WO2003068203A1

WO2003068203A1 - Use of a combination of a non-steroidal anti-inflammatory agent and guaifenesin for the treatment of acute pain

Info

Publication number: WO2003068203A1
Application number: PCT/CZ2003/000008
Authority: WO
Inventors: Tomàs DOLEZAL; Miloslav Krsiak; Vaclav Tomasek
Original assignee: Zentiva, A.S.
Priority date: 2002-01-30
Filing date: 2003-01-30
Publication date: 2003-08-21
Also published as: AU2003213987A1; CZ2002383A3; CZ292874B6

Abstract

The use of the combination of a non-steroidal anti-inflammatory agent and 3-(2-methoxyphenoxy)-1, 2-propanediol (guaifenesin) and optionally caffeine, for the manufacture of a pharmaceutical intended for the treatment of acute pains.

Description

USE OF A COMBINATION OF A NON-STEROIDA AN I -INFLAMMATORY AGENT AND GUAIFENESIN FOR THE TREATMENT OF ACUTE PAIN

Background Art

During past few years, the use of analgesic combinations, containing neuropsychopharmaceuticals, for the treatment of pain has been developing significantly. Due to application of often illogical and sometimes even dangerous combinations in the past (containing aminophenazone analgesics, barbiturates, anticholinergic drugs etc.) these combined analgesics have lost their credit. Combined painkillers, conceived in this manner, had a number of adverse effects (impairment of kidneys, liver, risk of addiction, negative effects on psychomotor functions). The above combinations did not meet the present requirements for rational analgesic combinations. The combinations of many agents did not show any enhanced analgesic effect - on the contrary, it were the adverse effects which accumulated.

Nevertheless, together with detailed understanding of cellular and molecular mechanisms of pain and of the mechanism of effects of various groups of analgesics and neuropsychopharmaceuticals, there is a revival of reasonably substantiated combinations taking place, based on synergic antinociceptive effect. The aim is to achieve a higher analgesic effect by combining two agents possessing analgesic effect, with lower doses being used and, thus the adverse reactions induced by the treatment reduced. An ideal situation is to achieve amplification of antinociceptive efficacy, whether on the basis of pharmacokinetic or pharmacodynamic potentiation of the effects. The prerequisite is a rational explanation of the mechanism of synergistic action and a thorough experimental and clinical proof, which is in accordance with the EU legislation on combined pharmaceuticals (CPMP/EWP/240/95).

An example of such combination of analgesics is the composition of paracetamol and guaifenesin, optionally caffeine, which is specified in patent CS 202328. The rationality of the stated combinations has been supported by both experimental and clinical studies. It has been proved that the combination of such composition does show enhanced analgesic effect, when compared to paracetamol alone, the increase being 81 %. The combinations have been widely used in clinical practice without any significant adverse effects.

A possible mechanism of potentiation of the analgesic effect showed by the combination was suggested in the pharmacokinetic study by Perlik et al. in 1988 (Perlik F, et al., "The effect of guaifenesin on absorption and bioavailability of paracetamol from composite analgesic preparations" in J Clin Pharmacol 1988; 26:413-416), which disclosed that guaifenesin doubles the rate of paracetamol absorption without affecting its bioavailability.

During the following years, nonsteroidal antiinflammatory drugs have been increasingly applied as painkillers. The effect of these agents consists in inhibiting formation of prostaglandins (by inhibiting the enzyme cyclooxygenase), which play an important role in pain origination and transfer. Another probable mechanism of the effect of non-steroidal anti- inflammatory drugs is inhibition of pain transfer on the spinal cord level. Nevertheless, the use of nonsteroidal antiinflammatory drugs is associated with some adverse effects, especially on the digestive tract (gastropathy caused by nonsteroidal antiinflammatory drugs).

Their administration may induce gastric irritation, which may lead to erosions in long-term use or, even to peptic ulcers. Life-threatening complications include bleeding, perforation and obstruction of the gastrointestinal tract. By extrapolating results of foreign trials, it has been estimated that there are 5,000 patients hospitalised due to this complication in the Czech Republic, 800 of whom die. When nonsteroidal antiinflammatory drag therapy applied for at least 2 months, one patient in 2,000 dies.

An important role, as far as the treatment of pain is concerned, is played by the onset of the analgesic effect. Basically, it depends on the absorption rate of the given anti-inflammatory drug from the digestive tract, on distribution of the agent into the affected tissue and, finally, on the inhibitory effect itself. In many cases, it is just the slow onset of the effect which prevents effective application of an anti-inflammatory drag as the treatment of acute pain.

This invention presents a solution to this problem based on potentiation of the effect of a nonsteroidal anti-inflammatory drug by means of using another agent, which alone has no analgesic effects. Reduction of the required dose of the non-steroidal anti-inflammatory drag may then reduce the incidence of the above stated adverse effects. Another innovation is that the agent accelerates the onset of the analgesic effect.

Disclosure of the Invention

The invention relates to the use of a combination of a non-steroidal anti-inflammatory drug with 3-(2-methoxyphenoxy)-l,2 propanediol (guaifenesin), and optionally caffeine, for the manufacture of a pharmaceutical destined for the treatment of acute pain.

The invention also relates to a pharmaceutical composition containing the above stated active agents, intended for the given application.

The term "non-steroidal anti-inflammatory drags (NSALDs)" includes a group of agents that have been proven to inhibit inflammatory processes within the body, and yet are not corticosteroids. They may have various chemical structures and somewhat different mechanisms of effect. Their common feature is that they are able to manage disorders, in which the pain is related to the intensity of the inflammatory process. They block cyclooxygenase at the level of the spinal chord and thus inhibit the transfer of pain into higher neural centres.

An example of NSAJD can be 2-(4-isobutylphenyl) propionic acid (ibuprofen) or its salts, N-(4-nitro-2-phenoxyphenyl) methane sulphonamide (nimesulide) and its salts, 2-[(2,6- dichlorophenyl)amino] benzene acetic acid (diclofenac) in the form of its sodium or potassium salts or, 2(3-benzoyl-phenyl) propionic acid (ketoprofen) and its salts, and many others.

Ibuprofen belongs among non-steroidal anti-inflammatory drugs with significant analgesic and anti-pyretic properties. It has been used for long periods and, thanks to its positive profile of undesirable effects, it has been ranked among over-the-counter drags. From the viewpoint of gastrointestinal tolerance, it belongs among the mildest anti-inflammatory drugs with the incidence of serious gastrointestinal complications of 0.94 cases per 100 patient-years (for comparison with other NSALD: piroxicam - 1.39, indomethacin - 2.96). Its analgesic effect has been verified in a number of controlled clinical studies, the PAIN study can be named of those recently led (Paracetamol, Aspirin and Ibuprofen New Tolerability Study), including more than 8,000 patients, which proved ibuprofen to show the same efficacy in inhibiting pain as acetylsalicylic acid and paracetamol but, better tolerance than acetylsalicylic acid and, a comparable one to that of as paracetamol. By chemical nature, it belongs among derivatives of propionic acid. The peak plasma concentration is reached within 1 to 2 hours after the administration and, the recommended dose in the treatment of acute pain is 200 to 400 mg three to four times a day.

Diclofenac (diklofenak) is a derivative of acetic acid with significant analgesic and anti- inflammatory effects. In the treatment of acute pain, the recommended dose is 50 mg three times a day. The peak plasma concentration is reached within 1 to 2 hours.

Ni esulide is a non-steroidal anti-inflammatory drag, belonging to the group of preferential inhibitors of cyclooxygenase 2. When administered in lower doses, it does not affect cyclooxygenase 1 and thus shows lower incidence of gastrointestinal adverse reactions. It has slow onset of the effect, the peak plasma concentration is reached in 3 hours. The dosage is 100 mg twice a day.

Ketoprofen is a derivative of propionic acid, resembling ibuprofen by its structure. The peak plasma concentration is reached within 0.5 to 2 hours. Analgesic doses range between 25 and 50 mg three to four times a day.

Guaifenesin has, in addition to its expectorant activity, also anxiolytic and central myorelaxant effects, due to which it can also inhibit the emotional and algognostic components of the pain. One of its benefits (e.g. when compared to barbiturates) is a wide spectre of therapeutic use and minimum risk of addiction.

Caffeine is a methylxanthine derivative, which is used as part of analgesic mixtures. It has been proven to enhance the analgesic effect of acetylsalicylic acid, paracetamol and nonsteroidal anti-inflammatory drugs by ca 30 %. The term "acute pain" means here severe suddenly occurred pain. It is especially any pain associated with an injury, surgical intervention or a painful disease. It may include headache, toothache or, pains during menstruation.

The term "pharmaceutical composition" means one or more active agents, combined with suitable excipients in such a form that the active ingredient be utilisable by the patient's organism. It is not essential for the term whether all the active ingredients are contained in a single dose of the pharmaceutical composition or, whether they are administered in several doses so that they act concurrently in the organism.

The term "pharmaceutical" being specified in this way, is best represented by a solid drag form, in which the active ingredient(s) is (are) contained in a defined dose and excipients are added properly. Solid drug forms like tablets, coated tablets, capsules, granulates are the most widely and most commonly used drug forms.

Based on the type and content of the active ingredient(s) in one dose it is possible to select the method of solid drag form preparation. For example, some of the methods of wet granulation, compacting or, possibly also direct tablet-making technology can be used.

The excipients to be contained in one dose are suitably chosen according to the type and content of the active ingredient(s) and according to the chosen technology. It is important to ensure their compatibility with the active ingredient(s). Excipients and their proper selection guarantee the quality of the whole drug form, its efficacy and stability. They also provide for good reproducibility of the selected manufacturing method. Based on their types and utilisation they can be classified as e.g. filling or binding agents, slip agents, disintegrants etc.

In cases where the content of the active ingredient(s) in one dose is high, for example, the problem of low apparent density is often encountered. Such substances show worsened apparent density and are difficult to dose evenly into a selected drag form. Active ingredients mentioned in this application rank among those substances, too.

The above-mentioned drawback can be solved by choosing an appropriate method of drug form preparation. The technology of wet granulation is preferably used. This method also supports the requirement for various combinations of the mentioned active ingredients in one dose, Thus, separate manufacture for making the granulates of the individual active ingredients can be preferably used, which are then homogenised in an appropriate ratio, thus achieving the required content of the active ingredients in one dose. On the other hand, it is also feasible to prepare a common granulate of a certain combination of the active ingredients, if possible as far as compatibilities are concerned.

The granulate or the mixture of granulates, together with other excipients added, are then processed into solid compacts of a pre-determined shape. Taking the character of the active ingredients used into consideration, it is reasonable to coat the resulting tablets, best with a thin layer of a film-forming agent, in combination with other excipients, like plasticizers, pigments and the like.

According to the selected combination of active ingredients, which are used therapeutically suitable doses, the content of one active ingredient will be 2 to 50 percent by weight, based on the total weight of the tablet and, the content of the other ingredient will be 10 to 80 weight percent, based on the total weight of the tablet.

It is possible to use fillers as the excipients, either separately or in various combinations. The usual total content of the fillers ranges between 5 and 75 weight percent, based on the total weight of the tablet. The contents of the individual fillers may range between 0.5 and 75 weight percent. It is preferable to use mannitol, starches, modified starches, microcrystalline celluloses, lactose or phosphates, possibly also hydrogen phosphates of alkaline metals or alkaline earth metals.

Binding agents suitable for the preparation of top-quality granulate(s) of the active ingredient(s) include modified starches, gelatine, various types of povidones, various cellulose derivatives and the like. The total amount of binding agents based on the total weight of the tablet may be 0.1 to 15 weight percent. Purified water is used as a suitable wetting agent, inter alia, because of ecological requirements. If required in order to provide stability of the active ingredient, a combination of water : ethanol or, pure ethanol can be used. For good quality, disintegrants and slip agents are further used in amounts of 0.5 to 10 %, and 0.1 to 10 weight percent, respectively, based on the total weight of the tablet. As disintegrants, one or a combination of more substances can be used, preferably starch, starch derivatives, cellulose derivatives, cross-linked povidones and the like. As the slip agents, it is possible to use one or a combination of more substances, like talc, stearic acid, stearic acid salts and derivatives etc.

Such compositions and manufacturing method comply with a number of requirements stipulated:

a. Good reproducibility of the combination of agents into one dose, which is easy to use, is achieved. b. The obtained compacts (tablets) have good mechanical properties, which enable their further processing into coated tablets. c. The tablets meet all the necessary quality parameters, like the content of active ingredients and their dissolution. d. The tablets show sufficient stability, i.e. they keep all the quality parameters for the whole usable life.

In a preferable embodiment, the tablet contains 7 to 50 weight percent of one active ingredient and 30 to 75 percent of the other active ingredient, 20 to 60 % of a filler or, a combination of fillers; 0.3 to 8 % of a binding agent or a combination of binding agents; 1.0 to 13.0 % of a disintegrant or a combination of disintegrants and, 0.4 to 11.0 % of a slip agent or a combination of slip agents.

The selection of the optimal composition of the tablet (core) will be illustrated in more detail by the following examples, demonstrating satisfactory stability of the drag form of various combinations of the active ingredients of this invention. The tablets (cores) are in most cases additionally coated, by common methods, using other appropriate excipients. The resulting drug forms are then mostly coated tablets.

Combining agents ensures enhancement of the analgesic effect, when compared to the effect of a separate agent, which leads to a reduction in the total dose of the non-steroidal anti- inflammatory drug required and, thus also a reduction in the risk of adverse effects, especially those on the digestive tract. Another benefit, to be used especially in sudden acute pain, is sooner onset of the analgesic effect. It is just the rate of the onset of analgesic effect which is the decisive factor in the patient's perception of pain alleviation in the therapy of acute painful conditions. Guaifenesin (optionally combined with caffeine) enhances the onset of the effect of the above stated analgesic drags.

The figures enclosed and the following examples, based on an experimental pharmacological study, shall illustrate the effect provided by the invention better.

Brief Description of the Drawings

Fig. 1 shows the results of measuring the latency until occurrence of the first stretching for the combination of ibuprofene and guaifenesin, in the writhing test according to the method described in Example 1.

Fig. 2 shows the total number of stretchings for the combination of ibuprofen and guaifenesin in the writhing test according to the method described in Example 1.

Fig. 3 shows the number of stretchings after 5 min. for the combination of ibuprofen and guaifenesin in the writhing test according to the method described in Example 1.

Fig. 4 shows the total number of stretchings for the combination of diclofenac and guaifenesin in the writhing test according to the method described in Example 1.

Fig. 5 shows the total number of stretchings for the combination of nimesulide and guaifenesin as determined in the writhing test according to the method described in Example 1.

Examples

Combination: ibuprofen + guaifenesin - testing of peritoneal irritation (writhing test):

Method used

It is a standard method, in which the painful reactions of tested animals (mice of the NMRI line) to peritoneal irritation were compared. The comparison was performed on one group, being administered only ibuprofen (12 individuals); one group, being administered ibuprofen in combination with guaifenesin (12 individuals); and, a control group (12 individuals). Peritoneal irritation was induced with acetic acid in the concentration of 0.7 %, the dose being 0.1 ml/10 g.

The analgesic drug or, a combination of analgesics, was administered orally, 30 min. prior to the administration of an intraperitoneal injection in the volume of 0.2 ml/10 g. The control group were orally administered distilled water with acacia gum.

The animals were monitored for spontaneous motions, in which a contraction rans across the abdominal muscles and ends by stretchi g out hind legs, so called „writhing".

The assessment of the analgesic effect was then made on the basis of two test parameters: number of stretching occurrences (total = over 20 min. and, divided into 5 min. intervals) and the latency until the first stretching.

Results

A synergic analgesic effect was observed in the combination of 30 mg/kg ibuprofen and 200 mg/kg guaifenesin, in both test parameters: the latency period until the first stretching (Figure 1) and the total number of stretching occurrences over 20 minutes (Figure 2).

It can be concluded that in the model used the combination of ibuprofen 10 mg/kg and guaifenesin 200 mg/kg had 1.5 times bigger efficacy than ibuprofen 10 mg/kg alone and that of ibuprofen 30 mg/kg and guaifenesin 200 mg/kg had 2.5 times bigger efficacy than ibuprofen 30 mg/kg.

The charts show that the selected doses do potentiate the analgesic effect of ibuprofen and guaifenesin. Based on the above stated results, the use of these agents in a combined analgesic drag is rational. The said differences were significant in the first five minutes of the test, when the combination of 10 + 200 was 2.4 times more effective than for ibuprofen alone and, the efficacy of the combination of 30 + 200 was even 6 times higher than that of ibuprofen alone (Figure 3).

We suppose that one of the probable mechanisms of the potentiation of the analgesic effect of ibuprofen by guaifenesin is acceleration of its resorption from the gastrointestinal tract.

Combination: diclofenac + guaifenesin - testing of peritoneal irritation (writhing test): Method used - see Example 1.

Results

Certain potentiation of analgesic effect was observed also in the combination of diclofenac (3 mg/kg) and guaifenesin (100 and 200 mg/kg), - see Figure 4. Adding guaifenesin to diclofenac increased its analgesic efficacy ca 3 times in the writhing test.

Combination: nimesulide + guaifenesin - testing of peritoneal irritation (writhing test): Method used - see Example 1.

Results

The above hypothesis was verified also in the third experiment, wherein guaifenesin (200 mg/kg) increased the analgesic efficacy of nimesulide - see Figure 5. When using a dose of 10 mg/kg nimesulide (the dose alone was not effective in our model), we observed 4.5 times higher analgesic effect and, when using the active dose of 20 mg/kg, 2.7 times higher analgesic effect.

Below are given examples of the pharmaceutical composition used for the given indication. Example A

Preparation of separate granulates of the active ingredients

Composition of one tablet (core) in [mg]

Procedure:

Ibuprofen, a portion of the pre-gelatinised starch, maize starch and stearic acid are wet granulated into granulate I, which is dried and sieved through a suitable screen.

Guaifenesin, the second portion of the pre-gelatinised starch and povidone are wet granulated into granulate II, which is dried and sieved through a suitable screen.

Then, granulate I, granulate II, crosscarmellose, talc and microcrystalline cellulose are homogenised.

The homogenised tablet mass is processed into lens-shaped cores, 12 mm in diameter, weighing 550 mg.

Example B

Preparation of a common granulate of the active ingredients

Composition of one tablet (core) in [mg]

Procedure:

Ibuprofen, guaifenesin, pre-gelatinised starch, maize starch and povidone are wet granulated into a granulate, which is dried and sieved through a suitable screen.

The granulate is homogenised with microcrystalline cellulose and sodium carboxymethyl starch.

Compositions from both the examples provided satisfactory cores. These cores are preferably further coated. For coating, common film-forming substances and common methods of their application, in a mixture with other excipients, to the cores can be used. The final drug form is then coated tablets.

Claims

C L A I M S

1. Use of a combination of a non-steroidal anti-inflammatory drug with 3-(2- methoxyphenoxy)-l.2-propanediol (guaifenesin) and optionally with caffeine, for the manufacture of an oral pharmaceutical composition intended for the treatment of acute pain.

2. The use of claim 1, wherein the non-steroidal anti-inflammatory drag is 2-(4- isobutylphenyl)proρionic acid (ibuprofen) or its biologically utilisable salts.

3. The use of claim 1 , wherein the non-steroidal anti-inflammatory drug is N-(4-nitro-2- phenoxyphenyl)methane sulphonamide (nimesulide) or its biologically utilisable salts.

4. The use of claim 1, wherein the non-steroidal anti-inflammatory drug is 2-[(2,6- dichlorophenyl)amino]benzene acetic acid (diclofenac) or its biologically utilisable salts.

5. The use of claim 1, wherein the non-steroidal anti-inflammatory drug is 2(3-benzoyl- phenyl)propionic acid (ketoprofen) or its biologically utilisable salts.

6. The use of claim 1, wherein one dose of the pharmaceutical composition contains 10 to 1,000 mg of 3-(2-methoxyphenoxy)-l,2 propanediol and 10 to 1,000 mg of the nonsteroidal anti-inflammatory agent.

7. An oral pharmaceutical composition, containing an anti-inflammatory agent and 3-(2- methoxyphenoxy)-l, 2-propanediol (guaifenesin) and optionally caffeine, intended for the treatment of acute pain.

8. The pharmaceutical composition of claim 7, in a solid drag form.

9. The pharmaceutical composition of claim 7, characterized as containing 7 to 50 weight percent of one active ingredient, 30 to 75 percent of the other active ingredient, 20 to 60 % of a filler or a combination of fillers, 0.3 to 8 % of a binding agent or a combination of binding agents, 1.0 to 13.0 % of a disintegrant or a combination of disintegrants and 0.4 to 11.0 % of a slip agent or a combination of slip agents..