WO2003049729A1

WO2003049729A1 - Use of creatine and/or creatine derivatives in muscle impairments and/or muscle disorders not caused by illness

Info

Publication number: WO2003049729A1
Application number: PCT/EP2002/013809
Authority: WO
Inventors: Hans Schuhbauer
Original assignee: Degussa Ag
Priority date: 2001-12-08
Filing date: 2002-12-05
Publication date: 2003-06-19
Also published as: DE10160485A1

Abstract

The use of creatine and/or one of its physiologically suitable derivatives allows muscle impairments and/or muscle disorders not caused by illness, such as in particular muscle soreness, muscle debility, loss of muscle strength and muscular myogelosis to be prevented or alleviated. The recommended individual dose of the creatine component for this application is between 10 mg and 10 g, amounting to a recommended daily dose of between 30 mg and 30.0 g. The inventive use of creatine, particularly when administered as part of a complementary or combination therapy, reduces or significantly reduces muscle function disorders not caused by illness, which are often subjectively felt intensely and restrict movement.

Description

Use of creatine and / or one of its physiologically suitable derivatives for the prevention or alleviation of non-disease-related impairments and / or disorders of muscle function

description

The present invention is the use of creatine and / or one of its physiologically suitable derivatives for the prevention or alleviation of non-disease-related impairments and / or disorders of muscle function.

In the context of the present invention, the term "not due to illness" excludes all pathogenic or pathological events, but also all age-related events, which are to be grouped together under the technical terms myopathies, dystrophies, atrophies and hypertrophies, but also all other muscle physiology Muscle function related acute or chronic disease or aging. The term "disease" should be understood as meaning all events and syndromes that are not transient but persistent and usually progressive and / or those that lead to massive and lasting impairments of quality of life through targeted changes in muscle or muscle cell structure and / or muscle function without targeted therapeutic measures ,

The non-disease-related impairments and / or disturbances of the muscle function in the sense of the present invention thus include all the above-mentioned or equivalent definitions not attributable, acutely occurring and acute creeping events, not the muscle (cell) structure and / or function change sustainably and do not permanently affect the quality of life. The symptoms covered by this definition thus occur only acutely and temporarily, they There is no reference to an already altered or worsening muscle or muscle cell structure and / or muscle function and no potentially intermittent but continuous treatment or therapeutic measures need to be performed.

The potential consequences of unfamiliar physical activities in the context of intensive short-term or sustained periods of stress usually occur in the most untrained or untrained people, they are therefore widely used and well known.

These colloquially referred to as "muscle soreness" manifested manifestations in particular in the occurrence of muscle pain, especially in and around moving body parts and usually 24 to 48 hours after the extraordinary muscular strain. In the English-speaking world, the term "delayed-onset muscle soreness" (DOMS) is widespread, which can be translated as the "delayed onset of muscle pain" and which describes the onset of symptoms, which is typically delayed by the causative event.

But also muscle weakness, muscle loss or pain events as a result of muscle overload can be associated with such extensive use of selected muscle. The severity of such muscular pains, in addition to the purely subjective sensation, is also dependent on the intensity and duration of the previous stress, on the type of muscle work as well as on the age and state of training of the person concerned.

Even if popular scientific often blamed a local acidification of the affected body parts by an increased accumulation of lactic acid as a result of anaerobic glucose degradation, the skilled person sees the cause of "muscle soreness" and its related or accompanying symptoms rather in the damage of myofibrils and the non-contractile muscle elements at the cellular level (multiple microfiber tears) with local edema formation and inflammation of the corresponding sites as a consequence. Not least for this reason, the affected musculature is restricted in its function and capacity for a longer period; a load during this phase should be avoided. Especially the latter is not possible in many cases. In addition, the avoidance of sudden onset and / or drastic increases in intensity of physical activities recommended for preventing muscle soreness is often ignored.

Especially older and / or untrained persons often suffer particularly from the consequences of an increased eccentric (braking) or isometric (continuous) load. The structure of the population pyramid and the widespread sedative lifestyle, which avoids regular physical activity and thus drastically reduces average physical activity, massively spread such muscle pain, especially in the Western world.

But also top athletes in the active training state can be affected by these negative effects, especially if type, intensity and duration of exercise significantly exceed the usual level.

For the treatment of such muscle pain, measures are generally recommended that promote blood flow or generally help to strengthen the physical regeneration mechanisms. In particular, a slight further movement of the affected muscles and the effect of heat on the corresponding parts of the body, for example through hot tub baths or repeated sauna visits, are advised. Also massages or light gymnastics are widespread, while extensive warming up measures, eg in the form of stretching, stretching or slowing down movements (eg "cool down" in the form of leakage or exhalation) seem to have little or no effect on the training and development of a "muscle sire" after the actual exercise.

The supplementation with creatine as an aid to the production of ergogenic (force-enhancing) effects is described in detail (see, for example, Physiol.Rev. 2000, 80, 1 107, and the references cited therein, 1, 46, 1 03, 1 28, 225, 305 , 336, 441, 583, 627, 674, 829, 91 1, 91 3, 952, 1038, 1041, 1 106). However, it only mentions the positive effects of creatine on increasing muscle power and stimulating muscle growth, especially during high-intensity short-term exercise with repetitions, as well as in intermediate-duration exercises. In addition, there is anecdotal evidence that oral creatine supplementation may also enhance substrate utilization and performance during extended submaximal loads (Clin. Sei. (ENGLAND) 1 994, 87, 707). However, a reference to preventive or soothing effects of creatine on muscle pain or muscle soreness is completely absent in these prior art comprehensive references.

WO 2001/28360 describes a food product of galactose, creatine and an optional third component as an ergogenic adjuvant on exercise, the benefit of the product being based on maintaining or increasing glycogen storage and glucose availability and according to which its ingestion improves the performance and efficiency of the product Athletes as well as causes a short-term energy supply under anaerobic and aerobic conditions.

US Pat. No. 6,193,973 describes a food supplement in the form of a combination of creatine with ginseng and astragalus and possibly glutamine, which promotes muscle growth, muscle strength and muscle strength increase. In addition, according to US 6,1,1,379 chelates of creatine with metals such as magnesium, calcium, copper, zinc or iron as a food supplement during periods of intense short-term stress relieve physical fatigue and shorten the recovery phase.

In Medicine and Science in Sports and Exercise (1999, 31, 1147), the effect of creatine supplementation in conjunction with resistance training on muscular creatine accumulation and muscle fiber hypertrophy was investigated, with the authors of the article Fat-free muscle mass, physical performance and muscle morphology were improved over placebo.

Various muscular diseases (dystrophies, atrophies, myopathies) are associated with decreased intracellular creatine concentrations; the treatment of these diseases by oral creatine supplementation has therefore been proposed (Medical Hypotheses 1 998, 51, 333). DE-OS 1 98 30 768 describes a creatine and lipoic acid and a number of other components containing medicinal tea for the treatment of muscular dystrophy. WO 00/10408 describes the preparation of food additives with lipoic acid and creatine with a third component (preferably dextrose) for athletes to increase individual strength and muscle size. No. 6,277,842 describes the supply of L-carnitine, chromium picolinate, coenzyme Q1 0, creatine, lipoic acid, niacin, pyruvate, riboflavin, and thiamine as a prerequisite for a reduction in body weight and fat reduction. EP-A 1 002 532 describes the use of creatine or creatine analogues for the treatment of muscle atrophies due to age or disease-related immobilization or limited physical activity, in particular for restoring muscle mass during rehabilitation training. According to Diabetes (2001), 50 (1), 18-33, oral creatine supplementation prevents the decrease in the level of muscle GLUT4 protein in the foot during a two-week immobilization period and increases the level during the subsequent rehabilitation phase. A topical dosage form of creatine in the form of an ointment can be used according to WO96 / 33707 for increasing the muscular efficiency in patients in the rehabilitation phase.

Furthermore, creatine: the power supplement (MH Williams, RB Kreider, JD Branch, Human Kinetics, Champaign 1 999) contains a large number of annotated studies that can be used to prove the ergogenic, ie power-enhancing, benefits of creatine (Page 1 1). The impact of creatine on athletic performance is described as "very helpful" (page 9), especially for one-off (sprints) or repetitive high-intensity short-term workloads, but also in less intense prolonged anaerobic exercise spurts (pages 34 and 41) and sports with resistance performance (eg weight lifting). Phosphocreatine may delay fatigue due to its buffering effect on the muscle tissue which prevents the pH from being lowered (page 23). Creatine supplementation, in turn, can be achieved by increasing the availability of phosphocreatine, by increasing phosphocreatine re-synthesis, by reducing muscle hyperacidity, by increasing oxidative metabolism, by enabling a "training load" and / or by An increase in the especially fat-free body mass to prevent fatigue of muscles (page 39 ff). Finally, creatine is considered to be suitable for maintaining strength (page 108), for increasing endurance in training exercises (page 1 55), and for having an advantageous influence on interval training sessions (page 156). All uses of creatine or one of its precursors or metabolites described so far according to the prior art thus relate exclusively either to the treatment of persistent or progressive diseases of the muscular system, the muscle, its fibers or cells or else to the administration of creatine. Derivatives usually as a dietary supplement for sustained increase in muscle mass, for a short-term increase in performance or to increase the tolerance limit for fatigue, the administration is always in multiple, repeating single doses and over a "Influence period" away, so as to adjust a certain level of creatine in the tissue ,

Relationships between the administration of creatine and subjectively perceived transient or muscular, muscle or muscle cell disorders, as well as their functions, which differ markedly in cause, genesis and physiology from the disease-related muscular dysfunctions known for the administration of creatine, have heretofore been understood but not described.

The object of the present invention is therefore to provide a new use of creatine and / or one of its physiologically suitable derivatives with regard to the muscular apparatus.

This object has been achieved by the use of creatine and / or one of its physiologically suitable derivatives for the prevention or alleviation of non-disease-related impairments and / or disorders of muscle function.

Surprisingly, it has now been found that the already well-known administration of creatine derivatives also avoids or drastically relieves symptoms in the area of the muscular apparatus diseases that are not attributable to or related to a disease, but which are usually subjective or malfunctioning or disturbances of the muscular function, which occur transiently and without late or accompanying consequences, the manifestations of which often depend on the individual predisposition of the patient Depend on those affected and are usually accompanied by pain sensations. That the positive effects of the administration of creatine derivatives can be achieved even with the help of single doses, was not to be expected due to the previously known mode of action of creatine, for example by an increase in muscle mass.

The use of the creatine (derivatives) according to the invention is particularly recommended for muscle soreness, muscle weakness, loss of muscle strength, muscle overload or muscle pain, particularly preferably delayed onset muscle soreness (DOMS), but also in muscle tremors (tremor), muscle twitching ( Myoclonus), spontaneous muscle contractions (myocardia), muscle hardening or muscle hardness (myogelosis), muscle bruising, muscle break (hernia, myocele), muscle callus, muscle stiffness (rigor), muscle tension, diffuse or localized myalgia (especially the head muscles with possibly headaches) Myasthenia syndrome, mechanically or chemically induced muscle inflammation, or muscle ossification (myositis), muscle metaplasia, muscle relaxation (paresis), muscle paralysis or muscle pleura, and any associated or associative symptoms.

Similarly broad as the symptoms which can be summarized under the term "non-disease-related impairments or disorders" is also the spectrum of creatine components which are preferred for their prevention or alleviation in the context of the present invention. The following compounds are particularly suitable: creatine, crea - monohydrate, creatinine, dicreatin, creatine ascorbates of the formula (creatine) _x (ascorbate) _y (H2O) _n where x = 1 to 100, y = 1 to 1 00 and n = 0 to 20, creatine dihydroascorbate, creatine-citric acid compounds in the molar ratio 1: 1 to 3: 1, creatine σ-ketoglutarate, creatine pyruvates of the formula (creatine) _x (pyruvate) _y (H2O) _n where x = 1 to 1 00, y = 1 to 10 and n = 0 to 10, creatine phosphate, phosphocreatine, creatine acetate, creatine maleate, creatine malate, creatine umarat, creatine gluconate, creatine formate, creatinase, creatine phosphoenol pyruvate, creatine folate, creatine dihydrolipoate or creatine lipoate or any mixtures thereof. Of course, all other suitable and physiologically acceptable creatine derivatives can be used following the inventive concept.

Since the inventive use of the creatine derivatives usually takes place in self-medication and the corresponding subjective perceived disorders or impairments of muscle function are very individually pronounced, the present invention takes into account single doses of the creatine component, which is between 10 mg and 10.0 g, preferably between 1, 0 and 5.0 g are. However, it may also be convenient to sum the single doses below a daily dose for which creatine levels between 30 mg and 30.0 g and preferably between 3.0 and 1 5.0 g are recommended. Essential not only in this context is the fact that the use according to the invention is prophylactic, ie preventive or for the purpose of alleviating manifesting non-disease-related impairments or disorders of muscle function. The use according to the invention is thus always coupled to a defined and temporally limited, muscle-loading measure.

However, the present invention also takes into account in addition to the administration of the creatine component as a single preparation corresponding dosage forms containing the creatine component in proportions of 1, 0 to 95.0 wt .-%, preferably in proportions of 5.0 to 90.0 wt .-% and particularly preferably in proportions of 25.0 to 85.0 wt .-%, each based on the total weight of the dosage form included. All doses or parts of the creatine component mentioned in the present context refer to pure creatine. This means that when creatine derivatives are used, the stated amounts of dosages must correspond to those of free creatine and thus have to be adapted to the altered molecular weight.

Irrespective of whether the creatine component is administered alone or in combination with other suitable components, in particular peroral, dermal, parenteral, enteral, rectal, vaginal or local (topical) application purposes have proven suitable in connection with the intended use according to the invention ,

However, the invention also takes into account that the creatine component is used in dosage forms which contain fillers, lubricants, flow aids, mold release agents, plasticizers, blowing agents, stabilizers, dyes, extenders, binders, disintegrants, wetting agents, flow agents, countercocks or mixtures contain, whereby the variety of applications is additionally increased. For certain dosage forms which are particularly suitable for the use according to the invention, it is therefore also possible to use the customary formulation auxiliaries, which, however, are then to be regarded only as additional optional components. Suitable fillers are oxides of magnesium, aluminum, silicon or titanium, microcrystalline cellulose and cellulose powder, starches and their derivatives (for example maltodextrins), lactose, mannitol and calcium diphosphate, which are suitable as fillers from the broad spectrum of all possible formulation auxiliaries. as lubricants, stearates of aluminum and calcium are also suitable, such as talc or silicones; Magnesium stearate, colloidal silicon dioxide, talc or Aerosil, as plasticizers low molecular weight polyalkylene oxide, low molecular weight organic plasticizers such as glycerol, pentaerythritol, glycerol monoacetate, diacetate or triacetate, propylene glycol, sorbitol or Na diethylsulfone succinate, as dyes azo dyes , (or-) niche pigments or natural colorants or other customary auxiliaries such as sugars (alcohols), polymers, phosphates, flavorings and surfactants in question. If necessary, these formulation auxiliaries may be present individually or in any desired combinations in a total proportion of between 0.05 and 90% by weight and in particular between 1.0 and 50% by weight, based in each case on the total weight of the dosage form.

Finally, the present invention also contemplates the use of the creatine component in aqueous solutions, gels, semi-solid dosage forms, solid solutions, in beverages, effervescent or instant powders, tablets, dragées, puddings, yogurts or bars. This listing reflects only the most appropriate dosage forms. Other forms such as patches, bandages, lozenges, sprays, etc. are just as suitable.

Due to the completely uncomplicated mode of administration and especially because of the good compatibility of the creatine, the invention provides the preferred use of the creatine component in the context of a supplement or combination therapy. However, it is also possible to have a corresponding supportive use, for example during therapeutic measures during healing, convalescence, remission or regeneration after open or closed fractures of grade 1 to 4 in the context of reduction, retention, immobilization, occupational therapy or physiotherapy.

In summary, it should be noted that, with the present invention, the already known possible uses of creatine with regard to the muscular apparatus undergo an advantageous supplement which can not be foreseen because of an obviously deviating mode of action of the creatine. The examples listed illustrate significant advantages of the use according to the invention of creatine or one of its suitable derivatives.

Examples

example 1

32 healthy, untrained individuals (1 8 m, 14 w) were randomized into four groups of n = 8 each. All four groups were asked to produce arm muscle overload through defined, negative-dynamic work (20% of the maximal isometric force over 45 min). Grouping:

Group 1: supplementation with 4 g creatine monohydrate 30 min before, with placebo 30 min after exercise.

Group 2: supplementation with placebo 30 min before, with 4 g creatine monohydrate 30 min after exercise. Group 3: Supplementation with 4 g creatine monohydrate 30 min before and 30 min after exercise. Group 4 (control group): supplementation with placebo 30 min before and 30 min after exercise. All measurements and interviews were made once or twice a day and one day before to three days after induced muscle overload.

Results: physiological parameters: Groups 1 to 3 did not show significantly different serum levels of creatine kinase, alanine aminotransferase and aspartate amino transferase compared to control group 4; this is in accordance with literature findings (Williams, Kreider and Branch, "Creatine: the Power Supplement",

Champaign 1 999, and literature cited therein). Muscle pain sensation: Subjects in groups 1 to 3 rated the extent of muscle pain on a subjective scale from 1 (low grade) to 1 0 (high grade) on average significantly less than control group 4 (G 1: 6; G2: 5; G3 : 3, G4: 8).

Time course of the maximum force: The subjects of the groups 1 to 3 had a significantly smaller reduction of the isometric maximum force compared to the control group 4. Again, this is consistent with most of the literature findings (Williams, Kreider and Branch, Creatine: the power supplement,

Champaign 1 999, and literature cited therein).

Example 2:

1 8 healthy, male and untrained individuals were randomized into two groups of n = 9 each. Both groups should reach and maintain a given power (1 70 ± 25 W) as long as possible on an electronic bicycle ergometer; the time was recorded. Two days after the first load, the same exercise was repeated. Grouping:

Group 1: Supplementation with 6 g creatine monohydrate 60 min before each exercise. Group 2 (control group): supplementation with placebo 60 min before each exercise. All measurements and interviews were made once or twice a day and one day before the first to three days after the last load.

Results: Physiological parameters: Group 1 showed a slight increase in serum levels compared to control group 2

Creatine kinase, especially after the second load. Ahn- Liche findings can be found in Medicine Sei. Sports Exercise 1998, 30, 73 and in FASEB J. 1996, 10, A791.

Muscle Pain Sensation: Group 1 subjects rated the extent of muscle pain on a subjective scale from 1 (low) to 10 (high) on average significantly less than control group 2, especially after the second exercise (exercise 1: G1: 5; G2: 7. load 2: G1: 3, G2: 8). mean endurance: The subjects of group 1 had a significantly higher average endurance compared to control group 2. The difference increased from the first to the second

Load unit. The number of failures within the first twenty minutes of each exercise unit was significantly lower in group 1 (n = 1 and 2, respectively) than in control group 2 (n = 3 and 5, respectively). This, in turn, is consistent with most of the literary findings (Williams, Kreider and Branch, "Creatine: the power

Supplement ", Champaign 1999, and literature cited therein).

Claims

Expectations

1 . Use of creatine and / or one of its physiologically suitable derivatives for the prevention or amelioration of non-disease-related impairments and / or disorders of muscle function.

2. Use according to claim 1 for muscle soreness, muscle weakness, loss of muscle strength, muscle overload or muscle pain, particularly preferably with delayed onset ("delayed-onset muscle soreness", DOMS), muscle tremors (tremor), muscle twitching (myoclonus), spontaneous muscle contractions (myokymia), Muscle hardening or muscle hardness (myogelosis), muscle bruising, muscle breakage (hernia, myocele), muscle calluses, muscle stiffness (rigor), muscle tension, diffuse or localized myalgias (especially the head muscles with headache, if applicable), myasthenia syndrome, mechanically or chemically induced muscle inflammation or muscle inflammation (Myositis), muscle meta- plasias, muscle relaxation (paresis), muscle paralysis or muscle plegia and associated symptoms.

3. Use according to one of claims 1 or 2, characterized in that the creatine derivative is creatine monohydrate, creatinine, dicreatine, creatine ascorbates of the formula (creatine) _x (ascorbate) _y (H ₂ O) _n with x = 1 to 1 00, y = 1 to 100 and n = 0 to 20, creatine dihydro-ascorbate, creatine-citric acid compounds in a molar ratio of 1: 1 to 3: 1, creatine-σ-ketoglutarate, creatine pyruvate of the formula (creatine) _x (pyruvate) _y (H ₂ O) _n with x = 1 to 100, y = 1 to 10 and n = 0 to 10, creatine phosphate, phosphocreatine, creatine acetate, creatine malate, creatine malate, creatine fumarate, creatine gluconate, creatine formate, creatine aspartate, creatine phosphopenol pyruvate, creatine folate , Creatine hydrolipoate or creatine lipoate or mixtures thereof can be used.

4. Use according to one of claims 1 to 3 in a single dose between 10 mg and 10.0 g, preferably between 1.0 and 5.0 g.

5. Use according to one of claims 1 to 4 in a daily dose between 30 mg and 30.0 g, preferably between 3.0 and 1 5.0 9-

6. Use according to one of claims 1 to 5 in dosage forms, which the creatine component in proportions of 1.0 to 95.0 wt .-%, preferably in proportions of 5.0 to 90.0 wt .-% and particularly preferably in proportions of 25.0 to 85.0% by weight, in each case based on the total weight of the dosage form.

7. Use according to one of claims 1 to 6 for oral, dermal, parenteral, enteral, rectal, vaginal or local (topical) application purposes.

8. Use according to one of claims 1 to 7, characterized in that the creatine component is used in dosage forms, the fillers, lubricants, flow aids, mold release agents, plasticizers, blowing agents, stabilizers, dyes, extenders, binders, disintegrants, wetting agents, flow agents , Counter-adhesive or mixtures thereof.

9. Use according to one of claims 1 to 8 in aqueous solutions, gels, semi-solid dosage forms, solid solutions, in drinks, effervescent or instant powders, tablets, dragees, puddings, yoghurts or bars.

0. Use according to one of claims 1 to 9 in the context of supplementary or combination therapy.