CN101229154B - Medicine compounds for treating osteoporosis - Google Patents
Medicine compounds for treating osteoporosis Download PDFInfo
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- CN101229154B CN101229154B CN200710002541A CN200710002541A CN101229154B CN 101229154 B CN101229154 B CN 101229154B CN 200710002541 A CN200710002541 A CN 200710002541A CN 200710002541 A CN200710002541 A CN 200710002541A CN 101229154 B CN101229154 B CN 101229154B
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Abstract
The invention which provides vitamin K and a strontium ranelate compound preparation is used for treating osteoporosis and is prepared into suitable formulations comprising granules, tablets, capsules, dropping pills and oral liquids. The vitamin K and the strontium ranelate compound preparation are not only significant in treatment effect but can also reduce the using dosage; at the same time, the adverse reactions of the drug are effectively reduced. The exact treatment effect of the preparation is satisfactory although the exact mechanisms of pharmacology and pharmaco dynamics are not so clear yet.
Description
Technical field
The invention belongs to new Western medicine compound recipe.
Background technology
1. vitamin K and osteoporosis
Disclosing vitamin K first relevant with bone metabolism is at 20th century the mid-1970s, research at present learns that vitamin K and osteoporotic relation are very close, though it is definite machine-processed not clear, but certainly thinking has confidential relation with bone metabolism, mainly influences bone metabolism in the following areas:
1) participating in the vitamin k-dependent bone protein, mainly is the proteic carboxylation of Bone Gla protein, and Bone Gla protein is the species specificity noncollagen protein in the osseous tissue, in bone matrix, can promote the bone mineralising by the synthetic justacrine of osteoblast.3 Gla residues are arranged in the Bone Gla protein molecule, are itself and Ca
2+In conjunction with indispensable structure, if after making the Gla residue be reduced to glutamic acid, Bone Gla protein just loses and Ca
2+Binding ability.Vitamin K is the coenzyme of glutamic acid gamma-carboxylase, and it is carboxylated to participate in the Bone Gla protein γ-position of glutamic acid, thereby promotes the bone mineral content deposition, and finally promotes bone formation.As seen the Gla residue is to promote the indispensable structure of bone calcium deposition in the Bone Gla protein.
2) suppress the bone resorption activity factor and suppress bone resorption, thereby vitamin K can suppress the active bone resorption that suppresses of osteocyte.
3) influence bone metabolism, vitamin K can influence bone metabolism by the discharge that reduces urine calcium, kidney calcium element in the kidney also is a kind of Gla albumen, the carboxylated participation that also needs vitamin K of its glutaminic acid residue γ-carboxyl, so the discharge of the influence that vitamin can be indirect urine calcium.
Vitamin K and osteoporotic in close relations, present many research datas prove that vitamin K has the osteoporotic effect of good preventing, but therapeutical effect is not clearly.And heavy dose of use may damage liver function and the hidden danger that promotes blood coagulation is arranged.Point out it can unite other medicines and be applied to prevention of osteoporosis and treatment.
2. Strontium Ranelate and osteoporosis
Strontium Ranelate (Strontium Ranelate) is the osteosporosis resistant medicament of new generation by the French Servier of drugmaker development, has the dual-use function of stimulating osteoblast bone formation and inhibition osteoclast bone resorption.Strontium Ranelate is made up of the thunder Buddhist nun acid of two stable strontium atoms and a part.Wherein strontium ion participates in the calcification of bone, is that strontium and calcium are similar, in intestinal absorption, are combined in the bone, do not have bonded strontium then to excrete by kidney and feces because strontium is its active component for skeleton.Thunder Buddhist nun acid is strong polar organic acid, and parmacodynamics-less activity, but can form stable chelate with the bivalence strontium ion can be used as carrier and makes the medicine can be oral.
Strontium Ranelate is good as a kind of novel osteoporosis therapy effect of drugs, few side effects, medication are convenient and simple, is fit to the sufferers of osteoporosis face long-term prescription.But studies show that at present its bioavailability reduces along with the increase of dosage, human oral 2g Strontium Ranelate, the oral administration biaavailability of strontium are 27%; Gastrointestinal absorption shows as low dosage (being less than 1g) and is active absorption, is passive absorption during the high dose unsaturation.And commercially available Strontium Ranelate preparation all is specifications of 2g at present, and its bioavailability is very low.
3. osteoporosis
Osteoporosis is to be a kind of general skeletal diseases of feature with low bone amount and the regression of osseous tissue micro structure, increase with bone fragility, easily to fracture. osteoporosis can be divided into constitutional and Secondary cases two classes, wherein primary osteoporosis accounts for about 95% of osteoporosis. and primary osteoporosis can be divided into 2 kinds of hypotypes again, be that I type and II type .I type claim postmenopausal osteoporosis again, the II type is a senile osteoporosis.
Secondary osteoporosis is because other diseases or medicine cause.The intensity of bone and complete, depend on from the osteoclast of hemopoietic tissue to the absorption of bone and from the osteoblast of bone marrow matrix to the balance between the reconstruction of bone.Along with age ageing or owing to the disease reason, if bone resorption has surpassed bone formation, bone loss will appear, secondary forms osteoporosis.
Osteoporosis is sent out old age well, and is relevant with multiple factor during generation, but principal element bone metabolism local modulation factor regulatory mechanism obstacle has endocrine regulation, calcium to take in minimizing etc.
Summary of the invention
We not only can overcome the drawback of both list times spent, and can heighten the effect of a treatment mutually in the treatment osteoporosis through experimental studies have found that vitamin K and Strontium Ranelate use in conjunction.With vitamin K and Strontium Ranelate use in conjunction, two medicines can reduce on consumption greatly, but have obtained satisfactory effect equally, and the untoward reaction of medicine has also obtained effective reduction simultaneously.Strontium Ranelate can strengthen the therapeutical effect of vitamin K, though its definite pharmacology, pharmacodynamics mechanism we also research is very unclear, the definite curative effect of its both couplings is still very satisfactory.
The invention provides the compound preparation of a kind of vitamin K and Strontium Ranelate, this compound preparation is used for osteoporotic treatment, particularly is applied to the treatment of the postclimacteric osteoporosis of women.Wherein vitamin K comprises vitamin K
1(2-methyl-3-(3,7,11,15-tetramethyl-2-hexadecene base)-1, the trans and cis-isomer of 4-naphthalenedione), vitamin K
2, vitamin K
3(being menadione sodium bisulfite or sulfurous acid nicotiamide menadione again), vitamin K
4(crying acetomenadione, chemical name the 2-methyl isophthalic acid again, 4-naphthalenediol diacetate) and vitamin K
5, vitamin K
6, vitamin K
7, vitamin K
8, vitamin K
9, vitamin K
10Preferred vitamin K wherein
1, vitamin K
2, vitamin K
3And vitamin K
4
The present invention is prepared into suitable dosage form with the compound recipe of vitamin K and Strontium Ranelate, comprises granule, tablet, capsule, drop pill and oral liquid.
The specific embodiment
Embodiment 1 vitamin K
1With the influence of the compound recipe of Strontium Ranelate to osteoporosis retinoic acid modeling rat
1. experimental technique
Select 50 of the SD female rat at 6 monthly ages for use, body weight derives from southern Shandong pharmacy group Experimental Animal Center between 180～220g, be divided into 5 groups at random:
The blank group; 10,1% sodium carboxymethyl cellulose normal saline 2ml irritates stomach, every day 1 time.
The osteoporosis model group of Induced by Retinoic Acid; 10, add retinoic acid with 1% carboxymethylcellulose sodium solution and be made into 4% retinoic acid suspension 2ml and irritate stomach, every day 1 time.
Vitamin K
1With Strontium Ranelate drug combination group; 10, as above molding method adds vitamin K with 1% carboxymethylcellulose sodium solution
1With the Strontium Ranelate wiring solution-forming, press vitamin K
14mg/kg+ Strontium Ranelate 200mg/kg administration, every day 1 time.
Vitamin K
1The treatment group; 10, as above molding method adds the vitamin K wiring solution-forming with 1% carboxymethylcellulose sodium solution, presses vitamin K
1The 4mg/kg administration, every day 1 time.
Strontium Ranelate treatment group; 10, as above molding method adds the Strontium Ranelate wiring solution-forming with 1% carboxymethylcellulose sodium solution, presses Strontium Ranelate 200mg/kg administration, every day 1 time.
Each treated animal was all raised 1 month in 25 ℃ of left and right sides environment, freely drank water, and ingested.
2. the processing of experimental result and observation index
Bone density (BMD); Test after 1 month,, respectively organize the rat body bone density with dual intensity x ray borne densitometers mensuration with each group rat anesthesia.
The rat bone weight coefficient; Put to death rat and get the bilateral femur, behind rejecting muscle and the soft tissue,, divided by body weight, get bone weight in wet base coefficient with the bone weight in wet base with electronics Libra weighing bone weight in wet base.Then bone is put into baking box, 120 ℃ were toasted 6 hours, and its dry weight of weighing is calculated key heavy coefficient with quadrat method then.
Serum calcium, phosphorus content are measured; After experiment finishes, water and chloralization rat, it is standby to adopt the carotid duct drain to get serum, it is to be measured to isolate serum, wherein methylthymol blue (MTB) method is adopted in blood calcium determination, and serium inorganic phosphorus is measured and adopted the molybdic acid method, and the concrete operations step is undertaken by the test kit description.
The serum alkaline phosphatase assay; With p-nitrophenyl disodium hydrogen phosphate method, the concrete operations step is undertaken by the test kit description.
Urinary hydroxyproline/urine creatine ratio measurement; Connect each experimental rat urine with metabolic cage the last week after experiment finishes, and the mensuration of urinary hydroxyproline adopts improvement toluene-sodium-sulfonchloramide oxidizing process to measure, and the concrete operations step is undertaken by the test kit description.
3. experimental data and analysis
Table 1 experiment is to the influence of rat bone density and bone weight coefficient
*Compare p＜0.05 with model group,
*Compare p＜0.01 with model group.
﹠amp;With vitamin K
1Group is p＜0.05 relatively,
﹠amp; ﹠amp;With vitamin K
1Group is p＜0.01. relatively
#Compare p＜0.05 with the Strontium Ranelate group,
##Compare p＜0.01. with the Strontium Ranelate group
Table 2 experiment is to the influence of rat blood serum calcium, phosphorus, content of alkaline phosphatase and urinary hydroxyproline/urine creatine ratio
*Compare p＜0.05 with model group,
*Compare p＜0.01. with model group
﹠amp;With vitamin K
1Group is p＜0.05 relatively,
﹠amp; ﹠amp;With vitamin K
1Group is p＜0.01. relatively
#Compare p＜0.05 with the Strontium Ranelate group,
##Compare p＜0.01. with the Strontium Ranelate group
Embodiment 2 vitamin Ks
3With of the influence of Strontium Ranelate compound recipe to castration osteoporosis modeling rat
1. experiment material and method
1) laboratory animal and modeling method
6 month female are not educated 50 of SD rats (providing the SPF level by southern Shandong pharmacy group Experimental Animal Center).
Modeling method: at first rat is used the 100g/L chloral hydrate, presses the 300mg/kg intraperitoneal injection of anesthesia, and by median abdominal incision, passivity is separated the laggard abdomen of abdominal muscle sarolemma, finds ovary, and it excision is sewed up the incision in the silk thread ligation, and 1 week of postoperative takes out stitches.
2) grouping
Model control group; 10, anesthesia, the same modeling method of operation pathway, spay, one week of postoperative irritates stomach and gives normal saline, and per two days are once, continuous 3 months.
The associating low dose group; 10, as above-mentioned modeling method, spay.One week of postoperative back filling stomach gives vitamin K
32mg/kg+ Strontium Ranelate 200mg/kg, per two days once, continuous 3 months.
The associating high dose group; 10, as above-mentioned modeling method, spay.One week of postoperative back filling stomach gives vitamin K
36mg/kg+ Strontium Ranelate 600mg/kg, per two days once, continuous 3 months.
Vitamin K
3Group; 10, as above-mentioned modeling method, spay.One week of postoperative back filling stomach gives vitamin K
36mg/kg, per two days once, continuous 3 months.
The Strontium Ranelate group; 10, as above-mentioned modeling method, spay.One week of postoperative back filling stomach gives Strontium Ranelate 600mg/kg, and per two days once, continuous 3 months.
Divide cage to feed during postoperative and the administration under the identical conditions, do not limit feedstuff and water.3 months laboratory observation phases of postoperative.
3) index observing of experimental result
With embodiment 1.
2. respectively organize experimental data and analysis
The influence of table 1 pair experimental rat bone density and bone weight coefficient
*Compare p＜0.05 with model group,
*Compare p＜0.01. with model group
﹠amp;With vitamin K
3Group is p＜0.05 relatively,
﹠amp; ﹠amp;With vitamin K
3Group is p＜0.01. relatively
#Compare p＜0.05 with the Strontium Ranelate group,
##Compare p＜0.01. with the Strontium Ranelate group
The influence of table 2 pair experimental rat rat blood serum calcium, phosphorus, content of alkaline phosphatase and urinary hydroxyproline/urine creatine ratio
*Compare p＜0.05 with model group,
*Compare p＜0.01. with model group
﹠amp;With vitamin K
3Group is p＜0.05 relatively,
﹠amp; ﹠amp;With vitamin K
3Group is p＜0.01. relatively
#Compare p＜0.05 with the Strontium Ranelate group,
##Compare p＜0.01. with the Strontium Ranelate group
The preparation of embodiment 3 Strontium Ranelates and vitamin K granule
Strontium Ranelate 1000g
Vitamin K
26g
Mannitol 2000g
Corn starch 2000g
Sucrose 8000g
Sodium carboxymethyl cellulose 800g
10% starch slurry is an amount of
Preparation technology:
With Strontium Ranelate, the vitamin K in the prescription
2, mannitol, corn starch, sucrose, sodium carboxymethyl cellulose crosses 100 mesh sieves respectively, takes by weighing by recipe quantity, mixing, adds 10% starch slurry and makes soft material, after granulating with 14 mesh sieves, puts that dry back is in 12 mesh sieve granulate about 80 ℃, packing gets final product.
The preparation of embodiment 4 Strontium Ranelates and the agent of vitamin K mix suspension grain
Strontium Ranelate 1000g
Vitamin K
26g
Sodium carboxymethyl cellulose 550g
Tragakanta 500g
Sucrose 8000g
Sodium citrate 700g
10% starch slurry is an amount of
Preparation technology:
With Strontium Ranelate, the vitamin K in the prescription
2, sodium carboxymethyl cellulose, tragakanta, sucrose, sodium citrate, cross 100 mesh sieves respectively, take by weighing by recipe quantity, mixing, add 10% starch slurry and make soft material, after granulating with 14 mesh sieves, put about 80 ℃ dry back with 12 mesh sieve granulate, packing gets final product.
The preparation of embodiment 5 Strontium Ranelates and vitamin K tablet
Strontium Ranelate 300g
Vitamin K
11g
Low-substituted hydroxypropyl cellulose 16g
Sucrose 40g
Sodium carboxymethyl cellulose 80g
Magnesium stearate 3g
10% starch slurry is an amount of
Preparation technology:
With Strontium Ranelate, vitamin K
1, low-substituted hydroxypropyl cellulose, sucrose, sodium carboxymethyl cellulose mix homogeneously, add 10% starch slurry and make soft material, after granulating with 14 mesh sieves, put about 80 ℃ dry back in 12 mesh sieve granulate, add the magnesium stearate mixing after, tabletting, promptly.
Embodiment 6 Strontium Ranelates and vitamin K
4Capsular preparation
Strontium Ranelate 300g
Vitamin K
41g
Pregelatinized Starch 150g
Microcrystalline Cellulose 40g
Sodium carboxymethyl cellulose 8g
10% starch slurry is an amount of
Preparation technology:
With Strontium Ranelate, vitamin K
4, pregelatinized Starch, microcrystalline Cellulose, sodium carboxymethyl cellulose mix homogeneously, add 10% starch slurry and make soft material, behind 14 sieve series grains, put that dry back is in 12 mesh sieve granulate about 80 ℃, capsule charge gets final product.
The preparation of embodiment 7 Strontium Ranelates and vitamin K drop pill
Strontium Ranelate 300g
Vitamin K
41g
Polyethylene glycol 6000 1500g
Preparation technology:
Taking polyethylene glycol 6000 heating and melting add Strontium Ranelate and vitamin K then
4, constantly stirring and make its whole fusions, filtered while hot is to reservoir, and insulation, drip system with dropper, drip 80 droplets/minute of speed, splash in liquid paraffin (the outer ice-water bath cooling) liquid coolant that contains 42% kerosene, be cooled to ball, wash ball with liquid paraffin, to there not being the kerosene flavor, promptly.
The preparation of embodiment 8 Strontium Ranelates and vitamin K oral liquid
Strontium Ranelate 300g
Vitamin K
31g
Glycerol 1500g
Sucrose 1000g
Sodium carboxymethyl cellulose 50g
Sodium benzoate 15g
Add water to 10000ml
Preparation technology:
With Strontium Ranelate, vitamin K
3, glycerol, sucrose, sodium carboxymethyl cellulose, be dissolved in the water of recipe quantity 60% earlier, after the dissolving, add sodium benzoate and also add water to full dose, stir.Potting, sterilization promptly.
Claims (6)
1. the osteoporotic pharmaceutical composition of treatment is characterized in that containing vitamin K and Strontium Ranelate.
2. compositions as claimed in claim 1 is characterized in that vitamin K is a vitamin K
1, vitamin K
2, vitamin K
3, vitamin K
4, vitamin K
5, vitamin K
6, vitamin K
7, vitamin K
8, vitamin K
9Or vitamin K
10,
3. compositions as claimed in claim 1 or 2 is characterized in that described vitamin K is a vitamin K
1, vitamin K
2, vitamin K
3Or vitamin K
4
4. compositions as claimed in claim 1 is characterized in that it is oral solid formulation or oral liquid.
5. compositions as claimed in claim 4 is characterized in that described oral solid formulation is granule, tablet, capsule or drop pill.
6. compositions as claimed in claim 4 is characterized in that described oral liquid is an oral liquid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710002541A CN101229154B (en) | 2007-01-26 | 2007-01-26 | Medicine compounds for treating osteoporosis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710002541A CN101229154B (en) | 2007-01-26 | 2007-01-26 | Medicine compounds for treating osteoporosis |
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| Publication Number | Publication Date |
|---|---|
| CN101229154A CN101229154A (en) | 2008-07-30 |
| CN101229154B true CN101229154B (en) | 2010-05-12 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200710002541A Active CN101229154B (en) | 2007-01-26 | 2007-01-26 | Medicine compounds for treating osteoporosis |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5128367A (en) * | 1989-09-01 | 1992-07-07 | Adir Et Compagnie | Divalent metal salts of 2-[N-N-di(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid |
| WO2005123130A2 (en) * | 2004-06-17 | 2005-12-29 | Osteologix A/S | Improved treatments of rheumatic and arthritic diseases comprising combinations of a 5-lipoxygenase inhibitor |
| CN1823764A (en) * | 2006-03-27 | 2006-08-30 | 重庆医药工业研究院有限责任公司 | Medicinal composition containing strontium fuminate and vitamin D |
| JP2006241098A (en) * | 2005-03-04 | 2006-09-14 | Univ Kurume | Medicine for preventing or treating osteopenia |
| CN1839827A (en) * | 2006-01-16 | 2006-10-04 | 重庆医药工业研究院有限责任公司 | Strontium ranelate chewing tablet and its preparation process |
| CN1887294A (en) * | 2006-08-01 | 2007-01-03 | 河南辅仁药业集团有限公司 | Orally taken liquid medicine composition containing strontium |
-
2007
- 2007-01-26 CN CN200710002541A patent/CN101229154B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5128367A (en) * | 1989-09-01 | 1992-07-07 | Adir Et Compagnie | Divalent metal salts of 2-[N-N-di(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid |
| WO2005123130A2 (en) * | 2004-06-17 | 2005-12-29 | Osteologix A/S | Improved treatments of rheumatic and arthritic diseases comprising combinations of a 5-lipoxygenase inhibitor |
| JP2006241098A (en) * | 2005-03-04 | 2006-09-14 | Univ Kurume | Medicine for preventing or treating osteopenia |
| CN1839827A (en) * | 2006-01-16 | 2006-10-04 | 重庆医药工业研究院有限责任公司 | Strontium ranelate chewing tablet and its preparation process |
| CN1823764A (en) * | 2006-03-27 | 2006-08-30 | 重庆医药工业研究院有限责任公司 | Medicinal composition containing strontium fuminate and vitamin D |
| CN1887294A (en) * | 2006-08-01 | 2007-01-03 | 河南辅仁药业集团有限公司 | Orally taken liquid medicine composition containing strontium |
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| CN101229154A (en) | 2008-07-30 |
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