IL85490A - Pharmaceutical compositions containing a combination of cholecalciferol derivatives for the treatment of osteitis fibrosa cystica - Google Patents

Description

Pharmaceutical compositions containing a combination of cholecalciferol derivatives for the treatment of osteitis fibrosa cystica TEVA PHARMACEUTICAL INDUSTRIES 2 The invention relates to pharmaceutical compositions for the treatment of human bone More particularly the invention provides compositions for the treatment of osteitis cystica disease in humans comprising 3 5 of 2k calciferol 25 in combination with to of or of 1 or to g of dihydrotachysterol Said pharmaceutical compositions being adapted to be administered to a patient in an amount per day which will maintain the calcium serum concentration at and the phosphate concentration at As used means and means Also and mean and means BACKGROUND OF THE INVENTION Cholecalciferol has been known to be intimately associated with bone metabolism and effectively used for the cure of rickets and osteomalacia since the early Studies carried out during the last decade have shown that vitamin D3 must be bolically activated before functioning biochemically in its target including the bone and The metabolite of vitamin namely was believed to be responsible all the known biological functions of the This compound is produced from cholecalciferol by hydroxylation in the liver followed by hydroxylation in the It was thus understandable why treatment with was found to be ineffective in metabolic bone such as renal in patients owing to chronic kidney are incapable of converting the cholecalci erol prohormone into its aforesaid dihydroxylated metabolite The use of 1 is established in the treatment of renal bone Its increases calcium absorption from the gut and plasma and suppresses secondary hyperparathyroidism and its skeletal co It also osteomalacia in the presence of secondary The putative roles of in the bone are controversial and many of its actions can be accounted for by its effect to increase the ionized fraction of plasma This therapeutic effect is also the cause of vitamin D namely Its use is therefore and indeed of limited value in patients with p hypercalcemia due to aluminum toxicity o tertiary The failure of 1 to control secondary hyperpara hyroidism in many patients on dialysis stimulated the continuing search for more effective therapeutic Intravenous of has been recently reported to be more effective than the same drug administered by the oral route in suppress ng secondary hyperparathyroidism sky et Invest it has not solved the problem of secondary hyperparathyroidism in dialysis is a synthetic analog of 1 It is converted into the latter in the liver by 1 at i on is now also in clinical renal and its therapeutic effect is equivalent to that of apart from small differences in iological and dose Although the treatment of chronic renal failure with 1 proved to be effective in maintaining normal conce t atio s of calcium and phosphate in the the beneficial results on the of bone matrix were highly incomplete and There has been recent interest in other metabolites of vitamin notably and 2 which may have different actions on target tissue than and Until recently it was still controversial whether 2 plays any role in man and in and whether it possesses a defined biological In early observations this was considered to be only a of renal The uncertainty surrounding the physiological importance of stems partially from observat ons in In animal the effect of 2 on of absorp was contingent upon prior hydroxy lat to 2d Thus in h e t i e d 24 failed to stimulate intestinal Conversely in man where 2 has been shown to be active in calcium metabolism 24 was found to exert et The increased calcium retention of is not associated with suggesting that may be directly or indirectly promoting calcium uptake in compartments other tha the extracell lar There is some evidence that skeletal retention of calcium is A number of experimental observations in animals suggest that both are for some aspects of skeletal These include the normal of cartilage the healing of and the mineralization of rachitic bone and cartilage the prevention of parathyroid gland RENAL Renal bone disease a common com in patients undergoing Osteitis fibrosa cystica and osteomalacia the two most common forms of uremic The typical histological features of osteitis fibrosa cystica are osteoclastic bone resorption forming cystic endosteal and marrow space fibrosis with aggregates of osteoclasts and brown In addition there are morphological indications of rapid bone turnover reflected by increased active osteoid increased formation of woven bone and enhanced t The characteristic roentgenograph ic features are sub bone cystic frequently associated with and tal c Secondary hyperparathyroidism that responsible for osteitis fibrosa emerges early in the course of chronic renal et al 38 In chronic renal loss of filtering units imposes increasing loads of phosphate on the remaining The increased burden of phosphate may have several secondary The high phosphate in serum level causes a reciprocal fall in serum ionized calcium and the latter triggers secretion of parathyroid hormone PTH restores both the serum phosphate and calcium to normal through its phosphaturic and reductions in nephron population will evoke a further rise in PTH leading to secondary hyperparathyroidism as an et al Reduced as demonstrated to be present in earl renal may cause secondary by severa reduced intestinal a sorption of diminished skeletal calcemic response to and loss o suppression of PTH Patients wit renal bone diseas es are often divided into tw gro an active bone subgroup and a bon This in accordance with the severity o the bone particularly with regard to osteoclastic activit and bone forming reflected by active an tetracycline uptake in active bone osteoclast number equals or exceed the active bone resorption equals or exceeds Patients who do not meet these two criteria are included in th ive disease Description of Prior Art Ornoy et al demonstrated that the combine administration of with produced a bette cure of ion defect than alone in vitamin deficient Gal us et al Tissue 1980 have shown that the administration of 2 in vitami dogs increases bone formation and mi an decreased bone while increased both and Pavlovitch et al demonstrated an inhibition of increased bone resorption after acute bilateral nephrectomy by 2 in In addition blocked partially the stimulating effect of on bone et al 6th Workshop demonstrated that suppressed the effect of in rats with chronic renal i 1 ure Tests in Huma Patients Kanis et al l suggested that may be an important regulator of skeletal metabolism in man with potential value as a therapeutic agent in patients with chronic renal and osteopo al indicated generally that treatment with both and 24 0H may be needed to prevent and heal renal 9 In Japanese Patent Application 55 published on October combinations of with either are claimed for the treatment of numerous bone and calcium metabolic amongst them also renal bone this patent application is very general and vague and fails to disclose how to use these combinations in any of the diseases including renal Although the Teijin application lists type bone in a very long list of diseases there is no mention of renal let alone osteitis fibrosa One skilled in the art could not learn from the publication that the combination could actually be used and how to use it in any of the many diseases and particularly in renal and more particularly in osteitis fibrosa which is the subject of the present The in vitro experiments of the Teijin application which serve as the only basis of the Japanese application are totally irrelevant to renal osteodystrophy disease and are therefore irrelevant to osteitis fibrosa 10 SUMMARY OF THE INVENTION The invention provides pharmaceutical compositions for the improved treatment of human renal osteodystrophy patients undergoing According to one aspect of the the new compositions on a daily dosage basis meg of 2k 25 in combination with daily amounts of or or DHT2 which will suffice to maintain normal calcium levels namely at and the phosphate concentration at and that the numerical value of the multiplication of the calcium and the phosphate concentrations in the serum should be about The ingredients in the combination may be administered orally by means of capsules if and parenterally The preferred form of administration is orally by means of capsules containing 5 meg of and various amounts of or such as meg and meg per The new compositions for treatment of chronic renal failure patients by means of the specific combinations of 2k with or in the relative amounts of each component as stated above offers significant improvements in the clinical symptoms in the various bone histological parameters and blood biochemistry of these 11 The pharmaceutical compositions of the invention comprising the novel combinations of 2k with OH or in the stated relative proportions can be used for treating CRF patients simultaneously with other drugs which may be used in their In addition dihydrotachysterol which has been shown to be effective in combination with in the treatment of renal osteodystrophy in adults and children can be used in combination with 2k OH 2D3 et DETAILED DESCRIPTION OF THE INVENTION The clinical treatment at present in practice for patients with renal bone including those undergoing comprises the administration of either or or DHT2 orally parenterally Although these cholecalciferol analogs proved to be effective in maintaining normal concentrations of calcium and phosphate in the plasma of the they showed little beneficial results on the bone mineralization of the bone The treatment consequently failed to improve clinical bone symptoms and bone histological paramenters of the patients suffering osteitis fibrosa cystica 12 resulting from secondary hyperparathyroidism and from Although some Prior publications indicated that both and may be necessary for skeletal metabolism and bone formation and and other publications suggested that the combined treatment of the above two metabolites in renal osteodystrophy may have some therapeutic advantages there was no disclosure in the Art of how to perform or use such a combination which will result in any advantageous therapeutic By virtue of the present invention there was discovered a specific pharmaceutical combination of with either or DHT2 which will offer considerable therapeutic advantages to renal osteodystrophy patients called chronic renal failure CRF Studies have been provided where the patients were randomly allocated into two One group of patients was treated with alone or alone the in daily dosages to maintain normal serum concentrations of calcium and To the second group of patients the was administered in daily dosages ranging from 10 meg to meg in combination with or in daily amounts which would maintain the patients calcium serum at and phosphate seru concentrat at and the Ca P numerical product should not exceed The daily dosages of or 1 both the and in the were adjusted for every patient in order to maintain the serum con of calcium and phosphate at the normal range levels as stated The actual daily doses of or 1 to the patients ranged from meg to The controlled studies have surprisingly shown that significant therapeutic improvements were achieved in the treatment group in comparison with the control Improvements observed i both aspects of the renal bone in the bone histological ers as well as in relief of the bone clinical Bone Hi s Two bone biopsies were obtained from the iliac one at the outset of the study and the other upon its Th hi of the biopsies showed the following favorabl The trabecular bone volume in the treatment group was l lower than in the control active surface was reduced in the treatmen group compared to the control This was shown in the secon especially in patients with relatively high active osteoi levels in the first In the resorption a statistically significant decrease wa observed in the treatment whereas no change could detecte in the control The improvements in the bone resorption were even pronounced i the bone which was defined as having a eocl s n equal to or and active bon resorpt i on equal to or exceeding 2 All patients active bon in the treatment group showed a ant decrease in bon whereas in the control group there was no change or eve an increase in bone symptoms With respect to clinical manifes at before and after treatment i the active bone disease such as one and te d muscle pains and pruritus there was a significant in th clinical symptoms in the treatment In the control th clinical symptoms remained or even Untoward Side Effects Careful observatio in all studies have not revealed untoward sid effects in the treatment group that could be attributed t 2 given orally at a daily dose of either 10 m g or 40 over the whole period of the Thus can b considered a safe when ed at the abovement i daily In it was found that 25 administered in with lated derivative increased the tolerance of these derivatives and risk of hy The best mode of carrying out the invention The clinical trials and studies of the present invention indicate tha the best mode of carrying out the invention is as The treatment of patients with renal including thos undergoing chronic should comprise the administration t each patient of 10 per day of combination wit either or DHT3 in daily doses which wil maintain the calcium concent at the upper norma levels of 10 to 11 and the phosphate serum at Another criterion for the daily dosage of 1 or DHT3 should be that the numer ical value of the m κ should not exceed the With the specific of 10 meg per day of 2 and the appropriate amounts of 1 the most favorable therapeutic effects were obtained in the treatment of renal osteodystrophy patients considering all the aspects of the The blood biochemical and l the bone hi stomorphometry and the clinical mani These favorable results are outlined in detail in example 7 The rationale for the of 10 meg of per day to patients can be based on calculations obtained from the physiological and therapeutic conducted in the The optimal dose of in the chick was found to be which is about 3 times that of 1 l As the therapeutic daily doses of the latter in the human are 20 times the physiological the daily therapeutic dose of in the human should be at least 20 namely 6 mc g The best daily of in patients was found by the present invention to be 10 which is only ess of the dose of 2 should best be administered by means of 2 soft gelatine capsules per containing 5 per one in the morning and one in the Even more preferable is the administration by means of soft gelatine capsules containing a combination of 5 meg and amounts of or meg of or in accordance with ds of each individual In the case where 1 i s e re d s eparat ely from 2 it can be done orally by means of t gel e capsules or tablets containing meg or g the act i ve it can also be admin i st e re d p rally by means of ampoules containing the des i re d n ts of tive ingredient and stabilized by means of sod i ascorbate d a buf f e r to pH of to o ft gelatine capsules of all the act i ve i n g re d i 1 or 24 may be pre i i s propylene glycerin and other solvents together with a stabilizer and a Another embodiment the invention is the use of of in the range given with which is usually administered orally by means of or s The beneficial effect of the simultaneous of and was demonstrated by an uncontrolled study in patients with dialysis related et al A more recent study showed also the benefits of this combination in children undergoing chronic dialysis with hyperparathyroi d bone resulting in a significant decrease in the number of et al The combination of the invention given simultaneously with is to give even more favorable results in cases of osteomalacia and renal bone disease of secondary Assumed Mode of Action of The Invention In vitro studies have demonstrated the effective anabolic action of in the presence of 1 and Only combined treatment of and PTH induce a significant increase in bone mineral deposition in bones in Eac h of the components operates on a different cellul function to bone jointly they have synergist o It is well known from the literature while both 1 a 2d are similar in stimulating calcium absorption at t intestinal mucosal they differ in the nature of their action the bone level in renal osteodystrophy While 1 in hysiological doses directly stimulates bo exerts an opposite action on the bone leve the advantage of s i of both metabolit the proportions of the invention to renal osteodystrophy patien is in the ability of to offset the effects of 1 its analogs and with regard to the resor i action on the but on the other hand a synergistic action wi respect to gut bone m i and less likel parathyroid hormone suppression The following examples provide an illustration of the b should not be construed as to limit the scope of the Exam l 1 Soft Capsules of Each capsule FEROL CITRIC ACID anhydrous mg PROPYL GALLATE mg VITAMIN E TOCOPHEROL mg ALCOHOL dehydrated mg PEANUT OIL mg Total weight mg 10 per cent Exam 2 Soft Gelatine Capsules of meg Each capsule 0 CITRIC ACID anhydrous mg PROPYL GAL LATE mg E TOCOPHE ALCOHOL dehydrated mg PEANUT OIL mg Total fill weight per mg 10 per cent excess 5 Soft Capsules of 1 Each meg 1 YCHOLECALCI 275 CITRIC ACID anhydrous mg PROPYL GALLATE mg VITAMIN E ALCOHOL dehydrated mg PEANUT OIL ARACH I S mg Total fill weight mg 10 per cent Exampl Soft Gelatine Capsules of meg of Each meg capsule HYDROXYCHOLECALCI FEROL 0 CITRIC ACID anhydrous mg PROPYL GALLATE mg VITAMIN E mg ALCOHOL dehydrated mg PEANUT OIL IS mg Total fill weight per mg 10 per cent Exam 5 Soft Gelatine Capsules of of Each meg capsule ACID anhydrous mg PROPYL GALLATE mg VITAMI E TOCOPHEROL mg ALCOHOL dehydrated mg PEANUT OIL mg Total weight per ca mg 10 per cent Exam le 6 Soft Gelatine Capsules of meg of 24 Each capsule CITRIC ACID anhydrous mg PROPYL GALLATE mg VITAMIN E mg ALCOHOL dehydrated mg PEANUT OIL mg Total fill weight per mg 10 per cent excess 7 Soft Capsules containing om of or of plus 5 of Each capsule 24R ECALCI FEROL CITRIC ACID anhydrous mg PROPYL GALLATE mg VITAMIN E mg ALCOHOL dehydrated mg PEANUT OIL 98 800 mg Total fill weight per mg 10 per cent Exam le Soft Gelatine Capsules containing of o of Plus 5 of Each capsule 24 IHYDROXYCHOLECALCI FEROL CITRIC ACID anhydrous mg PROPYL GALLATE mg VITAMIN E mg ALCOHOL dehydrated mg PEANUT OIL mg Total fill weight per mg 10 per cent 9 Treatment of Chronic Failure patients with a combinatio of and The study included 56 CRF male and female adult patients chronic hemodialysis at several medical The patients wer random allocated into two one group of 31 patients wa treated with a combination of and and the other group of patients was treated wit Patients of both groups were administered in capsules o meg or per The dose was adjusted for ever patient individually so as to maintain the calcium at the uppe normal but not higher than 11 and the phosphate leve not higher than or that the numerical multiplication produc of calcium x phosphate did not exceed The actual daily doses o from meg to The treatment group was administe ed in additon to also 2 at a daily dose of 10 by means of 2 capsules containing 5 per one in the morning and the other in the The dose of of was constant throughout the study which lasted Three major categories of variables were measured and monitored during the These blood biochemis bone h i and and clinical y As stated special attention was given to the blood levels of phosphate and to the product of calcium x The serum calcium concentration was found to be significantly higher in the treated group during the period months of the in comparison with the control group though the levels remained within the normal An increase in the serum levels in the treated groups was the only significant change between the two groups during the whole Bone hi stomorphometry One bone biopsy was taken from all patients under local anesthesia applied to both plates of the ili ac crest at the onset of the and a second was o ained in a similar fashion from the contralateral side of the iliac crest one year the completion of the The results obtained from the biopsies showed significant changes between the control group and the treatment These were as trabecular bone This measurement increased significantly during treatment in the group At the end of the study i was much lower the treatment group compared to the control The relatively high active osteoid surface levels shown by some patients at the first biopsy were significa ly at the second biopsy only in the treatment group and not in the control resorption a significant decrease in the resorption surface was shown only in the treatment There was no significant change in the control At the end of the the resorption surface in the treatment group was lower than that in the control Even more differences in the result were shown in those patients in whom the respective parameters exhibited high levels at the initial namely in patients with more severe bone In view of this observation the patients in the study were subdivide into two types of bone an disease subgroup and bone disease The was made according t the osteoclast number and the active resorption Patients with an osteoclast number equal to or exceeding an with active surface equal to or exceeding X wer included in the active bone and those with lowe values were included in the bone disease The results of this study show that all CRF patients with active bon in the treatment group a most decrease i active resorption whereas patients with active bone diseas in the control group either showed no change or even an increase i this also in the bone subgroup of ts who were treated with the combination showed a s i gn i f i reduction in the active resorption group showed no With respect to clinical man of the disease of the treated such as bone pains and muscle pruritus and there was generally a marked improvement only in the treatment This improvement was especially marked in the treatment active bone disease subgroup where most patients became ic No relief of these clinical symptoms was observed in the control No untoward side effects could be detected in the patients treat with the combination which to 24 orally at a daily dose of 10 This study thus demonstrates that the administratio of 2 to renal osteodystrophy patients in daily doses of 10 m g in combination with in doses sufficient to maintain the levels of calcium and phosphate in the upper normal results in marked improvements in the bone parameters as well as in clinical in comparison with the control group which was treated with alone in similar 10 of patients i 24 The study included 62 CRF male and female adult patients unde chronic hemodialysis and lasted for As in Study th CRF patients were randomly allocated into two 34 patients wer allocated to the combination treatment of an In this study the daily dose of was 4 and that of was sufficient to maintain th concentration of calcium and phosphate in serum at the uppe normal level in a manner as stated in Study The patients in the control group received alone i similar doses as in Study The blood chemistry results were similar to those obtained in Study I The bone i trie measurements performed in 50 patients in each showed that the combination treatment resulted in th following favorable a decrease in the trabecular bone volume a decrease in the resorption surface a slight decrease in the active resorption surface a slight decrease in osteoclast number and a slight decrease in fibrotic These improvements in the bone parameters were not as significant as in Study The improvements in the clinical symptoms were also not as prominent in the treatment group in comparison with the control group as was observed in Study 1 e Combined treatment of CRF with a 1 The study included 62 CRF patients with bone such as osteitis fibrosa cystica and The patients were randomly allocated into The oup A which included 25 patients who were treated with 2 alone at doses of 20 The control group B which included 24 patients who were treated with alone at varying daily doses ranging from meg to so as to maintain the concentration of calcium and phosphate at the upper normal range as in Study The group which included 13 These patients were adminis a combination of 24 25 at 20 and at daily doses similar to those admi to patients in control group The study showed the following The combined treatment induced a less marked increment in serum calcium than that observed in control group treated with 1 the decrement in alkaline phosphatase activity in the treatment group appeared to be less marked than in patients given The may be drawn from the The addition of with for the treatment of renal bone disease does not aggravate nor does it impair the apparent effectiveness of in the treatment of bone The combination of 25 and 24 in the treatment of bone disease is of value in those patients who had previously been shown to be refractory to treatment with insufficientOCRQuality

Claims (10)

- 32 - 85490/5 CLAIMS:

1. Pharmaceutical compositions containing, as a combination of active ingredients for the treatment of osteitis fibrosa cystica disease, . a combination of 3 - 5 \ig of 24,25-di- hydroxycholecalciferol , with 0.25 to 1.0 Ug of 1-alpha-hydroxycholecalciferol or of 1 , 5-dihydroxycholecalciferol , or 0.5 to 1.0 ug dihydrotachysterol (DHT2) in a mixture with an inert pharmaceutical carrier .

2. A pharmaceutical composition according to claim 1, containing as the combination of active ingredients a combination of 5 ]ig of 2k, 25-dihydroxycholecalciferol and 0.25 to 1.0 Ug of 1-alpha-hydroxycholecalciferol or of 1 , 25-dihydroxycholecalciferol , or 0.5 to 1.0 mg of DHT2.

3. A pharmaceutical composition in dosage unit form comprising an osteitis fibrosa cystica disease-combatting amount of a mixture of active ingredients according to claims 1 or 2, in the form of tablets, pills, dragees, capsules, ampoules or suppositories. k.

4. A pharmaceutical composition of claim 3 in the form of soft gelatin capsules.

5. A pharmaceutical composition according to claims 1 or 2 containing, as a stabilizing agent an inactive incipient Vitamin E, citric acid, propyl gallate and arachis oil.

6. The use of 2k , 25-dihydroxycholecalciferol in combination with 1-alpha-hydroxycholecalciferol or 1 , 25-dihydroxycholecalciferol for preparing a pharmaceutical composition or medicament for the treatment of osteitis fibrosa cystica disease in humans, substantially as described in the specification, said pharmaceutical composition or medicament being adapted to be administered to a patient in a dose of 6 to k3 Pg per day. - 33 - 85490/3

7. The use according to claim 6, wherein dihydrotachysterol is combined with the 2k , 25-dihydroxycholecalciferol .

8. The use according to claim 6, wherein the dose of 24,25-dihydroxychblecalciferol is 10 to 40 Pg/d.

9. The use according to claim 6, wherein the dose of 24, 5-dihydroxycholecalciferol is 10 Pg/d.

10. The combination of 24 , 25-dihydroxycholecalciferol with l-alpha-hydroxycholecalciferol or 1 , 25-dihydroxycholecalciferol for use as an agent for the treatment of osteitis fibrosa cystica disease wherein the dose of 24 , 5-dihydroxycholecalciferol is 6 to 40 Pg/d. For the Applicants , 74059cim .ND be21.6.1993