HU207224B - Process for producing selenium-supplementing composition of bioactive vehicle - Google Patents

Abstract

Medicinal selerium replenishment to continuously maintain required levels in humans has powdered fruit base as a carrier contg. biologically valuable ingredients

Description

FIELD OF THE INVENTION The present invention relates to a pharmaceutical sustained release selenium supplement for complex support of antioxidant protection of the human body.

The physiological role of selenium is known to be so-called. an essential trace element that humans (mammals in general) can only take from external sources, food. Selenium is present in the form of selenocystin on the cell as part of the glutathione peroxidase enzyme system. This enzyme consists of four basic units and each basic unit needs one selenium atom to ensure proper enzyme activity. The most important function of this enzyme system is to inactivate hydrogen peroxides and other organic radicals formed in the cell by reduction. These are the so-called. free radicals are formed partly naturally (during fat metabolism) and partly due to external factors (radiation, chemicals, environmental poisons).

Free radicals are molecules or molecular fragments that contain a unique electron on their outer electron shell. From a medical point of view, free radicals from oxygen play an important role in the human body. These are commonly referred to as reactive oxygen intermediates (hereinafter referred to as "ROIs"). In living organisms, free radicals can be formed by external influences (UV, X-rays, chemicals, etc.) or by physiological processes in the body. Under physiological conditions, free radical reactions occur in all parts of the cell (eg mitochondrial, microsomal electron transport chain, autooxidation of biomolecules, cytoplasmic enzymes, plasma membrane of phagocytes). Physiological free radical reactions are under strict control; if they are released for some reason, pathological free radical reactions can occur. For example, the autooxidation of lipids in a living organism is normally a slow process. Bringing the lipid (R) with a free radical hydrogenation to the lipid free radical (R *) state can more easily react with molecular oxygen to produce a peroxy free radical (ROO *). This process is called lipid peroxidation, which does not end with this reaction but proceeds as a chain reaction. The effect of lipid peroxidation (LPO) is not limited to lipids, but through the resulting ROIs it can damage all essential biomolecules (proteins, nucleic acids, carbohydrates) under pathological conditions.

There are several defense systems in the body with different mechanisms of action against pathological free radical reactions; such a

- membrane structure control.

The rate of root reactions is influenced by the amount of unsaturated fatty acids in the cell membrane and the degree of unsaturation. To a lesser extent, this is determined by the fat content of the diet and mainly by genetic factors.

- antioxidants, radical scavengers

These are compounds that protect against the toxic effects of the resulting ROI. Effective protection requires that they are present in the cell at a sufficient concentration. Antioxidants act at different stages of free radical formation

1. inhibition of initiation (eg vitamin E),

2. chain interruption (eg vitamin C, E),

3. degradation of formed ROIs [glutathione peroxidase (selenium), thiols,]

4. metal chelation,

5. free radical scavenging (eg E, vitamin A).

- cellular, enzymatic protection

These are enzyme systems that maintain low oxygen concentrations in the cell and thus inhibit the formation of ROI. Most important are superoxide dismutases (SODs), which are Fe; Mn, respectively

They contain metalloproteins containing Cu + Zn.

The protection of cells of the human body against pathological free radical reactions is thus essential for the normal functioning and prevention of disease. ROIs are capable of damaging and disrupting all agents. The role of pathological ROIs in the development of morbidity and mortality statistics ("arthrosclerosis, malignant neoplasms, inflammation, chronic liver, stomach, bowel, immunological disorders, etc.) is at the forefront of the development of morbidity and mortality statistics. There are basically two tools in medicine for preventing pathological free radical reactions:

- regular replacement of bodily identical natural substances that ensure the smooth and effective functioning of the anti30 oxidant defense system. This is particularly important at the time of prevention; and

- use of synthetic antioxidant drugs (MTDQ; CATERGEN, etc.)

They are used in the therapy of established diseases.

Normal human serum selenium levels are 50 to 130 pg / l. Selenium is excreted in the urine from 5 to 30 pg / day. The amount of selenium needed to supplement the intake by age 40 varies as follows:

- infants: 10-40 pg / day for 0.5 years

- infants: 0.5-1 years 20-50 μg / day

- children; 1-3 years 20-80 μg / day

- Children: 4-6 years 30-120 pg / day

- for adults:

50-200 pg / day

In conditions of selenium deficiency due to inadequate selenium supply, the cell protective effect of glutathione peroxidase is reduced and this circumstance may play a crucial role in the development of many serious diseases.

Thus, selenium deficiency is an important risk factor, while adequate selenium supply ensures the long-term, effective functioning of this important protective function of the human body [G. N. Schrauzer, Münchener Med. Wochenschrift 127: 731 (1985); Berry J .: Canc. Gap. 44 (1984) 286455 2868; Brecci A .: Radiotion Slit. 38, 483-492 (1969)]. Currently, the population in the world, especially in industrialized countries, is in a state of greater or less selenium deficiency. According to surveys, today, most Americans and Europeans have less than 20 pg selenium from the eye point of defense

H 207 224 B via the diet [Clark L. C .: Nutrition and Cancer 6 (1984) 13; Yang G .: Amer. J. Clin. Nutr. 37: 872-881 (1983) Hartfiel W: Aktuelle Emahrungsmedizin 3: 75-116 (1988). There are basically two reasons for this: on the one hand low food selenium content and on the other hand nutritional habits (high fat, sugar, meat consumption).

The most important reason for selenium deficiency is that modern tillage methods have depleted the soil in selenium.

This has been confirmed by extensive investigations in the United States and the Federal Republic of Germany. Selenium uptake in crop and fodder crops is further reduced by the fact that due to acidification of the soil (acid rain) most of the selenium content of the soil is converted into a form that is not usable by the plants.

As a result of selenium deficiency

- decreases the overall resistance of the body;

- immunocompromised conditions;

- increase the risk of malignancies, cardiovascular disease (infarction, thrombosis);

- cellular protection against heavy metal (Pb, Hg) intoxication is weakened (G, N. Schrauzer, Münchener Med. Wochenschrift 727, 731 (1985)); Berry J .: Canc. Gap. 44: 2864-2868 (1984); Salonen J. T .: Brit. Med. J. 290, 417-420 (1985)].

To the best of our knowledge, appropriate selenium supplementation may play a role in the prevention and treatment of the following diseases [G. N. Schrauzer Münchener Med. Wochenschrift 727: 731 (1985); Berry J.; Canc. Gap. 44: 2864-2868 (1984); Brecci A .: Radition Slit. 38: 483-492 (1969); Salonen J. T .: Brit. J. Med. 290, 417-420 (1985); Moore J. A .: Cling. Chem. 30/7, 1171-1173 (1984)]:

a) Cardiological disorders

In patients with cardiomyopathy, coronary heart disease and acute infarction, decreased blood selenium levels are often found. Patients with high blood pressure have low levels of selenium in erythrocytes and platelets compared to healthy control subjects. Because selenium-dependent glutathione peroxidase also plays an important role in prostaglandin synthesis, at reduced selenium levels, this process is reversed, leading to an increase in platelet aggregation and vasoconstriction.

(b) Anti-cancer effect

Selenium has to distinguish between cancer prevention and cancer therapy.

There are several mechanisms underlying the protective action against cancer. As an inhibitor of various enzymes, selenium acts as a slow regulator of cellular metabolism and thus acts as a sensitive regulator or modulator of cell division. Slowing down cell division reduces or inhibits the development of DNA replication and transcription errors. In the case of viral induction, selenium inhibits the expression of oncogene. By chemical induction, selenium reduces chromosome damage caused by carcinogenic substances. The proven immune potentiating effect of selenium also enhances the protective effect against cancer. Numerous in vivo and in vitro animal studies have demonstrated the role of selenium in the prophylaxis of cancer by exact, scientific methods. Epidemiological surveys of large populations have shown that levels of selenium in the blood of cancer patients are significantly lower than in healthy groups and have not reached physiologically desirable levels.

In this context, it should be emphasized that cancer is not a selenium deficiency disease, but that low selenium levels have been shown to reduce resistance to carcinogens and to increase the risk of cancer.

Selenium has an important role to play and can play in cancer therapy. Higher doses have been shown to inhibit the growth of malignant tumors and reduce the resistance of tumor cells to cytostatic agents. In addition, adriamycin reduces the cardiotoxic and nephrotoxic side effects of cisplatin without affecting their antitumor activity.

Formulations that provide the human body with adequate selenium are also of great importance in preventing cancer and improving the effectiveness of cancer therapies.

c) Immune boosting effect

Selenium therapy in combination with vitamin E can achieve a potent immune-potentiating effect by significantly increasing immunoglobulin levels. In experimental animals, this treatment achieves lasting immunity to various infections (virus, bacteria, fungus, etc.).

d) The role of selenium in eye diseases

Adequate intake of selenium is required to maintain eye vision. Eyeglass lens protein is particularly rich in selenium and thus protects against free radical damage. There is a clear correlation between selenium deficiency and an increased incidence of cataracts.

(f) Protection against radiation

Inflammatory skin reactions caused by ultraviolet rays can be reduced or prevented by the addition of selenium. Organic selenium compounds have a protective effect against radioactive radiation.

Because attempts to artificially enrich the soil with selenium were unsuccessful, solutions aimed at using selenium formulations as part of nutrition came to the forefront.

It can be stated that while the administration of selenium supplements in veterinary and animal husbandry is a commonly used procedure, only a few initial attempts have been made in the human field. In many countries eg. practical oncology has not yet recognized the importance of such formulations.

The prior art does not provide similar solutions. Thus, Japanese Patent 54059309 discloses anti-inflammatory pharmaceutical compositions containing selenium derivatives (C.A. 91, 96638s, 1979). Administration of 0.051.0 mg / day selenium for pharmaceutical purposes

It is observed to reduce inflammation in body tissues by the use of an acceptable vehicle or diluent (such as water).

European Patent 91762 (C.A. 99, 211 516e, 1983) discloses a solution containing iron and selenium in a polysaccharide complex which can be used in veterinary medicine to compensate for iron and selenium deficiency.

These solutions do not affect the novelty of the invention.

Among the currently available selenium substitutes for human use, the following can be mentioned:

- Preparation of G-N-PHARM Arzneimittel GmbH (Stuttgart, Germany):

- "SELENASE"; 1 ampoule contains 100 µg of selenium in 2 ml of 0.9% NaCl solution as sodium selenite. It is available in two different forms: intramuscular injection and oral capsule.

- A G. RICHTER and Co. Kg. WELS Preparation:

- "KUPFER SELEN": oral (capsule for drinking), manufactured under license from the former company. Composition: 100 pg selenium

120 pg copper (II) ion.

Sodium selenite used in the compositions is a well-known compound.

These selenium supplements are only a substitute for deficiency, although antioxidant protection implies a combination of several processes.

In contrast, the advantage of the composition of the invention lies essentially in achieving this complex effect.

The bioactive carrier selenium replacement composition of the present invention, as a therapeutic agent, is a novel, economical, readily available means for preventing and treating organ damage and disease associated with selenium deficiency.

Field of application: regular, long-term supplementation of natural substances required for the antioxidant defense system of the human body in a healthy person, prevention of pathological free radical reactions by complex administration of the substances necessary for the functioning of cellular defense.

The bioactive carrier used is dried fruit powders produced by conventional means (crushing, drying, grinding, etc.). The main ingredient used in fruit powder is apple or pear. The dried fruit powder is mixed with a selenium chemical compound and then compressed to form tablets weighing 2-5 grams. Each tablet has a selenium content of approx. 50 - approx. 100 pg depending on formulation and use (prevention, therapy).

The fruit powder used as a carrier contains nutritionally valuable nutrients (fiber, minerals, trace elements, etc.) but also has a very low calorie content (carbohydrate, fat, protein).

Consequently, the carrier itself is a valuable bioactive agent.

Thus, the preparation positively influences all important factors of antioxidant protection since

- provides selenium for glutathione peroxidase activity, while

- bioactive carrier (fruit powder)

a) has a beneficial effect on lipid metabolism, lowers cholesterol and thus improves the ratio of unsaturated fatty acids,

(b) it contains antioxidant vitamins (vitamin C, etc.); and

(c) contain, at appropriate concentrations, the elements necessary for the function and production of key enzymes (eg SOD) in the antioxidant defense (Fe, Zn, Cu, Mn, etc.)

Fruit powders produced by various technologies are generally used for food purposes (additive, juices, etc.) (C.A. 103, 103 752w, 1985). This application is only incidentally related to health and preventive purposes, where it is generally desirable that foods should be physically beneficial.

The use of fruit powder as a bioactive carrier in the composition of the invention is completely new and does not result from the general food industry use of fruit powder. Use in a pharmaceutical composition requires additional conditions

- the composition,

- the exact dose,

physical characteristics appropriate to the type of application, etc. respect.

Average chemical composition of apple powder (% by weight):

- water: max 5%

- fiber: 15-18%

- organic acids: 3.5-4.0%

- vitamins: (C, B, B ₂ , PP, etc.)

- calorie value: 270 kcal / 100 g

- accompanying substances (paint, aroma, etc.): 1,5-0,3%

- inorganic substances, trace elements

Element Koncentrace al 19 B 15 ca 230 CD Below 0.5 Co Below 0.5 Cu 3.0 cr Below 0.4 Fe 47 K 5300 mg 270 Mn 3.0 So 27 Ni Below 0.7 P 370 S 190 sn 1.5 You 0.4 Zn 4.1

Comparison results of known compositions with those of the present invention can be summarized as follows:

HU 207 224 Β

I. Selenium formulations currently marketed for similar purposes contain the active ingredient (sodium selenite) in 0.9% aqueous NaCl. Selenium administered orally or parenterally is absorbed from the duodenum and the upper part of the intestine. Absorption and elimination are simultaneous processes and the result of the two determines the amount of physiologically utilized selenium remaining in the body.

The rate of absorption and elimination from the aqueous solution is high, so that a relatively low proportion of selenium ingested is utilized.

The present invention, whereby the selenium compound is applied on a large surface, solid bioactive carrier, ensures that the absorption occurs at a lower rate but at significantly higher rates and with a significantly lower rate and extent of elimination. With this "retard" effect, the application of the preparation with the same intake of selenium maintains a more stable and uniform level of selenium in the blood and tissues.

Thus, the present invention provides for a significantly more effective selenium replacement than previously used, as illustrated in Table I below.

Table 1% Clearance

Form of selenium intake Absorption % Stool Urine SE-BAH 70 18 11 SE-VO 44 40 23

Notes:

SE - BAH Sodium Selenite Bioactive Carrier (Formulation of the Invention)

SE-VO sodium selenite in 0.9% aqueous NaCl solution (known formulation) has the same dose of selenium (100 µg).

Π. Currently available human selenium replacement formulations are single-component. In contrast, the bioactive carrier component of the composition of the invention contains, in sufficient concentration, selenium (Fe, Cu, Zn, Mn, etc.) elements necessary for the function and formation of key enzymes (e.g., SOD) in antioxidant protection.

In the composition of the invention, the chemical form of selenium is selected according to the following compounds:

(a) Sodium selenite (Na ₂ SeO ₃ )

(b) Sodium selenate (Na ₂ SeO ₄ )

c) selenomethionine

d) selenocystine.

From a technological, stability, solubility point of view

Solutions a) and b) are preferred.

During the preparation of the composition

- the raw materials are certified by standard prescribed food control tests;

- checking the selenium content of the finished product by atomic absorption.

For selenium supplementation, the selectable compounds of the present invention exhibit low toxicity; selenite; selenate, szelenocisztin, selenomethionine LD ₅₀ values of 36 mg Se / kg body weight.

Selenium intake below 500 g / day (in adults) is still within the nutritional physiological range.

The following example of the preparation of the composition of the present invention is provided by way of illustration only and is not to be construed as limiting.

example

1. Weigh out 2 ± 0.1 mg of a 580 ± 20 g / l apple powder in a solid powder dispenser.

2. Add 200 ± 5 g of an aqueous solution of sodium selenite to the metered portions of apple powder according to claim 1 using a precision liquid dispenser.

Preparation of Selenite Solution: 1.095 ± 0.005 g of Na ₂ SeO ₃ is dissolved in 1 liter of doubly distilled pharma- ceutical water.

3. Portions of selenium-containing apple powder according to claim 2 are tabletted.

The apple powder composition thus prepared contains 100 ± 5 g of selenium per tablet.

By selecting the appropriate amount of the components (as will be apparent to those skilled in the art), a composition containing less than 100 g of selenium is prepared for children.

Selenium supplements, made with apple powder as a bioactive carrier, are intended to be a medicament in the form of a tableted formulation.

Areas of application:

- Continuous provision of physiologically optimal selenium levels in adults (1-2 tablets daily) for prevention;

- for therapeutic purposes, to supplement medicinal treatments

- oncology patients

- cardiovascular disease

- in hypertensive, hyperlipaemic disorders

- in immunocompromised states

- rheumatic diseases, etc.

The following clinical experience with the use of the product is reported.

(a) A 79-year-old male patient was investigated with clinical symptoms of chronic throat, dysphagia, and difficulty in swallowing. X-rays showed a narrowing process in the larynx.

Tumor marker tests (LSA, Neopterin, CEA) showed abnormalities suggestive of malignancy. A laryngeal examination diagnosed "in situ" laryngeal cancer. 1 week elapsed between diagnosis and histological sampling. During this time, the patient received an oral powder containing 100 gg of selenium powder 3 times daily. Subsequent histological examination revealed no malignancy. Repeated laryngeal examination recorded the disappearance of the tumor.

The patient's swallowing complaints ceased. The values of the tumor marker tests were significantly reduced. The patient continued to receive the product continuously.

HU 207 224 B

Tumor marker tests performed after 1 month showed normal values.

The patient is 6 months later without complaints, well-being and no abnormal laboratory examination.

(b) a 51-year-old male patient presented for examination 2 months after receiving a colonic collapse II. stage II malignancy. Indicated digestive complaints. Tumor marker studies showed a moderate increase. The clinical trial was negative. The patient received continuous selenium-enriched apple powder. Her complaints disappeared within 1 week and her well-being continued to improve. Monthly laboratory control during the 8-month course showed a normal pattern.

As an added benefit, abnormally high total cholesterol and LDL cholesterol levels were also normalized.

The patient is still taking the product continuously.

c) A 6-year-old girl was diagnosed with combination therapy (vincristine, adriamycin, cyclophosphamide) against Ewing's sarcoma. Simultaneously, he received a selenium-enriched apple powder as an adjuvant.

The side effects (hair loss, nausea, etc.) that are required during cytostatic treatment - surprisingly few experienced or extremely mild by experienced physicians. However, the studies showed that the treatment was extremely effective.

Hepatic function tests showed no evidence of hepatic impairment, demonstrating that adjuvant treatment effectively prevented hepatic toxicity.

d) To investigate the effect of apple powder-selenium combination on the risk factors of cardiovascular disease. To this end, we set up a group of 60 people, with ages ranging from 34-67.

They all had significant excess body weight and were associated with hyperlipaemia. Patients were on a cholesterol-poor diet of 1000 cal / day for 6 weeks.

Patients were divided into two groups:

Group I (30 people) received a diet supplemented with selenium-enriched apple powder 3 times daily;

II. Group (30) received only a cholesterol-poor diet.

Results:

After treatment, changes in the studied parameters from baseline were assessed in both groups; the data are given in the following Annex II. is shown in Table.

II. spreadsheet

Group 1 II. group Weight - 9% - 5.8% Összkolesztcrin -30% -26.0% LDL cholesterol -39% -34.0% uric acid -42% -33.0% Serum iron + 27% + 7.0%

Group I members were more rapidly adapted to treatment conditions and reported improved well-being from the first week of treatment. Blood pressure values in the group, formerly suffering from hypertension, were rapidly reduced or normalized.

Claims (4)

PATENT CLAIMS A process for the preparation of a sustained release selenium formulation with a bioactive carrier, characterized in that: Thirty fruit powders as bioactive carriers are admixed with a physiologically degradable selenium compound and the mixture is formulated for oral administration. A process according to claim 1, characterized in that: 35 using powdered apple or pear powder as the fruit powder. The process according to claim 1, wherein the selenium compound which is degradable under physiological conditions is sodium selenite, sodium selenate, selenomethionine or selenocystine. 4. The method of claim 1, wherein the selenium compound is used in an amount of from 50 to 100 µg / dosage unit.