DE3343253A1 - Fluoride tablet with delayed release of active ingredient and process for its production - Google Patents

Abstract

The tablet contains 8 to 20 parts of a water-soluble fluoride, preferably sodium fluoride, 35 to 45 parts of sugar, 1 to 10 parts of talc and 1 to 5 parts of magnesium stearate per 100 parts by weight. These components are dispersed in 35 to 70 parts of a base composed of carnauba wax. To produce the tablet, the components are mixed in a particular particle size and sequence, and the mixture is compressed to a dense tablet. The tablet is used to treat bone disorders, especially osteoporosis.

Description

Fluoride tablet with delayed release of active ingredient

and a process for their preparation. The invention relates to a fluoride tablet with delayed release of active ingredient for the treatment of osteoporosis and a procedure for making the tablet.

It is known that osteoporosis with fluorides, especially with Sodium fluoride, can be treated. However, there are undesirable side effects which are due to high levels of sodium fluoride in the blood. Soluble With the exception of the beneficial effects on the bone system, fluorides are proportionate toxic; they inhibit various enzyme systems, reduce tissue ventilation and the anaerobic glycolysis in aroused organs and reduce oxygen consumption as well as the carbon dioxide production in the muscles. It is believed that the enrichment of fluoride in the muscles through decreased renal and enteral excretion Elimination comes about.

One of the main causes of the side effects of fluorides in the body Too high fluoride intake is the binding of calcium by the fluoride, which leads to leads to hypocalcemia. More serious side effects of too high a sodium fluoride concentration in the blood are expressed in salivation, nausea, abdominal pain. Diarrhea, increased Excitability of the nervous system and drop in blood pressure.

It is therefore important and necessary that in the human organism only moderate fluoride ion concentrations occur, necessary for obtaining optimal results sustained for long periods of time in the treatment of osteoporosis and other bone diseases Need to become. Because of the high resorbtion of the sodium fluoride it is so far it has not been possible to maintain blood concentrations above a minimum value over long periods of time Time to maintain without the side effects mentioned occurred because of A high starting dose should be given to achieve the desired minimum concentration got to. In a by J. E k s t r a n d G. Alvan, L. O. Boreus and A. Norlin from the institute for Pharmacology and Cardiology, Kalinska Institute, the Department of Clinical Pharmacology of the Karolinski Hospital and the Department of Clinical Pharmacology of the Huddinge Hospital, Stockholm, Sweden, on the in the European Journal of Clinical Pharmacology under the title "Pharmacokinetics of Fluoride in Man after Single and Multiple Doses "(Pharmacokinetics of Flucrid im People after oral administration of single and multiple doses) became sodium fluoride administered orally to controlled individuals, following multiple doses in four experiments Fasting for 12 hours each and single doses for 15 people. When trying with single administration, the fluoride concentration in the plasma reached its maximum value within 30 minutes of administration. In Figure 1 is the plasma fluoride concentration after a single administration of 10 mg of sodium fluoride and, in FIG. 2, the fluoride plasma concentration after oral administration of multiple fluoride doses of 4.5 mg every 12 hours reproduced in different patients. While usually at the various If there were differences between people, it was found that the total concentrations were essentially the same in all patients. The largest fluctuations in the Plasma concentrations occurred between administrations.

The task was therefore to provide a fluoride tablet for treatment of osteoporosis and other bone diseases that provide a contains soluble fluoride, such as sodium fluoride, when administered in therapeutic Doses the occurrence of undesirable Side effects largely this avoids that the effective fluoride is only released and on with a delay in this way the occurrence of toxic blood concentrations is prevented. Further was to specify a process for the production of such a fluoride tablet.

According to the invention, this object is achieved by the in claims 1 and 8 measures specified are resolved. Advantageous further developments of the invention are listed in the other claims. -At the previously known pharmaceutical "Retard" preparations are used as bases or coatings, either through Acids in the stomach or partly through acids in the stomach and another part in the alkaline environment of the small intestine can be dissolved, so that to a certain extent Degree controlled the amount of drug released and the duration of the release can be. In contrast to the basic masses usually used, with the invention for the first time used a wax that was previously used in pharmacy and tablet production only in extremely small quantities and only as an aesthetic improvement shiny, hard and thin coating has been used, the proportion of which is hardly any more than a thousandth of the weight of the tablet. This wax is preferable a carnauba wax or a derivative thereof. It has the advantageous property that it is extraordinarily hard and only moves slowly and gradually in the stomach and in the Small intestine loosens. By using this wax as a base for the production. a tablet in which the active ingredient is distributed substantially homogeneously achieve that the active ingredient is only released very slowly and gradually. In view of the problems associated with the administration of water-soluble fluorides result, a base material made from this wax is therefore excellently suited to through slow release of fluoride the occurrence of side effects due to high fluoride concentrations to avoid in the blood. There is one such tablet intended for oral administration from a base, the main component of which is carnauba wax, in which the active ingredient, a water-soluble fluoride, in particular an alkali fluoride and preferably sodium fluoride, is substantially homogeneously dispersed. The pill becomes more common Way made by pressing the base mass with the fluoride dispersed in it.

It has been found, however, that for best results a certain process must be used to produce the tablet. at This method uses sodium fluoride (as a typical water-soluble fluoride) and Carnauba wax is sieved through a 14-mesh USS sieve before dispersing, and After the homogeneous mixing of all ingredients, the finished mixture is before the Compression to form a tablet, sieved through a 12-mesh sieve. Magnesium stearate (NF), which is commonly used for the production of tablets, must be such Have particle size that it will pass through a 20 mesh sieve. Sugar, too a tablet component, must have such a particle size that it by a 14-mesh sieve passes through it.

A small amount of talc is also part of the tablet.

The proportions of the components mentioned can be proportionate large areas vary. They can be: sodium fluoride 8 to 20 parts, Sugar 30 to 65 parts, talc 1 to 10 parts, magnesium stearate 1 to 5 parts and 35 to 70 parts of carnauba wax for 100 parts by weight total. Advantageous proportions are 10 to 12 parts of sodium fluoride, 35 to 45 parts of sugar, 1 to 3 parts of magnesium stearate, which dispersed for 100 parts by weight in total in 40 to 50 parts of carnauba wax will. The total mixture is then compressed into tablets.

In detail, the process consists of the following steps: a) Sieving the alkali fluoride through a 14-mesh USS sieve, b) mixing the screened alkali fluoride with talc (USP), c) sieving the carnauba wax and sugar (NF) through a 1 4-mesh sieve, d) Mixing the sieved carnauba wax and the sugar with the mixture of alkali fluoride and talc, e) sieving off the magnesium stearate a 20-mesh sieve, f) Mixing the sieved magnesium stearate with the mixture of talc, alkali fluoride, carnauba wax and sugar for the production a homogeneous dispersion of talc, alkali fluoride and sugar in the base from carnauba wax, g) sieving the dispersed mixture through a 12-mesh sieve and h) compressing the sieved finished mixture into a tablet.

The invention is explained in more detail with reference to the figures. Show it: Figures 1 and 2: blood concentrations of fluoride in different patients oral administration of single and multiple doses of sodium fluoride; Figure 3: a table with information about the uniformity of the fluorine content (content uniformity) and results of administration trials with tablets according to the invention.

The fluoride tablets according to the invention increase in dosage of 25 mg twice a day reduces the fluoride content in the serum to therapeutic values. The serum fluoride rose to 46.1 + 15.7 SD ugil (P < 0.01). It rose to 63.2 i 31.3 pgtl six weeks after the end of treatment.

As stated above, the administration of sodium fluoride leads in capsules or in the form of tablets without release inhibitors is increasing rapidly of serum fluoride from 19 pg / l to values of up to 400 µg / after one hour in one Single dose of 10 mg NaF (E kst r an d, J. et al., Pharmacokinetics of fluoride in man after single and multiple oral doses, Europ. J. Clin. Pharmacol. 12: 311-317).

In contrast, initial studies showed that when the tablets were administered according to the invention, the serum fluoride during the whole day to 200 to 278 pg / l stayed.

The tablet size can be selected according to desire and convenience.

As children and the elderly do not swallow larger tablets well and to enable flexible dosing, a gradation is recommended the tablet size into those of 25 mg, 50 mg, 100 mg etc.

Although other waxes than carnauba wax are also used in the invention Carnauba wax is preferable as it will look different from those in question Waxes and wax derivatives has proven best.

As mentioned, carnauba wax has so far only been used for tablet coatings been. A sensitization of the skin to carnauba wax seems to be rare be. The wax is a hard, shiny mass that does not cause any discomfort when it melts Odor developed. The melting point is 82 to 85.5 ° C; the density of the wax is usually 0.990 to 0.999 g / cm3. It has a saponification number of 78 to 89. In oily solvents it is only sparingly soluble at 25 "C, but at 45 "C readily soluble. The hardness and the gloss of the wax are due to the presence of esters attributed to unsaturated hydroxy fatty acids with 12 carbon atoms in the chain. It forms a hard, green mass of crystalline structure.

As an example, the composition of a tablet of 230 mg weight stated: sodium fluoride (USP) 25 mg carnauba wax (NF) 100 mg talc (USP) 11 mg Magnesium Stearate (NF) 4 mg Pressable Sugar (Destab) (NF) 90 mg Die The specified proportions are typical; but they can be used within the further limits given above can be varied.

Claims (10)

Claims 1. Fluoride tablet with delayed release of active ingredient, it is noted that it consists essentially of a water-soluble Consists of fluoride salt, which is essentially homogeneously distributed in a matrix, whose main component is carnauba wax. 2. fluoride tablet according to claim 1, d a d u r c h g e k e n n -z It is noted that the water-soluble fluoride salt is an alkali fluoride salt. 3. fluoride tablet according to claim 2, d a d u r c h g e k e n n -z Note that the alkali fluoride salt is sodium fluoride. 4. fluoride tablet according to any one of claims 1 to 3, d a d u r c h e k e k e n n n e i n e t, that fluoride and base material are pressed in one Condition. 5. fluoride tablet according to claim 3 or 4, d a d u r c h g e -k e It is noted that the sodium fluoride and the matrix before the homogeneous Disperse particles of such a size that they both pass through a 14-ash USS sieve go through. 6. fluoride tablet according to claim 3 or 4, d a d u r-c h g e -k e It is noted that the sodium fluoride and the matrix before the homogeneous Disperse particles of such a size that they can pass through a 14-mesh USS sieve go through and that small amounts of talc (USP) and magnesium stearate (NF) which are of a particle size such that they can pass through a 20-mesh USS sieve go through, and which are homogeneously dispersed among each other, also in the The base mass is essentially homogeneously dispersed, with TaLkum and magnesium stearate after mixing and mutual dispersion, a substantially homogeneous mixture the particles of which pass through a 12-mesh USS sieve. 7. fluoride tablet according to claims 3 and 4, d a d u r c h g e - It is not indicated that they are in the basic mass sugar, talc (USP) and magnesium stearate contains homogeneously dispersed, all particles having such a size that they pass through a 12 mesh sieve and remove the sodium fluoride in an amount from 8 to 20 parts, the carnauba wax in an amount from 35 to 70 parts, talc in an amount of 1 to 10 parts and magnesium stearate in an amount of 1 to 5 parts for a total of 100 parts by weight are present. 8. Method of making a fluoride tablet with delayed Active ingredient delivery according to claim 1, d u r c h g e n n n -z e i c h n e t that a) an alkali fluoride is passed through a 14-mesh sieve, b) the screened-off alkali fluoride with talc (USP) mixes, c) sieved carnauba wax and sieved sugar with the mixture of alkali fluoride and talc, d) magnesium stearate through a 20-mesh sieve there, e) the sieved magnesium stearate with the mixture of alkali fluoride, talc, Carnauba wax and sugar mixes until a homogeneous dispersion of alkali fluoride, Talc and sugar in which carnauba wax is made as a base, and f) the homogeneous dispersion through a 12-mesh USS sieve, for 100 parts by weight of the finished product 8 to 20 parts of alkali fluoride, 35 to 70 parts of carnauba wax, 1 to 10 parts of talc, 1 to 5 parts of magnesium stearate and 30 to 65 parts of sugar begins. 9. The method according to claim 8, d a d u r c h g e k e n n z e i c h -n e t that the alkali metal fluoride 10 to 12 parts of sodium fluoride, 40 to 50 parts Carnauba wax, 4 to 6 parts of talc, 1 to 3 parts of magnesium stearate, and 35 to 45 Parts ucker used. 10. The method according to claim 8 or 9, d a d u r c h g e k e n n -z E i c h n e t that the homogeneous dispersion and the base mass can be converted into a tablet presses.