CN1155387C - Phosphonate medicine for treating osteoporosis and bone cancer transfer - Google Patents
Phosphonate medicine for treating osteoporosis and bone cancer transfer Download PDFInfo
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- CN1155387C CN1155387C CNB001000837A CN00100083A CN1155387C CN 1155387 C CN1155387 C CN 1155387C CN B001000837 A CNB001000837 A CN B001000837A CN 00100083 A CN00100083 A CN 00100083A CN 1155387 C CN1155387 C CN 1155387C
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Abstract
The present invention provides a phosphate medicine used for treating osteoporosis and cancer osseous metastasis. The main active ingredient of the phosphate medicine comprises one phosphate of a methylene biphosphate, a hydroxyl methylene biphosphate and an ethylenediamine tetramethylene phosphate, wherein the one-time dose of the methylene biphosphate is from 4 to 600 mg, the one-time dose of the hydroxyl methylene biphosphate is from 2 to 300 mg, and the one-time dose of the ethylenediamine tetramethylene phosphate is from 3 to 450 mg. Compared with the similar medicine for treating the osteoporosis and the osseous metastasis by inhibiting bone resorption, the three phosphates of the present invention have the advantages of good treating effect and low toxic or side function.
Description
Technical field
The present invention relates to the phosphonate medicine, be specifically related to be used for the treatment of the phosphonate medicine of osteoporosis and the transfer of treatment cancer bone.
Background technology
Osteoporosis is a kind of commonly encountered diseases, and along with the appearance of social senilization, sufferers of osteoporosis face is more and more, and China has surpassed 8,000 ten thousand people at present, after 2000, will be above 100,000,000 people, and this is a very serious social concern.Osteoporosis mainly increases the back endocrine by the age and weakens that (after women's menolipsis, estrogen secretion reduces; Male's androgen secretion reduces, and women and the secretion of male's calcitonin reduce), chronic disease (as skeletal diseases such as endocrinopathyes such as hyperthyroidism, hyperparathyroidism, diabetes, rheumatoid arthritis, PagetShi diseases) and take drug-induced such as hormone for a long time.Currently be used for the treatment of osteoporotic drug main gonadal hormone and calcitonin will be arranged, also have various calcium preparation in addition.Gonadal hormone and calcitonin are used for the deficiency of human endocrine hormone and calcitonin, to promote that osteoblast is active and to reduce osteoclast activity, making bone metabolism be less than or equal to osteoplastic positive balance direction greater than osteoplastic negative balance to bone resorption by bone resorption develops, to prevent osteoporotic formation or deterioration, thereby treatment osteoporosis, but since the various toxic and side effects of hormone, unsuitable life-time service.Various calcium preparation have certain effect to forming new bone, but can not fundamentally solve the osteoporosis problem.Developed the anti-bone resorption medicine of diphosphonates in recent years in the world, the trend that replaces hormone medicine has gradually been arranged, as HEDP salt (Etidronate); 1-dichloro-methylene diphosphonate (the Clodronate trade name: the bone phosphine), 3-amino-1-hydroxypropyl diphosphate (Pamidronate trade name: rich peaceful); 4-amino-1-hydroxybutyl diphosphate (Alendronate trade name: Allan) etc.
Cancer to late period since the diffusion of cancerous cell corrode or stimulated by some humoral factor, osteoclast or osteoblast increased activity, cause that the cancer bone shifts, make the bone metabolism trend uneven, because the kind difference of primary carcinoma can cause that skeletonization is that main cancer bone shifts (as carcinoma of prostate, breast carcinoma etc.) or molten bone is that main cancer bone shifts (as nasopharyngeal carcinoma, pulmonary carcinoma etc.).Part cancer bone shifts the patient will produce violent osteodynia or hypercalcemia, must give timely treatment.The violent osteodynia that transfer causes for cancer bone radionuclide therapy commonly used (as
153Sm-EDTMP,
186Re-HEDP,
89SrCl
2Deng) and diphosphonates Drug therapy (as bone phosphine, rich peaceful etc.), shift the hypercalcemia that causes for the cancer bone, calcitonin commonly used or diphosphonates Drug therapy, wherein phosphonate is used for the treatment of the transfer of cancer bone, the hematotoxicity (blood leukocytes and platelet reduce) that does not have radionuclide therapy to cause has the exploitation meaning.But the curative effect of existing diphosphonates medicine is still not ideal enough, and toxic and side effects also need further reduce.
Summary of the invention
The purpose of this invention is to provide the new drug that little treatment osteoporosis of better efficacy and toxic and side effects and treatment cancer bone shift.
Technical scheme of the present invention is: the main active ingredient of medicine comprise a kind of phosphonate in the middle of methylene diphosphonate or hydroxyl methylene diphosphonate or the ethylenediamine tetraacetic methylene phosphonic acid salt and technetium [
99Tc] complex, the amount of methylene diphosphonate is 4mg～600mg (in a phosphonic acids) in its per unit medicine, the amount of hydroxyl methylene diphosphonate is 2mg～300mg (in a phosphonic acids), and the amount of ethylenediamine tetraacetic methylene phosphonic acid salt is 3mg～450mg (in a phosphonic acids), technetium [
99Tc] amount be 0.04 μ g～2.00 μ g, also contain the Reducing agent that pharmacopedics allows in the medicine.The Reducing agent that said pharmacopedics allows is stannous chloride or stannous fluoride or thiourea dioxide, and its content is 0.3mg～1.0mg in the per unit medicine.Said technetium [
99Tc] phosphonate complex medicine in also contain antioxidants ascorbic acid or gentisic acid, its content is 0.2mg～1.0mg in the per unit medicine.In the above-mentioned medicine, the part by weight of its main active ingredient phosphonate is no less than 50% in overall active ingredient.
Provided by the present invention is to be the new drug that is used for the treatment of osteoporosis and the transfer of treatment cancer bone of main active ingredient with a kind of phosphonate in methylene diphosphonate or hydroxyl methylene diphosphonate or the ethylenediamine tetraacetic methylene phosphonic acid salt.Wherein the ampoule of methylene diphosphonate (is the per unit medicine, in phosphonic acids) be 4mg～600mg, the ampoule of hydroxyl methylene diphosphonate (is the per unit medicine, in phosphonic acids) be 2mg～300mg, the ampoule of ethylenediamine tetraacetic methylene phosphonic acid salt (being the per unit medicine, in phosphonic acids) is 3mg～450mg.Said phosphonate is meant the phosphonate that these phosphonic acids and sodium ion, calcium ion, zinc ion or ethylenediamine tetraacetic methylene phosphonic acid and ferric ion, samarium ion form.With sodium pertechnetate and phosphonate prepare phosphonate and technetium [
99Tc] complex the time, must be with 0.3mg～1.0mg stannous chloride or stannous fluoride or thiourea dioxide as Reducing agent so that high price technetium (positive septivalency) be reduced into can with the tetravalence technetium of phosphonate complexation [
99Tc].In addition, for improve technetium [
99Tc] stability of phosphonate complex, can also add antioxidants ascorbic acid or the gentisic acid of 0.2mg～1.0mg.Wherein, phosphonate, trace element technetium [
99Tc], pharmacy Reducing agent and antioxidant be effective active components, the part by weight of its main active phosphonate (in phosphonic acids) is being no less than 50% in overall active component.
Methylenediphosphonate (MDP), hydroxyl methylenediphosphonate (HMDP) be used for both at home and abroad the nuclear medicine skeletal imaging agent (technetium [
99mTc] methylene diphosphonate injection and technetium [
99mTc] hydroxyl methylene diphosphonate injection) carrier, ethylenediamine tetraacetic methylene phosphonic acid (EDTMP) be used for nuclear medicine cancer bone diversion medicaments samarium-153-ethylenediamine tetraacetic methylene phosphonic acid salt (
153Sm-EDTMP) carrier of injection, more than three kinds of phosphonates find no the effect that bone resorption, treatment osteoporosis and treatment cancer bone shift that suppresses in the past.The inventor (is Cl with the bone phosphine
2-MDP) made inhibition osteoclast effect experiment with these three kinds of phosphonates, method is: (body weight 100g～120g) long bone of limbs separates osteoclast with 10 age in days White Rabbits, be inoculated in (Φ 1.5cm) cultivation on the ivory bones slice, add said medicine or culture fluid after 5 hours.Cultivate and take out osteocomma after 4 days after the dyeing of 1% toluidine blue, light microscopic is observed counting absorption lacuna (medicine is diluted to desired concn with the a-MEM nutrient chemical) down.Experimental result shows: when four kinds of phosphonates are 10 in concentration
-4Activity to osteoclast during mol/L has obvious inhibitory action.Three kinds of phosphonates of the present invention to the suppression ratio of osteoclast activity apparently higher than the suppression ratio (result of the test see Table 6) of existing medicine bone phosphine to osteoclast.In addition, the methylene diphosphonate of one of above three kinds of phosphonates of invention person is that representative has been carried out prevention and treated osteoporotic whole drug effect animal experiment, be about to the excision of 8 monthly age SD female rats (body weight 200g-300g) bilateral ovaries and cause osteoporosis model, in two batches time give methylene diphosphonate by irritating stomach, give for the first time rat 200mg/kg, 100mg/kg, three dosage of 50mg/kg, be 50g/kg for the second time, two dosage of 25g/kg, be the contrast medicine with nilestriol in addition, all successive administration is 90 days, result of the test shows, each dosage group methylene diphosphonate all has preventive effect to the osteoporosis model rat bone loss of bilateral ovaries excision, and the effect of 50mg/kg dosage group is better than other dosage group, the effect of spongy bone is compared the effect of cortical bone and will be got well (seeing Table 7～9), and be better than the nilestriol matched group; Dosage is that 200mg/kg dosage group has certain inhibitory action to the ovariectomized rat uterus, serum E
2The trend that increases is also arranged, but not as matched group nilestriol (seeing Table 10).
Carried out of the preliminary clinical experiment of treatment osteoporosis with above phosphonate with the transfer of treatment cancer bone, the result shows, treating osteoporotic effective percentage is 100%, treating 334 routine cancer bones shifts, analgesic effect is fine, effective percentage reaches 85.33%, and wherein obvious effective rate reaches 35.63%, and part patient's cancer bone metastatic lesion dwindles and disappears in addition.
In addition, when patient's osteoporosis is when being caused by autoimmune diseasees such as rheumatoid arthritis, psoriasis arthropathicas, for treating both the principal and secondary aspects of a disease, when the treatment osteoporosis, must treat simultaneously and cause osteoporotic autoimmune disease, in phosphonate, should add this moment trace element technetium [
99Tc].Its preparation method is in the presence of the Reducing agent (as stannous chloride or stannous fluoride or thiourea dioxide) that pharmaceutically allows, with high technetium [
99Tc] sour sodium reduction become the lower valency technetium [
99Tc] (IV), and with the phosphonate complexation generate technetium [
99Tc] the phosphonate complex (as technetium [
99Tc] methylene diphosphonate), utilize this type of technetium [
99Tc] phosphonate treatment osteoarthrosis is damaged, osteoporotic serious patient with rheumatoid arthritis has taken place the osteoarthrosis end, can control the development of the patient with rheumatoid arthritis state of an illness, and can repair broken bone, the treatment osteoporosis, improve function of joint, the patient that some have been paralysed the walking of leaving the bed has recovered self care ability.
The above results shows three kinds of phosphonates of the present invention, and (being used for the transfer of cancer bone eases pain treat osteoporosis and the transfer of treatment cancer bone by the inhibition bone resorption, reducing the blood calcium concentration of hypercalcemia, make cancer bone metastatic lesion dwindle, disappear) aspect is compared with similar medicine that more superior effect and even more important clinical practice meaning and value are arranged.
The specific embodiment
The specific embodiment of the present invention is as follows:
Said phosphonate pharmaceutical pack is drawn together different dosage forms such as injection, oral agents, and is different with dosage form according to indication, amount of phosphonate (in phosphonic acids) and technetium [
99Tc] amount different, the amount of other metal ion has no special requirements, the pH value of only requiring phosphonate is near neutral (pH value is 4.0～8.0).
Wherein injection can be divided into Intravenous injection solution and quiet dropping liquid, and for the methylene diphosphonate Intravenous injection solution of per unit medicine, phosphonic content can be 4mg, 5mg, 10mg, 20mg or 50mg; For the hydroxyl methylene diphosphonate Intravenous injection solution of per unit medicine, phosphonic content can be 2mg, 5mg, 10mg or 20mg; For the ethylenediamine tetraacetic methylene phosphonic acid salt Intravenous injection solution of per unit medicine, phosphonic content can be 3mg, 5mg, 10mg, 20mg or 30mg.For the quiet dropping liquid of the methylene diphosphonate of per unit medicine, phosphonic content can be 100mg, 200mg or 300mg; For the quiet dropping liquid of hydroxyl methylene diphosphonate of per unit medicine, phosphonic content can be 50mg, 100mg or 150mg; For the quiet dropping liquid of ethylenediamine tetraacetic methylene phosphonic acid salt of per unit medicine, phosphonic content can be 75mg, 100mg or 200mg.
Oral agents can be prepared into oral capsule or tablet, and for the methylene diphosphonate oral agents of per unit medicine, phosphonic content can be 100mg, 200mg, 300mg, 400mg, 500mg or 600mg; For the hydroxyl methylene diphosphonate oral agents of per unit medicine, phosphonic content can be 50mg, 100mg, 150mg, 200mg or 300mg; For the ethylenediamine tetraacetic methylene phosphonic acid salt oral agents of per unit medicine, phosphonic content can be 75mg, 150mg, 200mg, 300mg or 450mg.
When medicine be technetium [
99Tc] during the phosphonate injection, phosphonate for above-mentioned each phosphonic acids content, the content of technetium can be 0.04 μ g, 0.05 μ g, 0.07 μ g, 0.1 μ g, 0.3 μ g, 0.5 μ g, 1 μ g or 2 μ g, and the content of stannous chloride or stannous fluoride or thiourea dioxide can be 0.3mg, 0.5mg, 0.6mg, 1.0mg.
Above-mentioned technetium [
99Tc] in the phosphonate medicine, can also add antioxidants ascorbic acid or gentisic acid, its content can be 0.2mg～1.0mg, and wherein 0.2mg, 0.3mg, 0.4mg, 0.5mg, 0.6mg, 0.7mg, 0.8mg, 0.9mg, 1.0mg are operable dosage.
Phosphonic acids content in the above-mentioned phosphonate and contain technetium [
99Tc] time technetium [
99Tc] content range sees Table 1 (other metal ion has no special requirements).
Table 1
The concrete preparation method and the optimum implementation of above-described various medicines are as follows:
1, the preparation of phosphonate Intravenous injection solution commonly used
In purifying factory, take by weighing the aequum phosphonic acids by sterile working's requirement, use the second distillation water dissolution, to pH value 5.0～7.0, the reuse normal saline is diluted to desired concn with 2N sodium hydroxide solution regulator solution acidity, after biofilter filters, be distributed into certain specification more on request, after gland seal, the high-temperature sterilization sterilization, clinical practice is direct intravenous injection.
The phosphonic acids content specification of table 2 5ml phosphonate Intravenous injection solution
| Phosphonate Intravenous injection solution title | Volume (ml) | Specification is (in phosphonic acids, mg) |
| The methylene diphosphonate Intravenous injection solution | 5 | 5，10，20 |
| Hydroxyl methylene diphosphonate Intravenous injection solution | 5 | 5，10 |
| Ethylenediamine tetraacetic methylene phosphonic acid salt Intravenous injection solution | 5 | 5，10 |
2, the preparation of the quiet dropping liquid of phosphonate commonly used
In purifying factory, take by weighing the aequum phosphonic acids by sterile working's requirement, use the second distillation water dissolution, to pH value 5.0～7.0, the reuse normal saline is diluted to desired concn (50～100mg/ml) with 2N sodium hydroxide solution regulator solution acidity, after biofilter filters, divide to put into 10ml glass bottle (every bottle of 2ml～2.5ml), in sterilizing room, be lyophilized into injectable powder, again gland seal more on request, face with preceding usefulness 250～500ml physiological saline solution dilution, intravenous drip.
The phosphonic acids content specification of the quiet dropping liquid of table 3 phosphonate
| The quiet dropping liquid title of phosphonate | Specification is (in phosphonic acids, mg) |
| The quiet dropping liquid of methylene diphosphonate | 100，200 |
| The quiet dropping liquid of hydroxyl methylene diphosphonate | 50，100 |
| The quiet dropping liquid of ethylenediamine tetraacetic methylene phosphonic acid salt | 75，150 |
3, phosphonate oral agents (capsule or tablet) preparation commonly used
Oral capsule or tablet producing technology routinely prepare the phosphonate oral agents of required specification.
The phosphonic acids content specification of table 4 phosphonate oral agents
| Oral agents phosphonate title | Specification is (in phosphonic acids, mg) |
| Methylene diphosphonate | 100，200，300 |
| The hydroxyl methylene diphosphonate | 50，100，150 |
| Ethylenediamine tetraacetic methylene phosphonic acid salt | 75，150，200 |
4, technetium [
99Tc] preparation of phosphonate injection
In purifying Factory Building, take by weighing the phosphonic acids of aequum by sterile working's requirement, high technetium [
99Tc] sour sodium, Reducing agent stannous chloride (SnCl
22H
2O) and antioxidants ascorbic acid (vitamin C) be mixed with desired concn solution, make the injection or the quiet dropping liquid (the content specification sees Table 5) of different size again.
The content specification of the various active ingredients of table 5 technetium phosphonate injection
| Technetium [ 99Tc] the phosphonate title | The high technetium of Intravenous injection solution specification phosphonic acids [ 99Tc] sour sodium stannous chloride ascorbic acid (mg) (μ g) (mg) (mg) | The high technetium of quiet dropping liquid specification phosphonic acids [ 99Tc] sour sodium stannous chloride ascorbic acid (mg) (μ g) (mg) (mg) |
| Technetium [ 99Tc] methylene diphosphonate | 5 0.05 0.5 0.5 10 0.10 0.5 0.5 | 100 0.30 0.6 1.0 200 0.50 1.0 2.0 |
| Technetium [ 99Tc] the hydroxyl methylene diphosphonate | 5 0.05 0.5 0.5 10 0.10 0.5 0.5 | 50 0.30 0.6 1.0 100 0.50 1.0 2.0 |
| Technetium [ 99Tc] ethylenediamine tetraacetic methylene phosphonic acid salt | 5 0.05 0.5 0.5 10 0.10 0.5 0.5 | 75 0.30 0.6 1.0 150 0.50 1.0 2.0 |
(concentration of phosphonate is 10 to table 6 phosphonate to the inhibition test result of osteoclast
-4Mol/L)
Table 7 MDP is to ovariectomized rat femur bone measurement amount result (X ± SD, n=8) after 90 days
| Grouping | Dry weight (g/cm 3) | Heavy (the g/cm of ash 3) | Calcium (g/cm 3) |
| The normal control group | 1.193±0.030 | 0.805±0.021 | 0.337±0.011 |
| Cut the ovum matched group | 1.118±0.018 △△△ | 0.759±0.020 △△△ | 0.284±0.017 △△△ |
| Cut ovum+MDP50mg/kg | 1.201±0.016 *** | 0.818±0.014 *** | 0.355±0.012 *** |
| Cut ovum+nilestriol 1mg/kg | 1.160±0.044 * | 0.792±0.047 * | 0.341±0.012 * |
Compare with normal group
△ △ △P＜0.001
With cut the ovum group relatively
*P＜0.05,
*P＜0.01,
* *P＜0.001
Table 8 pair ovariectomized rat is irritated stomach rat BMD measurement result after 90 days (X ± SD) with methylene diphosphonate (MDP)
| Grouping | Whole body BMD (n=6), g/cm 2 | ％ | Femur BMD (n=8), g/cm 2 | ％ |
| The normal control group | 0.413±0.018 | 0.231±0.017 | ||
| Cut the ovum matched group | 0.391±0.014 | ↓5.3 | 0.214±0.011 △ | ↓ 7.3 (with normal comparison) |
| Cut ovum+MDP50mg/kg | 0.406±0.024 | ↑3.8 | 0.219±0.011 | ↑ 2.3 (with cutting ovum relatively) |
| Cut ovum+nilestriol 1mg/kg | 0.386±0.011 | ↓1.3 | 0.217±0.018 | ↑ 1.4 (with cutting ovum relatively) |
△P＜0.05
Table 9 pair ovariectomized rat is irritated stomach rat lumbar vertebra girder area measurement result after 90 days (X ± SD) with methylene diphosphonate (MDP)
| Grouping | Number of animals | Bone trabecula percentage area |
| The normal control group | 6 | 35.183±2.159 |
| Cut the ovum matched group | 6 | 26.967±1.268 △△△ |
| Cut ovum+MDP50mg/kg | 6 | 35.433±3.098 *** |
| Cut ovum+nilestriol 1mg/kg | 6 | 33.783±3.616 ** |
Compare with normal group:
△ △ △P＜0.001
With cut the ovum group relatively:
*P＜0.05,
*P＜0.01,
* *P＜0.001
Table 10 pair ovariectomized rat usefulness methylene diphosphonate (MDP) filling stomach is rat uterus humidity and serum E after 90 days
2Measurement result (X ± SD)
| Grouping | Number of animals | Uterus humidity (g) | E 2(Pg/ml) |
| The normal control group | 8 | 0.534±0.080 | 37.418±11.608 |
| Cut the ovum matched group | 8 | 0.148±0.015 △△△ | 18.044±4.554 △△△ |
| Cut ovum+MDP50mg/kg | 8 | 0.190±0.037 *(n＝7) | 25.657±10.203 |
| Cut ovum+nilestriol 1mg/kg | 8 | 0.408±0.051 *** | 31.355±7.108 *** |
Compare with normal group:
△ △ △P＜0.001
With cut the ovum group relatively:
*P＜0.05,
*P＜0.01,
* *P＜0.001
Claims (4)
1. one kind is used for the treatment of the phosphonate medicine that osteoporosis and treatment cancer bone shift, and it is characterized in that: the main active ingredient of medicine comprise a kind of phosphonate in the middle of methylene diphosphonate or hydroxyl methylene diphosphonate or the ethylenediamine tetraacetic methylene phosphonic acid salt and technetium [
99Tc] complex, the amount of methylene diphosphonate is 4mg～600mg in the per unit medicine, the amount of hydroxyl methylene diphosphonate is 2mg～300mg, the amount of ethylenediamine tetraacetic methylene phosphonic acid salt is 3mg～450mg, technetium [
99Tc] amount be 0.04 μ g～2.00 μ g, also contain the Reducing agent that pharmacopedics allows in the medicine.
2. medicine as claimed in claim 1 is characterized in that: the Reducing agent that said pharmacopedics allows is stannous chloride or stannous fluoride or thiourea dioxide, and its content is 0.3mg～1.0mg in the per unit medicine.
3. medicine as claimed in claim 2 is characterized in that: also contain antioxidants ascorbic acid or gentisic acid in the medicine, its content is 0.2mg～1.0mg in the per unit medicine.
4. as claim 1 or 2 or 3 described medicines, it is characterized in that: the part by weight of its main active ingredient phosphonate is no less than 50% in overall active ingredient.
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|---|---|---|---|
| CNB001000837A CN1155387C (en) | 2000-01-06 | 2000-01-06 | Phosphonate medicine for treating osteoporosis and bone cancer transfer |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB001000837A CN1155387C (en) | 2000-01-06 | 2000-01-06 | Phosphonate medicine for treating osteoporosis and bone cancer transfer |
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| CN1155387C true CN1155387C (en) | 2004-06-30 |
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