WO1994028890A1

WO1994028890A1 - Drugs, their manufacture and their use to control pain and/or inflammation and/or fever in humans and animals

Info

Publication number: WO1994028890A1
Application number: PCT/EP1994/001518
Authority: WO
Inventors: Gerd Geisslinger; Kay Brune
Original assignee: Gerd Geisslinger; Kay Brune
Priority date: 1993-06-11
Filing date: 1994-05-11
Publication date: 1994-12-22
Also published as: AU6927294A; DE4319438C1

Abstract

Described are drugs, containing ketoprofene, intended for the treatment of painful and/or inflammatory conditions, the previously separated enantiomers of ketoprofene being incorporated, alone or as a recombined mixture, together with the usual pharmaceutical carriers and auxiliaries, to give drugs suitable for humans and animals.

Description

Drugs and their preparation and their use in the control of pain and / or Entzündun ^g s and / or fever in humans and animals

The present invention relates to pharmaceuticals containing ketoprofen _, consisting of a mixture of the previously separated ketoprofen enantiomers as active ingredient and their preparation, which act as analgesics, antiphlogistics and antipyretics for pain and / or inflammation and / or inflammation acting in a controlled and accelerating manner. or fever can be used on humans and animals.

Ketoprofen, 2- ₍ 3-benzoylphenyl) propionic acid of ^the following structure,

is a long-known drug, which is used on a large scale because of its anti-inflammatory, antipyretic and analgesic effect.

In the chemical synthesis ketoprofen normally is obtained as a racemate and is used in this form in the various ^¬ which medicines. It is also known that this substance particularly in the long term treatment of painful and inflammatory processes, substantial uner ^¬ desired drug reactions, particularly gastrointe- stinale irritation or damage (such as ulcers, perfo rations ^¬ etc.) has. Since it is known that with many pharmacologically active 2-arylpropionic acids, the biological in vitro activity (eg prostaglandm synthesis inhibition) of one enantiomer is greater than that of the other, while in many cases the undesired effects of both enantiomers or even DE-A 28 09 794 proposes that the pharmaceutically in vitro inactive enantiomers be attributed to increasing the proportion of the pharmacologically active enantiomer of arylpropionic acid compared to the racemate. Corresponding separation processes known per se are given. According to this reference, the (+) compounds or S isomers, to which the predominant activity has been ascribed, have preferably been isolated. However, pharmacological activities of the ketoprofen enantiomers are not specified in this literature.

From other publications it is known that S-arylpropionic acids can be used as analgesics. Sunshine et al. [Clm. Pharmacol. Ther., 41 (2), 162 (1987)] in the case of S-flurbiprofen about a stronger analgesic activity after treatment with S-flurbiprofen than with twice the amount of racemate. It was concluded from this that the S-enantiomer of 2-arylpropionic acids is responsible for the analgesic effect of everything. Recent studies have shown that the R enantiomer of flurbiprofen has an analgesic effect (Brune et al., Expententia, 47, 257-261, 1991).

Since many R-enantiomers of 2-arylpropionic acids are inverted in vivo in the optical S-antipodes, it was often impossible to assign the observed pharmacodynamic effects clearly. Rather, it was assumed that the R isomers act predominantly only by inversion to the S isomers. Recently Malmberg and Yaksh (Science, 257, 1276-1279, 1992; J. Pharmacol. Exp. Ther. , 263, 136-146, 1992) a modified pain model where they could rule out the possibility of inversion. You in¬ ^j izierten rats in one hind paw formalin and beobach¬ ended a typical 2-phase reaction. Hypoalgesia can be seen in the first phase and hyperalgesia in the second phase (10th to 40th minute). Burning followed by hyperalgesia was also observed in humans after subcutaneous injection of formalin. This hyperalgesia can be counteracted with 2-arylpropionic acids. Malmberg and Yaksh now applied various NSAIDs (non-steroidal anti-inflammatory drugs) including the enantiomers of ibuprofen. There was no inversion of R-ibuprofen in S-ibuprofen (intrathecal application), so that the pharmacodynamic activity can be clearly assigned to the enantiomers. In contrast to S-Ibuprofen, R-ibuprofen was almost not antihyperalgesic in these studies, although in previous studies R-Ibuprofen (due to the inversion to S-Ibuprofen with systemic application) was equally analgesic like S-Ibu¬ profen.

With the modified pain model described by Malmberg and Yaksh, however, the analgesic efficacy of R-flurbiprofen, as described in Experientia, 47, 257-261, 1991, was confirmed (lecture by William J. Wechter, April 22, 1993 at the Institute for Exp. and Clin. Pharmacology and Toxicology, Erlangen).

In summary, it can be stated that the state of knowledge of science is that R-enantiomers of 2-arylpropionic acids (with the exception of flurbiprofen) are therapeutically ineffective. Surprisingly, it has now been found that, contrary to this knowledge, not only the S (+) ketoprofen but also the R (-) ketoprofen showed an analgesic effect in vivo. This unexpected result was confirmed by tests on guinea pigs and jerboa (gerbils).

With the help of a pain model, which was described in 1988 by Hargreaves (Hargreaves et al., A new and sensitive method for measurable thermal nociception in cutaneous hyperalgesia, Pain, 32: 77-88, 1988), the analgesic effectiveness of the ketoprofen Enantiomers determined. In these experiments, the R enantiomer was analgesic contrary to expectations. Both enantiomers were able to significantly increase the pain threshold in a dose of 30 mg / kg body weight compared to control animals (Table 1). These results were checked pharmacokinetically and, unlike other species (rats, mice) or other representatives of 2-arylpropionic acids (ibuprofen), they can be clearly assigned to the enantiomers of ketoprofen, since both R-ketoprofen and S- Ketoprofen application no or only a very slight inversion (<6%, calculated on the basis of the areas under the concentration-time curve) took place in the respective optical antipodes.

According to the current state of knowledge on the mechanism of action of drugs in successfully combating pain of different origins, a distinction must be made as follows:

In the case of analgesics, the rapid onset of action is of paramount importance. This sets in oral, topical and other non-parenteral dosage forms First of all, an accelerated release and sufficient, good bioavailability of the active ingredient or the active ingredients beforehand. Furthermore, because the conduction of pain sensations via a conduit system rising from the periphery to the central nervous system (CNS), such pain relievers block the control mechanisms present at various levels of the CNS, in which receptors with chiral structures are involved.

It is also believed that inhibition of prostaglandin system is the common feature of the mechanism of action in analgesics and anti-inflammatory drugs (Vane, JR, Nature 231 ff, 1971, Higgs, GA, Bt. J. Clm. Pharmacol. 10, 233 ff, 1980) ). This effect is thus to be understood as the link between pain relief and anti-inflammatory. However, not all effects can be explained by this mechanism alone. In the case of acidic analgesics and / or anti-inflammatory drugs such as ketoprofen, neurophysiological effects as a result of the storage of such active substances in cell membranes are also likely.

Prostaglandms, together with other mediators, are held responsible for the development of classic inflammation symptoms (Rubor, Tumor, Calor, Dolor, Functio laesa). Such inflammatory changes can be weakened by anti-inflammatory agents, whereby the patient experiences pain relief at the same time. This is currently the main area of application for non-steroidal anti-inflammatories (anti-inflammatory drugs). Only a few representatives of the anti-inflammatory drugs can be used for differentiated or pure pain treatments. These include, for example, naproxen or ibuprofen, which are also analgesic in smooth muscle spasms. The much larger number of NSAIDs is not sufficient analgesic effect and due to a number of undesirable effects reserved for anti-rheumatic therapy.

The object of the invention is now to provide readily ingestible or parenterally administrable medicaments which are effective in pain and / or inflammation and which have the lowest possible incidence of undesirable effects. In addition, such drugs should be easy to manufacture, rise in level controls, is characterized by good ness Bioverfügbar¬ and can adapt by einfa¬ che variation of the frequently occurring medical conditions in diseases with differing ^¬ chen analgesia and / or Antiphlogese needs.

This object can surprisingly be achieved by the features set out in the main claim. This effect is further increased by the features characterized in the subclaims.

According to the invention in a known manner to the pure enantiomers by Razeraatspaltung separately or prepared by stereospezifi ^¬ specific synthesis therefore either mat of ketoprofen Raze-. The enantiomers are then processed by a matched for the _j eweiligen application Ver ^¬ ratio together with suitable pharmacologically verträgli ^¬ chen auxiliaries and excipients to give the novel medicines.

Surprisingly, it is found that the present invention previously separated and then ^¬ to the desired mix ratio in finished product reassembled enantiomers significantly faster drug Freiset- tongue than the racemate. This finding is important for therapeutic use, since the faster release of the active ingredient also results in a correspondingly rapid flooding of the active ingredient in the body, which is extremely important, especially with pain relievers.

Known adverse drug effects, such as Gastrointestinal complaints are largely linked to the mechanism of action in the case of non-steroidal anti-inflammatories. These are accepted when applied to diseases of the rheumatic type in medicine. In patients who primarily need pain relief, the rate of undesirable effects should be minimal. In the case of ketoprofen application, this can be achieved according to the invention by increasing the proportion of R (-) ketoprofen in the enantiomer combination or by applying the R (-) ketoprofen in pure form since the R (-) ketoprofen, on the one hand, as stated above, has a strong pain-relieving effect in the acute case and on the other hand also has a low degree of toxicity on the gastrointestinal tract.

Medicaments with ketoprofen are usually administered to humans and animals in the form of tablets, dragees or powder, granules, suppositories and as a sterile solution parenterally or as a non-sterile solution or suspension orally. A rapid onset of action is usually desired, but dosage forms with delayed release can also be produced, which ensure a longer-lasting action. Such forms of administration with delayed release are preferably those which are released only in the distal section of the intestine as in the colon, ie delayed after ingestion, but then spontaneously. Such an "evening before pill" can Take the patient with rheumatic complaints such as morning stiffness in the evening and wake up the next morning free of symptoms. The known recipes for racemic ketoprofen can also be used directly for the enantiomer mixture according to the invention.

Oral administration in the form of tablets, dragees, capsules or chewing mass is particularly preferred, the active substances in powder form being mixed with the known pharmaceutically compatible auxiliaries and excipients in a customary manner with a suitable particle distribution and further compressed or compressed into tablets or dragees be filled into gelatin capsules. The ketoprofen enantiomers are contained in the medicaments according to the invention either in pure form or with a mixing ratio of preferably 95: 5 to 5:95%, the active ingredient making up 2 to 60% of the formulation, depending on the dosage form. It follows from the method of preparation that the "pure" enantiomers used still contain up to 2%, preferably 0.2 to 1.0%, of other enantiomer which has not been separated off.

Solid dosage forms contain 20 to 80% fillers. As such, inter alia, starch, lactose, glucose, mannitol, calcium carbonate, calcium phosphate, cellulose and other products known in the art for this purpose can be used. In order to accelerate the release rate, an explosive in an amount of 2 to 10% is added to the recipe. Carboxymethyl starch, carboxymethyl cellulose, Ac-di-sol, Kollidon CL and silica gel have proven particularly suitable as disintegrants. In addition, the formulation can also contain lubricants in an amount of 0 to 5%, talc, magnesium or Calcium stearate or other auxiliaries with sliding properties cum powder can be added to facilitate processing.

The powders are usually mixed dry and then granulated and dried with a customary binder, for example starch paste or else water. The granules can then optionally be pressed into tablets with the addition of further lubricants or filled into capsules. It is then advantageous to provide the tablets with a coating, which coating can also contain flavorings and sweeteners to improve the applications. In addition to the coating agents customary in pharmaceutical technology (sugar, such as sucrose or lactose, various types of cellulose, such as methyl cellulose or cellulose acetate phthalate, polyacrylate, polymethacrylate or polyvinyl acetate phthalate), carnauba wax can preferably be used as the polishing agent.

The capsules can be filled either as powder, granules or pellets or as a suspension in a vegetable oil or other pharmaceutically acceptable liquid carrier. The active ingredients, which are relatively sparingly soluble in water, can also be suspended or dissolved in water in the presence of a suitable suspending agent such as tragacanth, methyl cellulose, etc.

It is also known to use the ketoprofen active ingredients in the form of suppositories for rectal or vaginal application, in addition to the active ingredient fats or polyglycols can be used as carriers, the melting point of which is either in the body temperature range or which dissolves after application. The dissolution rate can also be further improved by using salts of the ketoprofen instead. Alkali, alkaline earth, ammonium or amino acid salts which are water-soluble are preferred. Complex salts with basic amino acids can be used directly, mixed salts with neutral or acidic amino acids are converted beforehand into the alkali, alkaline earth metal or ammonium salts. The ketoprofen salts produced can then be processed further in a known manner, as described above. The ketoprofen salts are preferably prepared indirectly by adding the bases required for salt formation to the binder solution used for granulation, so that the corresponding salts form during the granulation process.

For pain treatment with the medicaments according to the invention containing ketoprofen, approximately 0.25 to 3 mg of active ingredient per kg of body weight are required, which are taken, for example, in 2 to 5 servings distributed over the day. The single dose should therefore contain between 10 and 100 mg of active ingredient.

Pharmacological experiments

1. Analgesic effectiveness of the ketoprofen enantiomers in guinea pigs

(Hargreaves et al., Pain, 32: 77-88, 1988)

Male guinea pigs (Pirbright White, Savo, Kisslegg) with a body weight of 250-300 g received either 30 mg / kg body weight S (+) - or 30 mg / kg body weight R (-) -ketoprofen or per group (n = 8) only the vehicle applied intraperitoneally. The animals received a subplanar injection of carrageenin (defined concentration) into the right hind paw 2 hours before ketoprofen application. The pain threshold was determined using a thermal stimulus. The time until the flexion reflex occurs, ie until the paw is pulled away, is defined as a measure of the pain threshold. The time that elapses between stimulus and stimulus response is defined as latency. A reduction in the latency period is an expression of a lowered pain threshold and corresponds to hyperalgesia.

Starting values were determined shortly before the carrageenin injection. Measurements were taken 1, 2, 3, 4 and 5 hours after ketoprofen application.

«

The results are shown in Table 1. 2. Analgesic effectiveness of the ketoprofen enantiomers in jerboa (Gerbils)

With the help of an animal activity measuring system, after the injection of Formalm into the right hind paw, the proportion of the locomotive path covered and the number of times the animals were raised per minute were measured. It was found that the movement activity of the animals decreased significantly after formalm injection. An increase in the distance covered was achieved both after administration of S and R ketoprofen. Since the limitation of movement after formal injection is due to pain relief, not only the S enantiomer has an analgesic effect, but surprisingly also the R ketoprofen. These results were checked pharmacocmetically and, in contrast to other species (rat, mouse) or other representatives of arylpropionic acids (ibuprofen), can be clearly assigned to the enantiomers of keto profen, since both S-ketoprofen and R-ketoprofen Application no or only a slight inversion took place in the eternal optical antipodes. The enantiomers of ketoprofen were administered 15 mg / kg body weight in each case at a dosage of _j. By Formalmin _j ection induced inhibition of nociceptive Lauf¬ stretch and erection of the animals is reduced by R- and S-Ke¬ toprofen. The results are shown in Table 2. Table 1 :

Analgesic effects of the ketoprofen enantiomers in guinea pigs. The

Enantiomers were administered intrapeπtoneai in a dosage of 30 mg / kg body weight.

An increase in the latency compared to the control group corresponds to an analgesic effect. The values represent mean values ± SEM of 8 animals per group.

^** : p <0.01 compared to the control group.

REPLACEMENT BLAπ (RULE 26) Table 2; Movement activity after formalin injection into the right hind paw in Sphngmäusen (Gerbiis), mean values (standard deviation): ^* : p <0.05 compared with control + formalin

ERSÄΓZBLÄΓT (RULE 26) Drug compositions

Tablets

One thousand tablets, each containing 100 mg of ketoprofen as a pseudo-racemate, are produced as follows:

R (-) ketoprofen (99% opt. Purity) 50 g

S (+) ketoprofen (99% opt. Purity) 50 g

Lactose 75 g

Corn starch 50 g

Magnesium stearate 4 g

Silicon dioxide 5 g

The enantiomers are finely ground (air jet mill), mixed with the auxiliary materials and pre-compressed. From this, a granulate is produced in a known manner, which is pressed into tablets of approximately 235 mg.

Based on this manufacturing instruction, tablets with different enantiomer contents per tablet can also be produced in the claimed ratio. Furthermore, tablets with, for example, a total active ingredient content of 25 or 50 mg can be produced on the basis of this composition.

Initiation solution

A sterile aqueous solution for parenteral administration, which contains 350 mg of the enantiomeric mixture per liter, is produced as an example as the sodium salt as follows: R (-) ketoprofen sodium salt *) 300 mg

Water p.i .; q.s. 1000 mg

*) 99.0% purity

Instead of the sodium salts it is also possible to use other salts which are obtained after neutralization of the enantiomerically pure active ingredients, for example with ammonia, amino acids such as lysine, etc., and taking into account the respective equivalent weights. The solutions are filtered into sterile containers and sealed.

Gelatin capsules

Approximately 1000 hard gelatin capsules containing 50 mg R (-) ketoprofen for oral administration are made as follows:

R (-) ketoprofen (99.0% purity) 50 g

S (+) ketoprofen 100 g

Lactose 20 g

Corn starch 20 g

Talc 20 g

Magnesium stearate 2 g

The finely ground R (-) ketoprofen is mixed homogeneously with the other ingredients and filled into capsules in a known manner. Analogously, capsules with 25, 75 or 100 mg R (-) ketoprofen, but also with ketoprofen-enantiomer mixtures in the claimed ratio, can be produced. Oral suspension

In order to prepare 1000 ml of an aqueous suspension, an oral dose unit (1 teaspoon = 5 ml) containing 5 mg R (-) - and 95 mg S (+) ketoprofen as aluminum salts, the following composition is used:

R (-) ketoprofen (99% purity)

S (+) ketoprofen (99% purity)

citric acid

Benzoic acid

sugar

Tragacanth

lemon oil

Water, desalt: qs

First, citric acid, benzoic acid, sugar, troganth and lemon oil are suspended with enough water to produce about 800 to 900 ml of suspension. The micronized ketoprofen enantiomers are then stirred in homogeneously and made up to 1000 ml of water.

Suppositons

A suppository that contains 10 to 100 mg of the active ingredient

Enantiomer mixture can contain and weighs about 2 g, is composed as follows:

R (-) ketoprofen (99% purity) 90 mg

S (+) ketoprofen (99% purity) 10 mg

Hard fat ^{1890 m} 9

Tocopherol 10 mg If the proportion of active substance (s) is / are reduced, the proportion of hard fat must be increased to the same extent.

cream

A cream with 4% ketoprofen enantiomers is prepared in a manner known per se, the following components giving a typical recipe:

R (-) ketoprofen

Triglycerides, medium chain

Glycerine monostearate-polyoxyethylene stearate mixture

Polyoxyethylene fatty acid esters

1,2-propanediol

4-hydroxybenzoic acid methyl ester atrium

Xanthan gum

Water, desalt: qs

The active ingredients are dissolved in the oily phase heated to about 60 ° C. The aqueous phase, which has likewise been preheated, is then stirred in and stirred until it cools evenly. A strand of about 2.5 cm contains about 100 mg of the active ingredient mixture . Film table P

Ketoorofen tablet recipe

38.5 kg of ketoprofen lysinate became dry with 7.5 kg of microcrystals. Cellulose mixed, granulated with 3 kg of gelatin (10% in water) and dried, mixed with 0.5 kg of Mg stearate, 1 kg of talc and 2 kg of Na-carboxymethyl cellulose and to form round tablets with a diameter of

6 mm and a weight (residual moisture: 0.8-1.5%) of 260 mg. The finished tablets are coated with a varnish from a solution of 0.7% glycerol, 4% methyl cellulose, 0.7% polyglycol 6000, 58% water and

36.6% acetone coated and dried.

The following was used:

R (-) ketoprofen essentially free of S (+) ketoprofen,

S (+) ketoprofen essentially free of R (-) ketoprofen and a pseudorazemate made of 50% S (+) - and 50% R (-) ketoprofen.

Claims

Patent claims

1. Medicament for the treatment of painful and / or inflammatory diseases with ketoprofen, characterized in that the previously separated enantiomers of ketoprofen are used alone or as a reassembled mixture combined with conventional pharmaceutical carriers and auxiliaries to form medicaments for humans and animals.

2. Medicament according to claim 1, characterized in that the enantiomers as a mixture in the ratio

95: 5% to 5:95% are present.

3. Medicament according to claims 1 to 2, characterized in that the enantiomers have an optical purity of over 98.0%, preferably 99.8-99.0%.

4. Medicament according to claims 1 to 3, characterized ge indicates that 50-100%, preferably 60-95% R-ketoprofen for pain or chronic diseases with dominant pain conditions and 50- for inflammation and chronic diseases with dominant inflammation 100%, preferably 60-95%, S (+) ketoprofen is included.

5. Medicament according to claims 1 to 4, characterized ge indicates that the medicament orally as Tablet¬ ten, dragees, solutions, suspensions, chewing mass etc., anal as Suppositoπen or parenterally as solutions or suspensions or cream or ointments or Pfla ^¬ ster is administered.

6. Medicament according to claims 1 to 5, characterized ge indicates that the active ingredient is contained as an alkali, alkaline earth metal, ammonium or amino acid salt, preferably as a lysinate.

7. Medicament according to claims 1 to 6, characterized in that the mixture contains retarding additives or coatings.

8. Medicament according to claims 1 to 7, characterized ge indicates that predominantly R-ketoprofen is used in patients with an anamnesis for the therapy of painful conditions.