DE2366498C2 - - Google Patents

Description

The invention relates to agents suitable for systemic administration with therapeutic and prophylactic effects on pathological calcium phosphate metabolism.

Numerous pathological conditions in warm-blooded animals are through abnormal mobilization of calcium and phosphate featured that go to general or specific Bone loss and / or excessively high calcium and lead to phosphate levels in the body fluids. These pathological conditions include osteoporosis, a pathological process in which bone hard tissue in the Disproportion to the development of new hard tissue lost goes. A distinction is made in osteoporosis post-menopausal, the senile and those caused by drugs (e.g. adrenocorticoids in steroid therapy) Osteoporosis, also caused by pathological changes (e.g., arthritis or tumors) and the like Osteoporosis. The symptoms are essentially the same.

Another, with abnormal mobilization of calcium and Phosphate-related disease is Paget's disease  (Osteitis deformans). With this disease, dissolution occurs normal bone, which is then replaced by soft, weakly mineralized tissue to be replaced so that the bones deformed by the weight on them especially the shins and thighs.

Until recently, medical treatment was unsatisfactory of diseases with abnormal mobilization of Calcium phosphates present, albeit dietary requirements, Administration of fluorides, estrogens and the hormone calcitonin (Thyrocalcitonin) proposed and tested in such cases were. Recently it has been found that certain Phosphate compounds in the treatment of these Diseases are effective. Address the following US PS deal with the use of various phosphates for treatment of the diseases described above: U.S. Patent 3,683,080; 36 78 164; 36 62 066; 35 53 314; 35 53 315; 35 84 124; 35 84 125; and 36 41 246.

With those proposed in the above patents Means and methods can be used to treat morbid effectively Conditions like osteoporosis can be achieved. Higher Doses of these agents, however, can be disadvantageous physiological Produce effects. At higher doses of compounds such as B. disodium ethane-1-hydroxy-1,1-diphosphonate Mineralization errors occur, d. H. lack of mineralization the trained bones (increased osteoid sutures) or inhibition of growth cartilage mineralization and / or inhibition of primary cancellous bone absorption in the epiphyseal area of the bones of rapidly growing animals.

It has now been found that therapeutic efficacy of ethane-1-hydroxy-1,1-diphosphonic acid or whose salts can be increased to an extent that lower dosages will be applicable if one at the same time certain Vitanim D₂- and D₃-like antirachitic Compounds administered. The invention Agents are therefore improved agents for treatment of diseases with abnormal mobilization of Calcium phosphate in animal tissues.

The invention relates to a for systemic administration suitable agent containing

• (1) ethane-1-hydroxy-1,1-diphosphonic acid or its pharmaceutically acceptable salts and
• (2) 100 to about 50,000 international units of a vitamin D₂- or D₃-like antirachitic compound in the form of vitamin D₂ (ergocalciferol), dihydrotachysterol₃, 25-hydroxycholecalciferol, 1α , 25-dihydroxycholecalciferol, 5,6-trans-cholecalcifcrol, 5,6-trans-25-hydroxycholecalciferol, and 1 α-hydroxycholecalciferol.

Suitable pharmaceutically acceptable salts of ethane-1-hydroxy-1,1-diphosphonic acid are z. B. alkali metal (Sodium or potassium), alkaline earth metal (calcium and magnesium) salts, non-toxic heavy metal salts (tin (II) and indium) and ammonium and low molecular weight substituted Ammonium (mono-, di- and triethanolamine) salts.

Mixtures of the above salts are used.  

The ethane-1-hydroxy-1,1-diphosphonic acid has the Formula CH₃O (OH) (PO₃H₂) ₂. The connection can also be used as 1-hydroxyethylidene diphosphonic acid can be called.

Although all pharmaceutical compatible salts of ethane-1-hydroxy-1,1-diphosphonic acid are useful, the use of the disodium dihydrogen salt a preferred embodiment. The other natrim, potassium, ammonium and mono-, di- and triethanol ammonium salts and mixtures thereof are also suitable, provided that the total picture of the individual cations in the salt mixture carefully observed becomes. These compounds can be any suitable Methods are made; a particularly suitable one The method is disclosed in US Pat. No. 3,400,149.

The vitamin D₂ or D₃-like usable according to the invention antirachitic compounds are commercially available or can from their precursors (ergosterol and 7-dehydro-cholesterol) under the influence of energy on the molecule getting produced. The energy can be generated by UV radiation, Electrons of high speed and the like are supplied. These precursors are themselves vitamin D-like antirachitic compounds and can be administered as such and then in vivo under the influence of Sunlight can be converted into D vitamins.

The connections and their properties are detailed in H.R. Rosenberg "Chemistry and Physiology of the Vitamins", Pp. 341-432 (1945).  

The following table contains the invention usable vitamin D₂ and D₃-like compounds with references to the manufacturer of these connections or on synthetic methods and also the activity in international units (I. U :) per µg.  

Table I

For the definition of international unity see. U.S. Pharmacopia, 15th edition of Mack Publishing Co. (1955).

The international unity is not only fully recognized for vitamin D itself. The activity of vitamin D₂- and D₃-like antirachitic compounds is often given in the literature in international units, and since this measure of biological activity is the most suitable determinant of the amounts of vitamin D-like compounds to be used according to the invention, this description describes this Term worked. The amount of vitamin D₂ and D₃-like antirachitic compound must be sufficient according to the invention to provide about 100 to about 50,000 international units per day. Antirachitic compounds preferred according to the invention are 1 α -25-dihydroxycholecalciferol and 1 α -hydroxycholecalciferol, since they are already effective in particularly low doses.

The amount of phosphonate required depends on the one to be treated Condition of disease, the severity of the condition and the duration of treatment from. Single doses can be between 0.01 and 500 mg / kg body weight and preferably between 0.1 and 50 mg / kg, with up to 4 doses administered daily can be. The higher doses within of the specified range refer naturally due to the limited absorption on oral administration. Repeated doses greater than about 400 mg / kg can cause toxic symptoms and should be avoided will. In addition, daily doses of more than about 2000 mg of active ingredient per kg of body weight to achieve the desired Effect not needed, moreover you can produce toxic side effects. With doses less than about 0.01 mg / kg will not pathological demineralization noticeably influenced, not even with intravenous administration.  

The following Table II shows doses for various disease states:

Table II

The phosphonates can also be administered parental in aqueous solution through subcutaneous, intradermal, intramuscular, intraperitoneal or intravenous injection. Here the following doses are preferred.

Subcutaneous 0.1-10 mg / kg Intradermal 0.1-10 mg / kg Intramuscular 0.05-5 mg / kg Intravenous 0.05-5 mg / kg Intraperitoneal 0.05-5 mg / kg

For oral administration, which is preferred, the Diphosphonates are in the form of elixirs or in Dose units may be formulated, e.g. B. in the form of capsules, Tablets or pills that are also the vitamin D₂ and D₃-like antirachitic compounds  and contain a pharmaceutical carrier, each Dose unit 5 mg to 10 g of diphosphonate and about 100 to has about 50,000 units of the antirachitic compound. The preferred diphosphonate amounts in unit doses for administration to humans and smaller pets between 10 and 100 mg, particularly preferably between 50 and 500 mg, while the preferred range of antirachitic Connection between 500 and about 50,000 international Units.

To demonstrate the technical progress of the invention Means in preventing or reducing EHDP-induced Mineralization errors, d. H. lack of mineralization the trained bones (increased osteoid sutures) the following experiments were carried out.

120 Sprague-Dawley rat males (160-180 g) were random divided into 15 groups of 8 animals, treated as follows were:

Treatments

EHDP, α 1, 25- (OH) ₂CC and the control compound (isotonic saline) were administered by subcutaneous injection. Treatments were started on day 1 of the trial and lasted 7 days. The trial was terminated after 14 days, after which all animals were sacrificed and shin samples were taken for histological examination. These samples were stained to distinguish mineralized bones from embedded osteoid tissue (non-mineralized bones) and sections were made. The sections were then scored using the point counting technique to determine the relative amounts of osteoid tissue present in the sections of the tibia. The data were expressed as% osteoid tissue, calculated using the following formula:

in which
O = osteoid counts and MB = mineralized bone counts.

The following results were obtained.

Effect of 1 α , 25- (OH) ₂CC on EHDP-Induced Inhibition of Mineralization in Rats; % Osteoid tissue in the tibia bark (mean value ± usual error limit)

Further attempts to keep up with technical progress the other embodiments of the invention Document by means of Boris et al., J. Nutr. 108: 1899-1906 (1978).

example 1

In a conventional way, capsules are made from the following ingredients produced:

The capsules are administered orally twice a day, thereby the bone decalcification of a patient of about 70 kg Body weight suffering from osteoporosis is noticeably restricted.

Example 2

In a conventional manner, tablets are made from the following Ingredients manufactured:  

With oral administration 4 times a day, the above Mixture of bone loss in a patient weighing approximately 50 kg Body weight suffering from Paget's disease noticeably reduced.

If you replace the lactose in the above formulation Sucrose and the magnesium stearate through sodium carboxymethyl cellulose, so will the properties of the tablet not changed.

Examples 3 to 10

Further tablet formulations are obtained from the following ingredients:

such as  3000 international units of the following vitamin D₂ or D₃-like antirachitic compounds:

The tablets are given to a patient weighing 70 kg administered who suffers from Paget's disease. The administration is such that a daily dose of about 500 mg of polyphosphonate is ensured. Hereby the bone loss is noticeably reduced, at the same time no negative symptoms are observed.

Similar results are obtained when using the above tablets administered to a patient weighing 70 kg, who has osteoporosis. The administration takes place in such a way that achieved a daily dose of about 250 mg polyphosphonate becomes.

Claims (1)

Agent suitable for systemic administration, containing

• (1) ethane-1-hydroxy-1,1-diphosphonic acid or its pharmaceutically acceptable salts and
• (2) 100 to about 50,000 international units of a vitamin D₂- or D₃-like antirachitic compound in the form of vitamin, D₂ (ergocalciferol), dihydrotachysterol₃, 25-hydroxycholecalciferol, 1 a , 25-dihydroxycholecalciferol, 5,6-trans-cholecalciferol , 5,6-trans-25-hydroxycholecalciferol and 1 α -hydroxycholecalciferol.