EA007844B1 - Use of fermented wheat germ extract as anti-inflammatory agent - Google Patents

Abstract

The present invention relates to a new therapeutic use of a fermented wheat germ extract under the trade name Avemar® , more specifically to use of Avemar® for the manufacture of a medicament useful as anti-inflammatory agent for preventing or treating or alleviating inflammatory conditions, particularly arthritis.

Description

The present invention relates to a new therapeutic use of a fermented wheat germ extract under the trade name Lueshat®, more specifically to the use of Lueshat® for the manufacture of pharmaceutical compositions useful as an anti-inflammatory agent for preventing, treating or alleviating inflammatory conditions, especially arthritis.

The method of manufacture, as well as the immunostimulating and antimetastatic effects of the fermented extract of wheat seedlings (hereinafter referred to as Loeshat®) are described in ^ 099/08694. This substance can be obtained by fermenting wheat seedlings with the help of Massagosse 5 segeyue in an aqueous medium and drying the filtered aqueous enzyme. The resulting substance is characterized by a content of 2,6-dimethoxy-p-benzoquinone, representing approximately 0.4 mg / g of dry matter.

Unexpectedly, in the course of research, the authors found that Loueshat® can be used to treat or prevent inflammatory diseases, especially rheumatoid arthritis, observed in mammals, including humans.

Arthritis is a common name for a number of arthritic diseases, such as rheumatoid arthritis, bacterial arthritis, and the like. Rheumatoid arthritis includes a large group of non-bacterial conditions, the most important symptoms of which are inflammation and deformity of the joints. In most cases, classic rheumatoid arthritis affects a number of joints (polyarthritis), but it can also be limited to a single joint (monoarthritis). Damage to the articular cartilage is only one of the factors that deform numerous cartilage and bone and destroy the function of the joint. This disease affects the membrane, ligaments of the joint, as well as bone tissue. In most cases, the disease is characterized by a changing course, including periods of aggravation and improvement, accompanying the patient throughout his life; however, joint deformity and general disability are continuously deteriorating. Only about 10% of patients recover spontaneously.

The prevailing treatments are aimed at alleviating pain and reducing symptoms; Currently, there is no treatment leading to full recovery from this disease. Most of the known treatments use anti-inflammatory agents such as steroids (prednisone, dexamethasone), nonsteroidal anti-inflammatory drugs (“8”), and anti-rheumatic drugs that act on the disease (ΌΜΛΌΜ). The “8” group includes salicylates, ibuprofen, fenoprofen, naproxen, piroxicam, tolmetin, indomethacin, and others, for example, cyclooxygenase enzyme inhibitors. These chemotherapeutic agents are characterized by low efficacy and high toxicity.

Groups ΌΜΑΚΌ or 8ΑΛΚ. (antirheumatic drugs with prolonged effect) include α-penicillinamine, gold salts, chloroquine, azathioprine, methotrexate, and cyclophosphamide. Considering their high toxicity, these drugs are usually selected by professionals only secondarily, when the patient's response to Ν8ΑΙΌ is less favorable. These agents are usually used in combination with "8".

Recently, non-steroidal anti-inflammatory agents have also been developed for the treatment of rheumatoid arthritis, including gamma-interferon and interleukin-6 antagonists, cyclosporine, ΡΑΓ antagonists, eicosapentanoic acid (EPA), somatostatin analogues, peptide derivatives, and immunomodulators.

Hungarian Patent No. 203044 describes a pharmaceutical preparation to relieve arthritis, in which the herbal extract is the active agent.

Despite the large number of drugs currently available, it is difficult or impossible to improve the condition of many patients through medical treatment.

Moreover, there is no way to prevent rheumatoid arthritis.

Thus, there is still a need for new types of antirheumatic drugs that are less toxic, cause less side effects, and are suitable for eliminating, alleviating and preventing the symptoms of rheumatoid arthritis. New agents are required to suppress or reduce inflammation, edema, and pathological neovascularization, erosions of bones and joints, which are also well tolerated.

Thus, the Dueshag® effect was studied on adjuvant arthritis (AA), which can be induced in rats, which are the most commonly used experimental model of rheumatoid arthritis (Κ.) in humans. It has been found that the development of adjuvant arthritis corresponds to human rheumatoid arthritis according to several characteristics, therefore, it can be properly used for screening compounds. In most cases, this model of chronic inflammation is used by pharmacologists to test the anti-inflammatory and immunosuppressive effects of drugs.

The time and degree of AA development in rats depends on several factors, such as the triggering agent and its dose, the injection site, the line of experimental rats, and the like. An acute inflammatory reaction (primary response) appears on the injected paws within 24 hours after administration, and the volume

- 1 007844 paws gradually increase over 4 or 5 days. Depending on the line of rats used, the degree of inflammation becomes constant (plateau effect) between the 6th and 11th days; then the intensity of the reaction increases further. An inflammatory reaction is also generated in the pad of the paw, in which the injection was not made (secondary or immune-mediated response), on the 10th-12th day after the injection. The inflammatory response, i.e., an increase in paw volume, peaks on both treated and non-treated paw pads between the 18th and 21st days.

Brief Description of the Drawings

FIG. 1 shows the effect of treatment p. for 22 days on AA (injected footpad);

FIG. 2 - effect of p. for 22 days on AA (non-injected footpad);

FIG. 3 - effect of the treatment of p. for 22 days on AA on the 14th day (injected footpad);

FIG. 4 - effect of p. for 22 days on AA on the 18th day (injected footpad);

FIG. 5 - effect of p. for 22 days on AA on day 22 (injected footpad);

FIG. 6 - effect of p. for 22 days on AA on the 14th day (non-injected footpad);

FIG. 7 - effect of p. for 22 days on AA on the 18th day (non-injected footpad);

FIG. 8 - effect of p. for 22 days on AA on the 22nd day (non-injected footpad);

FIG. 9 - effect of p. for 22 days per body weight of rats depending on time;

FIG. 10 - effect of p. for 22 days on body weight of rats on the 22nd day;

FIG. 11 - effect of p. for 35 days on AA (injected pad); FIG. 12 - effect of the treatment of p. for 35 days on AA (non-injected footpad);

FIG. 13 - effect of p. for 35 days on AA on the 28th day (injected footpad);

FIG. 14 - effect of p. for 35 days on AA on the 32nd day (injected footpad);

FIG. 15 - effect of the treatment of p. for 35 days on AA on the 35th day (injected footpad);

FIG. 16 - effect of p. for 35 days on AA on the 28th day (non-injected footpad);

FIG. 17 - effect of p. for 35 days on AA on the 32nd day (non-injected footpad);

FIG. 18 - effect of p. for 35 days on AA on the 35th day (non-injected footpad);

FIG. 19 - effect of p. for 35 days per body weight of rats depending on time;

FIG. 20 - effect of the treatment of p. for 35 days on body weight of rats on the 35th day;

FIG. 21 - severe chronic inflammatory infiltration of the synovial membrane and adjacent tissues in untreated rats exhibiting AA;

FIG. 22 - severe infiltration containing giant cells in the synovial membrane of untreated rats exhibiting AA;

FIG. 23 - microabscesses inside inflammatory infiltration in the periarticular tissue of untreated rats exhibiting AA;

FIG. 24 - СО4-positive lymphocytes in inflammatory infiltration found in the synovial membrane of untreated rats exhibiting AA;

FIG. 25 - the absence of inflammatory infiltration in the synovial and perisynovial tissues of rats previously demonstrated AA and treated with Lueshat®.

Effect of Aueshag® on Adjuvant Arthritis in Rats

In the authors' experiments, adjuvant arthritis was induced in female rats ^ 181at by injecting 0.1 ml of 0.5% of the killed Muscle еп ит Щ Snail (Όίίεο) suspended and homogenized in liquid paraffin under the skin of the sole of the foot of the right hind paw of the animal. The average initial body weight of experimental animals was 138 ± 5 g in the group treated for 22 days and 118 ± 5 g in the group treated for 35 days. The body weight of the animals was determined by plethysmography during the treatment of Luetag®, together with the volume of the injected right limb and the uninjected left limb (to observe the primary and secondary reactions) on day 0, 1, 4, 7, 12, 14, 18 and 22 in daily experiment, and on day 0, 3, 7, 11, 15, 18, 21, 25, 28, 32 and 35 in a 35-day experiment. The inflammatory reaction was started on day 1 (22-day test) and on day 14 (35-day test), respectively, after the start of treatment with Luetag®. In both experiments, the following experimental groups were used and

- 2 007844 methods: 1. Control 2x1.0 ml / 150 g (distilled water); 2. Aueteag® 2x2.5 g / kg / day; 3. Aueteag® 2x1.0 g / kg / day; 4. Aueteag® 2x0.25 g / kg / day; 5. Aueteag® 2x0.05 g / kg / day; 6. Indomethacin 2x0,5 mg / kg / day; 7. Dexamethasone 2x0.05 mg / kg / day. Each experimental group consisted of 10-16 rats.

Auteag® suspensions and dexamethasone solutions were always prepared or diluted immediately before administration. Indomethacin (manufactured by Syposh Rjagtaséibs1 aib SNet1Sa1 Aogkk, VibareM. Hungary), used as a positive control, was suspended in 0.5% carboxymethylcellulose and injected. Different doses of Aueteag®, as well as indomethacin and dexamethasone (manufactured by Ogdaioi) were administered via a stomach tube at a dose of 1.0 ml / 150 g body weight, twice a day, i.e. the first half of the daily dose was administered between 8.00 and 10.00 in the morning, and the second half - between 4.00 and 6.00 in the evening. The control group received 1 ml / 150 g of distilled water. Univariate analysis of variance (AIOUA) was carried out for statistical evaluation of the results.

results

The results of the 22-day treatment are shown in FIG. 1-10, and the results of the 35-day treatment are shown in FIG. 11-20. The figures show group average values with a standard deviation (± 8EM) (for 22-day experiments, n = 14-15, and for 35-day experiments, n = 10-12). Levels of significance compared with the control group are indicated * above the bars (* = p <0.05; ** = p <0.01; *** = p <0.001).

The results show that, depending on the dose, Aueteag® can significantly inhibit the development of both primary and secondary inflammatory reactions in rats, which indicates its anti-inflammatory effect. Like indomethacin and dexamethasone, Aueteag® minimized adjuvant arthritis in a dose-dependent manner in treated rats. (Although its effectiveness did not reach that of indomethacin and dexamethasone, which were used as positive controls, it was still able to significantly inhibit adjuvant arthritis). During the 14-day pre-treatment, he did not affect the volume of the limb, and this means that he did not cause a generalized inflammatory response. Depending on the duration of the pre-treatment, it inhibits the development of arthritis. Aueteag® pretreatment could not or could only slightly increase the body weight of rats with arthritis during the 22-day or 35-day treatment.

Histological examination

The affected joints of the pads of the right hind limb together with the epiphyses of the bones and the surrounding fibrous and muscular tissues were fixed in 4% formalin with neutral buffer. The decalcification was carried out using EITA, and the samples were embedded in paraffin. 8 μm longitudinal sections were cut and stained with hematoxylin (H) and eosin (E). In the selective positive control and in the treated cases, an immunoperoxidase reaction was carried out to detect the СО4-СО8-positive T-lymphocytes. The antibodies used were the product 8ap1a Sigkh (8a1a Sgikh, CA, USA), which were used at a dilution of 1: 100.

Histological examination of joints of untreated control rats suffering from AA revealed severe inflammatory changes in the synovial membrane and surrounding (perisinovial) tissues (Fig. 21, stained with H and E, an increase of 300 times). Cell infiltration consisted of lymphocytes, plasma cells, histiocytes, multinuclear giant cells and fibroblasts (Fig. 22, stained with H and E, an increase of 300 times). Microabscesses formed by neutrophilic granulocytes were also observed inside the inflammatory infiltration (Fig. 23, stained with H and E, magnification 300 times). Most lymphocytes turned out to be SE4-positive in the inflammatory infiltrates of rats A (Fig. 24, ΓΌ4 immunoperoxidase).

In the joints of Auteag®-treated rats, 2x1.0 or 2x2.5 g / kg / day, minimal inflammatory infiltration was not detected or was detected. Infiltration of SE4-positive lymphocytes in synovial or perisinovial cells almost completely disappeared, and fibrosis was minimized as a result of Aueteag® treatment (Fig. 25, stained with H and E, an increase of 300 times). Similar results were obtained in animals treated with indomethacin and dexamethasone, used as positive controls. Semi-quantitative assessment of the degree of inflammatory infiltrates in different groups is presented in Table. 1. There was no significant difference between groups receiving 24 hour and 14 day pre-treatment, respectively.

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Table 1. Semi-quantitative histological qualification of inflammatory infiltrates in AA rats, untreated and treated with Aueteag®, indomethacin and dexametozon

Treatment Histological gradation (average from 1 . until 3) 24 hour preliminary treatment 14-day pretreatment Control 2.8 2.2 2x2.5 g / kg / day 1.6 1.4 Acheshag® 2x1.0 g / kg / day 1.0 1.2 Acheshag® 2x0.25 g / kg / day 2.4 2.6 Aueshag® 2x0.05 g / kg / day 2.6 2.6 Aueshag® 2x0,5 mg / kg / day 1.0 1.2 indomethacin 2x0.05 mg / kg / day 1.4 1.2 dexamethasone

Consequently, histological studies clearly testified in favor of the anti-inflammatory effect of Aueschag®.

Based on these results, it can be assumed that the development of rheumatoid arthritis can be inhibited by suitable doses of Aueschag®.

Acute and subacute toxicity tests performed in accordance with the requirements of the SSR (Soob Baogog! Gugu Pngaeee) showed that, unlike steroid and nonsteroidal anti-inflammatory compounds, Aueshag® does not cause any toxic effects, including erosive gastritis and acute gastric ulcer (Corog !. Aee1e og1 1x1yyu Pibu o £ Aueshag® ΐη W1e.Sobe: 9901. υη .ν.Ye1 8et, Verb Räygshaeo1. Ver !. Roggshaeo1. Tokhteo1., VibareP, 1999; Sigmai! E oga1! Ohteyu zo u about o Aueetag®. Soba: 0001. υηΐν. Yea !. 8et, EURO Ragshaeo1. Toh1eo1., Vibarez !, 2000). In addition, this drug was not genotoxic when conducting tests on rat bone marrow micronules.

Based on the experimental results obtained, it was suggested that Aueteag® may be a suitable therapeutic tool for the treatment of rheumatoid arthritis in humans. Other immunopathological diseases can also be considered from this point of view.

The effect of Aueshag® on rheumatoid arthritis in humans

Treatment-resistant patients with confirmed rheumatoid arthritis were treated with Aueteag® at the Rheumatology Department of the National Institute of Rheumatology and Physiotherapy (Budapest, Hungary). This open, self-controlled clinical trial was designed to evaluate the effectiveness, tolerability and side effects of Aueteag®. The following is a report of the results of experiments obtained during the treatment of 15 patients, which lasted one year.

A. The selection of outpatient patients with confirmed SV based on their classification criteria for ASA, classified by the anatomical stages of the B1H3V1 <er from II to III, participated in this study. Their spacecraft was at the same level or deteriorated during the 3-month course of treatment before the start of treatment with Aueteag®. Patients were willing to participate in the study.

B. Exclusion criteria are less than 18 years old and over 80 years old;

severe diseases of the liver, heart, kidneys and hematopoietic organs;

active stomach ulcer;

mental illness, mental retardation;

lack of cooperation;

pregnancy or lactation.

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In case of drug failure, i.e., if the expected improvement did not occur in about 3 months, its administration was temporarily stopped.

C. The course of the study

In addition to the original drug treatment (basic therapy, steroid and "8"), 15 patients with CL were given a daily dose of 2x9 g of water-soluble granulated Aueschag® (9 g in the morning and 9 g in the evening). Patients were checked at the time of initiation of treatment and monthly; their statistical evaluation was performed after 6 and 12 months, respectively.

Ό. Test parameters

The clinical parameters of the study were as follows:

Kyée index;

UFO (Nai Azzzzzesp; Oie Duppat);

the duration of morning stiffness in hours;

erythrocyte sedimentation rate;

TFR;

hematocrit value.

A change in the dose of the steroid administered was also noted during the study. The average age of 15 patients with female CA who participated in the study was 54.5 years (44-68 years), with an average disease duration of 8 years (3025 years; all but one were seropositive. By the beginning of the study, 10 of the patients received basic therapy: 1 patient was treated with sulfasalazine (8a1a / oring1p); 5 patients with methotrexate (Meulinehexa, Baieesh); 3 patients with cyclosporine (8appleshirm, No.og1) and 1 patient with chloroquine (GeOIadhNN). 5 patients did not receive basic therapy: drugs previously used baseline therapy were ineffective and / or cause side effects. By the beginning of the study 11 patients received steroids and the highest oral steroid dose was 7.5-10 mg of prednisolone or an equivalent dose of methylprednisolone or dexamethasone. Patient characteristics are shown in Table. 2.

Table 2. Data on patients before the start of treatment with Aueshag®

A patient No Age (le *) Duration of illness (years) Classification by Z'ehpboskeg EZN (mm / h) SRV (C — reactive protein) no l / l / (hematocrit) index NigsMe Morning stiffness (hours) ON <3 Daily dose of steroid (mg) The dose of basic therapy per day one 53 9 3 54 eight 0.36 36 0 1.7 6 M 12.5 mg per week MTX 2 68 7 3 70 17 0.33 40 five sixteen 2 M - 3 62 12 3 40 five 0.35 28 3 1, o 0.8 Ό - four 54 five 3 76 thirty 0.38 34 2 2.1 - 2 d 5 five ⁵⁰ 25 2 36 ten 0, 35 24 2.5 2, 1 - - 6 44 five 3 46 ten 0, 31 20 one 1.2 10 Р 7.5 mg per week Mth 7 68 3 3 24 6 0, 40 four 1.5 1.1 - - eight 50 3 2 20 five 0.30 ten one 0, 8 4 T 7.5 mg per week Mth 9 58 five 2 90 18 0.31 20 2.5 eleven 10 Р - ten 44 four 2 36 eleven 0.38 eleven 1.5 0, 6 5 Р 175 mg C eleven 50 6 3 18 6 0.33 ten one 0.8 4 M 250 mg Sj. 12 60 five 3 3 106 0, 37 sixteen five 2, 6 6 M 200 mg C 13 48 five 2 84 182 0.37 32 6 1.8 6 M 225 mg C 14 50 25 3 40 sixteen 0, 36 24 0 sixteen 4 M 12, 5 mg per week MTX 15 58 four 2 56 14 0.38 12 1.5 0, 8 7.5 mg per week Mth

Dexamethasone Steroids: Ό

Basic therapy agents

Chloroquine: CH

E8K: erythrocyte sedimentation rate

UFO: NeaI Azzzzzesp! OCHeYuppie questionnaire to assess the overall health status

Methylprednisolone:

Triamcinolone: T Prednisolone: P

M Methotrexate: MTX

Cyclosporine: C

Sulfasalazine: 8

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results

Statistical calculations were performed using the Wilcoxon test. The results are presented in table. 3-9.

Table 3. Changes in the KieEe index compared with the initial value after 6 and 12 months

Time Ζ value Significance 0-6 months 2.574 p <0,010 0-12 months 2, 953 p <0.003 6-12 months 0.534 p <0.594 Ν.3.

Table 4. The change in the value of Naf compared with the initial value after 6 and 12 months

Time Ζ value Significance 0-6 months 3.020 p <0.003 0-12 months 2,448 p <0.014 6-12 months 1,433 p <0.152 Ν.5.

Table 5. The change in the duration of morning stiffness compared with the initial value after 6 and 12 months

Duration of treatment Terminated Improvement Without changes Intensified Significance of P 0-6 months 2 9 2 0 0,009 0-12 months 2 9 one one 0,002

Table 6. Change in erythrocyte sedimentation rate compared with the initial value after 6 and 12 months

Time Ζ value Significance 0-6 months 2,131 p <0,033 0-12 months 1,250 p <0,211 Ν.3. 6-12 months 0.559 p <0.576 Ν.3.

Table 7. Changes in the level of IBS

Time Ζ value Significance 0-6 months 1, 318 p <0.187 Ν.3. 0-12 months 0.426 p <0, 670 N. 3. 6-12 months 0.565 p <0.572 Ν.3.

Comparisons were made using T-criteria of a single sample.

Table 8. The change in hematocrit

Time Ζ value Significance 0-6 months 1,494 p <0.157 Ν.3. 0-12 months 3,011 p <0.009 6-12 months 0.722 p <0.482 Ν.3.

Comparisons were made using T-criteria of a single sample.

Table 9. Change of steroids dose after 6 and 12 months

Duration of treatment The dose has not changed Dose decreased Dose increased Significance R 0-6 months five 6 0 0.031 0-12 months five five one 0.116 Ν.3.

the patient did not receive steroids.

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In 5 of 11 patients treated with the steroid, the initial dose of the drug remained unchanged; 2 patients managed to reduce the initial dose in half, and 2 patients - from 7.5 mg to 5 mg. The dose of basic therapy drugs in 4 patients changed over the 12-month study period: one of them had MTX increased from 12.5 to 15 mg, and the other three had a dose of cyclosporine from 17 5 to 125 mg, from 225 to 100 mg, from 200 mg to 100 mg. In 5 patients, the dose did not change.

No significant difference was observed in hemoglobin, laboratory parameters of liver and kidney function.

The data obtained show that the treatment of drug-resistant patients with NL with Auetate® gave unexpectedly favorable results in the first six months. Regarding the clinical parameters of the patients, a significant improvement was achieved in all parameters without exception; moreover, it was also possible to reduce the dose of steroids for patients. By the end of the second half of the treatment, an even more significant improvement in the clinical parameters was achieved compared with the initial state.

Based on the foregoing, it is an object of the present invention to use an extract of fermented wheat seedlings (Lütat®) for the manufacture of pharmaceutical compositions for treating or preventing or alleviating inflammatory conditions.

Preferably, Luetat® can be used to make pharmaceutical compositions suitable for treating or preventing or relieving arthritis, more preferably rheumatoid arthritis.

Another objective of the present invention is a method of manufacturing pharmaceutical compositions containing fermented wheat germ extract as an active ingredient, including the manufacture of the specified active ingredient using commonly used pharmaceutical additives in a pharmaceutical composition suitable for treating, preventing or alleviating inflammatory diseases.

In addition, it was found that Luetat® can be used preferably with other non-steroidal anti-inflammatory agents (Ν8Ν), such as diclofenac, ibuprofen, piroxicam, tolmetin, and the like. Due to this co-administration, the dosage of drugs of type “8” can be significantly reduced, which is a great advantage from the point of view of the toxicity of these drugs. For example, co-administration with diclofenac reduces the amount of both agents by 50% and at the same time produces similar improvement effects.

Based on the foregoing, another objective of the present invention is the use of a fermented extract of wheat seedlings (Auetat®) and another active ingredient, especially an anti-inflammatory agent, for the manufacture of a medicament for the treatment, prophylaxis or relief of arthritis. According to the present invention, the nonsteroidal anti-inflammatory agent is preferably used as another anti-inflammatory agent.

In addition, the present invention also relates to a combination pharmaceutical composition containing an effective amount of a fermented wheat germ extract (Auetat®) in combination with another active ingredient, especially an anti-inflammatory agent, and a pharmaceutically acceptable carrier.

Preferred anti-inflammatory pharmaceutical compositions of the present invention contain an effective dose of a fermented wheat germ extract (Auetat®) and diclofenac.

The active ingredient used in the present invention can be formulated in several oral and parenteral dosage forms and administered for the treatment and prevention of rheumatoid arthritis. Typically, the active ingredient is present in an amount from about 5 to 95% by weight of the composition.

Pharmaceutically acceptable excipients used for the manufacture of pharmaceutical compositions can be in the solid or liquid phase. Examples of solid pharmaceutical compositions include powders, tablets, pills, capsules, starch capsules, diamond-shaped dosage forms, suppositories, and dispersible granules. Solid compositions can include several additives, such as thinners, flavoring agents, soluble agents, lubricants, suspending agents, binding agents, preservatives, disintegrating agents, or encapsulating agents.

As for powders, the filler is a finely divided solid which is a mixture with the finely dispersed active ingredient.

As for tablets, a carrier having the required binding properties is mixed in proper proportion with the active ingredient and compressed to obtain the required shape and size.

Preferably, the powders and tablets contain an agent in an amount of from 5 to 70%. Examples of suitable fillers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, cyclodextrin, maltodextrin, starch, gelatin, tragacanth, methylcellulose, sodium

- 7 007844 carboxymethylcellulose, waxes with a low melting point, cocoa butter, etc. Manufacturing involves manufacturing the active ingredient with an encapsulating substance as a filler, resulting in a capsule in which the active ingredient is surrounded with filler, with or without other carriers, the latter thus being associated with the active ingredient. Starch capsules and diamond-shaped dosage forms are made in a similar way. Tablets, powders, capsules, pills, starch capsules, and diamond-shaped dosage forms can be used for oral administration.

For the manufacture of suppositories, waxes with a low melting point, for example a mixture of fatty acid glycerides or cocoa butter, are first melted, and the active ingredient is dispersed homogeneously in it by stirring. Then the molten homogeneous mixture is poured into suppository molds of the appropriate size, left to cool and solidify.

Liquid pharmaceutical preparations include solutions, suspensions, emulsions, syrups and elixirs, such as aqueous or water-propylene glycol solutions. For parenteral injections, liquid pharmaceutical compositions can be made in water-propylene glycol solution.

Solutions suitable for oral administration can be made by dissolving the active ingredient in water and adding suitable colorants, flavoring agents, stabilizers and coagulants.

Suspensions suitable for oral administration can be made by dispersing the finely ground active ingredient in water together with a viscous substance, such as natural or synthetic rubbers, resin, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.

Solid pharmaceutical compositions also include those that are intended to be converted to liquid preparations in a short time before use for oral administration. Examples of such liquid pharmaceutical preparations include solutions, suspensions, and emulsions. In addition to the active ingredient, these pharmaceutical preparations may contain colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, coagulants, soluble agents and similar substances.

Sterile compositions for parenteral administration may preferably be aqueous or non-aqueous solutions, suspensions or emulsions. The following agents can be used as solvents: water, propylene glycol, some types of polyethylene glycol, vegetable oils such as olive oil, organic esters suitable for injection, such as ethyl oleate. These compositions may also contain other auxiliary agents, especially lubricating, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be carried out in various ways, including aseptic filtration, the inclusion of sterilizers in the composition, irradiation or heat treatment. Sterile solid compositions can also be manufactured in such a way that they can be dissolved in sterile water or any other medium for injection immediately before use.

Preferably, the pharmaceutical compositions are packaged in unit doses. In these dosage forms in which the drug is divided into standard doses, each of them contains a specific amount of the active ingredient. The unit dosage form can be a packaged preparation in which the package contains individual quantities of the preparation, such as packaged tablets, capsules and powders in vials or ampoules. The unit dosage form may also include capsules, tablets, starch capsules, diamond-shaped dosage forms, or a certain amount thereof, included in the package.

The amount of active ingredient may vary or may be in the range from 1 to 1000 mg, preferably from 10 to 100 mg in the standard dose preparations, in accordance with the use and potential of the active ingredient.

The pharmaceutical compositions may also contain other compatible therapeutic agents, if necessary.

The effective dose of the composition used in accordance with the present invention, and the frequency of dosing for the prevention, suppression or control of arthritis, depends on a number of factors. Suitable doses must be determined by a professional. Usually, such a professional is the attending physician, who determines the proper dose depending on the age, body weight and any other individual factors for the person being treated. Daily dosage levels can range from about 0.1 to 1000 mg / kg body weight, preferably from about 1 to 500 mg / kg body weight per day, and more preferably from 50 to 250 mg / kg body weight per day. For safety reasons, the total daily dose can be divided and administered in portions throughout the day, if necessary.

When pharmaceutical compositions include another active ingredient besides Aueshat®, the indicated other agent can be selected from the following group: corticosteroids, anti-inflammatory agents, antirheumatic agents, immunosuppressants, antimetabolites and immunomodulators. A list of compounds that fall into these categories can be found in the following guideline: Sohrgeeeia MeFs1 SyeshShtu, Rettashe reg§8, χίοτά, 970-986 (1990). This group includes, for example, sulfasalazine and aminosalicylates (anti-inflammatory agents); cyclosporine, PK-506 and brine

- 8 007844 Mitsin (immunosuppressants); cyclophosphamide and methotrexate (antimetabolites); dexamethasone, methylprednisolone, triamcinolone, prednisone (steroids); and interferons (immunomodulators). When Aueschag® is used in combination with one or more other agents, they can be packaged together or they can be administered in combination. The introduction of one or more agents in combination with Luesch® is carried out almost simultaneously or sequentially. Professionals can determine the most appropriate method of administration, depending on the agents released, the desired results, the patient and the condition for which the treatment is being carried out.

Taking into account the embodiments of the present invention described above in the present document, it will be understood by those skilled in the art that the present description is only an example, therefore various alternatives, devices and modifications are included in the scope of the present invention and are intended by the applicants. Accordingly, the present invention is not limited to particular embodiments, as illustrated above, but is defined by the following claims.

Claims (10)

1. The use of a fermented extract of wheat seedlings (Lueshag®) as an active principle in the manufacture of a medicinal product for the treatment, or prevention, or alleviation of arthritis. 2. The use according to claim 1, in which arthritis is rheumatoid arthritis. 3. A pharmaceutical composition for treating arthritis comprising an effective amount of a fermented wheat germ extract (Aueshag®) in combination with an anti-inflammatory agent and a pharmaceutically acceptable carrier. 4. The pharmaceutical composition according to claim 3, in which the anti-inflammatory agent is a non-steroidal anti-inflammatory agent. 5. The pharmaceutical composition according to claim 4, in which the non-steroidal anti-inflammatory agent is diclofenac. 6. The use of the pharmaceutical composition according to claim 3 as an active principle in the manufacture of a medicament for the treatment or prevention or relief of arthritis. 7. The use according to claim 6, in which the anti-inflammatory agent is a non-steroidal anti-inflammatory agent. 8. The use according to claim 7, in which the non-steroidal anti-inflammatory agent is diclofenac. 9. A method of treating, or preventing, or alleviating arthritis in a mammal, including humans, comprising administering to said mammal that requires said treatment or prophylaxis, or alleviating, an effective amount of a fermented wheat germ extract (Aueshag®). 10. The method according to claim 9, including the additional introduction of an anti-inflammatory agent.