Use of biodegradable microspheres that release an anticancer...

Details Use of biodegradable microspheres that release an anticancer... Use of biodegradable microspheres that release an anticancer...

2001-11-16

2004-10-12

Azpuru, Carlos A. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C424S501000, C424S502000

Reexamination Certificate

active

06803052

ABSTRACT:

The present invention relates to the use of biodegradable microspheres which release an anticancer agent, for treating glioblastoma.
Glioblastoma belongs to the group of rare diseases listed by the National Organization for Rare Disorders.
Malignant glial tumors are primary tumors of the central nervous system which represent, depending on the series, 13 to 22% of intracranial tumors. From a histological point of view, two types of malignant glial tumor are, in fact, distinguished, anaplastic astrocytomas and glioblastomas, the latter representing the most undifferentiated form of theses tumors.
There is currently no effective treatment against malignant glial tumors. The survival time of patients suffering from glioblastoma does not exceed one year, even if chemotherapy and radiotherapy are combined with surgery.
The treatment of malignant glial tumors is mainly limited by three phenomena.
The first is the existence of a blood-brain barrier (BBB) which isolates the central nervous system from the rest of the body. This BBB allows only liposoluble molecules which are small in size to pass. Other molecules must be administered at very high doses in order to reach the central nervous system, this being at the cost of considerable systemic side effects.
The second factor which limits the effectiveness of treatment for glial tumors is the infiltrating nature of these tumors. Since the brain is a highly functional organ, it is impossible to perform on it surgery which is exclusive in the carcinological sense of the word. The most complete exeresis possible will only be a macroscopically complete exeresis, leaving a large number of tumor cells infiltrated into the walls of the exeresis cavity. Many authors have, moreover, shown that 90% of malignant glial tumors which are operated on and treated with radiotherapy recur within a distance of two centimeters from the initial tumor site.
The last factor which limits the effectiveness of treatment for glial tumors is the low therapeutic index. Tumor cells shelter as it were behind normal tissue which is extremely fragile and sensitive to attacks, caused for example by radiotherapy or by certain anticancer agents. It is thus difficult to destroy the tumor cells without destroying the normal nerve cells.
The progress achieved in the treatment of glial tumors is insufficient (Kornblith P L, Walker M, Chemotherapy for malignant gliomas. J. Neurosurg, 68: 1-17, 1988; Shapiro W R, Green S B, Burger P C, Selker R G, VanGilder J C, Robertson J T, Mahaley S M, A randomized comparison of intra-arterial versus intravenous BCNU with or without intravenous 5-fluorouracil, for newly diagnosed patients with malignant glioma, J. Neurosurg. 76: 772-781, 1992).
Currently, conventional treatment for glioblastomas, subsequent to surgical resection, is based on external radiotherapy. It does not make it possible to achieve a survival time of more than one year. Combining radiotherapy with chemotherapy using 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (BCNU) is effective only on anaplastic astrocytomas. This contributes only modestly since it only increases the percentage of survivors at eighteen months, without modifying the survival time.
Furthermore, immunotherapy has never established itself in this area and gene therapy has yet to prove itself.
Experiments have been carried out on several techniques aimed at increasing the local concentration of anticancer agents, such as osmotic rupture of the blood-brain barrier, injection into the cerebrospinal fluid, intracarotid infusion and intratumor administration using subcutaneous reservoirs (Tamargo R J and Brem H, Drug delivery to the central nervous system, Neurosurgery Quarterly, 2: 259-279, 1992). None of these techniques has been able to increase the survival time of the patients and some have proved to be highly toxic.
Over the past few years, research in galenic pharmacy has allowed the development of implantable polymer systems which protect active substances against degradation and which allow their controlled local release over a given period of time while at the same time decreasing the systemic side effects. The advantages of these implantable polymer systems have recently prompted several teams to study their use in central nervous system pathologies (Langer R, Polymer implants for drug delivery in the brain, J. Controlled Release, 16: 53-60, 1991). In particular, such systems implanted into the tumor resection wall of malignant gliomas slow down tumor recurrence and prolong patient survival. Isolated malignant cells persist around the cavity left after the operation, which are responsible for 90% of recurrences, which occur within a distance of two centimeters from the operating locus. Within this area, the nervous tissue is functional and the blood-brain barrier is still intact, which limits the action of conventional chemotherapy and radiotherapy.
Diverse implantable polymer systems which release active molecules have been developed and tested in animals.
A system of biodegradable wafers which are composed of PCPP-SA (poly[1,3-bis(carboxyphenoxy)propane-co-sebacic acid]) and which release BCNU (GLIADEL®) has been developed despite modest results in clinical studies (Brem H, Polymers to treat brain tumors, Biomaterials 11: 699-701, 1990; Brem H, Mahaley M S, Vick N A, Black K L, Schold S C, Eller T W, Cozzens J W, Kenealy J N, Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas, J. Neurosurg 74: 441-446, 1991; Brem H, Walter K A, Langer R, Polymers as controlled drug delivery devices for the treatment of malignant brain tumors, Eur J Pharm Biopharm, 39 (1): 2-7, 1993; Brem H, Piantadosi S, Burger P C, Walker M, et al., Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent glioma, Lancet, 345: 1008-1012, 1995).
Microspheres which release BCNU have been developed but the results of studies in animals were relatively unencouraging (Torres Al, Boisdron-Celle M, Benoit J P, Formulation of BCNU-loaded microspheres: influence of drug stability and solubility on the design of the microencapsulation procedure, J. Microencapsulation, 13: 41-51, 1996; Painbéni T, Venier-Julienne M C, Benoit J P, Internal morphology of poly(D,L-lactide-co-glycolide) BNCU-loaded microspheres. Influence on drug stability, Eur. J. Pharm. Biopharm, 1998, 45, 31-39).
The subject of the present invention is the use of implantable biodegradable microspheres which release an anticancer agent, for treating glioblastoma. The use of these microspheres is combined with radiotherapy and with surgery. After exeresis of the tumor, the biodegradable microspheres which release an anticancer agent are implanted into the operating locus by intratissular injection. Radiotherapy is then carried out, within a maximum of seven days after the intervention.
By virtue of using these microspheres, the Applicant has succeeded, entirely advantageously, in doubling the survival time of patients suffering from a glioblastoma. Specifically, the use of the microspheres according to the invention makes it possible to achieve a survival time of at least 90 weeks.
Consequently, the present invention relates to the use of biodegradable microspheres which release a radiosensitizing anticancer agent, for manufacturing a medicinal product intended to be used simultaneously, separately or spread out over time with radiotherapy, for treating glioblastoma, said microspheres being intended to be implanted into the operating locus after exeresis of the glial tumor, characterized in that the microspheres containing the anticancer agent are coated with a polymer which delays the release of the anticancer agent and maintains, over time, a therapeutically effective concentration in the parenchymal space with a view to achieving a survival time for the patient thus treated at least equal to approximately 90 weeks, preferably approximately 130 weeks, even more preferably 160 weeks.
The microspheres used in the context of the invention c

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