DD300508A5 - Process for the preparation of a pharmaceutical preparation - Google Patents

Abstract

The invention relates to processes for the preparation of a pharmaceutical preparation which is analgesic and myotonolytic active. The invention provides processes for the preparation of a pharmaceutical preparation which is analgesic and myotonolytic in action, the effect being rapid and the substance being very well tolerated. The object of the invention is to provide processes for the preparation of an analgesic and myotonolytic effective preparation. According to the invention, a pharmaceutical preparation is prepared in which tizanidine and ibuprofen are formulated and optionally brought into a unitary form. {Pharmaceutical preparations; agents; tizanidine; ibuprofen; manufacture; Use, analgesic, myotonolytic}

Description

Field of application of the invention

The invention relates to methods for the preparation of a pharmaceutical preparation which are analgesic and myotonolytic active and containing tizanidine and ibuprofen, and their use for the production of analgesia and for the treatment of conditions associated with increased muscle tone.

Characteristic of the known state of the art

Ibuprofen (2- (4-lbubutylphenyl) propionic acid) is a known analgesic and anti-inflammatory agent. It is suitable for the treatment of pain and inflammatory diseases in doses up to 1800 mg. However, this medicine can lead to adverse side effects, such. B. gastrointestinal side effects, such as abdominal pain, indigestion, nausea or gastric ulcer lead. Further, its efficacy normally reaches a plateau at the upper limit of its effective dose range, above which supplemental drug administration does not cause an increase in analgesic or anti-inflammatory activity

 Tizanidine (5-chloro-4- (2-imidazolin-2-yl-amino) -2,1,3-benzothiadiazole) is a myotonolytic.

Object of the invention

With the invention process for preparing a pharmaceutical formulation are provided, the analgetiss .n and myotonolytisch effective, the effect being used quickly and a very good compatibility exists.

Explanation of the essence of the invention The object of the invention is to provide processes for the preparation of a pharmaceutical preparation, which has a

has analgesic and myotonolytic activity.

It has surprisingly been found that the administration of a solid combination of tizanidine and ibuprofen

has particularly advantageous and unforeseen properties, ζ. B. excellent analgesic and muscle relaxant activity which is effective and fast on use and very well tolerated; z. B. few and least serious

Side effects, eg. As gastrointestinal side effects are observed. Furthermore, smaller amounts of ibuprofen for

same effect required.

The analgesic action and tolerability of the preparations according to the invention can be determined in standard pharmacological tests and

clinical trials.

One such pharmacological test is the rat adjuvant arthritis pain test (A.W. Pircio et al., Europ, J. of Pharmacology 31, 207-215 [1975]), which is carried out as follows: Male rats (OFA strain) weighing 110-120g are injected with 0.1 ml of a Mycobacterium butyrium suspension Paraffin oil (0.6 mg mycobacterium / 0.1 ml oil) was applied subeutaneously to the tail root. The test attempts become after 18 Days, when a pronounced arthritis has developed in the hind paws. 30 minutes before application of Test substance, the ankle of the left or right hind paw is flexed using a Statham pressure transducer,

until a beep of the test animal occurs. Rats that do not beep will not be used for the trial. 1,2,3 and 5

Hours after oral administration of the test substance, the irritation is repeated. The applied pressure is in

given arbitrary units. The stimulus threshold is the mean of three consecutive measurements. Animals in which the threshold is doubled are considered protected. Tizanidine is given in doses of 0.1 mg / kg p. o. and

Ibuprofen in doses of 10 to 100mg / kg p.o. administered separately or in combination.

The beneficial effect of the preparations according to the invention can also be achieved in clinical trials, for. B. performed as follows are shown:

The study was performed on 105 patients (male and female) aged 18 to 70 years. The patients had acute low back pain of at least moderate intensity, first seen before onset, with no sciatica, with painful restriction of movement of the lumbar spine.

Pregnant or breastfeeding persons, persons with malignant tumors, osteoporosis or previous incidents of lumbar spine surgery or those requiring surgical intervention were excluded from the study. Also excluded were individuals with a history of significant Systemerkir.Kung, allergy or drug allergy to the tested drugs and those with rheumatic diseases of Osteoarthro were different that way.

During the study, patients were not allowed to take other analgesics, anti-inflammatory drugs, anti-spasmodics, muscle relaxants, anxiolytics, antihypertensives or anticoagulants.

The study was conducted in a randomized, double-blind arrangement. The patient was assigned to one of two treatment groups receiving either tablets containing 4 mg tizanidine and 400 mg ibuprofen 3 times daily (51 patients) or tablets containing 400 mg ibuprofen 3 times daily (54 patients). The treatment lasted 7 days.

The doctor assessed the condition of the patient at the beginning (day 1), on the 3rd and 7th day of treatment. The patient received an information sheet and had to keep daily diaries. The doctor had to record the following for each evaluation:

Date and time of the assessment,

whether the patient had sciatica (none, weak, medium, strong),

Pulse (beats / min.),

Blood pressure (sedentary, systolic and diastolic, mm Hg),

functional condition (severely limited, moderately restricted, slightly restricted, not restricted), pain in movement (none, weak, moderate, strong),

Rest pain (none, weak, moderate, strong),

Nachtschmer? (none, weak, moderate, strong),

the patient is fit for work (Jk, no, not busy).

In addition, the following was assessed on days 3 and 7:

Condition of the patient in comparison with the first control (1st day) (much better, better, equal, worse, much worse), tablets helped (no help, some help, big help),

Side effects and compliance (number of tablets).

Before and after the treatment blood was taken from the vein and the following parameters were determined:

Complete 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 were asked to enter the following information daily on a BJatt with a visual analogue scale (VAS):

Moving toy (VSA)

Resting pain (VSA)

Pain in the previous night (VSA)

Pain compared to the previous day (better, equal, worse) Impairment of everyday activities by pain (VSA).

The treatments were compared using Mann-Whithney U-Test. Within the treatments, comparisons were made using the Wilcoxon Assay for Associated Samples from the 1st to the 3rd day of treatment and from the 1st to the 3rd day of treatment

7th day of treatment. These data were summed by means of averages and standard deviations (SD) with the associated P-values from the various tests.

Categorical data was summed using frequency tables and the treatments compared using a chi-square test. Pain intensity categories were combined into no / weak and moderate / strong groups.

These tables were analyzed using a binomial test. The comparison of the assessments within the treatments, where appropriate, was again made using the Wilcoxon Assay for Associated Samples. A binomial test was also used to compare the frequency of specific adverse events in each treatment group.

The following results were obtained:

After 3 days of treatment with the combination, significantly fewer patients had moderate or severe night pain (18%) than those treated with ibuprofen (37%) (P = 0.025). After administration of the combination had on

3rd day of treatment (P = 0.018) and 7th day of treatment (P = 0.019) fewer patients had moderate or severe resting pain than those treated with ibuprofen. After 3 days of treatment, the combination improved significantly in more patients with moderate or severe sciatica (P = 0.039). In patient assessment with the visual Analogska '^"1 of pain when walking the combination after 3 days of treatment is significantly better than ibuprofen

(P = 0.029). In the assessment of the doctors, the combination had helped 88% of the patients after 3 days of treatment, while with ibuprofen only 69% of the patients had been helped (P = 0.05). After 7 days, the combination helped 89% of patients and ibuprofen 75% of patients (P = 0.13). Significantly more patients treated with ibuprofen suffered from gastrointestinal side effects, eg. Indigestion, nausea and abdominal pain, as those who have been treated with the combination (P = 0.002).

The results of the study show that the combination of tizanidine and ibuprofen has a faster onset of action, greater efficacy and fewer gastrointestinal side effects than ibuprofen alone.

The combinations according to the invention are therefore suitable for the production of analgesia, for. In the treatment of painful and inflammatory conditions associated with painful muscle spasms, particularly for the treatment of painful muscle spasms, e.g. as a result of static and functional disorders of the lumbar and

(Cervical spine syndrome, acute spasmodic torticollis, low back pain) or postoperative spasms, e.g. B. after

Interventions due to herniation or osteoarthritis of the hip or after accidents, musculoskeletal injuries

cause.

The invention further relates to the use of the pharmaceutical preparation containing tizanidine and ibuprofen for Generation of analgesia, e.g. For example, to treat painful inflammatory conditions that are painful Muscle passages go along, z. For the treatment of any of the above specific conditions. The doses of tizanidine and ibuprofen to be administered daily for the above applications depend on the type of Administration and the condition to be treated. A suitable daily dose of tizanidine is between about 1 to

about 20 mg, preferably 2 to 12 mg.

A suitable weight ratio of tizanidine to ibuprofen is between about 1:50 and about 1: 200, preferably 1: 100. As examples of preferred amounts of tizanidine in a unit dose, mention may be made of 1,2 and 4 mg of tizanidine. As examples

preferred amounts of ibuprofen in a unit dose are 100, 200 and 400 mg ibuprofen.

Conveniently, a unit dose is administered 1-3x daily. As an example of unit doses are called preparations,

containing 2mg of tizanidine and 200mg of ibuprofen or 4mg of tizanidine and 400mg of ibuprofen. Tizanidine can be in the form of the free

Base or in the form of pharmaceutically acceptable acid addition salts, for example as hydrochloride. As the pharmaceutically acceptable salts of ibuprofen, the potassium, sodium or aluminum salt may be mentioned. The preparations of the invention include any form suitable for enteral administration, especially oral Administration, and contain tizanidine and ibuprofen in solid combination. Oral Give Transmit Preparations are preferred

z. As tablets, capsules, dragees, granules or pills. Preferably, the erfindungsge are. wet preparations as

Forms in which each unit dose contains a predetermined amount of tizanidine and ibuprofen. The preparations according to the invention may contain tizanidine and ibuprofen mixed with suitable pharmaceuticals Diluents, carriers and other common pharmaceutical excipients. For example, tablets, Capsules, dragees, granules and pills may, in addition to the active ingredients fillers, granulating agents, binders, disintegrating agents, Lubricants, wetting agents, stabilizers and dyes included. Furthermore, the preparations according to the invention can be formulated so that they only or preferably in one

certain part of the intestinal tract, possibly delayed. Suitable dosage forms for a delayed

Active ingredient are z. Delayed release coating tablets, controlled-release polymer matrices Release impregnated with the active ingredients and formed into tablets, or capsules impregnating such

contain polymeric matrices.

The invention further relates to a process for the preparation of a pharmaceutical preparation, which is characterized in that

tizanidine is brought into a fixed combination with ibuprofen, in particular by mixing tizanidine and ibuprofen together with a pharmaceutically acceptable diluent or carrier, and optionally bringing the preparation into a unit dosage form.

The following example illustrates the present invention. embodiment Tablet for oral administration Film-coated tablets containing the ingredients listed below can be prepared in a conventional manner and

can be administered orally 1 to 3 times a day to treat pain.

ingredients Weight (mg) Tizanidine hydrochloride 2,288 (£ 2mg base) ibuprofen 200.00 Calcium sulfate dihydrate 186.712 Hydroxyropylcellulose 10.00 corn starch 45,00 stearic acid 6.00 450.00 hydroxypropyl methylcellulose 10.00

460.00

The ingredients are thoroughly mixed together and compressed into individual tablets each containing 2 mg of free tizanidine and 200 mg of free ibuprofen.

Claims (8)

1. A process for the preparation of a pharmaceutical preparation, characterized in that tizanidine and ibuprofen formulated and optionally brought into a unit dosage form. 2. The method according to claim 1, characterized in that a unit dosage form for oral administration is prepared. 3. The method according to claim 1, characterized in that the unit dose form is in the form of a table. 4. The method according to claim 1, characterized in that 1 mg of tizanidine is included. 5. The method according to claim 1, characterized in that 2mg of tizanidine are included. 6. A method according to claim 1, characterized in that the weight ratio of tizanidine to ibuprofen is between 1:50 and 1: 200. 7. The method according to claim 1, characterized in that the weight ratio of tizanidine to ibuprofen is 1: 100. 8. Use of tizanidine and ibuprofen or its pharmaceutically acceptable acid addition salts as active ingredients for the preparation of preparations against painful and inflammatory conditions associated with painful muscle spasms.