DE2220500B2 - analgesic - Google Patents

Description

The present invention relates to the analgesic specified in the claim.

It has been known since the synthesis of H. Stenzel in 1946 that phenylbutazone (l ^ -diphenyl-3 ^ -dioxo-4-n-butvl-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 effects on certain doses, it is associated with significant side effects related to enzymatic reactions in the body.

It is also known that these side effects are caused by a reducing dose of phenylbutazone in Combination with an analgesic can be avoided.

From British patent 10 81 105 is a jo drug with anti-inflammatory and analgesic effects, consisting of a mixture of Butazon (l-phenyl-3,5-dioxo-4-n-butyl-butazolidine) and d-Propoxyphene (1 ^ -Diphenyl ^ -propionoxy-S-ynethyl-4-dimethylaminobutazone hydrochloride) known, where r> the analgesic effect of d-propoxyphene is potentiated by the combination with butazone. It's over this patent also known that this potentiation in combination with phenylbutazone So propoxyphene does not occur in these combinations are unsuitable as medicinal products. On the other hand, however, there has long been a general need to straight Phenylbutazone because of its very strong anti-rheumatic effect with analgesics compared to butazone Combine to 4> to achieve a potentiating effect.

However, a potentiating effect of 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 w associated with the risk of addiction for the patient and are therefore less desirable.

In addition, from the Red List, 1971, page 156, a A mixture of drugs known which contains phenylbutazone and dextropropoxyphene. According to the given there · v> 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, Osteoarthritis, spondillosis, osteochondrosis, periarthritis, ho 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 bc-> 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 antineuritic (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 70 12 201, on which on 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 well-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.

In contrast to the well-known Ar Combinations of phenylbutazone with propoxyphene are unsuitable as drugs, this task was carried out now surprisingly solved in that the analgesic is the sole active ingredient

a) dextropropoxyphene and

b) contains phenylbutazone in a mol 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 Phenylbuiazon in a molar ratio of 1: 2. The following are for clarity This result is a table of some of the values obtained as an example. You give the Effectiveness of the individual mixtures, based on the molar ratio 1: 2, in percent again.

Table 1

Molar ratio d-prop- 16 45 ' W. oxyphene / phenylbutazone 8th I. 4th 57% 75% I. 2 81% 85% I. I. 94% 97% I. 100% 100% I. 74% 98%

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

In the analgesia test (writhing on mice) shows Dextropropoxyphene in a mixture with phenylbutazone under optimal conditions compared to dextropropoxyphene alone an up to 4.2-fold increased analgesia. like a comparison of the corresponding values of the EDw proves. Table II shows the relation to the various cell points.

Table II

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

ED50 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

I I 15.10

I 120

240

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

Table IU

Number very good good
of the falls

moderately ineffective

Degenerative spinal syndromes with or without radiculitis such as B. Spondylarthrosis ankylosing spondylitis
Osteochondrosis cervical spine, occipital syndrome, thoracic lumbar spine syndrome, luoibosacral syndrome, disc prolapse

Osteoarthritis

Arthritis

Neuralgia, neuritis

Soft tissue rheumatism

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 -

111

241

37

24

25th

total

In 85.2% of these cases, the examining doctors rated the treatment success as very good and good specified. The excellent analgesic effect is particularly evident when looking at post-traumatic cases clear. On the other hand, the treatment shows success in typical rheumatic diseases Form circle that the anti-rheumatic properties of phenylbutazone in this combination in spite of 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.

This made it possible, despite a reduction in the phenylbutazone dose to 1/3 of the usual, a successful one to ensure anti-rheumatic therapy.

That it is precisely the combination of two according to the invention that fulfills the task in such an excellent way Way solves, was neither from BR-PS 1081 105 nor

Table IV

Writhing test after ip injection of 1% acetic acid; 22 minutes observation time; 180 NMRI mice, 16-18 g; ED _{50 expressed} in mg / kg mouse as propoxyphene HCl.

60 "120" number of

used
animals

35 foreseeable on the basis of the medicament published in the Rote Uste, 1971, page 156. Compared to the latter, the object of the present application was to avoid a combination with a large number of components and their unmistakable side effects or to keep the spectrum of side effects manageable, ie to create a drug with the desired effect with as few components as possible .

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 with two different concentrations of the vitamin B-1 derivative benfotiamine combined and examined the analgesic effectiveness in the writhing test. The results are in the compiled below Table IV.

D-propoxyphene / phenylbutazone Molverh. 1: 2
+ 18.75 mg benfotiamine per 100 mg mixture
D-Piopoxyphen / Phenylbutazon Molverh. 1: 2
H-7.1 mg benfotiamine per 100 mg mixture

It clearly shows that the analgesic effectiveness of the mixture dextropropoxyphene / phenylbutazone its effectiveness is adversely affected by the presence of the vitamin B-1 derivative benfotiamine. The less benfotiamine is added, the better the analgesic effectiveness.

. The British Patent 12 85 361 and which also prepublished parallel French Application No. 20 42 342 have discouraged the skilled in the art from the registration day, 'to use the erfindungsge- b * Permitted mixture to achieve the object underlying the present invention: Table 4 of this publication Ergil. (convincingly that

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; 31.6 and 49.5 / for the mixture of phenylbutazone and dextropropoxyphene correspond to the dose information in the 2nd, 3rd and 4th lines for dextropropoxyphpn alone the fourth column are practically the same (4.50 versus 4.51; 4.75 versus 4.79 and 5.20 gegenübe ^r 5.12).

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

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

French patent no. 7 (> I2 2OI and the corresponding British patent no. 12 85 3hl According to Proxifezon is a salt made from dextropropoxyphene and diphenylbutazone in a molar ratio of 1: 1. According to the test results given in these patents, this salt is the mixture of dextropropoxyphene and Phenylbutazone in the molar ratio I: I far superior. 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 Diphenylbutazone and the weak base dextropropoxyphene. One such salt is in the acidic gastric pH not constant. The diphenylbutazone 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 is emphasized often enough in the relevant pharmacological literature. Several atitors even point it out. that this method is essentially only for a qualitative distinction of analgesic activities is suitable. It follows that, for example, the table 4 of FR-PS 20 42 342 values given are to be assessed with reservation.

If you take these considerations into account, then the salt is superior to the mixture Phenylbutazone / dextropropoxyphene in the molar ratio I: 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: I 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 over Proxifezon to see.

To clarify the extent to which a salt can be useful for oral use at all, an aggregation compound of propoxyphene and phenylbutazone in a molar ratio of 1: 2 was compared in the writhing test on mice with the mixture I: 2 and propoxyphene for its analgesic effectiveness. The results are shown in Table V.

Table V

Writhing test after ip injection of 1% acetic acid: oral application of the substances; 840 NMRI mice. 16 to 18 g; Observation time 22 minutes; EDs ₀ in mg / kg calculated on the proportion of propoxyphene HCl.

6ff

120 "180" 240 "

Λπ / ahl der

used

animals

Dextropropoxyphene HCl 24 23 31 71 135 180 360

Aggregation compound (molar ratio 1: 2) 69 92 82 91 102 110 240

Mixture propoxyphene / phenylbutazone (molar ratio I:. 2) 13 12 21 28 38 240 Ώ

This experiment also makes it clear that the oral application of such a salt is not necessarily advantageous for the analgesic effect. To achieve the same effect (ED ») will
much more analgesic needed.

apparently

Claims (1)

Claim: Analgesic, characterized in that it is used as the sole active ingredient a) Dextropropxyphen and b) contains phenylbutazone in a molar ratio la: 2b ! 0