DE202010012099U1 - Vitamin composition and dosage form comprising vitamin D3 suitable for osteoporosis prophylaxis and / or treatment - Google Patents

Abstract

Composition comprising vitamins B, D and optionally vitamin K or their physiologically suitable derivatives or salts in physiologically effective concentrations.

Description

The The present invention is directed to a vitamin-containing composition directed, wherein the vitamins are selected from the group consisting of vitamin D, vitamin B, and vitamin K and to a dosage form, comprising such a composition, wherein the composition and the dosage form preferably for the prevention and / or Treatment of osteoporosis are suitable, as well as for use the composition.

Technical background

The risk of osteoporosis, a disease of the skeleton, increases in men and women with age, especially post-menopausal women show symptoms of this disease, which is characterized mainly by low bone density, which leads to bone fractures. This condition is associated with a significant reduction in quality of life and an increase in mortality. Furthermore, for example, smoking, medications such as antiepileptic drugs, antidepressants, sedatives, glucocorticoids, diseases such as diabetes mellitus, Cushing syndrome and low vitamin D serum concentrations increase the risk of osteoporosis. The administration of vitamin D, in particular 25-hydroxyvitamin D ₃ (cholecalciferol) with a serum concentration of> 20 ng / ml or 1-alpha-hydroxy-vitamin D ₃ , improves the condition of the disease and leads to a lower fall rate.

One serious vitamin D deficit is preventable for example that the face and the arms daily 30 minutes of the daylight get abandoned. However, some factors can affect the individual Increase the need for daylight, such as the season, the skin type, age-related changes in the Skin (senile lentigo) and secondary conditions such as Diabetes mellitus. In case of insufficient daylight exposure or pre-existing prevalence for a serious one Vitamin D deficit, should be vitamin D as a dietary supplement or administered as a drug. The gift of vitamin D has a positive effect on the treatment of osteoporosis within less months.

Dual energy X-ray absorption (DXA, formerly DEXA) is the gold standard for the diagnosis of osteoporosis. Osteoporosis is when bone mineral density is less than or equal to 2.5 standard deviations below the reference adult population (T-score). According to the World Health Organization (WHO), a T-score of -1.0 or greater is "normal", a T-score between -1.0 and -2.5 is considered "low bone mass" (or osteopenia), while a T-score of -2.5 or lower classified as osteoporosis ( WHO Scientific Group for the Prevention and Management of Osteoporosis, Geneva, Switzerland (2003) ). In addition to bone mineral density based diagnosis, the occurrence of two or more typical osteoporotic fractures justifies the use of medical therapy. In the case of manifested osteoporosis, medication is given by prescribing medicines such as bisphosphonates (for example sodium alendronate, risedronate), selective estrogen receptor modulators such as raloxifene, estrogen replacement therapy and monoclonal antibodies such as RANKL inhibitors such as densumab.

However, before these symptoms, vitamin supplement is displayed with Vitamin D ₃ plays a significant role in the prevention and / or the concomitant treatment of osteoporosis.

Non-specific multivitamin supplements are not advisable to the quantities required for the osteoporosis prevention and / or treatment vitamins displayed as vitamin D ₃ and achieve folic acid, without this leading to an overdose of other active ingredients. For example, vitamin A is often included in multivitamin supplements, but this is associated with an increased risk of hip fracture when taken in high doses ( Feskanich D et al., JAMA, 2002; 287; 47-54 ).

Until recently, therapeutic limits for deficiencies in osteoporosis-relevant vitamins were an important topic of discussion regarding the toxicity of maximum intake limits, with only a modest approximation of actual needs ( Veith R, J of Nutr, 2006, 1117-1122 ). For example, in 2000, the German Nutrition Society (DGE) recommended 5 μg or 200 IU of vitamin D ₃ per day for people under 65 years and 10 μg or 400 IU for people over 65 years. In 2002, the European Food Safety and Health Commission (SCF) increased the upper tolerable level (UL) of vitamin D ₃ to 50 μg per day.

Vitamin D ₃ preparations which are suitable for the prevention and / or treatment of osteoporosis are, for example, in DE 203 10 493 U1 . WO 2007/046123 . WO 99/00135 , and EP 0 335 140 described. The content of vitamin D ₃ varied, for example, from a low level such as 1.0-15.0 μg to 5.0-20.0 μg and up to 10-40 μg.

Vitamin D ₃ generated with the help of UV light increases the serum concentration of vitamin D ₃ more slowly than vitamin D ₃ , which is administered orally, leading to the assumption that the toxicity is oral vitamin D _{3 is} higher, since this path is unnatural ( Haddad J et al., Journal of Clinical Investigation, 1993, 91 (6): 2552 ). In the case of an unlikely daily excess of vitamin D ₃ such as 50,000 IU (BfR 2004), unnaturally high levels of calcium (hypercalcemia) are caused which can lead to over-calcification of the bones, soft tissue, heart and kidneys. Furthermore, damage to the kidneys and the formation of kidney stones as well as hypertension can occur. Symptoms of a vitamin D ₃ overdose occur only a few months after excessive administration. Followed by a low calcium diet combined with corticosteroids, a full convalescence within one month is regularly observed.

WO 99/00135 . DE 203 10 493U1 , and WO 2007/046123 describe synergistic effects for the combination of vitamin K and vitamin D ₃ in the prevention and / or treatment of osteoporosis. The range of vitamin D ₃ concentrations used, for example, ranges from 120 μg, 100-300 μg to 70-1000 μg. However, recommended ULs vary between 10000 μg (SCF) and 80 μg according to the Federal Office for Risk Assessment in 2004.

vitamin D and calcium are commonly used in combination preparations administered together, preferably for prevention and / or treatment of osteoporosis, wherein the calcium concentration is "healthy" for normal People often too high and the vitamin D concentration often too low.

The problem underlying the present invention is a preparation, in particular a combination preparation that improved Compensation of vitamin deficiencies allowed and preferably prevention and / or treatment of osteoporosis.

description

The present invention relates to a composition comprising vitamins B, D and K for use in the prevention and / or treatment of osteoporosis, which is a disease of the skeleton characterized by low bone density and microarchitectural deterioration leading to progressive bone fragility and leads to fractures. Preferred vitamins of the composition are vitamin B ₆ , vitamin B ₉ (folic acid), vitamin B ₁₂ , vitamin D ₃ and optionally vitamin K, preferably vitamin K ₁ or vitamin K ₂ , or physiologically suitable derivatives or salts of the vitamins, preferably in physiologically effective Concentrations, as well as to a use of the composition.

Vitamin D ₃ is the physiological form of vitamin D in all eukaryotes except plants. The synthesis of the precursor 7-dehydrocholesterol is induced by UV light. In addition to its influence on autocrine functions, immunomodulation and apoptosis, D _{3 is} a determinant of calcium serum level regulation and consequently of bone formation. The incremental intake of 1 μg vitamin D ₃ per day increases serum concentrations by about 1 nmol / l or 0.4 μg / l. Currently, both the European and American guidelines for the daily dose (RDA) recommend a relatively low level of 400 IU or 10 μg, which corresponds to a serum concentration of 4 μg / L.

Toxic effects can only be expected from a serum concentration above a limit of 200 μg / l ( Veith R, J of Nutr, 2006, 1117-1122 ). It has been found that endogenous vitamin D ₃ synthesis reaches up to 10000 IU per day, which underlines the high physiological tolerance of elevated vitamin D ₃ levels ( Vieth R, The American Journal of Clinical Nutrition, 1999, 69 (5): 842-856 ).

Vitamin B ₆ (pyridoxine) is involved in the physiological balance of sodium and potassium and favors the production of red blood cells. Of particular importance in the field of osteoporosis is the finding that vitamin B _{6 contributes} to a reduction in homocysteine formation ( Christen W, Arch Intern Med. 2009; 169 (4): 335-341 ), which is associated with an increased risk of hip fractures in post-menopausal women ( LeBoff M, J Clin Endocrinol Metab, 2009, 94, 1207-1213 ).

Vitamin B ₉ (folic acid) is a water-soluble vitamin that plays a fundamental role in the synthesis of nucleic acids and therefore has great importance in phases of high cell proliferation rates, such as during pregnancy. The RDA for pregnant women is 400 μg vitamin B ₉ . There is a continuing scientific discussion that folate deficiency can lead to elevated homocysteine levels, which in turn leads to an increased risk of bone fractures, osteoporosis and reduction in BMD ( Haliloglu B et al., Arch Gynecol Obstet., 2009 Nov 28 ).

Vitamin B ₁₂ (cobalamin) is a water-soluble vitamin that is involved as a cofactor in enzyme-catalyzed reactions, including the reactions of isomerases and methyltransferases. Vitamin B ₁₂ is involved in the metabolism of every body cell, and has particular effects on DNA synthesis and regulation, but also on fatty acid synthesis and energy production. Although the functions of vitamin B _{12 can be} replaced by sufficient amounts of folic acid (vitamin B ₉ ) in many conditions, the control of the Homocysteine levels excluding vitamin B ₁₂ .

Vitamin K, for example, phylloquinone K ₁ and menaquinone K ₂ , mediates gamma-carboxylation of glutamyl residues on numerous bone proteins, especially osteoclacin. High serum concentrations of insufficiently carboxylated osteoclacin and low serum vitamin K levels are associated with low bone mineral density and increased risk of fractures ( Feskanich D et al., Am. J. Clin Nutr, 1999, 74-79 ).

The The present composition is preferably a dietetic one Product that is intended to help people's diet supplement to deficiencies of certain essential nutritional factors prevent or reduce it.

In In a preferred embodiment, the combination of Vitamins in the present composition have a synergistic Effect on the prevention and / or treatment of osteoporosis. osteoporosis is typically found in primary and secondary osteoporosis divided, with primary osteoporosis type I and type II Includes osteoporosis. Type I Osteoporosis (post-menopausal osteoporosis) generally develops in postmenopausal women when the amount of estrogen in the body drops significantly. This process leads to an increase in bone resorption (the bone loses substance). Type I osteoporosis occurs in 5% up to 20% of women on, most often between the ages 50 and 75, because of the sudden post-menopausal rubbish estrogen levels, resulting in a rapid release of Calcium from the skeleton leads. This is with bone fractures connected, which occur when the vertebrae press against each other which leads to the collapse of the spine and with fractures of the hip, the wrist, the Forearm caused by falls or minor accidents. Here, women show a significantly higher type I osteoporosis risk as men.

Type II Osteoporosis (senile osteoporosis) typically occurs after one Age of 70 years and meets women twice more often as men. Type II osteoporosis arises when the absorption and formation of bone is no longer coordinated and bone resorption outweighs bone formation. Type II osteoporosis affects trabecular and cortical bone, which is often too Fractures of the femoral neck, vertebrae, proximal Humerus, proximal tibia and pelvis. Type II osteoporosis may be due to an age-related condition Reduction in vitamin D synthesis or resistance to vitamin D Activity (possibly mediated by decreased or unresponsive vitamin D receptors in some patients). In older Women commonly experience type I and type II osteoporosis on.

secondary Osteoporosis is caused by other conditions such as hormonal imbalance, certain diseases or medications (such as corticosteroids). Secondary osteoporosis accounts for less than 5% of osteoporosis cases out. Causes include endocrine disorders (for example Glucocorticoid excess, hyperparathyroidism, hyperthyroidism, Hypogonadism, hyperprolactinemia, diabetes mellitus), drugs (for Example, glucocorticoids, ethanol, dilantin, tobacco, barbiturates, Heparin), and various conditions or clinical pictures (for example, immobilization, chronic renal failure, liver disease, Malabsorption syndromes, chronic lung disease, RA, sarcoidosis, Malignancy, longer weightlessness as with all-flights) one.

The Composition or dosage form of the present invention are in the prevention and / or treatment of primary and / or secondary osteoporosis most effective.

In a further preferred embodiment, the composition of the present invention comprises or consists of 1000-10000 μg, 1000-9000 μg, 1000-8000 μg, 1000-7000 μg, 1000-6000 μg, 1000-5000 μg, 1000-4000 μg, 1000 -3000 μg, 1000-2000 μg, or 500-1500 μg Vitamin B ₆ , 200-1000 μg, 200-900 μg, 200-800 μg, 200-700 μg, 200-600 μg, 200-500 μg, 200- 400 μg, 200-300 μg, or 100-200 Vitamin B ₉ (folic acid), 1.0-10.0 μg, 2.0-10.0 μg, 3.0-10.0 μg, 4.0- 10.0 μg, 5.0-10.0 μg, 6.0-10.0 μg, 7.0-10.0 μg, 8.0-10.0 μg, or 9.0-10.0 μg Vitamin B ₁₂ , 800-5000 IU, 800-4000 IU, 800-3000 IU, 800-2500 IU, 800-2000 IU, 800-1500 IU, or 800-1000 IU Vitamin D ₃ , with 1000 IU Vitamin D ₃ 25 μg of vitamin D ₃ and optionally 50-500 μg, 50-400 μg, 50-300 μg, 50-200 μg, or 50-100 μg of vitamin K. More preferably, the composition of the present invention comprises or consists of 800 μg, 1000 μg, 1200 μg, 1400 μg, 1600 μg, 2000 μg, or 2500 μg Vitamin B ₆ , 200 μg, 400 μg, 600 μg, 800 μg, 1000 μg, 1200 μg, 1500 μg, or 2000 μg Vitamin B ₉ (folic acid), 1.0 μg, 2.0 μg, 3.0 μg, 4.0 μg, 5.0 μg, 6.0 μg, 7.0 μg, 8.0 μg, 9.0 μg , or 10.0 μg of vitamin B ₁₂ , 1000 μg, 1500 μg, 2000 μg, 2500 μg, 3000 μg, 3500 μg, 4000 μg, 4500 μg, or 5000 μg of vitamin D ₃ and optionally 25 μg, 35 μg, 45 μg , 55 micrograms, 65 micrograms, 75 micrograms, 85 micrograms, 95 micrograms, or 110 micrograms of vitamin K. Most preferably, the composition or dosage form yields vitamin D ₃ serum levels greater than 75 nmol / l.

In a preferred embodiment, one or more Vitamins of the composition by a derivative or a salt of the Vitamin replaced, which is pharmaceutically suitable.

In addition, the composition optionally comprises one or more carriers selected from the group consisting of disintegrants, binders, lubricants, in particular internal lubricants, rheological agents, additives or additives, coatings or shell-forming polymers, in particular half-shell-forming polymers, and dyes. Preferred carriers are, for example, selected from the group consisting of starch, in particular maize starch, cellulose, hydroxypropylmethylcellulose, cholecalciferol dry powder, phylloquinone, magnesium salts of fatty acids, cyanobalamin, pyridoxine hydrochloride and folic acid, hydroxypropylmethylcellulose, cholecalciferol dry powder and / or phylloquinone being preferred coatings and magnesium salts of fatty acids, Cyancobalamin, pyridoxine hydrochloride and / or folic acid are preferred release agents.

In a preferred embodiment comprises the composition no calcium or salts thereof of the present invention. That reduces or prevents the risk of overdose of calcium over the daily limit of 1000-1500 mg.

The The present invention is further directed to a dosage form, which comprises the composition of the present invention or it consists. In a preferred embodiment the composition or dosage form of the present invention a solid dosage form, in particular a partially solid dosage form. Preferably, such a dosage form is selected from the group consisting of hard or soft shell capsules, which For example, plug-in, cylindrical molds or a soft, continuous shell, a tablet, a pill or dragee, drops or granular material. In a particularly preferred embodiment, the Composition released immediately from the dosage form, wherein the dosage form is particularly preferably a capsule.

The Composition or dosage form is preferably administered orally, wherein the composition or dosage form once or several times daily, preferably two, three or four times a day is administered. In another embodiment the composition or the dosage form once or several times per week, preferably two, three, four, five or six times per week, or once or several times a month, preferably two-, three, four, five, six, seven or eight times a month administered. Preferably, the composition or dosage form becomes taken with a meal.

In Another embodiment is the composition or the dosage form a complementary dietary one Food, in particular a supplementary balanced Diet.

Farther the present invention is directed to the use of the composition or the dosage form for prevention and / or treatment directed by osteoporosis. The gift of the composition or The dosage form is preferably carried out according to the above Patterns, z. B. once or several times a day, once or several times monthly etc., both for prevention and for treatment of osteoporosis.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• - DE 20310493 U1 [0008, 0010]
• - WO 2007/046123 [0008, 0010]
• WO 99/00135 [0008, 0010]
• - EP 0335140 [0008]

Cited non-patent literature

• - WHO Scientific Group for the Prevention and Management of Osteoporosis, Geneva, Switzerland (2003) [0004]
• Feskanich D et al., JAMA, 2002; 287; 47-54 [0006]
• Veith R, J of Nutr, 2006, 1117-1122 [0007]
• - Haddad J et al., Journal of Clinical Investigation, 1993, 91 (6): 2552 [0009]
• Veith R, J of Nutr, 2006, 1117-1122 [0015]
• Vieth R, The American Journal of Clinical Nutrition, 1999, 69 (5): 842-856 [0015]
• - Christians W, Arch Intern Med. 2009; 169 (4): 335-341 [0016]
• LeBoff M, J Clin Endocrinol Metab, 2009, 94, 1207-1213 [0016]
• Haliloglu B et al., Arch Gynecol Obstet., 2009 Nov 28 [0017]
• Feskanich D et al., Am. J. Clin Nutr, 1999, 74-79 [0019]

Claims (14)

Composition comprising vitamins B, D and optional Vitamin K or its physiologically suitable derivatives or salts in physiologically effective concentrations. A composition according to claim 1, wherein the vitamins are vitamin B ₆ , vitamin B ₉ , vitamin B ₁₂ , vitamin D ₃ and optionally vitamin K. A composition according to claims 1 or 2, wherein the vitamin K, vitamin K ₁ or vitamin is K ₂ . A composition according to any one of claims 1-3, wherein the vitamins are present in the following amount: a) Vitamin D ₃ 800-2000 IU b) Vitamin B ₆ 1000-3000 μg c) Vitamin B ₉ 200-800 μg d) Vitamin B ₁₂ 2.0-10.0 μg e) Vitamin K 50-100 μg. A composition according to any of claims 1-4, wherein the vitamins are contained in the following amounts: a) Vitamin D ₃ 1000 IU b) Vitamin B ₆ 1200 μg c) Vitamin B ₉ 400 μg d) Vitamin B ₁₂ 3.0 μg e ) Vitamin K 65 μg. Composition according to one of Claims 1-5, wherein the composition is free calcium or free of a calcium salt. Composition according to one of Claims 1-6, comprising one or more carriers selected from the group consisting of disintegrants, binders, lubricants, Theological additive, coating or shell-forming polymers and Dyes. Dosage form comprising a composition according to one of claims 1-7, which is a solid dosage form is. Dosage form according to claim 8, which is a capsule with a hard shell or a soft shell is, a tablet or granular material. Use of a composition according to one of claims 1-7 or a dosage form according to claim 8 or 9 for prevention and / or treatment of osteoporosis. Use of a composition or dosage form according to claim 10, wherein the administration is oral. Use of a composition or dosage form according to claims 10 or 11, which is 1-3 × per Day or once a day. Use of a composition or dosage form according to any one of claims 10-12, which results in a serum concentration of vitamin D ₃ greater than 75 nmol / l. Use of a composition or dosage form according to any one of claims 10-13, which is a complementary dietary food is.