LU87033A1 - NEW DRUG ASSOCIATION - Google Patents

Description

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NPInveniIoia Patent Application I. Application

The so-called company: SANDOZ S .A. , Lichtstrasse 35, CH-4002 Basel, Switzerland, j 2) represented by Mr. Louis EMRINGER, lawyer, residing in Luxembourg, acting in his capacity as agent depositing 1 this October 30 ..... 1900-quatre-v ingt-sept .. .................. ..................., 4) at ..... hours, to the Ministry of the Economy and the Middle Classes, in Luxembourg: 1. this request for obtaining a patent for invention concerning: .................. ..... New combination, medicinal _____________________ ________________________________________________________ 2. description in French ............... French __________ ... ... of the invention in three copies: 3. .. ................. // ...............-..... drawing boards, in three copies: 4. the receipt of the taxes paid to the Luxembourg Registration Office on 3.0.10. „19 87__________________; 5. the delegation of power, dated ____________....... ........................ ... on 27.10.1 9, 8 7. _________ :; 6. the successor document (authorization): rev & ndiqueint) for the above patent application the priority of one (or more) application (s) of (7'f patent ............ ........ ..... ..................................... .deposited (s) <33 ^ 8) at the Rep „Fed ______ of Germany .....-.

] e (g, 3 November 1986 ________________________________________________________________ _ _________ under N ° Π0) P 36 37 240.4 ................_............ ..... ...... _. , .......... ..............

in the name of (111 ..... SANDOZ -PAT ENT-GMBH, ..... Humboldtstrasse 3, D.-7.85Q. Lörrach, Germany elected) domicile for him (her) and. if appointed, for its representative, in Luxembourg. 141 * ïuê Albert.

Und en .265.2 ...... Luxembourg ....................................... .............................. .................... ...................................... _........... .......... (12) requests (s) the grant of a patent for invention> the object described and represented in the abovementioned appendices,

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with postponement of this issue to ............................... ....................................... ........... ............. ............... ...... months. iL \ t

The depositor / agent: __ "Λ., -............................. .......... ....... ................ ......... · 14 '· * iLProeès-v erba] de Dépôt

The aforementioned patent application has been filed with the Ministry of the Economy and the Middle Classes.

IntelleçiueHe-àJ-uxembourg Property Service. dated: § ^ *, λτ ^, α_> * '. * · · ^ VUi »iÜOf, · X Pr. The Minister of Economy and> Middle Classes.

* at d / .f hours> {. ; p. d.

- \ J The head of the intellectual property department.

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CLAIM OF THE PRIORITY of the patent application In the Federal Republic of Germany From November 3, 1986 DESCRIPTIVE MEMORY filed in support of an application for

PATENT

at

LUXEMBOURG

in the name of: SANDOZ S.A.

for: New drug combination

The present invention relates to a new drug combination having analgesic and myotono-lytic activity.

In particular, the invention relates, as a medicament, to a medicinal combination comprising, as active principles, tizanidine or one of its pharmaceutically acceptable salts, and Vibuprofen or one of its pharmaceutically acceptable salts. .

The invention also relates to a pharmaceutical composition comprising, as active principles, a) tizanidine or one of its pharmaceutically acceptable salts and b) Vibuprofen or one of its pharmaceutically acceptable salts, in combination with a vehicle or pharmaceutically acceptable diluent.

Ibuprofen or 2- (4-isobutylphenyl) propionic acid is a known analgesic and anti-inflammatory. It is used appropriately in the treatment of pain and inflammatory diseases in daily doses not exceeding 1800 mg. However, this drug can cause unwanted side effects, for example gastrointestinal side effects 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 analgesic or anti-inflammatory effect.

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. In addition, the combination of the invention requires lower amounts of ibuprofen to obtain the same analgesic effect.

2 The analgesic effect and the tolerance of the composition according to the invention can be observed in standard pharmacological tests and in clinical trials.

One of the pharmacological trials is in particular trial 5 of adjuvant arthritis in rats [A.W. Pircio et al., Europ.

J. of Pharmacology 31, p. 207-215 (1975)] which is carried out as follows: In male rats (of OFA strain) weighing between 110 and 120 g, the base of the tail is injected subcutaneously 10 0 , 1 ml of a suspension of Mycobacterium butyricum in paraffin oil (0.6 mg of mycobact./ΟΟΙ 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 paw joint is flexed using a Statham transducer until the animals respond with 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 pressure applied 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, 30 from 18 to 70 years old. The patients selected present with acute pain in the lower back of at least moderate severity and of recent appearance, with or without sciatica, associated with limited painful movements of the lumbar part.

Patients who are pregnant or breast-feeding, 35 patients suffering from a malignant disease, osteoporosis, who have had 3 operations on the lumbar part of the spine and those requiring an operation, are excluded from the trial. Patients with a history of systemic disease, allergy or sensitivity to any of the test drugs and those with rheumatic diseases other than osteoarthritis are also excluded from the trial.

Patients are not permitted to take other analgesics, anti-inflammatories, antispasmodics, muscle relaxants or anxiolytics, antihypertensives or anti-coagulants for the duration of the trial.

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 15 tablets containing 400 mg of ibuprofen 3 times a 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. The patient is given an information sheet and asked to complete a daily record.

20 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).

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

Functional capacity (severely restricted, moderately restricted, slightly restricted, not restricted).

Pain during movements (none, weak, moderate, strong).

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

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

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

4

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).

5 Did the drug have an effect (no effect, little effect, a lot 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) 20 Pain during the previous night (VAS)

Pain compared to the previous day (less, identical, stronger) Interference of pain in daily activities (VAS).

The treatments are compared using the Mann-Whitney ü 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 appropriate P values. 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 the evaluations of each treatment when necessary is also carried out 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 (18¾), 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 the 7th day (P = 0.019) after treatment with the drug combination, compared to those treated with ibuprofen.

A significantly larger number of patients who started the trial with moderate or severe sciatica felt better after three days of treatment with the new drug combination (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 ibuprofen after 3 days of treatment (P = 0.029).

After 3 days of treatment, the doctors recognized that the new drug combination provided relief in 88% of the patients while the same results were achieved only in 69% of the 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 more patients treated with ibuprofen experienced gastrointestinal side effects, such as indigestion, nausea, and abdominal pain, compared to those treated with the drug combination (P = 0.002 ).

6

The results of this study show that the combination of tizanidine and ibuprofen has a faster onset of action, better efficacy and fewer gastrointestinal side effects 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 painful muscle spasms, 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 has post-operative spasms, for example following a herniated disc or osteoarthrosis operation 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 condition to be treated.

A suitable daily dose of tizanidine is between about 1 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, preferably 1: 100.

w 7

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 200 mg of ibuprofen or 4 mg of tizanidine and 400 mg of ibuprofen.

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

The compositions of the invention include any of the forms suitable for enteral administration, preferably for oral administration, and comprising tizanidin and ibuprofen in fixed combination. 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 unit dose form, each containing a predetermined amount of tizanidin and ibuprofen.

The compositions of the invention may contain tizanidin and ibuprofen mixed with diluents, vehicles or other pharmaceutically acceptable excipients suitably selected in accordance with standard pharmaceutical practice.

For example, tablets, capsules, dragees, granules or pills may contain, in addition to the active ingredients, fillers, granulating agents, disintegrating agents, binders, lubricating agents, dispersion, wetting agents, stabilizers and colorants.

9 ”8

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 active ingredients. active subtances. 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 by way of illustration but not limitation.

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 to 3 times a day in the treatment of pain.

Ingredients Weight (mg) 20 Tizanidine hydrochloride 2,288 (= 2 mg base)

Ibuprofen 200.00

Calcium sulfate dihydrate 186,712

Hydroxypropyl cellulose 10.00

Corn starch '45.00 25 Stearic acid 6.00 450.00

Hydroxypropyl-methylcellulose 10.00 460.00

The ingredients are thoroughly 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 vehicle or diluent. 3. A composition according to claim 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 oral administration. 5. A composition according to any one of claims 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 of tizanidine. 7. A composition according to any one of claims 2 to 5, characterized in that it contains 1 mg of tizanidine. 8. A composition according to any one of claims 2 to 5, characterized in that it contains 2 mg of tizanidine. 9. A composition according to any one of claims 2 to 8, characterized in that the weight ratio of tizanidine to ibuprofen is between 1:50 and 1: 200. 10. The use of the combination according to claim 1 or a pharmaceutical composition according to any one of claims 2 to 9, for the treatment of painful and inflammatory conditions associated with painful muscle spasms.