IE40268L - A calcium-containing medicament - Google Patents

Description

40268 The present invention relates to preparation I of a novel medicament, which in addition to a pronounced anti-rheumatic and antiphlogistic action has a very strong analgesic component and therefore is indicated in cases of r> particularly painful rheumatic disease. In particular the invention relates to a medicament which comprises the calcium salt of 2-butyl-N,N'-diphenyl-malonomonohydrazide in an anhydrous or water-containing form. This active substance will in what follows be referred to as bumadizone-calcium. lo The production of bumadizone-calcium is des cribed in the German patent specification (Offenlegungs-schrift) 2,055,84 5 while the production of the trihydrate of bumadizono-calcium is described in the German patent specification (Offenlegungsschrift) 2,253,242. - 2 - 40268 *t is known that bumadizone-calcium possesses paramount anti-rheumatic and antiphlogistic effects.

For the treatment of particularly painful rheumatic diseases as for example arthritis a powerful ^ analgesic action which rapidly starts with the treatment and has a long period of action would be desirable.

This can be achieved by the combination with highly effective analgesic. Commercially available analgesics are, however , generally more toxic than anti-lO phlogistics. One would thus have to fear that the combination with such an analgesic would put an end to the satisfactory pharmacological compatibility of bumadizone-calcium.

Surprisingly a medicament has now been found which in addition to an excellent anti-phlogistic and anti-15 rheumatic action has a long duration analgesic action which rapidly starts with the treatment, and furthermore the medicament has an unexpectedly low toxicity.

The new medicament is characterized by a content of bumadizone-calcium and a-d-4-dimethylamino-3-methyl-l,2-20 diphenyl-2-propionoxybutane, referred to in what follows as dextropropoxyphen. The production of dextropropoxyphen is described in the U.S. patent specification 2,738,779 and in J. Amer.Chem.Soc.77, 3400 (1955).

For the new medicament preparations bumadizone-25 calcium is preferably used in a form comprising water, more particularly as the semi-hydrate or trihydrate, while dextropropoxyphen is used in the form of the free base. The weight ratio of bumadizone-calcium to dextropropoxyphen in the new medicament lies preferably between 4 to 1 and 30 1 to 1 on the basis of water-free bumadizone-calcium and dextropropoxyphen as the base. - 3 - 402US It has been found that the acute toxicity of dextropropoxyphen ds substantially reduced by combination with bumadizone-calcium. This finding is particularly surprising and could in no circumstances have been for- 5 seen.

Low toxicity is, however, very important in the case of a long duration therapy as is very often necessary in general in the treatment of rheumatic diseases . lO The Table given in what follows clearly indic ates the toxicity reducing effect of the addition of bumadizone-calcium to dextropropoxyphen as compared with dextropropoxyphen alone.

TABLE 1. 15 Comparison of the lethal effect of dextropropoxyphen and dextropropoxyphen/humadizone-calcium in the case of male albino rats.

Mixing ratio of dextropropoxyphen/bumadi2one-calcium 1 to 2.4. 20 x% Lethality LDx(Dextropropoxyphen in mg/kg) LD (Dextropropoxy- x phen in combination with bumadizone-calcium in mg/kg) 25 5 55 115 16 60 150 50 lOO 260 84 150 360 It can he scon from the table that the I.n^-vnluos of floxtropropoxyphon In the combination of dextro- - A - 4036B propoxyphen and bumadizone-calcium are increased by a factor of 2.6 as compared with dextropropoxyphen alone.

The combination in accordance with the invention therefore constitutes a valuable enrichment in the therapy of painful rheumatic diseases.

The toxicity-reducing effect of the addition of bumadizone-calcium to dextropropoxyphen was surprisingly in the case of the mixing ratios of bumadizone-calcium to dextropropoxyphen of 4 to 1 and 1 to 1, approximately in the same order of magnitude as in the case of the mixing ratio. Indicated in Table 1 of 1 to 2.4.

If a comparison is made between the duration of the analgesia of dextropropoxyphen with the dextro-propoxyphen/bumadizone-calcium combination it will be seen that there is a prolongation of the duration of analgesia, something which leads one conclude that protraction is involved.

A substantial requirement, which a modern medicament has to meet, is therapeutic safety. In order to determine this therapeutic safety of the dextropropoxy-phen/bumadizone-calclum combination, the quotient made up of the LD^-value of dextropropoxyphen and tl.«» ED-value ("effective dose"-value) was determined for a certain planimetrically determined surface integral of the time action curve. (Note: An effective dose of the effective substance or of the combination of effective substances is applied and the reaction time in seconds (vertical axis of the graph) is plotted against the time of the measurement in minutes following the application of the substances (horizontal axis). The curve resulting from this is termed the time-action-curve. The same operation is carried out - 5 - •10 2 6 8 20 25 with a so-called starting value (blank value) and a curve in nnaln obtained. Tin* area between these twi» curves, which Is limited by the end time point of the measurement (in the present case it amounts to approxim-5 ately 120 minutes) is measured planimetrically and termed th» area Integral of the time action curve) in the Heat Rodiation jet Test on an albinb mouse after oral application of dextropropoxyphen. The surface Integral amounted to 28.1 square centimeters for a dose of 50 mg/kg of i lr) dextropropoxyphen. For the dextropo*poxyphen/bumadizone- calcium combination the surface integral of the time action curve cimounted to 27.2 square centimeters for a dose of 45 mg/kg of dextropropoxyphen and 110 mg/kg bumadizone-calcium. As both surface integrals do not statistically significantly differ, and can be regarded practically as equal, the quotients so formed from the and ED-values of dextroporpoxyphen and of the combination respectively can be compared directly in order to be able to estimate the therapeutical safety.

In this rosjxic»- the following values aro obtained: lOO mg LD5Qdextropropoxyphen kg ED »2g ^square centimeters(dextro- 50 mg propoxyphen) = 2 kg 225 mg LD^0dextropropoxyphen/bumadizone-calcium kg combination ED^ 2square centimeters dextropropoxy- 45 mg 20 ' phen/bumadizone-calcium combina tion = 5.6 kg - 6 - 40268 It can be seen from this that the therapeutical safety of the dextropropoxyphen/bumadizone-calcium combination is increased by more than twice the above value for dextropropoxyphen alone. 5 The pharmaceutical preparations generally consist of the active substances according to the Invention and non-toxic pharmaceutically acceptable medicament vehicles, which come into question as admixtures in solid, semi-solid or liquid form or as casing means, for example in the form of a capsule, of a tablet coating, a sachet 10 or another container, for the therapeutically active component. A vehicle material can for example serve as a means for administering the medicament to the body, as ar adjuvant for formulation, as a sweeteniny agent, as a flavours-improving material, as a dye or as a preserving material. 15 Additionally the new effective substance combina tion can also comprise additional active substances as for example corticosteroids, more particularly prednisolon, dexamethason or fluorometholon, vitamin or vitamin combinations as for example B-vitamins and more particularly 20 B,-, B,-, and B,vitamin additives. 1 o XZ, For oral application it is possible to use for example tablets, dragees, hard and soft capsules for example gelatine, dlspersible powders or granules.

Tablets can comprise inert diluents as for example 25 calcium carbonate, calcium phosphate, sodium phosphate or lactose; granulating and distributing materials, as for example maize starch or alginates, binding agents as for example starch, gelatine or gum acacia; and lubricants, as for example aluminum or magnesium stearate, talcum or silicone .! 0 2 tl H oil. Thi»y I'.III .lilil I I I • >il.l 1 I V 1 • |>l'a>V I iIihI Willi .1 rn.il lin| I'or fx,iiii|>lf ill i*i>I IiiIii:i<* »'lh«T, which con alsi> bo so made that it brings about delayed dissolution and resorption of the medicament in the gastrointestinal r> tract and therefore, for example, produces a longer period of action. Gelatine capsules can contain the medicament mixed with a solid diluent as for example calcium carbonate or kaolin or an oily diluent, as for example olive oil or pea nut oil or liquid paraffin. 1° If the unitary dose is in the form of a tablet, tho preferred weight ratio of bumadizone-calcium to dextropropoxyphen lies in the range extending from 3.5 to 1 up to 1 to 1 on the basis of anhydrous bumadizone-calcium and dextropropoxyphen as the base. It is more particularly 15 preferred to use a weight ratio of bumadizone-calcium to dextropropoxyphen in the range extending from 2.4 up to 2.5 to 1 on the basis of anhydrous bumadizone-calcium and dextropropoxyphen as the base. For example in a film-coated tablet 80 to 140 mg of bumadizone-calcium semi-hydrate 20 would be contained as well as 40 to 70 mg of dextropropoxyphen. fn addition such n tablet nan comprise for example 5 to lOO mg of vitamin Bj, 5 to 250 mg of vitamin Bg and 50 to 2500 micrograms of vitamin Taking into account these standards the weight ratios of the different hydrates or 25 of the anhydrous form of bumadizone-calcium to dextropropoxyphen can easily be calculated. This also applies for the vitamin additions, if the content of one form of medicament of bumadizone-calcium is changed. The vitamin content can then be adapted to suit the unitary dose. 30 The new combination of effective substances can also be used in a retard form. In this case the preferred - 8 - 40268 weight ratio of bumadizone-calcium to dextropropoxyphen lies within the range extending from 4 to 1 up to 2 to 1 on the basis of anhydrous bumadizone-calcium and dextropropoxyphen as a base.. For example in a retard tablet or 5 retard capsule for 200 to 220 mg of bumadizone-calcium semi-hydrate there will be 50 to 80 mg of dextropropoxyphen. In this respect for example dextropropoxyphen is provided with a suitable retard coating and pressed together with the bumadizone-calcium semi-hydrate to form a retard lO tablet.

Instead of the bumadizone-calcium semihydrate it is also possible to use bumadizone calcium trihydrate or a bumadizone-calcium, which has a different degree of hydration. 156 The therapeutic administration of the pharmac eutical preparation can be carried out one time to four times a day, for example in each case during or after the meal times. In the case of oral administration for example 1 to three times 1 to 2 tablets can be administered. In 20 particularly severe cases it is possible to administer 2 tablets four times a day. The dose administered is to be determined In accordance with the unitary dose, in accordance with the frequency of administration, the duration of the treatment and also the nature and severity of the disease 25 and also in accordance with the weight, the age and the general condition of the patient.

The daily dose is so selected that the patient receives 4 to 9 mg of dextropropoxyphen and 9 to 13 mg of bumadizone-calcium per kilogram of body weight. 30 It has been found surprisingly that bumadizone- calcium with dextropropoxyphen in the form of the free base - 9 - 40268 can be processed to form a pharmaceutically compatible medicament preparation which has an excellent storaqo life, something which Is to be regarded as a further advantage. 5 The novel medicament has a very good pharmacol ogical compatibility.

The production of the new pharmaceutical preparation is described in the following examples: Example 1. 10 (a) Production of 100,000 cores each of 310 mg (1) Bumadizone-calcium 11.00 kg (2) Dextropropoxyphen ' 4.50 kg (3) Pyridoxol base l.OO kg (4) Thiamirie disulfide l.OO kg 15 (5) Hydroxycobal amine acetate 1% by weight 1.50 kg (6) Potato starch 7.70 kg (7) Polyvinylpyrrolidone (mean molecular weight 25,000) l.OO kg 20 (8) Carboxymethyl cellulose 3.00 kg (9) Magnesium stearate 0.30 kg The weighed-out quantities 1 to 6 are sprayed in smooth fluidised bed spraying granulator with a solution of component 7 in lO liters of water. After drying to a 2r> relative moisture of 60% the components 8 and 9 are added and homogeneously mixed in. After sieving the granulate is pressed to form dragee core each of 310 mg having a diameter of lO mm. - lO - 40268 (b) Coating of the dragee cores produced in accordance with part (a) (1) Hydroxypropylmethylcellulose *io cps 700 g *» (2) .Sli«*lln«: 12<) «j (3) Polyvinylpyrrolidone (mean molecular weight 25,OCX)) lOO g (4) Polyethyleneglycol (mean molecular weight 4,000) 40 g lO (5) Titanium dioxide 70 g (6) Coloured lacquer 30 g The weighed-out quantities 1 to 4 are dissolved in a mixture of 10 liters of dlchloromethane and 10 liters of denatured alcohol. 5 and 6 are suspended in this solution. 15 The suspension is homogenised by grinding with a carborundum disc mill and sprayed on to cores rolling in a dragee pan.

Example 2.

Production of a batch of 100,000 tablets (1) Bumadizone-calciam 11.OO kg 20 (2) Dextropropoxyphen 4.50 kg (3) Prednisolon 0.25 kg (4) Potato starch 7.75 kg (5) Polyvinylpyrrolidone (mean molecular weight 25,000) 0.50 kg 25 (6) Carboxymethylcellulose 1.80 kg (7) Magnesium stearate 0.20 kg The weighed-out quantities 1 to 4 are sprayed in a smooth fluidised bed spraying granulator with a solution of - 11 - 40268 component 5 in 7 liters of water. After drying to a relative moisture of 60% the components 6 and 7 are added and homogeneously mixed in. After sieving the granulate Is pressed to form dragee cores each of 250 mg having a diameter of 9 mm.

Example 3.

Production of a charge of 100,000 capsules. (1) Bumadizone-calcium 9,000 kg (2) Dextropropoxyphen . 9.000 kg (3) Amorphous silic acid 0.050 kg Tho weighed-out quantities of 1, 2 and 3 aro thoroughly mixed with each other and filled into size 4 hard gelatine capsules. A capsule contains 90 mg of bumadizone-calcium and 90 mg of dextropropoxyphen.

Example 4.

Production of a batch of 100,000 tablets. (1) Bumadizono-calcium 18.OO kg (2) Dextropropoxyphen 4.50 kg (3) Potato starch 10.20 kg (4) Polyvinylpyrro1idone (mean molecular weight 25,000) 0.65 kg (5) Carboxymethylcellulose 2.53 kg (6) Magnesium stearate 0.30 kg.

Tho woiqhed-out quantities 1 to 3 aro sprayed In a smooth fluidised bed spraying granulator with a solution of component 4 in 9 liters of water. After drying to a relative moisture of 60% the components 5 and 6 are added and homogeneously mixed in. After sieving the granulate is pressed to form - 12 - i o a « « draqee coros each of 360 mq. As n result tablets are obtained Willi ISO mq of Immad 17one-cal.c*Ium and 45 mq oT ili'Xl mpVn|m>cy|)lii<n. "

Claims (12)

1. A medicament containing the calcium salt of 2-butyl-NjN'-diphenyl-malomonozlde (a) and a-4-dimethylaraino-3-methyl-l,2-diphenyl-2-propionoxybutane (b) In the form of the free base.

2. A medicament in accordance with claim 1, characterised in that the weight ratio of active substance a to active substance b lies between 4 to 1 and 1 to 1.

3. A medicament in accordance with claim 1, characterised in that the weight ratio of active substance a to active substance b lies between 2.4 to 1 and 2.5 to 1.

4. A medicament in accordance with any one of the preceding claims, containing one or more B-vitamins.

5. A medicament in accordance with any one of the preceding claims, containing one or more corticosteroids.

6. A medicament in accordance with any one of the preceding claims in the form of a film-coated tablet or in the form of a capsule.

7. A medicament in accordance with any one of the preceding claims, in which active substance a is present - 13 - 40268 as a semi-hydrate.

8. A medicament in accordance with any one of claims 1 to 6, in which the active substance a is present as a trihydrate. 5

9. A medicament in accordance with any one of the preceding claims, containing 80 to 140 mg of the active substance a and 40 to 70 mg of the active substance b.

10. A method for the production of a medicament in accordance with any one of the preceding claims, character- lO ised in that a mixture of the active substances a and b is made up into a form suitable for therapeutic administration.

11. A medicament as claimed in claim 1 substantially as described with reference to any one of the specific 15 examples hereinbefore set forth.

12. A pharmaceutical preparation comprising the calcium salt of 2-butyl-N,N'-diphenylmalomonohydrazide and a-d-4-dimethylamino-3-methyl-l,2-diphenyl-2-propionoxy-butane in the form of the free base in admixture with one or 20 more non-toxic pharmaceutically acceptable solid or liquid Inert carriers. F.R.KELLY & CO., AGENTS FOR THE APPLICANTS. - 14 -