Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-23
2003-03-04
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06528524
ABSTRACT:
The present invention provides pharmaceutical compositions containing cinchonine dihydrochloride as active ingredient. More precisely, pharmaceutical compositions according to the invention contain cinchonine dihydrochloride with a purity of at least 95%.
The invention also provides a process for preparing cinchonine dihydrochloride.
Pharmaceutical compositions according to the invention may be used as inhibitory substances for the phenomenon called “multiple drug resistance” (MDR). In particular, pharmaceutical compositions according to the invention may be used for treating certain types of cancer-linked diseases which exhibit this MDR phenomenon.
Pharmaceutical compositions according to the invention may also be used for treating arrhythmia, as antispasmodic substances, and also in the treatment of malaria, in the event of resistance to known conventional medicaments and in association with these medicaments.
The MDR phenomenon is known in particular in connection with cancers, but it is also exhibited in the case of other diseases such as malaria. On the one hand there are cancers with innate MDR and, on the other hand, cancers with which MDR develops following treatment based on anti-cancer agents, such as anthracyclines in particular. The MDR phenomenon with cancers has the effect of inhibiting the cytotoxicity of certain anti-cancer drugs or even of rendering them ineffective.
Cinchonine is a naturally-occurring substance, extracted from the bark of quinquina, and is a member of the alkaloid family. Cinchonine has an inhibitory effect with regard to the MDR phenomenon. Its use for preparing pharmaceutical compositions intended for the treatment of cancerous tumours which develop the MDR phenomenon is described in European patent no. EP 0052608 in the name of the applicant, DEBIOPHARM SA.
Pharmaceutical compositions containing cinchonine and intended for treatment of the MDR phenomenon, however, have a certain number of disadvantages.
These disadvantages stem mainly from the fact that cinchonine is very sparingly soluble in water. This makes it difficult to administer to patients in the form of a drinkable or parenterally administered solution. Moreover, the low solubility of cinchonine in water means that its bioavailability properties are unsatisfactory with regard to oral administration. Since cinchonine is a toxic substance, with unwanted side effects, it is desirable to improve its bioavailability as this would permit a reduction in the orally administered doses and, thus, the side effects.
The applicant company has now found that a salt of cinchonine, cinchonine dihydrochloride, not only complies with the solubility and bioavailability criteria required for a pharmaceutical formulation, while maintaining the therapeutic properties required, but that it is also very stable in solution, thus favouring the formulation of aqueous preparations, in particular in an injectable form.
Furthermore, the applicant company has also noted that the bioavailability of cinchonine dihydrochloride is more constant from one patient to another. In other words, the variability of the therapeutic effect is lower when treating patients with cinchonine dihydrochloride than with cinchonine or cinchonine monohydrochloride.
The pharmaceutical composition according to the invention contains, as active ingredient, cinchonine dihydrochloride. More precisely, the pharmaceutical composition according to the invention contains cinchonine dihydrochloride with a purity of at least 95%. Cinchonine dihydrochloride in the pharmaceutical composition according to the invention preferably has a purity of at least 99%, and in particular of at least 99.9%.
In accordance with a preferred embodiment, the pharmaceutical composition provided by the invention contains cinchonine dihydrochloride combined with at least one other active ingredient compatible with cinchonine dihydrochloride and optionally at least one other pharmaceutically acceptable compound.
The other active ingredients may advantageously be chosen from the group consisting of anti-cancer agents, antimalarial agents and multiple drug resistance inhibitors.
In a non-exhaustive manner, the following may be mentioned as anti-cancer agents: doxorubicine, vinorelbine, etoposide, taxol, puromycin and, in a general manner, all cytotoxic agents involved in multiple resistance to drugs.
In a non-exhaustive manner, the following may be mentioned as antimalarial agents: quinine, chloroquinine and any other agent which induces a resistance phenomenon.
In a non-exhaustive manner, the following may be mentioned as MDR inhibitors: one or more known substances chosen from among amiodarone, quinine, quinidine, cinchonidine, verapamil, cyclosporine A, cephalosporines, biperidene, lidocaine, chlorpromazine, pentazocine, promethazine, potassium canmrenoate, amitriptyline, propanolol, demethoxyverapamil, diltiazeme, thioridazine, trifluoperazine, chloroquine, sdb-ethylene diamine, reserpine, tamoxifene, toremifene, hydrocortisone, progesterone, salbutamol and their acylated or esterified derivatives.
As another pharmaceutically acceptable compound used in compositions according to the invention, cytotoxic substances which are sensitive to the MDR phenomenon and which increase the effect of cinchonine dihydrochloride may advantageously be used.
Substances of this type are mentioned below; this list is not exhaustive in any way.
Essentially, these are hydrophobic substances, all of which have a positively charged nitrogenated group, such as, for example, vinca alkaloids, anthracyclines or similar products, epipodophyllotoxines or anti-tumour antibiotics. The following may be mentioned in particular, vincristine, vinblastine, vindesine, vinorelbine, doxorubicine, deoxydoxorubicine, tetrahydropyranyladriamycine, epidoxorubicine, aclacinomycine, demethoxydaunorubicine, daunorubicine, m-amsa, mitoxantrone, bisanthrene, demethoxydaunorubisanthrene, mithramycine, actinomycine D, puromycin, etoposide, tenoposide, emetine, ethidium bromide, cytochalasine, colchicine and taxol.
Other pharmaceutically acceptable compounds may of course be incorporated into the composition according to the invention, such as fillers, colorants, excipients, sweeteners, etc.
The optimum doses and frequency of administration of the composition according to the invention depend on the type of cancer or other disease being treated, the nature of the other active ingredients optionally used in combination with cinchonine dihydrochloride and also on the patient being treated or also on other factors that the skilled person is able to understand.
The invention thus enables an appropriate therapeutic treatment to be offered for diseases with various degrees of resistance to the classical medicaments used to treat them. In particular, thanks to the invention, there is the capacity to offer an appropriate therapeutic treatment for a number of cancerous diseases which have various degrees of resistance to anti-cancer agents. In this connection, inter alia, the following may be mentioned: acute myeloblastic leukaemia, acute lymphoblastic leukaemia, neuroblastoma, small cell lung cancer, ovarian cancer, malignant non-Hodgkinson's lymphoma and diffuse plasmacytoma. These are cancers which can involve induced MDR in response to treatment with a cytotoxic agent.
Cancers with innate MDR may also be treated. These are, for example, colonic adenocarcinoma, renal adenocarcinoma, corticosuprarenal carcinoma, pheochromocytoma, infantile sarcomas and secondary leukaemia. However, this list is not exhaustive.
Cinchonine dihydrochloride is very stable in aqueous solution and thus is suitable for preparing injectable solutions. Therefore, cinchonine dihydrochloride may be readily administered locally, near to areas to be treated, thus restricting any secondary effects in healthy parts.
The applicant company has also refined a process enabling cinchonine dihydrochloride to be obtained with a purity of at least 95%.
According to the process in accordance with the invention, cinchonine dihydrochloride is prepared by addi
Genne Philippe
Ibrahim Houssam
Debiopharm SA
Goldberg Jerome D.
Kelber Steven B.
Piper Rudnick LLP
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