DE2220500C3 - analgesic - Google Patents

Description

The present invention relates to what is set out in claim precisely designated analgesic.

It has been known since H. Stenzel's synthesis in 1946 that phenylbutazone (1,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine) is analgesic and anti-rheumatic Has been effective Since then, phenylbutazone has been one of the most effective anti-inflammatory drugs alongside the steroids. The use of phenylbutazone in effective However, due to its inhibitory influences on certain doses, it is associated with significant side effects related to enzymatic reactions in the body. 2s

It is also known to have these side effects can be avoided by taking a reducing dose of phenylbutazone in combination with an analgesic.

From British patent specification 1081 105 is a Medicines with anti-inflammatory and analgesic effects, consisting of a mixture of BuMZon (1-phenyl-3,5-dioxo-4-n-butyl-butazolidine) and d-Propoxyphene (1,2-diphenyl-2-propionoxy-3-methyl-4-dimethylaminobutazone hydrochloride) known where the analgesic effect of d-propoxyphene is potentiated by the combination with butazone It is off this patent also known that this potentiation in combination with phenylbutazone Propoxyphene does not occur these combinations so are unsuitable as drugs. On the other hand, there is however, there has long been a general need, especially phenylbutazone because of its compared to butazone very strong anti-rheumatic effect with analgesics to achieve a potentiating effect combine.

However, a potentiating effect of the phenylbutazone has so far only been possible in combination with z. B. Morphine, codeine or methadone can be obtained. However, these combinations have the disadvantage that they associated with the risk of addiction for the patient and are therefore less desirable.

It is also from the red list. 197t. Page 156, a Drug mixture named the phenylbutazone and Contains dextropropoxyphene. According to the there stated In the same indication, the task of the drug described above is to treat rheumatic diseases with particularly painful symptoms such as B. primary and secondary chronic polyarthritis, Arthrosis, spondilosis, osteochondrosis, penarthritis, to cure radicular syndromes, sciatica and lumbago. This task is accomplished by the indicated remedy dissolved, which consists of 77.3 mg phenylbutazone, 20 mg benfotiamine, 47.2 mg d-propoxyphene HCl and 150 mg aluminum hydroxide'magnesium carbonate dry gel stands.

The problem posed was achieved in a conventional manner by the specified combination of three known active ingredients Dosage with the analgesic dextropropoxyphene in a slightly reduced dose and one is known Vitamin B 1 derivative (benfotiamine) with an anti-neurotic (sub-area of rheumatic diseases) also mixed in the usual dosage

Regarding the state of the art, reference is finally made to GB-PS 12 85 361 and FR-PS 7012 201, which on the Is discussed in detail at the end of the description.

The object of the present invention is therefore to create a phenylbutazone-based analgesic while maintaining the known antirheumatic effect of phenylbutazone, but with a high analgesic effect while reducing the Doses to eliminate or at least reduce the known side effects.

Contrary to the popular belief that combinations of phenylbutazone with propoxyphene as drugs are unsuitable, this object has now surprisingly been achieved in that the Analgesic as the sole active ingredient

a) dextropropoxyphene, and

b) contains phenylbutazone in the molar ratio la: 2b With a simultaneous application of

Phenylbutazone and dextropropoxyphene had an extraordinarily high analgesic potentiation Effect and an additional retardation of this analgesia achieved It has thus become possible to keep therapeutic doses of the individual components in the mixture so low that the known Side effects are largely avoided.

In the following the invention is explained in more detail with the aid of exemplary embodiments

Series tests have shown that particularly good results are achieved when the analgesic is off Dextropropoxyphene and phenylbutazone in a molar ratio of 1: 2 are made below for clarity this result, some of the values obtained are compiled in tabular form as an example Effectiveness of the individual mixtures, based on the molar ratio 1: 2, in percent again.

Table 1

Molar ratio d-prop- 45 ¹ 75% oxyphene / phenylbutazone 85% 1: '6 57% 97% 1: 8 81% 100% I: 4 94% 98% 1. 2 100% 1: 1 74%

This optimal mixture with a molar ratio phenylbutazone / dextropropoxyphene -2: 1 was shown in the experiments listed below have new, interesting pharmacological effects:

Im Analgesie-Tejt (writhing on mice) shows Dextropropoxyphene mixed with phenylbutazone under optimal conditions compared to dextropropoxyphene alone an up to 4.2-fold increased analgesia, as a comparison of the corresponding values of the EDm shows. The relation at different points in time shows Table II.

Table U

Substances 15th 30th 60 120 180 240 A- 24 23 31 71 135 150 B- 13th 11th 16 27 32 37 C- 33 30th 53 72 85 97 D- 350 360 390 650 650 900 - dextropropoxyphene - dextropropoxyphene in the Gem. calculated, from C - Dextroprop mixture oxyphene / phenylbutazone, Molverh. 1: 2 - phenylbutazone

ED ₅₀ in mg / kg body weight Duration of action (min) Number of animals used in the test series:

A: 360 animals B: 240 animals C: 240 animals D: 420 animals The following diagram I illustrates the exponentiation factors resulting from the table:

Diagram I exponentiation factor

15th

I 30

1 120

240

The results of extensive clinical and field tests on 413 patients are shown in the following overall statistics (Table III).

Table ΠΙ

Number very good good moderately ineffective

of the falls

Degenerative spinal syndromes with or without radiculitis such as B. Spondylarthrosis ankylosing spondylitis Osteochondrosis of the cervical spine, occipital syndrome, thoracic syndroin Lumbar spine, lumbosacral syndrome, disc prolapse

Osteoarthritis

Arthritis Neuralgia, neuritis Soft urheumatism Periarthritis Post-traumatic states

49

115

19th

14th

44 9 24 9 2 35 2 31 1 1 46 14th 24 5 3 22nd 8th 12th - 2 14th 5 5 2 2 55 24 30th 1 -

total

The B '"was successful in 85.2% of these cases The examining doctors gave it very good and good. The excellent analgesic effect will when looking at post-traumatic cases in particular, this becomes clear. On the other hand, the treatment shows success in the typical diseases of the rheumatic group that the anti-rheumatic properties of phenylbutazone in this combination despite the significantly reduced dose, the effects observed so far with treatment with the hitherto observed observed effects when treated with the known high doses of phenylbutazone.

Thus it has been possible to ensure the normal one-erfolgrei Che antirtteumatische therapy despite a reduction of phenylbutazone dose to Ui.

That it is precisely the combination of two according to the invention that fulfills the task in such an excellent way Weis * »solves, was neither from GB-PS 10 81 105 nor

111

241

37

24

predictable based on the drug published in the Rote Liste, 1971, page 156. Compared to the latter, the task at hand was the one at hand Registration in it, the modern lines of therapy accordingly a combination with a variety of Components and their obvious side effects to avoid or the range of To keep side effects manageable, d. H. a drug of the desired effect with as much as possible to create few components.

To prove the technical progress compared to that previously published in the Red List Mixture of three (dextropropoxyphene, phenylbutazone, benfotiamine) the mixture dextropropoxyphene / Phenylbutazone in a molar ratio of 1: 2 combined with two different concentrations of the vitamin B-1 derivative benfotiamine and the analgesic effectiveness examined in the writhing test. The results are in the compiled below Table IV

Table IV

Writhing test after i.p. injection of 1% acetic acid; 22 minutes observation time; 18C NMRI mice, 16 to 18 g; ED »expressed in mg / kg mouse as propoxyphene HCl

6ff 120 * number of

used animals

D-propoxyphene / phenylbutazone Molverh. 1: 2 + lg. 75 mg benfotiamine per 100 mg mixture D-propoxyphene / phenylbutazone Molverh. 1: 2 4-7.1 mg benfotiamine per 100 mg mixture

It is clearly shown that the analgesic effectiveness of the mixture dextropropoxyphene / phenylbutafcone is adversely affected in its effectiveness by the presence of the Vitamir B-1 derivative benfotiamine. The less benfotiamine is added, the better the analgesic effectiveness

The British patent specification 12 85 361 and the also pre-published parallel French application No. 20 42 342 have advised those of ordinary skill in the art from the filing dates against using the mixture according to the invention to solve the invention The task set to be used: From Table 4 of this publication it can be seen convincingly that

63 84 39

100
80

a mixture of phenylbutazone and dextropropoxyphene has no increased analgesic effect compared to dextropropoxyphene alone. The dose information in the third column in the last three lines (19;

μ 31,6 and 494) for the mixture of phenylbutazone and Dextropropoxyphene correspond to the lectures given in 2.3. and 4th line for dextropropoxyphene alone. the The measured values in the 4th column are practically the same (430 versus 4.51; 4.75 versus 4.79 and 5.20 versus

65 5.12). Below the table, on page 5, lines 7 ff. Of the English patent it is stated that the analgesic effectiveness of the salt from d-propoxy-

phen and phenylbutazone is greater than that of the pure mixture of the components in the same Quantity ratio.

The French patent 70 12 201 and the Corresponding British patent 12 85 361 according to Proxifezon is a salt of dextropropoxyphene and diphenyibutazone in a molar ratio of 1: 1. According to the test results given in these patents, this salt is the mixture of dextropropoxyphene and Far superior to phenylbutazone in a molar ratio of 1: 1. Furthermore, the results listed there show that the mixture is no more effective than the propoxyphene alone.

The following can be said about the first claim: The salt Proxifezon is a salt made from the weak acid Diphenyibutazone and the weak base dextropropoxyphene. One such salt is in the acidic gastric pH not constant. The diphenyibutazone is a weak acid due to the strong acidity of the gastric juice failed. Accordingly, under normal stomach conditions, this salt is also available as a mixture like the mixture itself.

The second claim that the mixture of propoxyphene and phenylbutazone was not more analgesic Should be effective than propoxyphene alone, seems implausible. Even if propoxyphene as medium strength Analgesic essentially caused the analgesic effectiveness of this mixture, so it has Phenylbutazone an analgesic component. This would definitely have to be in such a mixture make it also noticeable. In addition, it should be noted that in such animal experiments always with An error rate of 20 to 30% is to be expected. This particular method has much higher error rates afflicted, as in the relevant pharmacological

Table V

Literature is emphasized often enough. Several authors even point out that this method is used in the essential is only suitable for a qualitative differentiation of analgesic efficacies. From it it follows that, for example, the values given in Table 4 of FR-PS 20 42 342 should only be assessed with reservations are.

If you take these considerations into account, then the salt is superior to the mixture Phenylbutazone / dextropropoxyphene in a molar ratio of 1: I hardly to be accepted. It follows accordingly also the technical progress of the mixture; it does not necessarily have to be a salt will.

To further differentiate it from Proxifezon, the following can be said: From Table 1 of the This patent application clearly shows that the mixture 1: 2 compared to the mixture I: 1 is clearly superior. This is true at least for the 45-minute value that is required for practical use in therapy is important. The sense of such combinations is ultimately to be seen in the fact that Patients with very painful rheumatic diseases get rid of theirs as quickly as possible Pain should be relieved. Here, too, is a clear technical advance compared to Proxifezon to seer

To clarify to what extent a salt can be useful for oral use at all, a Aggregation compound of propoxyphen and phenylbutazone in a molar ratio of 1: 2 irr. Writhing test on Mice with the mixture 1: 2 and propoxyphene were compared for their analgesic effectiveness. The results are compiled in Table V.

Writhing test after ip injection of 1% acetic acid: oral application of the substances; 840 NMRI mice, 16-18 g; Observation time 22 minutes; ED ₅₀ in mg / kg calculated on the proportion of propoxyphene HCl.

I2tr 181 /

number of

used

animals

Dextropropoxyphene HCl

Aggregation compound (molar ratio 1: 2)

Mixture of propoxyphene / phenylbutazone (molar ratio 1: 2)

This experiment also makes it clear that the oral application of such a salt for the analgesic Effect is not necessarily beneficial To achieve

23
92
12th

31
82
21

71 135 180 360 91 102 110 240 28 3i 38 240 ine (ED ₅₀ ) will apparently

the same V

much more analgesic needed.

Claims (1)

Claim: Analgesic, characterized in that it is used as the sole active ingredient a) dextropropoxyphene, and b) contains phenylbutazone in a molar ratio la: 2b 10