compositions and preparations for treatment of metabolic bone disease |
| CN1751690A (en) * | 2005-09-12 | 2006-03-29 | 广东先强药业有限公司 | Compound injection contg. alendronate sodium and vitamin D3 |
| CN1993134A (en) * | 2004-05-19 | 2007-07-04 | 默克公司 | Composition for inhibiting bone resorption comprising bisphosphoric acid (alendronic acid) and vitamin D (cholecalciferol) |
| CN101305988A (en) * | 2007-05-17 | 2008-11-19 | 北京利乐生制药科技有限公司 | Compound alendronate sodium vitamine D3 orally disintegrating tablets and preparation method thereof |
-
2010
- 2010-04-02 CN CN 201010137896 patent/CN102210697B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1420777A (en) * | 1999-10-20 | 2003-05-28 | 柳柳产业株式会社 | Pharmaceutical compositions and preparations for treatment of metabolic bone disease |
| CN1993134A (en) * | 2004-05-19 | 2007-07-04 | 默克公司 | Composition for inhibiting bone resorption comprising bisphosphoric acid (alendronic acid) and vitamin D (cholecalciferol) |
| CN1751690A (en) * | 2005-09-12 | 2006-03-29 | 广东先强药业有限公司 | Compound injection contg. alendronate sodium and vitamin D3 |
| CN101305988A (en) * | 2007-05-17 | 2008-11-19 | 北京利乐生制药科技有限公司 | Compound alendronate sodium vitamine D3 orally disintegrating tablets and preparation method thereof |
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