Combination of Silicon and Magnesium for the Prevention and Treatment of Muscle Cramps

Abstract

Pharmaceutical composition comprising a pharmaceutically effective amount of bioavailable silicon in a daily dose of at least 3 mg elemental silicon, and a pharmaceutically effective amount of a magnesium compound in a daily dose of 50-500 mg elemental magnesium. The composition is used for prevention, inhibition and/or treatment of muscle cramps, such as skeletal muscle cramps.

Claims

1. A pharmaceutical composition of matter comprising a pharmaceutically effective amount of bioavailable silicon, and a pharmaceutically effective amount of a bioavailable magnesium compound for use in prevention, inhibition or treatment of muscle cramps.

2. The pharmaceutical composition as claimed in claim 1, wherein the combination is for use in prevention, inhibition or treatment of recurrent and/or idiopathic muscle cramps.

3. The pharmaceutical composition as claimed in claim 1, wherein the muscle cramps comprise skeletal muscle cramps and/or smooth muscle cramps.

4. The pharmaceutical composition as claimed in claim 3, wherein the skeletal muscle cramps are cramps in the extremities, such as in leg, foot and hand.

5. The pharmaceutical composition as claimed in claim 3, wherein the smooth muscle cramps are cramps of digestive tract smooth muscles, such as oesophageal, stomach, and intestinal smooth muscles, or cramps of cervical smooth muscle.

6. The pharmaceutical composition as claimed in claim 1, wherein silicon and magnesium are concomitantly, separately, or time-delayed administered orally or parenterally.

7. The pharmaceutical composition as claimed in claim 1, wherein silicon and magnesium are administration on a daily basis.

8. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically effective amount of bioavailable silicon is in a dose at least 3 mg/day elemental silicon, preferably at least 5 mg/day, more preferably at least 8 mg/day, and the pharmaceutically effective amount of a magnesium compound is in a dose 50-600 mg/day elemental magnesium, preferably in a dose of 100-500 mg/day.

9. Pharmaceutical composition of matter comprising a pharmaceutically effective amount of bioavailable silicon corresponding to a daily dose of at least 3 mg elemental silicon, preferably at least 5 mg, more preferably at least 8 mg, and a pharmaceutically effective amount of a magnesium compound corresponding to a daily dose of 50-500 mg elemental magnesium, preferably a daily dose of 100-450 mg, such as 200-400 mg.

10. The pharmaceutical composition as claimed in claim 9, wherein the pharmaceutical composition of matter is a pharmaceutical combination of separate dosage forms or wherein the bioavailable silicon and bioavailable magnesium compound are part of a single pharmaceutical formulation.

11. The pharmaceutical composition as claimed in claim 9, wherein the bioavailable silicon is a silicon compound of the formula Y.sub.xSi(OH).sub.4-x or an oligomer thereof, wherein Y is optionally substituted (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.5)-alkenyl, (C.sub.1-C.sub.4)-alkoxy, amino, and wherein x is 0-2, wherein preferably the silicon compound is chosen from the group of orthosilicic acid or an oligomer thereof (x=0 in the formula), and mono(C.sub.1-C.sub.4)alkyl-trisilanol and combinations thereof, and more preferably the silicon compound is orthosilicic acid or an oligomer thereof.

12. The pharmaceutical composition as claimed in claim 11, wherein the silicon compound is provided with a stabilizing agent inhibiting polymerisation of the silicon compound, wherein the stabilizing agent is preferably chosen from the group of amino acids, peptides and protein hydrolysates, organic acids, phenol and polyphenolic compounds, polyalcohols such as maltodextrine, quaternary ammonium compounds and aldehydes, preferably wherein the stabilizing agent is or comprises a quaternary ammonium compound, and wherein most preferably the stabilizing agent is choline.

13. The pharmaceutical composition as claimed in claim 9, wherein the magnesium is provided for oral administration as a magnesium salt, such as an inorganic magnesium salt and/or an organic magnesium salt, preferably an organic magnesium salt, more preferably at least two organic magnesium salts.

14. The pharmaceutical composition as claimed in claim 9, wherein the silicon compound is further provided with a binder material, said combination of silicon compound, stabilizing agent and binder being in granulate form, wherein the magnesium is in solid form and the granulate and the magnesium are present in the pharmaceutical formulation as a solid mixture.

15. The pharmaceutical composition as claimed in claim 14, wherein the binder is a water-soluble binder material, for instance a cold-water soluble starch.

16. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition of matter is a pharmaceutical combination of separate dosage forms or wherein the bioavailable silicon and bioavailable magnesium compound are part of a single pharmaceutical formulation.

17. The pharmaceutical composition as claimed in claim 1, wherein the bioavailable silicon is a silicon compound of the formula Y.sub.xSi(OH).sub.4-x or an oligomer thereof, wherein Y is optionally substituted (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.5)-alkenyl, (C.sub.1-C.sub.4)-alkoxy, amino, and wherein x is 0-2, wherein preferably the silicon compound is chosen from the group of orthosilicic acid or an oligomer thereof (x=0 in the formula), and mono(C.sub.1-C.sub.4)alkyl-trisilanol and combinations thereof, and more preferably the silicon compound is orthosilicic acid or an oligomer thereof.

18. The pharmaceutical composition as claimed in claim 1, wherein the silicon compound is provided with a stabilizing agent inhibiting polymerisation of the silicon compound, wherein the stabilizing agent is preferably chosen from the group of amino acids, peptides and protein hydrolysates, organic acids, phenol and polyphenolic compounds, polyalcohols such as maltodextrine, quaternary ammonium compounds and aldehydes, preferably wherein the stabilizing agent is or comprises a quaternary ammonium compound, and wherein most preferably the stabilizing agent is choline.

19. The pharmaceutical composition as claimed in claim 1, wherein the magnesium is provided for oral administration as a magnesium salt, such as an inorganic magnesium salt and/or an organic magnesium salt, preferably an organic magnesium salt, more preferably at least two organic magnesium salts.

20. The pharmaceutical composition as claimed in claim 1, wherein the silicon compound is further provided with a binder material, said combination of silicon compound, stabilizing agent and binder being in granulate form, wherein the magnesium is in solid form and the granulate and the magnesium are present in the pharmaceutical formulation as a solid mixture.

Description

EXAMPLE 1

[0061] A male patient at an age of 79 years had recurrent muscle cramps during a period of 23 years. Muscle cramps occurred in skeletal muscles in hands, lower arms and legs, as well as in intercostal muscles. The patient was otherwise healthy, did not take any other medications, did not smoke and used coffee and alcohol as common, without being addicted thereto. Muscle cramps occurred during the day as well as during the night, at a frequency of several cramps per day. As a consequence, the muscle cramps prohibited working as a doctor and further prohibited swimming or any other sport. The patient had been subjected to a therapy of magnesium (as a salt), in a daily dose of 450 mg per day, which was not effective and did not provide any relief or inhibition of the muscle cramps. This ineffective result is consistent with the conclusions of Garrison (supra) and Young (supra), that magnesium supplementation is not effective in the treatment of muscle cramps.
The patient thereafter switched to a therapy comprising on a daily basis 10 mg stabilized silicic acid, wherein the silicic acid was in the form of orthosilicic acid and/or oligomers. The stabilizer was choline, which was administered at a daily dose of 200 mg. This combination is sold as Biosil® and is commercially available from Bio Minerals N.V., Destelbergen, Belgium. Use was made of the solid form of Biosil®. Two capsules per day were administered. The magnesium dose was 450 mg, and was in the form of magnesium phosphate, magnesium citrate, and magnesium bicarbonate. It was a dosage form of magnesium commercially supplied as Promagnor™ by Merck Consumer Healthcare nv, Overijse, Belgium.
The patient was free of cramps as of the night following the day at which he started with the therapy.

EXAMPLE 2

[0062] The patient of Example 1 continued therapy with the combination of bioavailable silicon and magnesium in the said daily doses for a period of 1 year. He remained free of cramps.

EXAMPLE 3

[0063] A 59-year old person underwent a foot operation to straighten the position of two toes and shorten two other toes. During revalidation after the operation, the person got muscle cramps in the operated foot. The muscle cramps occurred daily, in the course of the day and much more when the foot was tired. Furthermore, certain foot positions, such as those necessary for putting on socks and shoes, led to muscle cramps.
This person was given the combination of bioavailable silicon in the form of Biosil® in solid form (capsules) and magnesium in the form of Promagnor™. The daily doses were 10 mg Silicon (elemental weight) and 450 mg Magnesium (elemental weight). The choline stabilizer was therewith administered at a daily dose of 200 mg. Thereafter, cramps disappeared.

EXAMPLE 4

[0064] An 80-year old person had nocturnal muscle cramps during several years, leading to significant sleep disturbance and related tiredness. He was administered bioavailable silicon as Biosil® in solid form and magnesium as Promagnor™. The daily doses were 10 mg Silicon (elemental weight) and 450 mg Magnesium (elemental weight). The choline stabilizer was therewith administered at a daily dose of 200 mg. The cramps disappeared completely.

EXAMPLE 5

[0065] A 52-year old person employed as a nurse faced several muscle cramps during the day and at night. Furthermore, the person had issues with the joints. She was administered bioavailable silicon as Biosil® in solid form and magnesium in the form of Promagnor™′ The daily doses were 10 mg Silicon (elemental weight) and 450 mg Magnesium (elemental weight). The choline stabilizer was therewith administered at a daily dose of 200 mg. The person was free of cramps after a treatment of 10 days. Joint pains disappeared as well.

EXAMPLE 6

[0066] A 43-year old person being a nurse got cramps during running (sport). The cramps started after running about 2 km. The cramps occurred only during sport, hence incidental. She was administered bioavailable silicon as Biosil® in solid form and magnesium, in the form of Promagnor™. The daily doses were 10 mg Silicon (elemental weight) and 450 mg Magnesium (elemental weight). The choline stabilizer was therewith administered at a daily dose of 200 mg. The incidental cramps during running did not occur again.

EXAMPLE 7

[0067] A 75-year old person employed as a journalist was a kidney patient, undergoing dialysis three times per week, for four hours. Muscle cramps occurred during the day, at least once or twice a week, and particular in the hands, which made writing cumbersome. He was administered bioavailable silicon as Biosil® in solid form and magnesium, in the form of Promagnor™. The daily doses were 10 mg Silicon (elemental weight) and 450 mg Magnesium (elemental weight). The choline stabilizer was therewith administered at a daily dose of 200 mg. The cramps disappeared.

EXAMPLE 8

[0068] Female and male patients (age 33 to 86 years) experiencing frequent muscle cramps participated in a cross-over trial. The design of the cross-over trial is as follows: [0069] Period 1: 2 weeks orally 400 mg Mg/day (magnesium citrate), [0070] Period 2: 2 weeks orally 400 mg Mg/day+10 mg Si/day (magnesium citrate and choline-stabilized orthosilicic acid), [0071] Period 3: 2 weeks orally 200 mg Mg/day+5 mg Si/day (magnesium citrate and choline-stabilized orthosilicic acid). [0072] Parameters: patients recorded the frequency of cramps daily in a diary.

TABLE-US-00001 Case studies part 1 cramps/day Gender Previous B: 2 weeks C: 2 weeks Patient (M/F), treatment A: 2 weeks 400 mg Mg* + 200 mg Mg* + ID age (y) for cramps 400 mg Mg* 10 mg Si** 5 mg Si** 1 F, 78 magnesium 0.43 0.14 0.07 supplement 2 F, 86 magnesium 0.5 0.21 0.14 supplement 3 M, 56 quinine 0.43 0.57 0   sulfate 4 F, 33 magnesium 1.07 0.07 0.14 supplement 5 F, 52 none 0.36 0.36 0.07 6 F, 61 None 1.79 0.81 0.78 Mean 0.76 0.36    0.20 (****) SE (***) 0.23 0.12 0.12 *Magnesium (Mg) as magnesium citrate. **Silicon (Si) as choline-stabilized orthosilicic acid (ch-OSA ®, Bio Minerals N.V.). (***) SE: standard error. (****) Friedman analysis of variance p < 0.05. Post-test (Wilcoxon signed rank test): Treatment “A” versus “C”, p = 0.03.
These results illustrate clearly, that magnesium alone is not effective in reducing the frequency of cramps compared to the combination of the bioavailable magnesium supplement with a bioavailable silicon supplement. Moreover since several of these patients (1, 2, and 4) already took a magnesium supplement before the start of the study and continued to experience cramps. The results of patient (5) may show that the two-weeks period with 400 mg Mg/day+10 mg Si/day may be too short for achieving a reduction of muscle cramps.

EXAMPLE 9

[0073] Seven female and 4 male patients (age 27 to 86 years, mean age 56 years) experiencing frequent muscle cramps participated in a comparative trial with the following design: [0074] Period 1: During 1 week 11 patients either [0075] (a) continued with their oral magnesium supplement (6 patients), or [0076] (b) changed from their oral magnesium treatment (2 patients) to an oral magnesium supplement of 180 mg Mg/day (magnesium malate), or [0077] (c) changed from “no magnesium” pretreatment (3 patients) to an oral magnesium supplement of 180 mg Mg/day (magnesium malate). [0078] One patient had taken quinine sulfate prior to period 1. [0079] Period 2: all patients (n=11) took 4 weeks 360 mg Mg/day (magnesium malate)+10 mg Si/day (choline-stabilized orthosilicic acid, ch-OSA®) [0080] Parameters: patients recorded daily the frequency of cramps in a diary.
The results are as follows:

TABLE-US-00002 Number of cramps* Treatment Mean ± SE Week 1: magnesium 18.9 ± 7.4.sup.  Week 2: magnesium malate + ch-OSA ® 9.8 ± 4.6.sup.a Week 3: magnesium malate + ch-OSA ® 4.2 ± 6.9.sup.b Week 4: magnesium malate + ch-OSA ® 4.0 ± 2.8.sup.c Week 5: magnesium malate + ch-OSA ® 1.9 ± 3.9.sup.d *Friedman analysis of variance p < 0.05. Post-test (Wilcoxon signed rank test): .sup.aweek 1 versus week 2, p = 0.138; .sup.bweek 1 versus week 3, p = 0.026; .sup.cweek 1 versus week 4, p = 0.005; .sup.dweek 1 versus week 5, p = 0.0005.
These results show clearly that monotherapy of oral magnesium is not effective in relieving muscle cramps. As soon as the therapy is combined with a bioavailable, oral silicon compound such as choline-stabilized orthosilicic acid (ch-OSA®, Bio Minerals N.V.) the number of cramps are reduced compared to the magnesium monotherapy, reaching statistical significance after 2 weeks of combined treatment.
So, in summary, a pharmaceutical composition is provided that includes bioavailable silicon and bioavailable magnesium. The bioavailable silicon is preferably orthosilicic acid and/or oligomers thereof that is combined with a stabilizing agent for inhibition of polymerisation of orthosilicic acid. Most preferably, the stabilizing agent is a choline compound. The pharmaceutical composition can also be in the form of a combination of two or more separate formulations. Suitably, the said pharmaceutical composition and/or the formulations of the combination are both for oral administration. However, rectal administration is not excluded. In case of the use of separate formulations, both formulations may be administered at the same time, but can also be administered at different times during the day. In case of the use of separate formulations, it is preferred that a first formulation contains the silicon compound and a second formulation contains the bioavailable magnesium. However, it is not excluded that a first formulation comprises both bioavailable silicon and bioavailable magnesium, and a second formulation comprises one of bioavailable silicon and bioavailable magnesium. The use of the said pharmaceutical composition and the use of said pharmaceutical combination is deemed advantageous both in a method for prevention of muscle cramps, such as skeletal muscle cramps, and in a method for the inhibition and/or treatment of muscle cramps, such as skeletal muscle cramps. The use for the prevention of skeletal muscle cramps may include the administration prior to performance of a muscular activity, such as sports, running, yoga, competitive activities, such as exams, sport competition; travelling by car, bicycle and/or motor, more particularly during rush hours, Daily doses of bioavailable magnesium are in the range of 50-500 mg/day, preferably 50-200 mg/day for the prevention and 200-500 mg/day for the treatment of existing and recurrent skeletal muscle cramps. For emergency cases, a dose of 400-500 mg/day may be provided. The specified amount is on the basis of elemental magnesium as orally administered. Daily doses of bioavailable silicon are 3-20 mg/Si. For the prevention, a dose of up to 12 mg/day Si, such as up to 10 mg/day Si is preferred. For the treatment, a dose of at least 10 mg/day Si is preferred. The doses are herein specified on the basis of elemental silicon as orally administered.