FR2605884A1 - NEW DRUG ASSOCIATION - Google Patents

Abstract

THE OBJECT OF THE INVENTION IS A DRUG ASSOCIATION OF TIZANIDINE AND IBUPROFEN HAVING INCREASED ANALGESIC AND MYOTONOLYTIC ACTIVITY.

Description

The subject of the present invention is a new asso-

  medication with analgesic and myotonic activity

  lytic. In particular, the invention relates, as a medicament, to a medicinal combination comprising, as.

  active ingredients, tizanidine or one of its pharmaceutical salts-

  acceptable, and ibuprofen or a pharmaceutical salt thereof-

acceptable.

  The invention also relates to a pharmaceutical composition.

  ceutique comprising, as active principles, a) tizanidine or one of its pharmaceutically acceptable salts and b) ibuprofen or one of its pharmaceutically acceptable salts, in combination

  with a pharmaceutically acceptable carrier or diluent.

  Ibuprofen or 2- (4-isobutylphenyl) propionic acid is a known pain reliever and anti-inflammatory. It is used appropriately in the treatment of pain and inflammatory diseases in daily doses not exceeding 1800 mg. However, this medicine may cause side effects.

  unwanted side effects, such as gastrointestinal side effects

  intestinal such as abdominal pain, indigestion, nausea, gastric ulcer. In addition, its effectiveness usually reaches a plateau at the effective upper dose limit, above which the additional administration of the drug does not increase the effect.

analgesic or anti-inflammatory.

  Tizanidine or 5-chloro-4- (2-imidazoline-2-ylamino) -

  2,1,3-Benzothiadiazole is a known myotonolytic agent.

  The Applicant has now surprisingly found that the administration of a fixed combination of tizanidine and ibuprofen has particularly advantageous and unexpected properties, for example an excellent analgesic and muscle relaxant activity in an effective and rapid manner accompanied by good tolerance. . There are, for example, far fewer serious side effects, for example gastrointestinal side effects. Of

  more, the combination of the invention requires lower quantities

  ibuprofen for the same pain relieving effect.

  The analgesic effect and the tolerance of the composition

  according to the invention can be observed in pharmacolo-

  classic gics and in clinical trials.

  One of the pharmacological trials is in particular the adjuvant arthritis trial in rats [A.W. Pircio et al., Europ. J. of Pharmacology 31, p. 207-215 (1975)] which is carried out in the following manner: In male rats (of OFA strain) weighing between and 120 g, the base of the tail is injected subcutaneously 0.1 ml of a suspension of Mycobacterium butyricum in paraffin oil (0.6 mg of mycobact. / 0.1 ml of oil). The effects of this treatment are examined 18 days later when severe hind leg arthritis develops. 30 minutes before administration of the test substance, the right or left hind leg joint is flexed using a Statham transducer until the animals react

  by a cry. Unreacted rats are eliminated from the test.

  1, 3 and 5 hours after the oral administration of the test substance, a new flexion is caused. The applied pressure is expressed in arbitrary units. The threshold is expressed as the average value of three successive measurements. Animals in which the threshold has doubled are considered to be protected. Tizanidine is administered orally at doses between 0.1 and 15 mg / kg and ibuprofen is administered at doses between 10 and 100 mg / kg orally separately or in combination. The beneficial effect of the combination of the invention can also be demonstrated in the following clinical trial: The trial is carried out on 105 patients, men and women, from 18 to 70 years old. The selected patients present with acute pain in the lower back of at least moderate severity and of recent onset, with or without sciatica, associated with limited painful movements of

the lumbar part.

  Patients who are pregnant or breast-feeding, patients with malignant disease, osteoporosis, who have been operated on the lumbar part of the spine and those in need of surgery, are excluded from the trial. Patients with a history of systemic disease, allergy or sensitivity to any of the trial drugs and those with rheumatic diseases other than osteoarthritis are also

excluded from the test.

  Patients are not allowed to take other analgesics, anti-inflammatories, antispasmodics, muscle relaxants or anxiolytics, antihypertensives or

  anti-coagulants throughout the duration of the test.

  The study was carried out in a randomized double-blind trial. Each patient is placed in one of the two treatment groups, and receives either the tablets containing 4 mg of tizanidine and 400 mg of ibuprofen 3 times a day (51 patients), or tablets containing 400 mg of ibuprofen 3 times per day

  (54 patients). The treatment lasts 7 days.

  The doctor examines the patient on the first day of the test and after 3 and 7 days of treatment. We give the patient a sheet

  of information and he is asked to fill in a daily file.

  The following information is noted by the doctor:

Date and time of the exam.

  Does the patient have sciatica or not (no / weak / moderate / severe)

  Pulse rate (beats / minute).

  Blood pressure (seated, systolic and diastolic, mmHg).

  Functional capacity (severely restricted, moderately restricted,

  slightly restricted, not restricted).

  Pain in movement (none, weak, moderate, strong).

  Pain at rest (none, weak, moderate, strong).

  Pain at night (none, weak, moderate, strong).

  Is the patient able to work (yes, no, without work).

  In addition, on the third and seventh day of treatment, the following parameters are examined: State of the patient compared to the first visit (Day 1)

  (significantly better, better, identical, worse, much worse).

Did the drug have an effect

  (no effect, little effect, lots of effect).

Adverse effects.

  Adherence to treatment- (counting tablets).

  Venous blood samples are taken before and after the test to measure the following parameters: Blood count, hemoglobin, blood sedimentation, aspartate, aminotransferase, alanine aminotransferase, gamma-GTP, alkaline phosphatase, bilirubin, total protein, albumin, globulin , uric acid, urea, creatinine, calcium, phosphate,

  glucose, cholesterol and triglycerides.

  All patients are asked to complete a daily record with similar visual scales (VAS) including: Pain during movement (VAS) Pain at rest (VAS) - Pain during the previous night (VAS) Pain compared to the previous day (less, identical, stronger)

  Pain interference in daily activities (VAS).

  The treatments are compared using the Mann-Whitney U test. Comparisons are made in each treatment using the Wilcoxon test for matched samples from day 1 to day 3 and from day 1 to day 7. These data are summarized by means and standard deviations (SD) with P values

  appropriate from different tests.

  The categorical data are summarized in frequency tables and the treatments are compared using the chi-square test. The pain intensity categories are combined to give two groups: non-existent / weak and moderate / strong. These tables are analyzed using a binomial test. Comparison of evaluations of each treatment when necessary is also done using the Wilcoxon test for matched samples. A binomial test is also used to compare the frequency of specific adverse effects in each treatment group. The following results are obtained: A smaller number of patients experienced moderate or severe pain at night after 3 days of treatment with the combination drug (18%), compared to those treated with ibuprofen (37%) P = 0.025. A smaller number of patients had moderate or severe pain at rest on the 3rd day (P =

  0.018) and on the 7th day (P = 0.019) after treatment with the combination

  compared to those treated with ibuprofen.

  Significantly more patients who started the trial with moderate or severe sciatica felt better after three days of treatment with the new combination

medicated (P = 0.039).

  The patient's assessment of pain using the analog visual scale while walking shows that the new

  drug combination is significantly better than ibupro-

  after 3 days of treatment (P = 0.029).

  After 3 days of treatment, doctors recognized that the new drug combination provided relief in 88% of patients, while the same results were achieved only in 69% of patients treated with ibuprofen (P = 0.05). After 7 days of treatment, these percentages were 89% with the new drug combination and 75% with

ibuprofen (P = 0.13).

  Significantly greater number of patients treated

  with ibuprofen suffered from gastrointestinal side effects

  such as indigestion, nausea and abdominal pain

  compared to those treated with the medical association

liar (P = 0.002).

  The results of this study show that the combination of tizanidine and ibuprofene has a faster onset of action, a

  better efficacy and fewer gastrointestinal side effects

  intestinal than ibuprofen administered alone.

  The drug combination of the invention is therefore useful for causing analgesia, for example in the treatment of

  painful and inflammatory conditions associated with muscle spasms

  painful pain, especially for the treatment of painful muscle spasms due, for example, to static and functional disorders of the lumbar or cervical region of the spine (cervical syndrome, acute torticollis, low back pain) or to post-operative spasms example following an operation for a herniated disc or osteoarthrosis of the hip joint or following accidents which have caused trauma to the

musculoskeletal system.

  The exact daily dose of tizanidine and ibuprofen to be used will depend, among other things, on the method of administration and

the state to be treated.

  An appropriate daily dose of tizanidine is between about i and about 20 mg, preferably between 2 and

  12 mg, more preferably between 2 and 4 mg.

  The appropriate weight ratio of tizanidine to ibuprofen is between about 1:50 and about 1: 200, from

preferably 1: 100.

  As examples of preferred amounts of tizanidine in the form of unit doses, mention may be made of 1, 2 and 4 mg. As examples of preferred amounts of ibuprofen in the form of unit doses, mention may be made of 100, 200 and 400 mg. Unit doses are administered appropriately 1 to 3 times a day. As examples of unit doses, mention may be made of those containing 2 mg of tizanidine and

  mg ibuprofen or 4 mg tizanidine and 400 mg ibuprofen.

  Tizanidine can be administered as a free base or a pharmaceutically acceptable acid addition salt, for example hydrochloride. Pharmaceutically acceptable salts of ibuprofen are, for example, potassium, sodium salts

or aluminum.

  The compositions of the invention comprise any of the forms suitable for enteral administration, preferably for oral administration, and comprising tizanidine and ibuprofen in fixed association. The preferred compositions according to the invention are the forms suitable for oral administration, such as tablets, capsules, dragees, granules or pills. The preparations of the invention are preferably in the form of unit doses, each containing a predetermined amount of

tizanidine and ibuprofen.

  The compositions of the invention can contain tizanidine and ibuprofen mixed with diluents, vehicles or other pharmaceutically acceptable excipients chosen so

  appropriate according to usual pharmaceutical practices.

  For example, tablets, capsules, dragees, granules or pills may contain, in addition to the active ingredients,

  filling, granulating agents, disintegrating agents

  gration, binders, lubricants, dispersing agents

  persion, wetting agents, stabilizers and colorants.

  Furthermore, the compositions of the present invention can be formulated in such a way that the release of the active ingredients occurs only or preferably in a specific place of the intestinal tract, or that the release is prolonged in order to control the rate of release of the ingredients. assets. Suitable sustained release forms include tablets coated with an extended release coating, controlled release polymer matrices impregnated with the active ingredients and made into tablets, and

  capsules containing such impregnated polymer matrices.

  The following example of compositions is given as

illustrative but not limiting.

  EXAMPLE: Tablet suitable for oral administration Film-coated tablets containing the ingredients listed below can be prepared according to the usual methods and used for oral administration 1

  3 times a day in the treatment of pain.

  Ingredients Weight (mg) Tizanidine hydrochloride 2,288 (= 2 mg base) Ibuprofen 200.00 Calcium sulphate dihydrate 186,712 Hydroxypropylcellulose 10.00 Corn starch 45.00 Stearic acid 6.00

450.00

  Hydroxypropyl-methylcellulose 10.00

460.00

  The ingredients are intimately mixed according to conventional methods and tablets are prepared by compression, each containing 2 mg of free tizanidine and 200 mg of free ibuprofen.

Claims (10)

  1. As a medicament, the medicament combination comprising, as active principles, tizanidine or a pharmaceutically acceptable salt of this compound, and ibuprofen or a pharmaceutically acceptable salt of this compound. 2. A pharmaceutical composition, characterized in that it comprises, as active principles, a) tizanidine or a pharmaceutically acceptable salt of this compound, and b) ibuprofen or a pharmaceutically acceptable salt of this compound, in combination   with a pharmaceutically acceptable carrier or diluent.   3. A composition according to claims 2,   characterized in that it is in the form of unit doses. 4. A composition according to claim 2, characterized in that it is in the form of unit doses for a oral administration.   5. A composition according to any one of the claims   cations 2 to 4, characterized in that it is in the form of tablets. 6. A composition according to any one of   claims 2 to 5, characterized in that it contains from 2 to 4 mg tizanidine.   7. A composition according to any one of the claims   cations 2 to 5, characterized in that it contains 1 mg of tizanidine.   8. A composition according to any one of the claims   cations 2 to 5, characterized in that it contains 2 mg of tizanidine.   9. A composition according to any one of the claims   cations 2 to 8, characterized in that the weight ratio of the   tizanidine h ibuprofen is between 1:50 and 1: 200.   10. The use of the combination according to claim 1 or of a pharmaceutical composition according to any one of   claims 2 to 9 for the treatment of painful conditions and   inflammatory conditions associated with painful muscle spasms.