Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1995-09-21
1997-10-28
Cook, Rebecca
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
514560, 514 23, 514 78, 514529, 514573, 514738, 514937, 514970, A61K 3119
Patent
active
056818556
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
The present invention relates to a kit for the preparation of a fat emulsion which contains prostaglandin E.sub.1 (PGE.sub.1) for direct parenteral use.
In particular, the invention relates to a kit consisting of for administration, by mixing, and extruding through the filter c), the anhydrous, lyophilized PGE.sub.1 -containing emulsion composition a) with the aqueous dispersion medium b).
PGE.sub.1 is a highly active tissue hormone which is successfully used, for example, for the treatment of arterial occlusive disease. Used for this purpose is a PGE.sub.1 -.alpha.-cyclodextrin complex which, dissolved in physiological saline solution, is infused parenterally, preferably intraarterially, as close as possible to the body region to be treated. However, high pressure conditions and small dilution effects during the intraarterial infusion make high demands on the equipment and the training of the treating physician. Although intravenous infusion is simpler to perform by comparison, even in this case infusion is possible only slowly and in relatively high dilution because of the local irritant effect of PGE.sub.1. Overall, the extended residence time of the active substance in the vascular system before reaching the target site and, in particular, the additional passage through the pulmonary circulation leads to increased degradation of active substance. Both intraarterial and intravenous infusions make high demands on the equipment and careful adjustment of the infusion rate and are therefore usually performed in hospital and not by the established physician, which impedes wide use of the valuable active substance in the therapy of arterial occlusive disease.
Fat emulsions are disperse systems in which the internal, disperse phase consists of very fine fat particles which are homogeneously dispersed in the external, continuous phase composed of water.
As a predominantly lipophilic substance, PGE.sub.1 can be partly or completely incorporated into the internal phase of fat emulsions, from which it is then released in a delayed manner. This avoids high local concentrations, degradation of the active substance is reduced and the duration of action is increased so that incorporation into fat emulsions is suitable for overcoming the problems described.
PGE.sub.1 -containing fat emulsions for parenteral use can be prepared by dissolving PGE.sub.1 in the oil phase which is subsequently processed further in accordance with a customary preparation process to give a fat emulsion. This can take place, for example, by the heated oil and water phases initially being roughly preemulsified with a mixer and then microfine emulsification being carried out with a high-pressure homogenizer, and the resulting fat emulsion subsequently being sterilized with superheated steam. Microfine emulsification is necessary in order to avoid changes in blood pressure and the risk of embolism as a consequence of large fat particles. Although such PGE.sub.1 -containing fat emulsions are suitable for solving the described disadvantages of the conventional use of PGE.sub.1, their storage stability is low as a consequence of hydrolytic degradation of the active substance, which impedes their general utilizability.
According to U.S. Pat. No. 4,684,633, a fat emulsion which contains prostaglandins and consists of vegetable oils, phospholipids and water can be stabilized by using phospholipids which have been freed of phosphatidylethanolamine. However, stabilization of the active substance is shown only for the condition of brief sterilization at 125.degree. C. for 2.2 min. Data on the stability on long-term storage are lacking. The formulation also contains water so that degradation of active substance as a consequence of hydrolysis cannot be ruled out in principle.
Besides stabilization of the active substance in a fat emulsion ready for administration, fat emulsions containing intact active substance can also be used by preparing them only immediately before use. One example of this is given in EP 0 331 755, consisting of active sub
REFERENCES:
patent: 4684633 (1987-08-01), Imagawa et al.
The United States Pharmacopeia, The National Formulary, USP 23, NF 18, 1995, pp. 2241, 2269.
Mika Hans-Jurgen
Schutz Andreas
Sievert Frank
Cook Rebecca
Schwarz Pharma AG
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