Rehydratable pharmaceutical product
A pharmaceutical product comprising lyophilized polymer matrix including a biologically active compound, of particular utility for embolization, having improved rehydration properties is packaged in an airtight package under vacuum.
1. A method for formulating a dried packaged product suitable for direct administration to an animal after rehydration to form a suspension comprising:
i) providing particles of polymer matrix swollen with water and having absorbed therein a non-volatile biologically active compound wherein the polymer is a water-insoluble water-swellable pharmaceutically acceptable polymer;
ii) cooling the swollen particles from step i) in a freezing step to a temperature below the freezing point for water;
iii) in a lyophilisation step subjecting the cooled particles from step ii) to a reduced pressure at which ice sublimes for a period during which at least a portion of the ice sublimes and water vapour is removed to form dried particles; and
iv) in a packaging step, packaging the dried particles under reduced pressure and into a package that is substantially airtight and has an interior under vacuum to form packaged particles,
wherein the particles of polymer matrix swollen with water provided in step i) have sizes selected such that upon rehydration of the dried particles in 0.9% saline at room temperature, an average particle size of the particles of polymer matrix is in the range of 40 to 2000 μm.
2. The method according to claim 1 , in which the said package comprises a vessel which is substantially rigid and has a mouth closed by a stopper and in which the pressure inside the package is less than 0.95 bar.
3. The method according to claim 1 , in which the particles of swollen polymer are contained in the vessel during the freezing and lyophilisation steps and in which the stopper is fitted into the mouth of the vessel in the packaging step.
4. The method according to claim 1 , in which the temperature to which the particles are cooled in the cooling step is less than −20° C.
5. The method according to claim 1 , in which the lyophilisation step is carried out at a temperature less than −20° C.
6. The method according to claim 1 , in which the pressure in the lyophilisation step is reduced to less than 100 mbar for.
7. The method according to claim 1 , in which the polymer is cross-linked.
8. The method according to claim 1 , in which the polymer is based on poly(vinyl alcohol).
9. The method according to claim 1 , in which the polymer is formed by polymerisation of ethylenically unsaturated monomers.
10. The method according to claim 1 , in which the particles are substantially spherical in shape.
11. The method according to claim 1 , in which the biologically active compound is selected from anti-proliferatives, anti-neoplastics, anti-migratories, immunosuppressants, analgesics, anti-inflammatories, anti-pyretics, anaesthetics and anti-bacterials.
12. The method according to claim 11 , in which the biologically active is an anti-neoplastic agent selected from angiopeptin, statins, azacitidine, bleomycin and bleomycin sulphate, carboplatin, cisplatin, streptozoticin, capecitabine, vinorelbine, cyclosporin, cytabanine, dacarbazine, anthracyclines, fluorouracil, haropiridol, gemcitabine, ifosfamide, methotrexate, mitoxantrone, banoxantrone, mitomycin, mustine hydrochloride, lomustine, carmustine, meclorethamine, vincristine, vinblastine and cytosar/cytarabine, paclitaxel, docetaxel, rapamycin and derivatives, tetradecylselenoacetic acid, tetradecyl thioacetic acid, ethylisopropylamiloride, antithrombin, aggrastat, cilostazol, clexane, clopidogrel, dipyridamole, persantine, integrillin, abciximab, trapidil, matrix metalloproteinase inhibitors, VEGF, carvedilol, estradiol, L-arginine, nitric oxide donors, probucol, quinaprilat, thioctacid, telmisartan, zoledronate, and irinotecan.
13. The method according to claim 12 , in which the statin is sandostatin.
14. The method according to claim 12 , in which the anthracycline is selected from the group consisting of daunorubicin hydrochloride and doxorubicin hydrochloride.
15. The method according to claim 12 , in which the rapamycin or rapamycin derivative is selected from the group consisting of tyrphostin, tacrolimus, everolimus, biolimus, zotarolimus and RAD001.
16. The method according to claim 12 , in which the matrix metalloproteinase inhibitor is selected from the group consisting of batimastat and marimastat.
17. The method according to claim 1 , in which gas is not allowed to ingress into the package between steps iii) and iv).