Pharmaceutical formulation consisting of a plant dry extract with a calcium coating

The present invention relates to a pharmaceutical formulation according to the preamble of claim 1, to its use according to claim 11 and to a process for its manufacture according to claim 13.

17P ~ estradiol, which is normally produced in the ovaries (also designated as E₂) usually increases (stimulates) proliferation in humans and animals. In addition, it regulates a woman's cycle and, by the way, has a homeostatic effect on bone metabolism and prevents atherothelial plaque formation in vessels.

During menopause, a decrease in oestradiol levels occurs due to ovarian function: interruption. In the absence of high levels of estradiol in the blood, osteoclast activity, and thus bone loss - called osteoporosis - dominates the bone tissue, which increases the risk of skeletal (skeletal) fractures.

Recently, it has been found that this osteoporosis syndrome due to lack of sex hormones is not limited to women, but that men also have osteoporosis due to sex hormone deficiency at a certain age, especially in prostate disease.

Classic prevention and treatment for women is to supplement natural estrogen deficiency with natural or synthetic estrogens. Particularly for prophylactic purposes, men and women are exposed to calcium doses of about 1 gram of calcium per day.

The use of estrogens such as 17β-estradiol or its derivatives, accompanied by known side effects such as uterotrophic effects (effects on uterine trophies), increased risk of thromboembolism, weight gain and so on.

Considerable efforts have been made to find drugs that produce the same effects as estrogens, but without their undesirable side effects or greatly reduce them. In this way, they often used plant extracts which had the desired prophylactic effect on osteoporosis but had no undesirable effect on uterotrophism.

Thus, for example, Applicant WO 99/47149 (= EP 1064009A1) discloses that extracts from the wormwood family, in particular from Cimicuga racemosa and Belamcanda chinensis and their isoflavone tectorigenin do not have estrogen-specific effects on the uterus, and even on the hypothalamus and pituitary system, cardiovascular system and bone, so that these plant extracts can be used (used) for the prevention and treatment of osteoporosis.

In addition, calcium preparations for the prevention of osteoporosis have been known in the past. For this purpose, the solution for injection, without the need for solutions, is the most commonly used bubble-release tablet during the boom (oral). These bubble-release tablets may, for example, be composed of:

Tablets containing 500 mg Ca: 1250 mg calcium carbonate, 2050 mg citric acid, the other ingredients are: lactose IH2O, macrogol 6000, povidone, sodium cyclamate, sodium saccharin 2H2O, dimethicone 350, fine dispersion silica, macrogol stearate 400, sorbic acid fragrances.

Tablets containing 1000 mg Ca.²⁺: 4954 mg of calcium lactogglutonate, 900 mg of potassium carbonate, the other ingredients are: citric acid, sodium cyclamate, sodium saccharin, mannitolSy macrogol 4000, sodium bicarbonate, flavorings.

Calcium-rich calcium-rich formulations would be desirable²⁺ in combination with a dry herbal extract that has anti-osteoporotic effects, as this would reduce the frequency of drug use as well as their cost.

Thus, a simple mixture with a calcium-containing bubble-release tablet mass is not suitable on the one hand, since dry extracts are very unstable in acidic aqueous media, and on the other hand, many dry extracts have poor solubility in acidic media. In addition, the dry extracts are also very hygroscopic and the moisture-impervious bubble-releasing mass may decompose.

Encapsulation in conventional gelatine capsules should also be avoided as the capsules are generally impermeable to water vapor and could break down and / or clump dry plant extracts so that the quality of the drug cannot be assured due to undetermined bioactivity, release and / or efficacy. In addition, the stability of such gelatin capsules is not guaranteed, as literature data indicate, for example, that gelatin stitching occurs when plant extracts are encapsulated in gelatin and that significant changes in the ingredients may occur due to water absorption by the dry extract.

Thus, for example, sugar-coated tablets or dragees in the form of calcium and dry plant extract could be optimal. As mentioned earlier, the high calcium content of 500 mg Ca combined with the relatively high amount of excipients needed to make the dragee would result in the size and weight of the dragee being unacceptable to patients.

Known solid forms are a vitamin D calcium supplement₃ combination in the form of chewable tablets, such as Ossofortin® forte chewable tablets manufactured by Strathmann AG + Co, Sellhopsweg 1, D-22459 Hamburg.

Such chewable tablets for the treatment of osteoporosis consist of:

1500.3 mg calcium carbonate (equivalent to 600 mg Ca *⁴), colecalciferol dry concentrate (100000 IU (IU - International Units) / g) 400 IU (IU), other ingredients: xylitol, corn starch, saccharin sodium, flavorings, magnesium stearate.

To date, no combination of calcium preparations with plant extracts has been found to be suitable for the prophylaxis and / or treatment of osteoporosis described above for the reasons stated above.

Thus, it is an object (object) of the present invention to provide a dosage form which combines both calcium substitutes and vitamin D₃ the benefits of alternatives as well as the benefits of dry plant extract for the prevention and / or treatment of osteoporosis.

This task is solved by the intrinsic features of point 1. By use, this task is solved by the features of item 14 and technologically (by the method of production) it is solved by the features of item 16.

The invention is particularly directed to a dosage form comprising calcium salt and dry plant extract, wherein the dosage form comprises at least one inner extract (core) of a plant extract surrounded by at least one coat (layer) consisting of at least one calcium salt.

For the first time, the formulation according to the invention can provide quantitative combinations of dry extract of osteoporosis-acting plants, such as Cimicuga racemosa, Belamcanda chinensis, Vitex agnus castus or Urtica dioica radix, as well as a mixture thereof with calcium. In addition, it is particularly useful that the coating, unlike conventional hitherto, is composed of excipients but contains exclusively the active ingredient, that is, calcium.

PCT application WO 99/47149 of this applicant is fully incorporated by reference^andgt^a, referring to the production of dry plant extracts. In addition to the solvents discussed therein, the said plants can also be extracted with mixtures of organic-aqueous solvents, especially aqueous or supercritical CO.₂ (as in the case of the Serenoa rapper).

This formulation achieves the fact that usually very hygroscopic extracts of plants which, after the addition of water-binding excipients, for example, in the form of a dragee or film-coated tablet, can be made in low weight and low volume, enclosed with an inert moisture-proofing active ingredient. calcium salts.

In this way, a very suitable (acceptable) ratio of dry plant extract / calcium to excipients is achieved, so that excipients other than small amounts of lubricants can be partially eliminated.

In this way, it is possible for the first time (first) to provide a combination of dry plant extract, calcium salts and, if necessary, vitamin D₃, wherein the amount of calcium is such that about 1000 mg Ca is required for prophylaxis and / or treatment²⁺ ions per day can be achieved without the use of calcium supplements.

An advantageous embodiment of the present invention is that it further comprises, in the calcium-containing casing and / or in the inner pressed mass of the dry extract of the plant, cholecalciferol, in particular coecalciferol (vitamin D).₃).

Additionally, the dosage form could additionally contain at least one fluoride salt, in particular sodium fluoride, whereby the fluoride salt is preferably contained within the inner pressed mass (core).

The most common formulation is characterized in that the dry plant extract is selected from the group consisting of extracts from: Vitex agnus castus (true luminance), Belamcanda chinensis, Cimicuga racemosa, Trifolium pratense L. (red clover); Oenothera biennis hom. (bunk bed); Glycine soya (soybeans); Serenoa rapper ·, Urtica dioica (nettle) especially its roots; Cucurbita pepo (gourd) especially its seeds; Pygeum ąfricanum ·, and also their suitable mixtures.

A preferred embodiment of the pharmaceutical formulation of the invention consists in the calcium salt being selected from the group consisting of: calcium carbonates; calcium hydrogen carbonates; calcium halides, in particular calcium chloride and iodide; calcium phosphate; calcium hydrogen phosphate; especially calcium hydrogen phosphate; dicalcium hydrogen phosphate; calcium lactate; calcium lactonates; calcium succinates; calcium tartrate; calcium gluconates; others and their respective (appropriate) mixtures.

A more preferred dosage form of the present invention is a film-coated tablet, wherein the coating is the smallest extruded mass of one calcium salt and the core is the lowest extruded mass of one of the specified dry plant extracts, wherein vitamin D3 may also be contained in the core.

However, the dosage form may be a small tablet (tablet dragee) with the core even though it is not fully centered inside the shell.

It is also possible in this dosage form to form a coating of a plurality of calcium layers, where each layer usually contains a different calcium salt.

In an acceptable dosage form, for example, calcium is present in an amount of about 50 to 1000 mg per tablet, in the form of a coating, and about 0.5 to 100 mg of dry plant extract. In this way, using drugs 1-3 times a day, what is acceptable to patients, can satisfy all the Ca offered²⁺ of ions at about 1000 mg Ca²⁺ daily dose with the intake of necessary phytoextracts for osteoporosis and also vitamin D3.

In addition, an acceptable dosage form may contain a polymer film as the outer layer, since this can improve the swallowing and sliding tensile properties. In addition, the polymer film can protect against dust and moisture to prevent it from getting into the sheath. However, such a layer of polymer is generally not required.

The dosage form of the present invention requires little or no excipients. However, additives which are customary for galenicals, such as disintegrants, may be used, however, especially those based on starch or its derivatives; binder, in particular microcrystalline cellulose, acacia; lubricants, in particular stearic acid and / or magnesium stearate; as well as glidants, especially polyethylene glycol, etc.

The dosage forms of the invention are particularly suited as medicaments for the treatment of osteoporosis of different origins, and especially for the prophylaxis and / or treatment of osteoporosis caused by sexual hormone deficiency in women and older men.

The preparation of dosage forms of the invention is carried out in accordance with the following rules:

Initially, a dry plant extract is made from a pressed pulp core, where dry plant extracts are selected from the group consisting of extracts from: Vitex agnus castus, Belamcanda chinensis, Cimicuga racemosa \ Trifolium pratense L.

(red clover); Oenothera biennis hom. (bunk bed); Glycine soya (soybeans); Serenoa repens \ Urtica dioica (nettle) especially its root; Cucurbita pepo (gourd) especially its seeds; Pygeum africanum ·, and their respective mixtures.

This core is applied to the first partial amount of the shell mixture consisting of at least one calcium salt, then immediately filled with the second partial amount of the shell mixture; and the whole form consisting of a core, a mixture of both parts of the calcium-containing shell mixture, is compressed to form a dosage form. The calcium salt is selected from the group consisting of: calcium carbonates; calcium hydrogen carbonates; calcium halides, in particular calcium chloride and iodide; calcium phosphate; calcium hydrogen phosphate; especially calcium hydrogen phosphate; dicalcium hydrogen phosphate; calcium lactate; calcium lactonates; calcium succinates; calcium tartrate; calcium gluconates; others and their respective mixtures.

In most cases, the core of the first partial amount of the shell mixture is centered to form a so-called shell tablet. However, it is also possible to make so-called dragee tablets (small tablets), which are not centered (centered) but surrounded by a shell and partially translucent.

Tablet presses are commercially available tablet presses such as FETTE, KORSCH and KILIAN. Especially suitable are MANESTY's synchronous two-sided rotary press. Using a two-sided rotary press, the cores are made in one tower of the rotary press and passed through an intermediate transfer and centering mechanism to the tower of the second rotary press where the shell is pressed.

Substantially the dosage form of the present invention may also be obtained using two rotary presses, one of which is pressed into a core while the other is pressed into a shell.

The advantage of producing a tablet according to the invention in the form of a double-sided rotary press is that the core in the first tower is compressed relatively soft. The final compaction (pressing) is carried out in the second tower of the press in such a way that the core of the dry plant extract with the calcium shell is firmly adhered.

The film-coated tablet thus made comprises, for example:

Coating: CaCCb 1250 mg (equivalent to 500 mg Ca²⁺) Vitamin D3 200 IU (tv)

Core: Cimicuga racemosa 20 mg (dry extract preparation)

Excipients: Magnesium stearate 8 mg Stearic acid 4 mg Microcrystalline cellulose 40 mg Gum arabic 50 mg

An exemplary film-coated tablet combines oral calcium and vitamin D₃ benefits of Cimicuga racemosa dry extract. For oral use only 2 tablets daily are available for the prevention and / or treatment of osteoporosis

^ .1 suggested doses of calcium and vitamin D3 from about 1000 mg Ca / day or 4001.U. (tv) Vitamin D3 and at the same time the required intake of 40 mg of Cimicuga racemosa dry extract.

Thus, it is possible and useful to produce a dry extract core from any of the above phytoextracts and from a mixture of different extracts, according to the indication. Thus, for example, in the case of prostate disease, the film-coated tablet according to the invention may contain Serenoa rapper extract in the core.