Subcutaneous osteoporosis compositions

Details Subcutaneous osteoporosis compositions Subcutaneous osteoporosis compositions

2001-05-03

2004-01-13

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Matrices

C424S423000, C424S422000, C424S484000

Reexamination Certificate

active

06676970

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention is concerned with a pharmaceutical preparation for subcutaneous, parenteral administration, which contains bisphosphonic acids or their salts as the active substance, as well as the production of this preparation. By means of the preparation in accordance with the invention it is possible to administer locally relatively high concentrations of bis-phosphonates without the occurrence of incompatibilities.
Bisphosphonates and their salts have been in use for years as highly effective medicaments for the treatment of various disorders of bone metabolism. Thus, a variety of bisphosphonates are used for the treatment of hypercalcaemia, malignant bone growth disorders (metastatic bone disease) as well as osteoporosis, while others are in clinical development. Clodronate, ibandronate, tiludronate, etidronate, alendronate, risedronate, zoledronate among others can be named as examples. Bisphosphonates are used in a broad dosage range taking into consideration the widest variety of factors, especially the medical indication. Thus, parenteral preparations for intravenous infusion and injection are preferably made available and utilized.
The subcutaneous, parenteral administration of clinically relevant amounts of bisphosphonic acids or their salts is, however, problematic. Inflammations, pains and necroses occur when bisphosphonate solutions are administered subcutaneously in therapeutically relevant concentrations, which are, for example, well tolerated in the case of intravenous administration. Of course, the subcutaneous administration is especially attractive in many respects, because this mode of administration is perceived by the majority of patients to be much more pleasant than intravenous administration. It can be performed by medical auxiliaries or by patients themselves.
The pharmacokinetic differences which can occur in the case of subcutaneous administration vis-à-vis intravenous administration are not of significance for the fields of indication osteoporosis and osteoporosis prophylaxis which are at the centre of interest, since bis-phosphonates display their activity after binding to bones, are accumulated there for a very long time and therefore their residence times in the blood after injection or also after oral administration are only of secondary importance.
Thus, only a few, not completely satisfactory proposals for the development of subcutaneously usable bisphosphonate preparations have hitherto become known.
Difficulty soluble zinc and magnesium salts of 1,1-bisphosphonic acids are described in DE 42 44 422 A1, with the object of releasing therapeutically relevant amounts of active substance slowly by dissolution from a local depot.
However, for various reasons this principle is not well suited to achieve a significantly improved compatibility. Thus, even if the dissolution kinetic is altered a good compatibility does not, however, result, since a particulate system is formed by the difficultly soluble salt. It has been established that this not only has numerous disadvantages upon administration, but also leads to additional difficulties. From the technological viewpoint not only the production, dosing and decantation, but also the storage, quality control and quality guarantee of such systems is very difficult. Particulate systems are mainly suspensions which are physically unstable and, for this reason, in the case of short-term storage already undergo changes which are relevant to quality. As mentioned above, the administration of such particulate systems is not simple. Thus, dosing problems, which are caused by phase separation or sedimentation, can occur immediately upon administration. The obstruction of injection needles by suspension particles is likewise a problem which has to be taken into consideration seriously.
The subcutaneous administration of difficultly soluble particles is not optimal also from the toxicological viewpoint. The presence of foreign particles induces specific and non-specific defence mechanisms which lead to diverse reactions, especially to local cellular changes. Phagocytes accumulate, other cells accompany the degradation and an encapsulation of the foreign particles may occur. In summary, particulate systems lead to generally undesired reactions which decrease compatibility.
On the other hand, water-soluble calcium salts of ibandronate for the production of medicaments are described in DE 42 44 423 A1. These eliminate the disadvantages of difficultly soluble salts and, on the basis of a lower solubility than the usual alkali or ammonium salts, they should have a better tissue compatibility than these without exhibiting the disadvantages of the suspensions.
This formulation strategy is, however, not completely conclusive and in practice does not lead to the desired, medically relevant improvement in compatibility. As a molecular dispersed solution (“true solution” in the physico-chemical sense) is present, then its concentration of dissolved active substance (e.g. 1 mg/ml) alone determines the compatibility and not on the other hand the saturation solubility. While the saturation solubilities of e.g. Na
+
and Ca
2+
salts of bisphosphonates, especially ibandronate, differ significantly, their individual physiological irritating effects are on the other hand the same in the case of the same dissolved concentration.
It has been established that the achievable compatibility limits or active substance concentrations of water-soluble Ca
2+
salts, which are well tolerated after subcutaneous administration, are so low that they are not usable in practice. In particular, the treatment interval of only one or a few injections every three months, which is especially desirable and attractive from the viewpoint of patients and of medical personnel, can therefore not be realized.
The underlying purpose of the invention accordingly lay in the provision of pharmaceutical preparations suitable for subcutaneous administration which contain bisphosphonic acids or their physiologically compatible salts and with which it is possible to administer locally high, therapeutically relevant concentrations of bisphosphonates compatibly such that medically significant treatment regimens with administrations at long time intervals (≧4 weeks) are possible.
SUMMARY OF THE INVENTION
The problem of the invention is solved by an aqueous pharmaceutical preparation which contains the active substance or the active substance mixture and at least one compound which inhibits a diffusion of the active substance in the tissue, with the active substance being present in dissolved form in the preparation and the active substance and diffusion-inhibiting compound being selected such that the pharmaceutical preparation contains no solid particulate components. If desired, other usual pharmaceutical carriers and/or adjuvants, which, however, should not form particles, are present in the preparation.
The invention is concerned with a pharmaceutical preparation for subcutaneous, parenteral administration, which contains bisphosphonic acids or their salts as the active substance, as well as the production of this preparation. By means of the preparation in accordance with the invention it is possible to administer locally relatively high concentrations of bis-phosphonates without the occurrence of incompatibilities. The pharmaceutical composition of this invention comprises an aqueous gel having a viscosity of ≧220 mPa*s containing as an active ingredient for combating osteoporosis a bisphosphonate acid or its pharmaceutically acceptable salt dissolved in aqueous solution and a polymeric gel forming agent capable of inhibiting diffusion of the active ingredient with human tissue. This composition is in a dosage form for subcutaneous administration.
DETAILED DESCRIPTION OF THE INVENTION
In a preferred embodiment the present invention comprises a gel-like, aqueous pharmaceutical preparation for subcutaneous administration containing bisphosphonic acids or their physiologically acceptable salts, characterized in th

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