Use of direct intracranial drug delivery system in brain tumor treatment

Abstract

The present invention relates to a composition for use in treating brain tumor in a subject, the composition comprising 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner. Said composition is particularly useful in treating glioblastoma in combination with artemisinin compounds and optionally anti-glioblastoma drugs. Said composition is particularly useful in combination with radiotherapy and / or photodynamic therapy.

Description

[0001] < ABK

[0002] 1

[0003] Use of direct intracranial drug delivery system in brain tumor treatment Field of the invention

[0004] The present invention relates to a composition for use in treating brain tumor in a subject, the composition comprising 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner. Said composition is particularly useful in treating glioblastoma in combination with artemisinin compounds and optionally anti-glioblastoma drugs. Said composition is particularly useful in combination with radiotherapy and / or photodynamic therapy.

[0005] Background of the invention

[0006] 5-Aminolevulinic acid (5-ALA) is an early metabolite of the hemoglobin biosynthesis pathway. Exogenous 5-ALA is used as an imaging agent to detect malignant tissue during brain tumor surgery. When provided systemically, 5-ALA is metabolized to the fluorescent metabolite protoporphyrin IX (PpIX), which specifically accumulates in brain tumor tissue. The tumor-specific accumulation has been attributed to i) an impaired blood-brain barrier, ii) upregulation of 5-ALA import carriers, and iii) an altered metabolic configuration of the heme biosynthesis pathway in malignant tissue. The increased production of PpIX in malignant brain tumor cells allows the visualization of malignant tumor tissue by violet-red fluorescence after excitation with blue light at a wavelength of 405 nm.

[0007] For the patient, oral administration of 5-ALA several hours prior to surgery facilitates tumor resection and increases the total area of resection linked to overall improved treatment outcome. While a single per oral dose of 20 mg / kg 5-ALA is considered safe, multiple dosing has shown significant adverse events in animals including strong phototoxicity and elevated markers of liver toxicity (Journal of Hepatology, 2003, 38, 476–482). It is therefore conceivable that regular systemic treatments with 5-ALA in humans leads to accumulation of heme metabolites, strong phototoxicity and potential hepatotoxicity, particularly when combined with other antineoplastic medications.

[0008] WO 2021 / 165405 discloses the use of 5-ALA in combination with artemisinin derivatives for the treatment of glioblastoma in systemic administration, demonstrating in vitro growth inhibition in human cerebral tumor organoid models. Mechanistically, PpIX and heme accumulation in glioblastoma cells activate the JLP-P04628WO13 Application (final) docx< ABK

[0009] 2

[0010] Artemisinin compound by catalyzing the cleavage of its endoperoxide bridge. Further, synergistic effects of the combination of 5-ALA and an artemisinin compound with temozolomide are reported.

[0011] The prior art demonstrates that sustained drug delivery from intracranial implants is highly dependent on the physicochemical properties of the active substance and the design of the delivery system. Shapira-Furman et al. (Journal of Controlled Release 295 (2019) 93–101) discloses temozolomide-loaded PLGA wafers in which temozolomide must first be encapsulated by multiple PLGA coatings to prevent immediate burst release and chemical degradation and only through this complex process is a substantially linear release achieved. Turek et al (Pharm Res (2020) 37: 90) describes idarubicin-loaded PLGA or PLC-PLGA wafers and shows that all formulations displayed a biphasic release with an initial burst phase followed by slower release, with kinetics being strongly dependent on polymer composition and preparation method. Korelidou et al. (International Journal of Pharmaceutics 665 (2024) 124710) reports acriflavine-loaded 3D-printed reservoir implants, which provided sustained release over up to 90 days, though with a faster initial phase and a gradual decrease thereafter, again demonstrating the influence of polymer ratios on release. Tan et al. (Biotechnol Bioeng, 82(3), 2003, 278), presents a computational model of etanidazole release from PLGA wafers, demonstrating a biphasic release profile characterized by an initial burst effect followed by a very slow release phase until the polymer matrix is fully hydrated. It is concluded that therapeutic penetration and efficacy are critically determined by release profile shape, while acknowledging that the mechanisms governing wafer behavior and tumor physiology remain incompletely understood. Alhnan et al. (J. Pharm. Sci. 99:4576–4583, 2010) systematically investigated the factors influencing burst release of drugs from polymeric microparticles. Their analysis demonstrated that drug molecular weight is the most critical determinant of release, with small molecules of low molecular weight (<300 Da) and high aqueous solubility showing the highest burst effects and being the most difficult to control. In contrast, larger molecules above approximately 300 Da exhibited significantly reduced release rates and could be more readily retained within polymeric matrices. This finding is directly relevant to 5-aminolevulinic acid, which is a very small molecule (131 Da) with strong hydrophilicity and negligible affinity for PLA or PLGA.

[0012] Taken together, these disclosures confirm that achieving constant intracranial drug release is technically challenging, multifactorial, and not predictable. Burst release, degradation-related issues, and the need for multiple formulation iterations are consistently reported, even for lipophilic, amphiphilic, or moderately water soluble JLP-P04628WO13 Application (final) docx< ABK

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[0014] drugs.

[0015] Thus, it is the objective of the present invention to provide a composition containing 5-ALA useful for the treatment of a brain tumor in a subject without severe adverse side effects.

[0016] The objective of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, the figures, and the examples of the present application.

[0017] Superiority over the state of the art embodiments

[0018] On the following pages the inventive contribution to the state of the art embodiments and the superiority over the state of the art embodiments is summarized.

[0019] The inventors are not aware that an intracranial drug delivery system for release of 5-aminolevulinic acid is known, so that the intracranial drug delivery system disclosed herein is novel.

[0020] As outlined above, 5-aminolevulinic acid is a small highly hydrophilic molecule which tends to immediate and burst release which has to be avoided due to the occurrence of undesired side effects. Therefore, a 5-aminolevulinic acid treatment regimen for brain tumors had to be invented which avoids a bolus or burst release and which benefits from the antitumor activity of 5-aminolevulinic acid by simultaneously avoiding the side effects of a not optimized treatment regimen (see Examples).

[0021] The inventors conclude that low dose and constant intracranial or intratumoral release of 5-aminolevulinic acid (5-ALA) for several days and up to weeks postsurgery is highly tolerable and shows superior efficacy over other known application routes in the treatment of brain tumor and brain metastases such as metastases in the brain caused by lung cancer cells.

[0022] The invention provides a novel dosage regimen in which 5-ALA is administered locally and continuously at low dose into the resection cavity for several days up to weeks following tumor surgery. This regimen maintains constant intracranial exposure to 5-ALA without bolus toxicity and achieves robust antitumor efficacy, in contrast to systemic high-dose administration or intermittent intracranial injections which were associated with systemic adverse effects.

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[0025] Due to the special properties of 5-ALA the development of such a composition faced certain challenges so that such a composition could not be derived from the state of the art embodiments in an obvious manner.

[0026] This is why 5-aminolevulinic acid (5-ALA) poses a particularly distinct challenge in this context due to its special chemical and pharmacokinetic properties. Unlike the lipophilic or amphiphilic chemotherapeutics of the prior art (like carmustine, idarubicin, acriflavine, etanidazole) or the moderately water soluble and chemically unstable temozolomide, 5-ALA is a very small, strongly hydrophilic and chemically stable zwitterionic molecule with a calculated log P value of -3.5 which is significantly lower than of the molecules used in the prior art embodiments. 5-ALA shows negligible affinity to hydrophobic polymers and diffuses immediately once water penetrates the matrix. Consequently, attempts to formulate 5-ALA in conventional intracranial wafer systems lead to rapid burst release and exhaustion of the payload within hours, a behavior that cannot be controlled by routine polymer blending or compression.

[0027] The inventors identified a novel dosing regimen of continuous, low-dose intracranial administration of 5-aminolevulinic acid (5-ALA) which provides a safe and effective treatment strategy for brain tumors.

[0028] While intermittent intracranial bolus injections of 5-ALA in mice (initially 100 pg / day, reduced to 50 pg / day due to toxicity) showed a positive trend toward tumor growth restriction (see Example 1), this regimen was associated with systemic adverse effects, including weight loss and reduced survival.

[0029] Surprisingly, an intracranial, continuous, low-dose release of 5-ALA (delivering 50 pg / day) yielded robust antitumor activity without compromising body weight (see Example 2). Notably, this approach was more effective than a systemic high-dose (120 mg / kg) regimen, underscoring the benefits of localized, constant drug delivery.

[0030] The inventors were able to further demonstrate the favorable safety profile in mouse studies. In healthy, non-tumor-bearing mice, the continuous intracranial delivery of 5-ALA over one month did not affect body weight, blood cell parameters, or serum toxicity markers (see Example 3).

[0031] In addition, testing various 5-ALA doses, either alone or in combination with artesunate (ARS = 1e), revealed that even an extremely low 5-ALA dose (10 pg / day) JLP-P04628WO13 Application (final) docx< ABK

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[0033] significantly reduced tumor growth, while maintaining excellent tolerability (see Example 4).

[0034] Although constant intracranial 5-ALA delivery alone significantly reduced tumor growth (see Example 5), its combination with orally administered ARS produced a synergistic antitumor effect. ARS administered as a monotherapy did not limit tumor growth, highlighting the enhanced efficacy achieved through their combination (see Example 6).

[0035] The clinical relevance of this regimen is demonstrated in Example 7, where constant intracranial release of 5-ALA in combination with oral artesunate in a resection model resulted in marked inhibition of tumor regrowth, significant prolongation of survival, and excellent tolerability. In this study, patient-derived glioblastoma cells were implanted into mouse brains, followed by surgical removal of approximately 80% of the tumor mass after two weeks. Continuous intracranial exposure to 5-ALA, combined with daily oral artesunate, left body weight unaffected while strongly reducing tumor progression and significantly extending survival, thereby closely reproducing the intended clinical setting of applying a slow-releasing 5-ALA implant to the resection cavity during brain tumor surgery. These results confirm that the invention is directly translatable to post-resection therapy in mammalian, including human, patients.

[0036] Accordingly, the claimed dosage regimen establishes a safe and effective therapeutic strategy that cannot be derived from the prior art. It solves the specific problem of delivering 5-ALA in a constant, tolerable manner directly to the resection cavity, and achieves therapeutic results that are not obtainable with systemic dosing or with intracranial delivery regimens designed for other chemotherapeutics.

[0037] Even though WO 2021 / 165405 discloses the systemic administration of 5-ALA in combination with artemisinin derivatives for the treatment of glioblastoma, and Shapira-Furman et al. report on intracranial delivery of lipophilic and chemically unstable agents such as temozolomide and carmustine, the improved survival and tolerability observed when administering effective intracranial doses of 5-ALA by means of an implantable delivery system, in combination with systemic artesunate, remains remarkable and unforeseen due to the fundamentally different release behavior and pharmacokinetics of 5-ALA compared to the agents addressed in the prior art. The intracranial release systems of Shapira-Furman et al. are optimized for lipophilic and chemically unstable drugs such as temozolomide and carmustine, and therefore do not work with 5-ALA, because of its small size, strong hydrophilicity, and JLP-P04628WO13 Application (final) docx< ABK

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[0039] lack of polymer affinity, which would cause immediate burst release and rapid depletion from monolithic polymer wafers. For the same reasons, initial attempts to translate the systemic administration concepts of WO 2021 / 165405 directly to a local intracranial delivery format by merely substituting the active ingredient with 5-ALA were unsuccessful, confirming that 5-ALA requires a fundamentally different delivery strategy than that used for systemic dosing or for lipophilic chemotherapeutic agents.

[0040] Metabolomic analyses further indicate that systemic administration of 5-ALA leads to an increase of heme pathway intermediates in peripheral organs such as liver and serum, whereas intracranial sustained delivery according to the present invention limits heme biosynthesis activation to the brain (see Example 10 and Figure 12). This local exposure can prevent systemic side effects - particularly when 5-ALA is combined with Artemisinin derivatives which are activated by heme.

[0041] Initial formulation studies demonstrated that simple monolithic matrix wafers or multilayer coatings of the type reported by Shapira-Furman et al. are unsuitable for 5-ALA. The uncontrolled coating strategy of Shapira-Furman et al. would not permit a linear, sustained release of highly hydrophilic molecules like 5-ALA, and the desired release behavior cannot be obtained by a monolithic matrix design. This is in line with the conclusions of Alhnan et al. that drug molecular weight is the most critical determinant of release, with small molecules of low molecular weight (<300 Da) and high aqueous solubility showing the highest burst effects and being the most difficult to control. Thus, from the teaching of the prior art the skilled person would reasonably expect that 5-ALA undergoes uncontrolled, immediate burst release from monolithic polymer systems, whereas relatively larger and more lipophilic drugs such as temozolomide, carmustine, idarubicin or acriflavine can achieve more sustained release. Consequently, the controlled linear release of 5-ALA required for safe and effective therapy cannot be obtained using conventional monolithic wafer approaches and required the development of intracranial delivery systems specifically designed for 5-ALA. This required specific treatment regimen for 5-ALA could only be obtained by the specifically engineered multilayer core-shell architectures described herein.

[0042] The inventors found out that this expectation is fully confirmed by experimental data. In Example 8, various monolithic PLA and PLGA formulations prepared by film casting and vacuum compression (MF1–MF4, C1–C10) were tested. Despite successful fabrication, all systems displayed unfavorable release profiles: either a rapid burst with near-complete depletion within hours or incomplete release plateauing early. These findings confirm that monolithic PLA and PLGA wafers are JLP-P04628WO13 Application (final) docx< ABK

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[0044] inherently unsuitable for 5-ALA delivery and for obtaining the 5-ALA release kinetic of the present invention.

[0045] When 5-ALA was incorporated into such PLGA-based compression-molded wafers, rapid hydration of the polymer led to an immediate burst release and exhaustion of the payload within a few hours, failing to provide any sustained delivery. Only the specifically designed release systems described herein, in particular multilayer coreshell architectures with defined polymer compositions and weight ratios, were capable of providing the desired prolonged and near zero-order release of 5-ALA without bolus effects.

[0046] Consequently, due to the specific chemical and pharmacokinetic properties of 5-ALA, a 5-ALA containing wafer could not be derived from the state of the art wafer, like a temozolomide wafer, in an obvious manner by simply replacing the known drug by 5-ALA as demonstrated by the comparative examples. A new and inventive wafer composition and wafer design had to be developed for 5-ALA in order to obtain a constant intracranial or constant intratumoral release of 5-ALA for at least several days post-surgery by avoiding a side effect causing bolus dose. Moreover, this 5-ALA wafer showed to be perfectly designed in order to be administered in combination with ARS.

[0047] Therapeutic outcome and advantages

[0048] Under the application scheme illustrated in Figure 7A, continuous low-dose intracranial release of 5-ALA in combination with weekday oral administration of ARS produced a pronounced suppression of tumor regrowth after surgical resection and significantly prolonged survival, as demonstrated in Example 7. The treatment had no adverse effects on body weight, blood-cell parameters, or serum toxicology markers, confirming its safety in vivo (Example 3). Moreover, the combination therapy showed clear superiority over either high-dose bolus 5-ALA treatment or ARS monotherapy (Examples 1 and 6).

[0049] These findings establish a distinct temporal–pharmacological regimen in which sustained intracranial 5-ALA exposure and systemic artesunate administration are aligned to achieve prolonged heme-dependent activation and apoptotic tumor cell death in certain embodiments. The regimen thus provides an effective and well-tolerated therapeutic strategy for postoperative management of glioblastoma and related brain tumors.

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[0052] Description of the invention

[0053] Therefore, the present invention is directed to a composition for use in treating brain tumor in a subject, the composition comprising 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner.

[0054] The direct intracranial drug delivery system preferably provides the composition comprising 5-ALA in the subject during and after the at least partial surgical brain tumor resection. During the brain tumor resection, the surgeon removes the tumor, as thoroughly as possible. Nevertheless, infiltrative tumor cells may remain. The surgeon assures the hemostasis of surrounding tissues. Following the tumor resection, the tumor bed or tumor cavity or resection cavity is formed, i.e. the area formerly occupied by the cancerous growth. Afterwards, the surgeon proceeds, in case of an implantable direct intracranial drug delivery system, such as a wafer or a patch or a plurality of wafers or a plurality of patches, to the surgical implantation of the direct intracranial drug delivery system in the tumor bed, formed after the tumor resection.

[0055] Thus, the present invention is also directed to a composition for use in treating brain tumor in a subject, the composition comprising 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the direct intracranial drug delivery system is implanted in a tumor bed formed after tumor resection.

[0056] The term “at least partial surgical resection” as used herein refers to the surgical procedure in which a portion or entirety of a brain tumor mass is removed from the brain. This includes partial resection, i.e. removal of some, but not all, of the tumor tissue, which may be necessitated by factors such as the tumor's proximity to critical brain structures, patient health considerations, or surgical feasibility, and total resection, i.e. complete removal of the visible tumor mass as determined by intraoperative imaging or post-operative assessment. Thus, the term “at least partial surgical resection” encompasses any surgical intervention aimed at debulking the tumor, reducing its volume, or excising as much of the pathological tissue as is safely JLP-P04628WO13 Application (final) docx< ABK

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[0058] achievable, with the intent of minimizing symptoms, improving prognosis, or facilitating adjunct therapies such as radiation or chemotherapy.

[0059] Reworded, the present invention is directed to a composition for use in treating brain tumor in a subject, the composition comprising 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after complete surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner.

[0060] Reworded, the present invention is directed to a composition for use in treating brain tumor in a subject, the composition comprising 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into remaining brain tumor tissue, i.e. intratumorally and / or a resection cavity in a controlled-release manner.

[0061] A “therapeutically effective amount” or “therapeutically effective dosage” of the composition, 5-ALA or a therapeutic agent, is any amount of said composition, 5-ALA or the therapeutic agent that, when used alone or in combination with another therapeutic agent after at least partial surgical resection of the brain tumor, prevents or slows tumor regrowth / recurrence, protects a subject against the onset of the brain tumor or promotes tumor regression evidenced by a decrease in severity of cancer symptoms, particularly tumor size, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. The ability of the therapeutic agent to promote tumor regression and / or inhibit tumor progression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays. By way of example, an anti-tumor agent promotes tumor regression in a subject. In preferred embodiments, a therapeutically effective amount of 5-ALA promotes tumor regression to the point of eliminating the brain tumor. “Promoting cancer regression” means that administering an effective amount of 5-ALA, alone or in combination with an anti-cancer agent, results in a reduction in tumor growth or size, necrosis of the tumor, a decrease in severity of at least one disease symptom, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. In addition, the terms “effective” and “effectiveness” with regard to a treatment includes both JLP-P04628WO13 Application (final) docx< ABK 10

[0062] pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of the drug to promote tumor regression and / or inhibit tumor progression in the patient. Physiological safety refers to the level of toxicity, or other adverse physiological effects at the cellular, organ and / or organism level (adverse effects) resulting from administration of the agent.

[0063] As used herein, the terms "5-aminolevulinic acid", “delta-aminolevulinic acid”, " ALA" and "5-ALA" are used interchangeably and encompass 5-amino-4-oxopentanoic acid. The term,,5-aminolevulinic acid“ as well as the synonyms thereof encompasses also salts such as the hydrochloride, hydrobromide, and hydroiodide salt and especially the hydrochloride salt thereof.

[0064] Suitable salts of "5-aminolevulinic acid" include, but are not limited to, salts with acids such as maleic, fumaric, benzoic, ascorbic, succinic, acetic, formic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, oleic, tannic, aspartic, stearic, palmitic, glycolic, glutamic, gluconic, glucaronic, saccharic, isonicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, benzenesulfonic acids, or pamoic (e.g, 1,1’-methylene-bis-(2-hydroxy-3-naphthoate)) acid. Suitable inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, or nitric acid. Preferred is the HCI salt of 5-ALA.

[0065] For the purposes of this application, all dose and daily dose values for 5-aminolevulinic acid are expressed on the basis of the corresponding hydrochloride salt (5-ALA·HCl), unless explicitly stated otherwise. Accordingly, if a different pharmaceutically acceptable salt of 5-aminolevulinic acid or the free base is used in practice or in experiments, the numerical dose values reported herein correspond to the molar equivalent of the hydrochloride salt form. In the in vivo experiments disclosed herein the HCI salt of 5-ALA was used.

[0066] The term “wt.%” refers to »weight %<< and »percent per weight«.

[0067] The disclosure of a component, such as the core, consist of 25 wt.% to 75 wt.% of compound A and 75 wt.% to 25 wt.% of compound B has to be understood in the way that both compounds together have to add up to 100 wt.%.

[0068] Consequently, the disclosure

[0069] a) a core consisting of:

[0070] 5-aminolevulinic acid in a range from 25 wt.% to 75 wt.%,

[0071] the core polymer in a range from 75 wt.% to 25 wt.%, and

[0072] optionally the excipient in the core in a range of 5 wt.% to 15 wt.%, based on the total weight of the core,

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[0074] has to be understood in the way that in case the excipient is present, e.g. in an amount of 15 wt.%, the remaining 5-ALA and core polymer have to add up to 85 wt.% so that all ingredients together add up to 100 wt.%. Consequently, the core polymer cannot be present in the amount of 75 wt.% anymore, because 5-ALA must be present at least in the amount of 25 wt.% so that the maximum amount of the core polymer is 60 wt.%.

[0075] As used herein, the term "treating" or “treatment” encompasses to reversing, alleviating or inhibiting the progress of a disease, disorder or condition, or improvement of one or more symptoms of such disease, disorder or condition, to which such term applies. As used herein, "treating" or “treatment” may also refer to decreasing the probability or incidence of the occurrence of a disease, disorder or condition in a mammal as compared to an untreated control population, or as compared to the same mammal prior to treatment. For example, as used herein, "treating" may refer to preventing a disease, disorder or condition, and may include delaying or preventing the onset of a disease, disorder or condition, or delaying or preventing the symptoms associated with a disease, disorder or condition. As used herein, "treating" may also refer to reducing the severity of a disease, disorder or condition or symptoms associated with such disease, disorder or condition prior to a mammal's affliction with the disease, disorder or condition. Such prevention or reduction of the severity of a disease, disorder or condition prior to affliction relates to the administration of the composition of the present invention, as described herein, to a subject that is not at the time of administration afflicted with the disease, disorder or condition. As used herein the term "treating" may also refer to preventing the recurrence of a disease, disorder or condition or of one or more symptoms associated with such disease, disorder or condition. The terms "treatment" and "therapeutically," as used herein, refer to the act of treating, as "treating" is defined above.

[0076] Preferably, a disease, disorder is a cancer selected from brain cancer, in particular glioblastoma.

[0077] The term “intracranial” or “intracranially” refers to the injection or administration of 5-ALA and / or an artemisinin compound into the brain tissue. This covers intracerebral delivery, injection or administration into the cerebrospinal fluid (e.g. via intracerebroventricular (ICV) or intrathecal injection), as well as delivery into cavities emerging from brain surgeries.

[0078] The term "patient" or "subject," as used herein, refers to a mammalian subject (primates (e.g. humans, cows, sheep, goats, pigs, horses, dogs, cats, rabbits, rats, JLP-P04628WO13 Application (final) docx< ABK 12

[0079] mice and the like), preferably a human subject (e.g. a man, a woman or a child), that has, is suspected of having, or is or may be susceptible to a condition associated with brain cancer

[0080] The term “resection cavity” refers to an anatomical space created in the brain after the surgical removal of a tumor. It comprises the tumor bed, i.e. the area that was occupied by the tumor, and may include surrounding peritumoral tissue that potentially harbors residual microscopic tumor cells. This cavity is clinically significant because it serves as a treatment target (such as direct drug delivery systems) that aim to locally release therapeutic agents to eliminate remaining infiltrative tumor cells and reduce the risk of recurrence.

[0081] The term “released into resection cavity” refers to the direct release of the composition comprising 5-ALA into the resection cavity and its immediately adjacent (peritumoral) brain tissue after at least partial surgical resection of the brain tumor and intratumoral, i.e. into the remaining tumor cells, in case, the tumor was not removed completely during surgery. Said release mode is designed to target residual infiltrative tumor cells that remain at the margins of the resection cavity and are a primary cause of recurrence, thereby helping to prevent recurrence while minimizing systemic toxicity.

[0082] The term “in a controlled-release manner” refers to the delivery or release of a composition or therapeutic agent such as 5-ALA at a predetermined and regulated rate over a specified period. This mode of release is designed to maintain consistent therapeutic levels of the composition in the target site, minimizing fluctuations in drug concentration that could lead to subtherapeutic effects or toxicity. Controlled release encompasses, but is not necessarily limited to, substantially continuous delivery, and patterned delivery (e.g., intermittent delivery over a period of time that is interrupted by regular or irregular time intervals).

[0083] Controlled release as used herein does not refer to delivery of a bolus of the composition, 5-ALA or any therapeutic agent described herein, i.e. administration of a single, concentrated dose of at least 1 mg of 5-ALA or any therapeutic agent over a short period of time of several minutes to a human subject. Controlled release as used herein particularly does not refer to the administration of a single, concentrated dose of at least 1 mg of 5-ALA or any therapeutic agent within seconds to 10 minutes, preferably within 1 to 10 minutes. This includes also a daily bolus application of the composition, 5-ALA or any therapeutic agent described herein. Thus, controlled release as used herein does not refer to the daily administration of a JLP-P04628WO13 Application (final) docx< ABK 13

[0084] single, concentrated dose of at least 1 mg of 5-ALA or any therapeutic agent within 1 to 5 minutes. The conclusion can be drawn from the mouse data that a bolus administration of 1.00 mg or more of 5-ALA administered within 5 minutes or less should strictly be avoided in order to avoid toxic side effects of the 5-ALA administration.

[0085] Reworded, the present invention is directed to a composition for use in treating brain tumor in a subject, the composition comprising 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system continuously releases a therapeutically effective amount of the composition into a resection cavity at a constant or nearly constant rate over time.

[0086] Reworded, the present invention is directed to a composition for use in treating brain tumor in a subject, the composition comprising 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system continuously releases a therapeutically effective amount of the composition into a resection cavity at a linear or nearly linear rate over time.

[0087] “Linear release” and “constant release” are used synonymously herein, since in practice, when a controlled release system is designed to deliver a drug at a fixed rate, the cumulative release is linear over time (linear release). In this sense, “linear” and “constant” release describe the same ideal scenario, where the rate of drug release does not vary with time.

[0088] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity over 1 to 30 days, preferably 7 to 29 days, more preferably 14 to 28 days.

[0089] Specifically, in a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, JLP-P04628WO13 Application (final) docx< ABK 14

[0090] the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity over 1 to 30 days, preferably 7 to 29 days, more preferably 14 to 28 days after implantation of the direct intracranial drug delivery system in the subject.

[0091] Reworded, in a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity over 1 to 30 days, preferably 7 to 29 days, more preferably 14 to 28 days after at least partial surgical resection of the brain tumor.

[0092] In an alternative embodiment, the composition is continuously released into the resection cavity over 1 to 50 days or 1 to 40 days or 1 to 30 days, more preferably over 2 to 30 days, more preferably over 3 to 30 days, more preferably over 4 to 30 days, and most preferably over 8 to 30 days.

[0093] In a preferred embodiment, the composition is continuously released into the resection cavity over at least 4 days. Thus, the composition for use in treating brain tumor in a subject, comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the composition is continuously released into the resection cavity over at least 4 days.

[0094] Preferably, the composition is continuously released into the resection cavity over at least 4 days, more preferably at least 5 days, more preferably at least 6 days, more preferably at least 7 days, more preferably at least 8 days, more preferably at least 9 days, more preferably at least 10 days, more preferably at least 11 days, more preferably at least 12 days, more preferably at least 13 days, more preferably at least 14 days, more preferably at least 15 days, more preferably at least 16 days, more preferably at least 17 days, more preferably at least 18 days, more preferably at least JLP-P04628WO13 Application (final) docx< ABK 15

[0095] 19 days, more preferably at least 20 days, more preferably at least 21 days, more preferably at least 22 days, more preferably at least 23 days, more preferably at least 24 days, more preferably at least 25 days, more preferably at least 26 days, more preferably at least 27 days, more preferably at least 28 days, more preferably at least 29 days, and more preferably at least 30 days after at least partial surgical resection of the brain tumor.

[0096] In an alternative embodiment, the composition is continuously released into the resection cavity between 2 to 40 days or 4 days to 30 days, more preferably between 5 days and 30 days, more preferably between 10 days and 29 days, more preferably between 14 days and 28 days, and most preferably between 16 days and 27 days after at least partial surgical resection of the brain tumor.

[0097] In an alternative embodiment, the composition is continuously released into the resection cavity between 3 days to 15 days, more preferably between 4 days and 14 days, more preferably between 5 days and 13 days, more preferably between 6 days and 12 days, and most preferably between 7 days and 11 days after at least partial surgical resection of the brain tumor.

[0098] In an alternative embodiment, the composition is continuously released into the resection cavity between 8 days to 20 days, more preferably between 9 days and 19 days, more preferably between 10 days and 18 days, more preferably between 11 days and 17 days, and most preferably between 12 days and 16 days after at least partial surgical resection of the brain tumor.

[0099] In an alternative embodiment, the composition is continuously released into the resection cavity between 13 days to 25 days, more preferably between 14 days and 24 days, more preferably between 15 days and 23 days, more preferably between 16 days and 22 days, and most preferably between 17 days and 21 days after at least partial surgical resection of the brain tumor.

[0100] In an alternative embodiment, the composition is continuously released into the resection cavity between 18 days to 30 days, more preferably between 19 days and 29 days, more preferably between 20 days and 28 days, more preferably between 21 days and 27 days, and most preferably between 22 days and 26 days after at least partial surgical resection of the brain tumor.

[0101] In an alternative embodiment, the composition is continuously released into the resection cavity between 23 days to 35 days, more preferably between 24 days and JLP-P04628WO13 Application (final) docx< ABK 16

[0102] 34 days, more preferably between 25 days and 33 days, more preferably between 26 days and 32 days, and most preferably between 27 days and 30 days after at least partial surgical resection of the brain tumor.

[0103] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of 0.1 mg – 100 mg per day.

[0104] For the purposes of the present application, the release rates indicated throughout the specification, including values expressed such as “0.1 mg – 100 mg per day” refer to the total daily amount of 5-aminolevulinic acid released at the tumor site, in particular into the tumor tissue and / or the tumor resection cavity, unless explicitly stated otherwise.

[0105] The stated daily release rate may be achieved by the direct intracranial drug delivery system, which may comprise a single implant, a plurality of implants administered simultaneously or sequentially, or a continuous delivery device such as an implantable pump. Where the direct intracranial drug delivery system comprises multiple implants, the indicated amount corresponds to the cumulative daily release of all implants present at the tumor site.

[0106] It will be understood by the skilled person that not all release rates within the indicated range can necessarily be achieved by a single implant of a given size or composition. The skilled person, applying routine considerations regarding implant dimensions, drug loading, and release kinetics, will select an appropriate mode of administration, including the use of multiple implants and / or an alternative continuous delivery system, in order to achieve the desired total daily release.

[0107] Preferably, the 5-aminolevulinic acid in the composition is continuously released at a constant rate of 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, JLP-P04628WO13 Application (final) docx< ABK 17

[0108] more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.47 mg – 15 mg per day, and most preferably at a constant rate of 0.5 mg – 10 mg per day.

[0109] Preferably, the 5-aminolevulinic acid in the composition is continuously released at a constant rate of 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.5 mg – 50 mg per day, more preferably at a constant rate of 1 mg – 30 mg per day, more preferably at a constant rate of 2 mg – 20 mg per day, and most preferably at a constant rate of 3 mg – 15 mg per day.

[0110] Preferably, the 5-aminolevulinic acid in the composition is continuously released at a constant rate of 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day.

[0111] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of0.1 mg – 50 mg per day, preferably 0.5 mg – 50 mg per day, preferably 1.0 mg –40 mg per day, preferably 0.5 mg – 25 mg per day, more preferably 1.0 mg – 30 mg per day, more preferably 0.8 mg – 10 mg per day, more preferably 0.9 mg – 5 mg per day, more preferably 3.0 mg – 5.0 mg per day, and most preferably 1.0 mg – 3 mg per day into the resection cavity after at least partial surgical resection of the brain cancer. As already stated above, the indicated release rate refers to the total amount of 5-aminolevulinic acid released by the direct intracranial drug delivery system. Where the system comprises more than one implant, the stated amount corresponds to the cumulative release of all implants used for the treatment of the brain tumor, including brain metastases.

[0112] JLP-P04628WO13 Application (final) docx< ABK 18

[0113] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of 0.5 mg – 20 mg per day.

[0114] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of 2 mg – 20 mg per day.

[0115] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of 3 mg – 15 mg per day.

[0116] In an alternative embodiment, the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg per day; more preferably at a constant rate of about 0.2 mg per day; more preferably at a constant rate of about 0.3 mg per day; more preferably at a constant rate of about 0.4 mg per day; more preferably at a constant rate of about 0.5 mg per day; more preferably at a constant rate of about 0.6 mg per day; more preferably at a constant rate of about 0.7 mg per day; more preferably at a constant rate of about 0.8 mg per day; more preferably at a constant rate of about 0.9 mg per day; more preferably at a constant rate of about 1.0 mg per day; more preferably at a constant rate of about 1.1 mg per day; more preferably at a constant rate of about 1.2 mg per day; more preferably at a constant rate of about 1.3 mg per day; more preferably at a constant rate of about 1.4 mg per JLP-P04628WO13 Application (final) docx< ABK 19

[0117] day; more preferably at a constant rate of about 1.5 mg per day; more preferably at a constant rate of about 1.6 mg per day; more preferably at a constant rate of about 1.7 mg per day; more preferably at a constant rate of about 1.8 mg per day; more preferably at a constant rate of about 1.9 mg per day; more preferably at a constant rate of about 2.0 mg per day; more preferably at a constant rate of about 2.1 mg per day; more preferably at a constant rate of about 2.2 mg per day; more preferably at a constant rate of about 2.3 mg per day; more preferably at a constant rate of about 2.4 mg per day; more preferably at a constant rate of about 2.5 mg per day; more preferably at a constant rate of about 2.6 mg per day; more preferably at a constant rate of about 2.7 mg per day; more preferably at a constant rate of about 2.8 mg per day; more preferably at a constant rate of about 2.9 mg per day; more preferably at a constant rate of about 3.0 mg per day; more preferably at a constant rate of about 3.1 mg per day; more preferably at a constant rate of about 3.2 mg per day; more preferably at a constant rate of about 3.3 mg per day; more preferably at a constant rate of about 3.4 mg per day; more preferably at a constant rate of about 3.5 mg per day; more preferably at a constant rate of about 3.6 mg per day; more preferably at a constant rate of about 3.7 mg per day; more preferably at a constant rate of about 3.8 mg per day; more preferably at a constant rate of about 3.9 mg per day; more preferably at a constant rate of about 4.0 mg per day; more preferably at a constant rate of about 4.1 mg per day; more preferably at a constant rate of about 4.2 mg per day; more preferably at a constant rate of about 4.3 mg per day; more preferably at a constant rate of about 4.4 mg per day; more preferably at a constant rate of about 4.5 mg per day; more preferably at a constant rate of about 4.6 mg per day; more preferably at a constant rate of about 4.7 mg per day; more preferably at a constant rate of about 4.8 mg per day; more preferably at a constant rate of about 4.9 mg per day; more preferably at a constant rate of about 5.0 mg per day; more preferably at a constant rate of about 5.1 mg per day; more preferably at a constant rate of about 5.2 mg per day; more preferably at a constant rate of about 5.3 mg per day; more preferably at a constant rate of about 5.4 mg per day; more preferably at a constant rate of about 5.5 mg per day; more preferably at a constant rate of about 5.6 mg per day; more preferably at a constant rate of about 5.7 mg per day; more preferably at a constant rate of about 5.8 mg per day; more preferably at a constant rate of about 5.9 mg per day; more preferably at a constant rate of about 6.0 mg per day; more preferably at a constant rate of about 6.1 mg per day; more preferably at a constant rate of about 6.2 mg per day; more preferably at a constant rate of about 6.3 mg per day; more preferably at a constant rate of about 6.4 mg per day; more preferably at a constant rate of about 6.5 mg per day; more preferably at a constant rate of about 6.6 mg per day; more preferably at a constant rate of about 6.7 mg per day; more preferably at a constant rate of about 6.8 mg per day; more preferably at a constant JLP-P04628WO13 Application (final) docx< ABK 20

[0118] rate of about 6.9 mg per day; more preferably at a constant rate of about 7.0 mg per day; more preferably at a constant rate of about 7.1 mg per day; more preferably at a constant rate of about 7.2 mg per day; more preferably at a constant rate of about 7.3 mg per day; more preferably at a constant rate of about 7.4 mg per day; more preferably at a constant rate of about 7.5 mg per day; more preferably at a constant rate of about 7.6 mg per day; more preferably at a constant rate of about 7.7 mg per day; more preferably at a constant rate of about 7.8 mg per day; more preferably at a constant rate of about 7.9 mg per day; more preferably at a constant rate of about 8.0 mg per day; more preferably at a constant rate of about 8.1 mg per day; more preferably at a constant rate of about 8.2 mg per day; more preferably at a constant rate of about 8.3 mg per day; more preferably at a constant rate of about 8.4 mg per day; more preferably at a constant rate of about 8.5 mg per day; more preferably at a constant rate of about 8.6 mg per day; more preferably at a constant rate of about 8.7 mg per day; more preferably at a constant rate of about 8.8 mg per day; more preferably at a constant rate of about 8.9 mg per day; more preferably at a constant rate of about 9.0 mg per day; more preferably at a constant rate of about 9.1 mg per day; more preferably at a constant rate of about 9.2 mg per day; more preferably at a constant rate of about 9.3 mg per day; more preferably at a constant rate of about 9.4 mg per day; more preferably at a constant rate of about 9.5 mg per day; more preferably at a constant rate of about 9.6 mg per day; more preferably at a constant rate of about 9.7 mg per day; more preferably at a constant rate of about 9.8 mg per day; more preferably at a constant rate of about 9.9 mg per day; and most preferably at a constant rate of about 10.0 mg per day.

[0119] In an alternative embodiment, the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 100 mg per day; more preferably at a constant rate of about 98 mg per day; more preferably at a constant rate of about 96 mg per day; more preferably at a constant rate of about 94 mg per day; more preferably at a constant rate of about 92 mg per day; more preferably at a constant rate of about 90 mg per day; more preferably at a constant rate of about 88 mg per day; more preferably at a constant rate of about 86 mg per day; more preferably at a constant rate of about 84 mg per day; more preferably at a constant rate of about 82 mg per day; more preferably at a constant rate of about 80 mg per day; more preferably at a constant rate of about 78 mg per day; more preferably at a constant rate of about 76 mg per day; more preferably at a constant rate of about 74 mg per day; more preferably at a constant rate of about 72 mg per day; more preferably at a constant rate of about 70 mg per day; more preferably at a constant rate of about 68 mg per day; more preferably at a constant rate of about 66 mg per day; more preferably at a constant rate of about 64 mg per day; more preferably at a constant JLP-P04628WO13 Application (final) docx< ABK 21

[0120] rate of about 62 mg per day; more preferably at a constant rate of about 60 mg per day; more preferably at a constant rate of about 58 mg per day; more preferably at a constant rate of about 56 mg per day; more preferably at a constant rate of about 54 mg per day; more preferably at a constant rate of about 52 mg per day; more preferably at a constant rate of about 50 mg per day; more preferably at a constant rate of about 48 mg per day; more preferably at a constant rate of about 46 mg per day; more preferably at a constant rate of about 44 mg per day; more preferably at a constant rate of about 42 mg per day; more preferably at a constant rate of about 40 mg per day; more preferably at a constant rate of about 38 mg per day; more preferably at a constant rate of about 36 mg per day; more preferably at a constant rate of about 34 mg per day; more preferably at a constant rate of about 32 mg per day; more preferably at a constant rate of about 30 mg per day; more preferably at a constant rate of about 28 mg per day; more preferably at a constant rate of about 26 mg per day; more preferably at a constant rate of about 24 mg per day; more preferably at a constant rate of about 22 mg per day; more preferably at a constant rate of about 20 mg per day; more preferably at a constant rate of about 19 mg per day; more preferably at a constant rate of about 18 mg per day; more preferably at a constant rate of about 17 mg per day; more preferably at a constant rate of about 16 mg per day; more preferably at a constant rate of about 15 mg per day; more preferably at a constant rate of about 14 mg per day; more preferably at a constant rate of about 13 mg per day; more preferably at a constant rate of about 12 mg per day; more preferably at a constant rate of about 11 mg per day; more preferably at a constant rate of about 10 mg per day; more preferably at a constant rate of about 9 mg per day; more preferably at a constant rate of about 8 mg per day; more preferably at a constant rate of about 7 mg per day; more preferably at a constant rate of about 6 mg per day; more preferably at a constant rate of about 5 mg per day; more preferably at a constant rate of about 4.5 mg per day; more preferably at a constant rate of about 4 mg per day; more preferably at a constant rate of about 3.5 mg per day; more preferably at a constant rate of about 3.0 mg per day; more preferably at a constant rate of about 2.5 mg per day; more preferably at a constant rate of about 2.0 mg per day; more preferably at a constant rate of about 1.5 mg per day; more preferably at a constant rate of about 1.0 mg per day; more preferably at a constant rate of about 0.9 mg per day; more preferably at a constant rate of about 0.8 mg per day; more preferably at a constant rate of about 0.7 mg per day; more preferably at a constant rate of about 0.6 mg per day; and most preferably at a constant rate of about 0.5 mg per day.

[0121] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the JLP-P04628WO13 Application (final) docx< ABK 22

[0122] composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity over 1 to 50 days or 1 to 40 days or 1 to 30 days after at least partial surgical resection of the brain tumor, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day.

[0123] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity for at least 3 days after at least partial surgical resection of the brain tumor, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day.

[0124] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after JLP-P04628WO13 Application (final) docx< ABK 23

[0125] at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity for at least 10 days after at least partial surgical resection of the brain tumor, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day.

[0126] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity for at least 20 days after at least partial surgical resection of the brain tumor, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day.

[0127] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct JLP-P04628WO13 Application (final) docx< ABK 24

[0128] intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity for at least 25 days after at least partial surgical resection of the brain tumor, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day.

[0129] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity for at least 30 days after at least partial surgical resection of the brain tumor, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day.

[0130] Brain tumor

[0131] The inventive composition is particularly useful for treating brain tumor. A brain tumor is an abnormal growth of cells within the brain or its surrounding structures, which can be classified as benign (non-cancerous) or malignant (cancerous). Brain tumors may arise from the brain's own tissues, supporting cells, or from metastatic JLP-P04628WO13 Application (final) docx< ABK 25

[0132] spread from other parts of the body. Brain tumors can be broadly categorized into primary brain tumors (originating in the brain) and secondary / metastatic brain tumors (originating elsewhere and spreading to the brain). Primary brain tumors can be categorized as solid tumors comprising dense, localized masses of abnormal tissue like meningiomas, medulloblastomas, and pituitary adenomas, and gliomas which are tumors arising from glial cells, which support and protect neurons in the central nervous system (CNS).

[0133] The term “brain cancer” or “brain tumor” as used herein refers to the subtypes proneural (PN), mesenchymal (MES), and classical (CL) glioblastoma, pilocytic astrocytoma, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, fibrillary astrocytoma, anaplastic astrocytoma, oligodendrogliomas, anaplastic oligodendroglioma, ependymoma, subependymoma, choroid plexus tumor, choroid plexus papilloma, and choroid plexus carcinoma and comprises also brain metastases caused by other cancer cells such as lung cancer cells. As used herein the term “brain tumor” or “brain cancer” should also encompass the term “brain metastases”

[0134] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the brain tumor is a glioma.

[0135] Gliomas are the most common type of primary malignant brain tumors, classified based on the type of glial cell they originate from and their grade of malignancy. Gliomas can be divided into different astrocytomas, including glioblastomas, oligodendrogliomas, ependymomas, and oligoastrocytomas.

[0136] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the brain tumor is a glioblastoma multiforme.

[0137] JLP-P04628WO13 Application (final) docx< ABK 26

[0138] Reworded, in a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the composition is continuously released into the resection cavity over 1 to 50 days after at least partial surgical resection of the brain tumor, and wherein the brain tumor is a glioblastoma multiforme.

[0139] Preferably, the composition is continuously released into the resection cavity over 4 to 50 days, more preferably over 5 to 45 days, more preferably over 6 to 40 days, more preferably over 7 to 35 days, and most preferably over 8 to 30 days.

[0140] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the composition is continuously released into the resection cavity over at least 4 days after at least partial surgical resection of the brain tumor, and wherein the brain tumor is a glioblastoma multiforme.

[0141] Preferably, the composition is continuously released into the resection cavity over at least 5 days, more preferably at least 6 days, more preferably at least 7 days, more preferably at least 8 days, more preferably at least 9 days, more preferably at least 10 days, more preferably at least 11 days, more preferably at least 12 days, more preferably at least 13 days, more preferably at least 14 days, more preferably at least 15 days, more preferably at least 16 days, more preferably at least 17 days, more preferably at least 18 days, more preferably at least 19 days, more preferably at least 20 days, more preferably at least 21 days, more preferably at least 22 days, more preferably at least 23 days, more preferably at least 24 days, more preferably at least 25 days, more preferably at least 26 days, more preferably at least 27 days, more preferably at least 28 days, more preferably at least 29 days, and more preferably at least 30 days after at least partial surgical resection of the brain tumor.

[0142] In an alternative embodiment, the composition is continuously released into the resection cavity over 1 to 50 days or 1 to 40 days or 1 to 30 days, more preferably over 2 to 30 days, more preferably over 3 to 30 days, more preferably over 4 to 30 JLP-P04628WO13 Application (final) docx< ABK 27

[0143] days, more preferably over 8 to 30 days, more preferably between 10 and 29 days, more preferably between 14 and 28 days, more preferably between 16 and 27 days after at least partial surgical resection of the brain tumor.

[0144] In an alternative embodiment, the composition is continuously released into the resection cavity between 3 days to 15 days, more preferably between 4 days and 14 days, more preferably between 5 days and 13 days, more preferably between 6 days and 12 days, and most preferably between 7 days and 11 days after at least partial surgical resection of the brain tumor.

[0145] In an alternative embodiment, the composition is continuously released into the resection cavity between 8 days to 20 days, more preferably between 9 days and 19 days, more preferably between 10 days and 18 days, more preferably between 11 days and 17 days, and most preferably between 12 days and 16 days after at least partial surgical resection of the brain tumor.

[0146] In an alternative embodiment, the composition is continuously released into the resection cavity between 13 days to 25 days, more preferably between 14 days and 24 days, more preferably between 15 days and 23 days, more preferably between 16 days and 22 days, and most preferably between 17 days and 21 days after at least partial surgical resection of the brain tumor.

[0147] In an alternative embodiment, the composition is continuously released into the resection cavity between 18 days to 30 days, more preferably between 19 days and 29 days, more preferably between 20 days and 28 days, more preferably between 21 days and 27 days, and most preferably between 22 days and 26 days after at least partial surgical resection of the brain tumor.

[0148] In an alternative embodiment, the composition is continuously released into the resection cavity between 23 days to 35 days, more preferably between 24 days and 34 days, more preferably between 25 days and 33 days, more preferably between 26 days and 32 days, and most preferably between 27 days and 30 days after at least partial surgical resection of the brain tumor.

[0149] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the JLP-P04628WO13 Application (final) docx< ABK 28

[0150] composition into a resection cavity in a controlled-release manner, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of 0.1 mg – 100 mg per day, and wherein the brain tumor is a glioblastoma multiforme.

[0151] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of 2 mg - 20 mg per day, and wherein the brain tumor is a glioblastoma multiforme.

[0152] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of 0.5 mg - 20 mg per day, and wherein the brain tumor is a glioblastoma multiforme.

[0153] Preferably, the 5-aminolevulinic acid in the composition is continuously released at a constant rate of 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day.

[0154] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the JLP-P04628WO13 Application (final) docx< ABK 29

[0155] composition is continuously released into the resection cavity over 1 to 50 days after at least partial surgical resection of the brain tumor, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day, and wherein the brain tumor is a glioblastoma multiforme.

[0156] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity for at least 3 days after at least partial surgical resection of the brain tumor, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day, and wherein the brain tumor is a glioblastoma multiforme.

[0157] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity for at least 4 days after JLP-P04628WO13 Application (final) docx< ABK 30

[0158] at least partial surgical resection of the brain tumor, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day, and wherein the brain tumor is a glioblastoma multiforme.

[0159] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity for at least 10 days after at least partial surgical resection of the brain tumor, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day, and wherein the brain tumor is a glioblastoma multiforme.

[0160] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity for at least 20 days JLP-P04628WO13 Application (final) docx< ABK 31

[0161] after at least partial surgical resection of the brain tumor, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day, and wherein the brain tumor is a glioblastoma multiforme.

[0162] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity for at least 25 days after at least partial surgical resection of the brain tumor, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day, and wherein the brain tumor is a glioblastoma multiforme.

[0163] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the JLP-P04628WO13 Application (final) docx< ABK 32

[0164] composition is continuously released into the resection cavity for 15 to 30 days after at least partial surgical resection of the brain tumor, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day, and wherein the brain tumor is a glioblastoma multiforme.

[0165] Direct intracranial drug delivery system

[0166] The term “direct intracranial drug delivery system” or “local intracranial drug delivery system” refers to a drug delivery system designed to administer a composition comprising 5-aminolevulinic acid directly into the intracranial compartment, thereby bypassing the blood-brain barrier, in a controlled-release manner. This system may comprise direct devices, such as wafers or patches, or externally applied devices, such as pumps, or other delivery devices that enable localized, controlled release of a therapeutically active amount of the composition comprising 5-aminolevulinic acid directly into brain tissue, the cranial cavity or the surrounding intracranial environment. This system facilitates localized, controlled, and sustained release of 5-ALA, thereby improving therapeutic efficacy and minimizing systemic side effects. Drug delivery systems in which a therapeutic agent is delivered systemically and which relies on mechanisms (e.g., nanoparticles, prodrugs, or exosomes) to cross the blood-brain barrier are not direct intracranial drug delivery systems. Drug delivery systems which are not capable of administering a composition comprising 5-aminolevulinic acid directly into the intracranial compartment in a controlled-release manner, such as systems for bolus application (e.g. administering a therapeutic agent whereby a single, discrete dose is delivered rapidly to a target site, thereby providing an immediate, high concentration of the agent within a short time frame) are not direct intracranial drug delivery systems according to the present invention.

[0167] In a preferred embodiment, the direct intracranial drug delivery system is designed as a pump. Suitable pumps for direct, localized drug delivery to the brain are, for instance, direct peristaltic infusion pumps, electric pumps, osmotic pumps, and microelectromechanical systems-based micropumps. Direct peristaltic infusion JLP-P04628WO13 Application (final) docx< ABK 33

[0168] pumps are well established clinically and have been shown to safely bypass the blood-brain barrier. These infusion pumps are usually based on peristaltic pump technology, which uses a rotating mechanism to push fluid at a controlled rate, thereby providing continuous, low-rate infusion directly to a target site in the brain. The direct peristaltic infusion pump can be implanted subcutaneously and connected via a catheter to a precise intracranial location. Osmotic pumps use osmotic pressure differences to drive fluid delivery at a constant rate, thereby achieving a nearly constant (zero-order) release rate with stable drug levels and minimized fluctuations. Osmotic pumps are often used in preclinical studies. Direct intracranial delivery of 5-ALA can be achieved with different types of implantable pump systems that provide continuous or near constant release over multiple days. One category is osmotic pumps, such as those in the ALZET® series, which are small, fully passive systems that use osmotic pressure across a semipermeable membrane to drive fluid at a constant rate without any external power source. Another category comprises gas-driven constant-flow pumps, such as the Codman® 3000 Constant-Flow Infusion Pump (Codman / Johnson & Johnson) or the Tricumed IP2000V Infusion Pump (Tricumed Medizintechnik GmbH). These devices employ a propellant chamber that generates constant pressure and thereby achieve zero-order infusion independent of physiological conditions or patient posture. A further category includes programmable electronic pumps, such as the SynchroMed™ II Infusion System (Medtronic). These are battery-powered and rely on a peristaltic mechanism to deliver continuous infusion at adjustable flow rates, allowing precise control of dosing regimens in clinical use. All these pumps are particularly useful as a direct intracranial drug delivery system for delivering a composition comprising 5-ALA directly into brain tissue, the cranial cavity or the surrounding intracranial environment in a controlled-release manner over a period of multiple days. These pumps are engineered to provide a constant, zero-order infusion rate, making them especially attractive for intracranial applications. Each of these systems can be coupled to a catheter positioned in the resection cavity or adjacent brain tissue to achieve controlled and sustained local delivery of 5-ALA according to the present invention. This approach minimizes fluctuations in drug concentration and reduces the need for repeated handling or external refilling, which is critical in the sensitive intracranial environment. Thus, in a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the direct intracranial drug delivery system is a pump system. Preferably, the direct JLP-P04628WO13 Application (final) docx< ABK 34

[0169] intracranial drug delivery system is an osmotic pump or an electric pump. Preferably, the direct intracranial drug delivery system is an osmotic pump. Preferably, the direct intracranial drug delivery system is an electric pump. More preferably, the direct intracranial drug delivery system is a direct osmotic pump system.

[0170] In a preferred embodiment, the direct intracranial drug delivery system is designed as a patch system. A “patch system” as used herein is a direct intracranial drug delivery system designed to deliver a composition comprising 5-ALA to the surface of brain tissue, the resection cavity or the surrounding intracranial environment, and which incorporates a reservoir of the composition comprising 5-ALA along with a ratecontrolling membrane or matrix. The patch may optionally adhere to the surface of brain tissue, the resection cavity or the surrounding intracranial environment. The patch may optionally be designed to contact the surface of brain tissue, the resection cavity or the surrounding intracranial environment. The patch is engineered to deliver the composition in a controlled, sustained manner directly to the tissue site, maintaining therapeutic concentrations over an extended period. The patch system may also be designed for conformal contact with irregular tissue surfaces to optimize drug delivery efficiency.

[0171] Thus, in a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the direct intracranial drug delivery system is a patch system.

[0172] In a preferred embodiment, the direct intracranial drug delivery system is designed as a wafer system. A “wafer system” is a thin, solid, and often biodegradable polymeric device embedded with a therapeutic agent. Designed for implantation during surgical procedures, the wafer is placed directly onto the brain tissue, the cranial cavity or the surrounding intracranial environment to provide localized and controlled drug release over a predetermined period. Its structure allows for gradual degradation or diffusion, ensuring a sustained delivery profile while minimizing systemic exposure.

[0173] Thus, in a preferred embodiment, the composition for use in treating brain tumor in a subject comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system JLP-P04628WO13 Application (final) docx< ABK 35

[0174] releases a therapeutically effective amount of the composition into a resection cavity in a control led-release manner, wherein the direct intracranial drug delivery system is a wafer system.

[0175] Surprisingly, such direct intracranial drug delivery system described herein are able to provide a linear release of 5-ALA over 3 or 4 or 5 or more days such as 10 or 20 or 30 days. During this linear release preferably 1 mg to 100 mg, more preferably 5 mg to 75 mg, more preferably 10 mg to 50 mg, more preferably 15 to 30 mg of 5-ALA are released by one single implantable system into the cavity / cavities emerging from the brain surgery, i.e. the resection cavities and intratumoral, i.e. into the remaining tumor cells, in case the tumor was not removed completely. Subsequently, 5-ALA might still be released but not necessarily in a linear manner. However, 5-ALA is released in a continuous manner over the time and this continuous release includes the time of the linear release. This release kinetic is crucial and an important aspect of the brain implants of the present invention.

[0176] The total amount of 5-ALA released linearly by all implantable systems placed after at least partial removal or preferably almost complete removal of the brain tumor in the resection cavity or the resection cavities is in the range of 5 mg to 500 mg, more preferably 25 mg to 400 mg, more preferably 50 mg to 300 mg, more preferably 75 to 200 mg, more preferably 100 to 150 mg.

[0177] Consequently, in a preferred embodiment, the composition for use in treating brain tumor in a subject comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the direct intracranial drug delivery system comprises a brain implant releasing 5-aminolevulinic acid linearly, i.e. with zero-order or near zero-order release kinetic, over at least 3 days in an amount of 1 mg to 100 mg, preferably in an amount of 5 mg to 75 mg, more preferably in an amount of 10 mg to 50 mg, more preferably 15 mg to 30 mg into cavities emerging from a brain surgery.

[0178] In a particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell comprising a second biodegradable polymer;

[0179] wherein the shell encloses the core.

[0180] JLP-P04628WO13 Application (final) docx< ABK 36

[0181] The intracranial drug delivery system may consist of one or more than one implantable system.

[0182] The term “shell” refers to the part of an intracranial drug delivery system that completely encloses the core.

[0183] As used herein, the term “biodegradable” refers to a material, in particular a polymer, that is capable of undergoing degradation when implanted in the intracranial environment of a living subject, especially within brain tissue or in contact with cerebrospinal fluid. The degradation occurs under physiological intracranial conditions, in particular at a temperature of about 37 °C and a pH of about 6.8 to 7.4, and results in a reduction of molecular weight and / or structural integrity of the material over time. Such degradation may occur by hydrolytic, enzymatic, or other biological processes present in the intracranial environment and typically leads to the formation of lower molecular weight species that are resorbed, metabolized, or cleared from the implantation site.

[0184] Preferably, the biodegradable polymer degrades in situ after implantation in the brain without requiring surgical removal.

[0185] Suitable biodegradable polymers include, but not limited to, poly(lactic acid) (PLA), poly(L-lactide) (PLLA), poly(D-lactide) (PDLA), poly(D, L-lactide) (PDLA), poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), poly(ε-caprolactone) (PCL), poly(dioxanone) (PDO), poly(trimethylene carbonate) (PTMC), aliphatic polycarbonates, poly(ethylene oxide) (PEG), poly(ethylene glycol) (PEG), PEG-based copolymers, polyanhydrides, including poly[3-bis(p-carboxyphenoxy)propane-co-sebacic acid], poly(ortho esters), polyphosphazenes, collagen, gelatin, chitosan, hyaluronic acid, alginate, starch derivatives, cellulose derivatives, and copolymers, blends, or combinations thereof.

[0186] In a preferred embodiment, the first biodegradable polymer is selected from the group consisting of poly(lactic acid) (PLA), poly(ethylene oxide) (PEO), poly(ethylene glycol) (PEG), and poly(lactic-co-glycolic acid) (PLGA).

[0187] In a preferred embodiment, the first biodegradable polymer is poly(D, L-lactide) (PDLA) or poly(ethylene oxide) (PEO).

[0188] In a preferred embodiment, the second biodegradable polymer is poly(lactic acid) (PLA).

[0189] JLP-P04628WO13 Application (final) docx< ABK 37

[0190] In one embodiment, the core and the shell comprise the same polymer. Thus, in one embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising

[0191] a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell comprising a second biodegradable polymer;

[0192] wherein the shell encloses the core, and

[0193] wherein the first biodegradable polymer and the second biodegradable polymer are identical.

[0194] In a preferred embodiment, the core has the shape of a disc.

[0195] An implantable system as described herein can be manufactured using conventional implant preparation methods readily available to the skilled person, including compression molding, extrusion, casting, or other polymer processing techniques suitable for forming biodegradable core-shell structures.

[0196] For instance, the implantable system is produced by vacuum compression molding (VCM). In a first step, the core is prepared by homogeneously mixing 5-aminolevulinic acid with a first biodegradable polymer, optionally in powder or granulate form. The mixture is introduced into a cylindrical mold cavity and subjected to vacuum and compression at a temperature suitable to soften or partially melt the first biodegradable polymer without causing degradation of 5-aminolevulinic acid. The material is compressed to form a cylindrical core having the desired diameter and height.

[0197] In a second step, the shell components are manufactured separately by vacuum compression molding. A second biodegradable polymer is placed into corresponding mold cavities and compressed under vacuum to form the individual shell components, e.g. an upper membrane, a lower membrane, and a spacer. The shell components may be formed as substantially planar elements, except in embodiments of the shell comprising a spacer, the spacer may be formed as a circumferential wall configured to laterally surround the core. The geometry of the mold determines the thickness, inner and outer diameters, and overall dimensions of the respective shell components.

[0198] In one embodiment, the spacer and the lower membrane are manufactured such that they integrally form a vessel defining a cavity configured to receive the core. The vessel may be produced in a single compression molding step or by subsequently joining the spacer and the lower membrane. The upper membrane is manufactured JLP-P04628WO13 Application (final) docx< ABK 38

[0199] separately from the second biodegradable polymer and configured to close the vessel after insertion of the core.

[0200] In a final step, the core is positioned within the shell assembly. In embodiments comprising separate upper membrane, lower membrane, and spacer elements, the core is arranged between the membranes and laterally enclosed by the spacer. In embodiments comprising a vessel, the core is inserted into the cavity defined by the vessel and subsequently closed by the upper membrane. The assembly is then subjected to controlled compression under reduced pressure and elevated temperature to fuse the components together. The applied temperature and pressure are selected to enable interfacial bonding between the first biodegradable polymer and the second biodegradable polymer without substantial degradation of the active compound. Upon cooling, a mechanically stable fused implant is obtained in which the shell encloses the core.

[0201] Alternatively, the implantable system for linear release of 5-aminolevulinic acid as described herein can be prepared as follows:

[0202] Step 1”) Preparing a core comprising 5-aminolevulinic acid and a first biodegradable polymer by compression moulding under reduced pressure and heating the core above the softening temperature of the first biodegradable polymer, wherein the first biodegradable polymer is selected from the group consisting of poly(lactic acid), polyethylene oxide), poly(ethylene glycol), and poly(lactic-co-glycolic acid);

[0203] Step 2”) preparing an upper shell portion of a shell comprising a second biodegradable polymer by compression moulding under reduced pressure and heating the upper shell portion above the softening temperature of the second biodegradable polymer; wherein the upper shell portion defines an upper cavity portion;

[0204] Step 3”) preparing a lower shell portion of a shell comprising the second biodegradable polymer by compression moulding under reduced pressure and heating the lower shell portion above the softening temperature of the second biodegradable polymer; wherein the lower shell portion defines a lower cavity portion; and

[0205] Step 4”) inserting the core prepared in the step 1”) between the lower shell portion and the upper shell portion such that the lower cavity portion and the upper cavity portion together form a cavity receiving the core, and applying a predetermined pressure to seal the upper and lower shell portions and heating the formed implantable system above its softening temperature.

[0206] JLP-P04628WO13 Application (final) docx< ABK 39

[0207] In a particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell comprising a second biodegradable polymer;

[0208] wherein the shell encloses the core,

[0209] the core contains 5-aminolevulinic acid in a range from 20 wt.% to 60 wt.%, and the core polymer in a range from 40 wt.% to 80 wt.% based on the total weight of the core.

[0210] In a particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell comprising a second biodegradable polymer;

[0211] wherein the shell encloses the core,

[0212] the second biodegradable polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system.

[0213] In a particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell comprising a second biodegradable polymer;

[0214] wherein the shell encloses the core,

[0215] wherein the first biodegradable polymer and / or the second biodegradable polymer may independently comprise a mixture or blend of biodegradable polymers, a block copolymer, a random copolymer, a graft copolymer, or any combination thereof.

[0216] In one embodiment, the shell consists of an upper membrane which covers the top of the core, a spacer which horizontally surrounds the core, and a lower membrane which covers the bottom of the core. In such embodiments, the spacer and the lower membrane may together form a receptacle or vessel configured to receive the core, which receptacle may subsequently be closed by the upper membrane (Figure 11B).

[0217] In another embodiment, the shell comprises an upper membrane, a spacer, and a lower membrane, wherein the upper membrane and the lower membrane are substantially flat elements and the spacer forms a circumferential lateral wall arranged between the upper and lower membranes, thereby laterally enclosing the core (Figure 11A).

[0218] JLP-P04628WO13 Application (final) docx< ABK 40

[0219] In another embodiment, the shell comprises an upper shell portion and a lower shell portion, each defining a cavity portion, the cavity portions being opposed aligned and together forming a cavity configured to receive the core such that the core extends into both cavity portions. Preferably, the upper shell portion and the lower shell portion, each comprise a substantially planar base region and a circumferential wall defining a dish-shaped or cup-shaped cavity portion (see Figure 11 C).

[0220] As used herein, the term “spacer” does not denote a distance-keeping or gap-forming element. Instead, the spacer refers to a lateral enclosing structure forming part of the shell. The spacer may be configured as a circumferential wall that at least partially surrounds the lateral surface of the core and connects an upper membrane with a lower membrane. The spacer may also be configured as a circumferential wall that completely surrounds the lateral surface of the core and connects an upper membrane with a lower membrane. The spacer is not limited to a circular geometry and may have any closed peripheral shape, including circular, oval, polygonal, or irregular shapes.

[0221] Together with the lower membrane, the spacer may form a receptacle for receiving the core, which may be closed by the upper membrane.

[0222] The spacer is an integral part of the shell and is not configured as a separate spacing element for maintaining a distance between the upper membrane and the lower membrane.

[0223] Thus, in a particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising

[0224] a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell comprising a second biodegradable polymer;

[0225] wherein the shell encloses the core,

[0226] wherein the shell consists of an upper membrane, a lower membrane, and a spacer arranged between the upper membrane and the lower membrane, wherein the upper membrane, the lower membrane, and the spacer each comprise the second biodegradable polymer.

[0227] In a particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell comprising a second biodegradable polymer;

[0228] JLP-P04628WO13 Application (final) docx< ABK 41

[0229] wherein the shell encloses the core,

[0230] wherein the first biodegradable polymer is selected from the group consisting of poly(lactic acid), polyethylene oxide), poly(ethylene glycol), and poly (lactic-co-glycolic acid); and

[0231] the second biodegradable polymer is selected from poly(lactic acid);

[0232] the implantable system characterized in that

[0233] the second biodegradable polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; and

[0234] when the first biodegradable polymer is poly(lactic acid), polyethylene glycol), or poly(ethylene oxide), the core contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the first biodegradable polymer in a range from 75 wt.% to 55 wt.% based on the total weight of the core; or

[0235] when the first biodegradable polymer is poly(lactic-co-glycolic acid), the core contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the first biodegradable polymer in a range from 25 wt.% to 35 wt.% based on the total weight of the core.

[0236] In a particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell comprising a second biodegradable polymer;

[0237] wherein the shell encloses the core,

[0238] the core consists of: 65 wt.% to 75 wt.% of 5-aminolevulinic acid, and 35 wt.% to 25 wt.% of poly(lactic-co-glycolic acid), based on a total weight of the core; and the shell consists of poly(lactic acid);

[0239] wherein in the system poly(lactic acid) is in a range from 40 wt.% to 50 wt.%, based on a total weight of the implantable system.

[0240] In a particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell comprising a second biodegradable polymer;

[0241] wherein the shell encloses the core,

[0242] the core consists of: 25 wt.% to 45 wt.% of 5-aminolevulinic acid and 75 wt.% to 55 wt.% of poly(lactic acid), based on a total weight of the core; and

[0243] the shell consists of poly(lactic acid);

[0244] wherein in the system poly(lactic acid) is in a range from 75 wt.% to 85 wt.%, based on a total weight of the implantable system;

[0245] In a particularly preferred embodiment, the direct intracranial drug delivery system is JLP-P04628WO13 Application (final) docx< ABK 42

[0246] an implantable system for constant release of 5-aminolevulinic acid comprising a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell comprising a second biodegradable polymer;

[0247] wherein the shell encloses the core,

[0248] the core consists of: 25 wt.% to 35 wt.% of 5-aminolevulinic acid and 75 wt.% to 65 wt.% of poly(ethylene oxide), based on a total weight of the core; and

[0249] the shell consists of poly(lactic acid);

[0250] wherein in the system poly(lactic acid) is in a range from 45 wt.% to 60 wt.%, preferably 50 wt.% to 55 wt.%, based on a total weight of the implantable system;

[0251] In a particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell comprising a second biodegradable polymer;

[0252] wherein the shell encloses the core,

[0253] the core consists of: 65 wt.% to 75 wt.% of 5-aminolevulinic acid and 35 wt.% to 25 wt.% of poly(lactic-co-glycolic acid), based on a total weight of the core; and the shell consists of 5 wt.% to 15 wt.% of 5-aminolevulinic acid, and 95 wt.% to 85 wt.% of poly(lactic acid) based on a total weight of the shell;

[0254] wherein in the system poly(lactic acid) is in a range from 35 wt.% to 45 wt.%, based on a total weight of the system;

[0255] In a particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell comprising a second biodegradable polymer;

[0256] wherein the shell encloses the core,

[0257] the core consists of: 25 wt.% to 30 wt.% of 5-aminolevulinic acid, 5 wt.% to 15 wt.% of citric acid or fumaric acid, and 60 wt.% to 70 wt.% of poly(lactic acid), based on a total weight of the core; and

[0258] the shell consists of poly(lactic acid);

[0259] wherein in the system poly(lactic acid) is in a range from 75 wt.% to 85 wt.% and preferably in the range from 65 wt.% to 70 wt.%, based on a total weight of the system;

[0260] In a particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell comprising a second biodegradable polymer;

[0261] JLP-P04628WO13 Application (final) docx< ABK 43

[0262] wherein the shell encloses the core,

[0263] the core consists of: 65 wt.% to 75 wt.% of 5-aminolevulinic acid, and 35 wt.% to 25 wt.% of poly (lactic-co-glycolic acid) based on a total weight of the core; and the shell consists of 35 wt.% to 45 wt.% of poly(ethylene glycol) 400, and 55 wt.% to 65 wt.% of poly(lactic acid), based on a total weight of the shell

[0264] wherein in the system poly(lactic acid) is in a range from 25 wt.% to 35 wt.%, based on a total weight of the system.

[0265] In a particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell comprising a second biodegradable polymer;

[0266] wherein the shell encloses the core,

[0267] the core consists of: 25 wt.% to 45 wt.% of 5-aminolevulinic acid, and 75 wt.% to 55 wt.% of poly(lactic acid) or polyethylene glycol) or poly(ethylene oxide) based on the total weight of the core;

[0268] or

[0269] 65 wt.% to 75 wt.% of 5-aminolevulinic acid, and 25 wt.% to 35 wt.% poly(lactic-co-glycolic acid) based on the total weight of the core;

[0270] and

[0271] the shell consists of poly(lactic acid);

[0272] wherein in the system the shell is present in a range from 20 wt.% to 60 wt.%, based on a total weight of the system.

[0273] In another particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising

[0274] a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell consisting of an upper membrane, a lower membrane, and a spacer arranged between the upper membrane and the lower membrane, wherein the upper membrane, the lower membrane, and the spacer each comprise a second biodegradable polymer;

[0275] wherein the shell encloses the core,

[0276] wherein the first biodegradable polymer is poly(lactic acid) or polyethylene oxide) and the second biodegradable polymer is poly(lactic acid);

[0277] characterized in that

[0278] the core contains 5-aminolevulinic acid in a range from 20 wt.% to 50 wt.%, and the first biodegradable polymer in a range from 80 wt.% to 50 wt.% based on the total weight of the core;

[0279] JLP-P04628WO13 Application (final) docx< ABK 44

[0280] the core has a diameter (d₁) in a range of 9 mm to 14 mm, preferably 9 mm to 12 mm, more preferably 10 mm to 12 mm and a height (h₁) in a range from 1 mm to 3 mm;

[0281] the second biodegradable polymer is in a range from 30 wt.% to 60 wt.% based on the total weight of the system;

[0282] the upper membrane has a diameter (d₂) in a range of 11 mm to 17 mm, preferably 10 mm to 15 mm, preferably 10 mm to 14 mm, more preferably 12 mm to 14 mm and a height (h₂) in a range from 0.10 mm to 0.60 mm; preferably 0.2 mm to 0.5 mm; and the lower membrane has a diameter (d₃) in a range of 11 mm to 17 mm, preferably 10 mm to 15 mm, preferably 10 mm to 14 mm, more preferably 12 mm to 14 mm and a height (h₃) in a range from 0.10 mm to 0.60 mm; preferably 0.2 mm to 0.5 mm.

[0283] The terms d₁, d₂, d₃, d₄, h₁, h₂, h₃, h₄ and t₄ as used herein are depicted in Figures 11 and 12.

[0284] In another particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising

[0285] a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell comprising a second biodegradable polymer;

[0286] wherein the shell encloses the core,

[0287] wherein the second biodegradable polymer is poly(D, L-lactide) having carboxyl end groups and a weight-average molecular weight (Mw) of 18,000–24,000 g / mol, as determined by gel permeation chromatography.

[0288] In another particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising

[0289] a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell comprising a second biodegradable polymer;

[0290] wherein the shell encloses the core,

[0291] wherein the second biodegradable polymer is poly(D, L-lactide) having ester end groups and a weight-average molecular weight (Mw) of 10,000–18,000 g / mol, as determined by gel permeation chromatography.

[0292] In another particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising

[0293] a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and JLP-P04628WO13 Application (final) docx< ABK 45

[0294] b) a shell comprising a second biodegradable polymer;

[0295] wherein the shell encloses the core,

[0296] wherein the first biodegradable polymer is poly(D, L-lactide) having carboxyl end groups and a weight-average molecular weight (Mw) of 18,000–24,000 g / mol, as determined by gel permeation chromatography.

[0297] In another particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising

[0298] a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell comprising a second biodegradable polymer;

[0299] wherein the shell encloses the core,

[0300] wherein the first biodegradable polymer is polyethylene oxide).

[0301] In another particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising

[0302] a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell comprising a second biodegradable polymer;

[0303] wherein the shell encloses the core,

[0304] wherein the implantable system has a total height of 1.5 mm to 4.0 mm.

[0305] In another particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising

[0306] a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell comprising a second biodegradable polymer;

[0307] wherein the shell encloses the core,

[0308] wherein the core has a diameter (d₁) of about 10 mm and a height (h₁) in a range from 1.4 mm to 3.0 mm.

[0309] In another particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising

[0310] a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell comprising a second biodegradable polymer;

[0311] wherein the shell encloses the core,

[0312] wherein the shell is free of 5-aminolevulinic acid.

[0313] JLP-P04628WO13 Application (final) docx< ABK 46

[0314] In another particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising

[0315] a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell consisting of an upper membrane, a lower membrane, and a spacer arranged between the upper membrane and the lower membrane, wherein the upper membrane, the lower membrane, and the spacer each comprise a second biodegradable polymer;

[0316] wherein the shell encloses the core,

[0317] wherein the core consists of 5-aminolevulinic acid and poly(D, L-lactide),

[0318] the core contains 5-aminolevulinic acid in a range from 35 wt.% to 45 wt.%, and the poly(D, L-lactide) in a range from 55 wt.% to 65 wt.% based on the total weight of the core;

[0319] the core has a diameter (d1) in the range of 9 mm to 11 mm and a height (hi) in a range from 1.2 mm to 1.8 mm;

[0320] the shell consists of poly(D, L-lactide) and is in a range from 40 wt.% to 50 wt.% based on the total weight of the system;

[0321] the upper membrane has a diameter (d2) in a range of 11 mm to 13 mm and a height (h2) in a range from 0.20 mm to 0.30 mm;

[0322] the lower membrane has a diameter (d3) in a range of 11 mm to 13 mm and a height (h3) in a range from 0.20 mm to 0.30 mm;

[0323] In another particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising

[0324] a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell consisting of an upper membrane, a lower membrane, and a spacer arranged between the upper membrane and the lower membrane, wherein the upper membrane, the lower membrane, and the spacer each comprise a second biodegradable polymer, wherein the shell encloses the core,

[0325] the core consists of 5-aminolevulinic acid and poly(D, L-lactide),

[0326] the core contains 5-aminolevulinic acid in a range from 35 wt.% to 45 wt.%, and the poly(D, L-lactide) in a range from 55 wt.% to 65 wt.% based on the total weight of the core;

[0327] the core has a diameter (d1) in the range of 9 mm to 11 mm and a height (hi) in a range from 1.2 mm to 1.8 mm;

[0328] the shell consists of poly(D, L-lactide) and is in a range from 45 wt.% to 55 wt.% based on the total weight of the system;

[0329] the upper membrane has a diameter (d2) in a range of 11 mm to 13 mm and a height JLP-P04628WO13 Application (final) docx< ABK 47

[0330] (h2) in a range from 0.30 mm to 0.40 mm;

[0331] the lower membrane has a diameter (d3) in a range of 11 mm to 13 mm and a height (h3) in a range from 0.30 mm to 0.40 mm;

[0332] In another particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising

[0333] a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell consisting of an upper membrane, a lower membrane, and a spacer arranged between the upper membrane and the lower membrane, wherein the upper membrane, the lower membrane, and the spacer each comprise a second biodegradable polymer, wherein the shell encloses the core,

[0334] the core consists of 5-aminolevulinic acid and poly(D, L-lactide),

[0335] the core contains 5-aminolevulinic acid in a range from 25 wt.% to 35 wt.%, and the poly(D, L-lactide) in a range from 65 wt.% to 75 wt.% based on the total weight of the core;

[0336] the core has a diameter (d1) in the range of 9 mm to 11 mm and a height (hi) in a range from 2.0 mm to 3.0 mm;

[0337] the shell consists of poly(D, L-lactide) and is in a range from 30 wt.% to 45 wt.% based on the total weight of the system;

[0338] the upper membrane has a diameter (d2) in a range of 11 mm to 13 mm and a height (h2) in a range from 0.30 mm to 0.40 mm;

[0339] the lower membrane has a diameter (d3) in a range of 11 mm to 13 mm and a height (h3) in a range from 0.30 mm to 0.40 mm.

[0340] In another particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising

[0341] a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell consisting of an upper membrane, a lower membrane, and a spacer arranged between the upper membrane and the lower membrane, wherein the upper membrane, the lower membrane, and the spacer each comprise a second biodegradable polymer, wherein the shell encloses the core,

[0342] the core consists of 5-aminolevulinic acid and poly(D, L-lactide),

[0343] the core contains 5-aminolevulinic acid in a range from 25 wt.% to 35 wt.%, and the poly(D, L-lactide) in a range from 65 wt.% to 75 wt.% based on the total weight of the core;

[0344] the core has a diameter (d1) in the range of 9 mm to 11 mm and a height (hi) in a range from 2.0 mm to 3.0 mm;

[0345] JLP-P04628WO13 Application (final) docx< ABK 48

[0346] the shell consists of poly(D, L-lactide) and is in a range from 30 wt.% to 45 wt.% based on the total weight of the system;

[0347] the upper membrane has a diameter (d2) in a range of 11 mm to 13 mm and a height (h2) in a range from 0.20 mm to 0.30 mm;

[0348] the lower membrane has a diameter (d3) in a range of 11 mm to 13 mm and a height (h3) in a range from 0.20 mm to 0.30 mm.

[0349] In another particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising

[0350] a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell consisting of an upper membrane, a lower membrane, and a spacer arranged between the upper membrane and the lower membrane, wherein the upper membrane, the lower membrane, and the spacer each comprise a second biodegradable polymer;

[0351] wherein the shell encloses the core,

[0352] the core consists of 5-aminolevulinic acid and poly(ethylene oxide),

[0353] the core contains 5-aminolevulinic acid in a range from 25 wt.% to 35 wt.%, and the poly(ethylene oxide) in a range from 65 wt.% to 75 wt.% based on the total weight of the core;

[0354] the core has a diameter (d1) in the range of 9 mm to 11 mm and a height (hi) in a range from 1.2 mm to 1.8 mm;

[0355] the shell consists of poly(D, L-lactide) and is in a range from 45 wt.% to 55 wt.% based on the total weight of the system;

[0356] the upper membrane has a diameter (d2) in a range of 11 mm to 13 mm and a height (h2) in a range from 0.30 mm to 0.40 mm;

[0357] the lower membrane has a diameter (d3) in a range of 11 mm to 13 mm and a height (h3) in a range from 0.30 mm to 0.40 mm.

[0358] In another particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising

[0359] a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, and b) a shell consisting of an upper membrane, a lower membrane, and a spacer arranged between the upper membrane and the lower membrane, wherein the upper membrane, the lower membrane, and the spacer each comprise a second biodegradable polymer;

[0360] wherein the shell encloses the core,

[0361] the core consists of 5-aminolevulinic acid and poly(ethylene oxide),

[0362] JLP-P04628WO13 Application (final) docx< ABK 49

[0363] the core contains 5-aminolevulinic acid in a range from 25 wt.% to 35 wt.%, and the poly(ethylene oxide) in a range from 65 wt.% to 75 wt.% based on the total weight of the core;

[0364] the core has a diameter (d1) in the range of 9 mm to 11 mm and a height (hi) in a range from 1.2 mm to 1.8 mm;

[0365] the shell consists of poly(D, L-lactide) and is in a range from 50 wt.% to 60 wt.% based on the total weight of the system;

[0366] the upper membrane has a diameter (d2) in a range of 11 mm to 13 mm and a height (h2) in a range from 0.45 mm to 0.55 mm;

[0367] the lower membrane has a diameter (d3) in a range of 11 mm to 13 mm and a height (h3) in a range from 0.45 mm to 0.55 mm.

[0368] In a particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising a) a core comprising:

[0369] 5-aminolevulinic acid and a core polymer,

[0370] wherein the core polymer is selected from the group consisting of poly(lactic acid) (PLA), poly(ethylene oxide) (PEO), polyethylene glycol) (PEG), and poly (lactic- co-glycolic acid) (PLGA); and

[0371] b) a shell consisting of an upper membrane, a spacer, and a lower membrane, wherein the upper membrane, the spacer, and the lower membrane each comprise a shell polymer, wherein the shell polymer is selected from poly(lactic acid) (PLA);

[0372] characterized in that

[0373] the shell polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; and

[0374] when the core polymer is poly(lactic acid) (PLA), polyethylene glycol) (PEG) or poly(ethylene oxide) (PEO), the core contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the core polymer in a range from 75 wt.% to 55 wt.% based on the total weight of the core; or

[0375] when the core polymer is poly(lactic-co-glycolic acid) (PLGA), the core contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the core polymer in a range from 25 wt.% to 35 wt.% based on the total weight of the core.

[0376] Thus, the composition for use in treating brain tumor in a subject comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, wherein the direct intracranial drug delivery system releases a JLP-P04628WO13 Application (final) docx< ABK 50

[0377] therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising a) a core disc comprising:

[0378] 5-aminolevulinic acid and a core polymer,

[0379] wherein the core polymer is selected from the group consisting of poly(lactic acid) (PLA), poly(ethylene oxide) (PEO), polyethylene glycol) (PEG), and poly (lactic- co-glycolic acid) (PLGA); and

[0380] b) a shell consisting of an upper membrane, a spacer, and a lower membrane, wherein the upper membrane, the spacer, and the lower membrane each comprise a shell polymer, wherein the shell polymer is selected from poly(lactic acid) (PLA);

[0381] characterized in that

[0382] the shell polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; and

[0383] when the core polymer is poly(lactic acid) (PLA), polyethylene glycol) (PEG) or poly(ethylene oxide) (PEO), the core disc contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the core polymer in a range from 75 wt.% to 55 wt.% based on the total weight of the core disc; or

[0384] when the core polymer is poly(lactic-co-glycolic acid) (PLGA), the core disc contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the core polymer in a range from 25 wt.% to 35 wt.% based on the total weight of the core disc.

[0385] Reworded, the composition for use in treating brain tumor in a subject comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the direct intracranial drug delivery system is delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising

[0386] a) a core matrix comprising:

[0387] 5-aminolevulinic acid and a core polymer,

[0388] wherein the core polymer is selected from the group consisting of poly(lactic acid) (PLA), poly(ethylene oxide) (PEO), polyethylene glycol) (PEG), and poly (lactic- co-glycolic acid) (PLGA); and

[0389] b) a shell consisting of an upper membrane, a spacer, and a lower membrane, wherein the upper membrane, the spacer, and the lower membrane each comprise a shell polymer, wherein the shell polymer is selected from poly(lactic JLP-P04628WO13 Application (final) docx< ABK 51

[0390] acid) (PLA);

[0391] characterized in that

[0392] the shell polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; and

[0393] when the core polymer is poly(lactic acid) (PLA), polyethylene glycol) (PEG) or poly(ethylene oxide) (PEG), the core matrix contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the core polymer in a range from 75 wt.% to 55 wt.% based on the total weight of the core disc; or

[0394] when the core polymer is poly(lactic-co-glycolic acid) (PLGA), the core matrix contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the core polymer in a range from 25 wt.% to 35 wt.% based on the total weight of the core matrix.

[0395] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the composition is continuously released into the resection cavity over 1 to 30 days after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising

[0396] a) a core comprising:

[0397] 5-aminolevulinic acid and a core polymer,

[0398] wherein the core polymer is selected from the group consisting of poly(lactic acid) (PLA), poly(ethylene oxide) (PEO), polyethylene glycol) (PEG), and poly (lactic- co-glycolic acid) (PLGA); and

[0399] b) a shell consisting of an upper membrane, a spacer, and a lower membrane, wherein the upper membrane, the spacer, and the lower membrane each comprise a shell polymer, wherein the shell polymer is selected from poly(lactic acid) (PLA);

[0400] characterized in that

[0401] the shell polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; and

[0402] when the core polymer is poly(lactic acid) (PLA), polyethylene glycol) (PEG) or poly(ethylene oxide) (PEO), the core contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the core polymer in a range from 75 wt.% to 55 wt.% based on the total weight of the core; or

[0403] JLP-P04628WO13 Application (final) docx< ABK 52

[0404] when the core polymer is poly(lactic-co-glycolic acid) (PLGA), the core contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the core polymer in a range from 25 wt.% to 35 wt.% based on the total weight of the core.

[0405] In an alternative embodiment, the composition is continuously released into the resection cavity by the implantable system over 1 to 50 days or 1 to 40 days or 1 to 30 days, more preferably over 2 to 30 days, more preferably over 3 to 30 days, more preferably over 4 to 30 days, and most preferably over 8 to 30 days.

[0406] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the composition is continuously released into the resection cavity over at least 4 days after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising

[0407] a) a core comprising:

[0408] 5-aminolevulinic acid and a core polymer,

[0409] wherein the core polymer is selected from the group consisting of poly(lactic acid) (PLA), poly(ethylene oxide) (PEO), polyethylene glycol) (PEG), and poly (lactic- co-glycolic acid) (PLGA); and

[0410] b) a shell consisting of an upper membrane, a spacer, and a lower membrane, wherein the upper membrane, the spacer, and the lower membrane each comprise a shell polymer, wherein the shell polymer is selected from poly(lactic acid) (PLA);

[0411] characterized in that

[0412] the shell polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; and

[0413] when the core polymer is poly(lactic acid) (PLA), polyethylene glycol) (PEG) or poly(ethylene oxide) (PEO), the core contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the core polymer in a range from 75 wt.% to 55 wt.% based on the total weight of the core; or

[0414] when the core polymer is poly(lactic-co-glycolic acid) (PLGA), the core contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the core polymer in a range from 25 wt.% to 35 wt.% based on the total weight of the core.

[0415] JLP-P04628WO13 Application (final) docx< ABK 53

[0416] Preferably, the composition is continuously released into the resection cavity over at least 4 days, more preferably at least 5 days, more preferably at least 6 days, more preferably at least 7 days, more preferably at least 8 days, more preferably at least 9 days, more preferably at least 10 days, more preferably at least 11 days, more preferably at least 12 days, more preferably at least 13 days, more preferably at least 14 days, more preferably at least 15 days, more preferably at least 16 days, more preferably at least 17 days, more preferably at least 18 days, more preferably at least 19 days, more preferably at least 20 days, more preferably at least 21 days, more preferably at least 22 days, more preferably at least 23 days, more preferably at least 24 days, more preferably at least 25 days, more preferably at least 26 days, more preferably at least 27 days, more preferably at least 28 days, more preferably at least 29 days, and more preferably at least 30 days after at least partial surgical resection of the brain tumor.

[0417] In an alternative embodiment, the composition is continuously released into the resection cavity between 4 days to 50 days, more preferably between 15 days and 50 days, more preferably between 15 days and 45 days, more preferably between 20 days and 45 days, and most preferably between 20 days and 35 days after at least partial surgical resection of the brain tumor.

[0418] In an alternative embodiment, the composition is continuously released into the resection cavity by the implantable system between 4 days to 30 days, more preferably between 5 days and 30 days, more preferably between 10 days and 30 days, more preferably between 15 days and 30 days, and most preferably between 20 days and 30 days after at least partial surgical resection of the brain tumor

[0419] In an alternative embodiment, the composition is continuously released into the resection cavity between 8 days to 20 days, more preferably between 9 days and 19 days, more preferably between 10 days and 18 days, more preferably between 11 days and 17 days, and most preferably between 12 days and 16 days after at least partial surgical resection of the brain tumor.

[0420] In an alternative embodiment, the composition is continuously released into the resection cavity between 13 days to 25 days, more preferably between 14 days and 24 days, more preferably between 15 days and 23 days, more preferably between 16 days and 22 days, and most preferably between 17 days and 21 days after at least partial surgical resection of the brain tumor.

[0421] In an alternative embodiment, the composition is continuously released into the JLP-P04628WO13 Application (final) docx< ABK 54

[0422] resection cavity between 18 days to 30 days, more preferably between 19 days and 29 days, more preferably between 20 days and 28 days, more preferably between 21 days and 27 days, and most preferably between 22 days and 26 days after at least partial surgical resection of the brain tumor.

[0423] In an alternative embodiment, the composition is continuously released into the resection cavity between 23 days to 35 days, more preferably between 24 days and 34 days, more preferably between 25 days and 33 days, more preferably between 26 days and 32 days, and most preferably between 27 days and 30 days after at least partial surgical resection of the brain tumor.

[0424] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of 0.1 mg – 100 mg per day, and wherein the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising a) a core comprising:

[0425] 5-aminolevulinic acid and a core polymer,

[0426] wherein the core polymer is selected from the group consisting of poly(lactic acid) (PLA), poly(ethylene oxide) (PEO), polyethylene glycol) (PEG), and poly (lactic- co-glycolic acid) (PLGA); and

[0427] b) a shell consisting of an upper membrane, a spacer, and a lower membrane, wherein the upper membrane, the spacer, and the lower membrane each comprise a shell polymer, wherein the shell polymer is selected from poly(lactic acid) (PLA);

[0428] characterized in that

[0429] the shell polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; and

[0430] when the core polymer is poly(lactic acid) (PLA), polyethylene glycol) (PEG) or poly(ethylene oxide) (PEO), the core contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the core polymer in a range from 75 wt.% to 55 wt.% based on the total weight of the core; or

[0431] when the core polymer is poly(lactic-co-glycolic acid) (PLGA), the core contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the core polymer in a range from 25 wt.% to 35 wt.% based on the total weight of the core.

[0432] JLP-P04628WO13 Application (final) docx< ABK 55

[0433] Preferably, the 5-aminolevulinic acid in the composition is continuously released at a constant rate of 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day. Of course, more than one composition can be used for the treatment of the brain tumor including brain metastases.

[0434] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity over 1 to 50 days after at least partial surgical resection of the brain tumor, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day, and wherein the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising a) a core comprising:

[0435] 5-aminolevulinic acid and a core polymer,

[0436] wherein the core polymer is selected from the group consisting of poly(lactic acid) (PLA), poly(ethylene oxide) (PEO), polyethylene glycol) (PEG), and poly (lactic- co-glycolic acid) (PLGA); and

[0437] b) a shell consisting of an upper membrane, a spacer, and a lower membrane, JLP-P04628WO13 Application (final) docx< ABK 56

[0438] wherein the upper membrane, the spacer, and the lower membrane each comprise a shell polymer, wherein the shell polymer is selected from poly(lactic acid) (PLA);

[0439] characterized in that

[0440] the shell polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; and

[0441] when the core polymer is poly(lactic acid) (PLA), polyethylene glycol) (PEG) or poly(ethylene oxide) (PEG), the core contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the core polymer in a range from 75 wt.% to 55 wt.% based on the total weight of the core; or

[0442] when the core polymer is poly(lactic-co-glycolic acid) (PLGA), the core contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the core polymer in a range from 25 wt.% to 35 wt.% based on the total weight of the core.

[0443] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity for at least 3 days after at least partial surgical resection of the brain tumor, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day, and wherein the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising a) a core comprising:

[0444] 5-aminolevulinic acid and a core polymer,

[0445] wherein the core polymer is selected from the group consisting of poly(lactic acid) (PLA), poly(ethylene oxide) (PEO), polyethylene glycol) (PEG), and poly (lactic- co-glycolic acid) (PLGA); and

[0446] b) a shell consisting of an upper membrane, a spacer, and a lower membrane, JLP-P04628WO13 Application (final) docx< ABK 57

[0447] wherein the upper membrane, the spacer, and the lower membrane each comprise a shell polymer, wherein the shell polymer is selected from poly(lactic acid) (PLA);

[0448] characterized in that

[0449] the shell polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; and

[0450] when the core polymer is poly(lactic acid) (PLA), polyethylene glycol) (PEG) or poly(ethylene oxide) (PEG), the core contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the core polymer in a range from 75 wt.% to 55 wt.% based on the total weight of the core; or

[0451] when the core polymer is poly(lactic-co-glycolic acid) (PLGA), the core contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the core polymer in a range from 25 wt.% to 35 wt.% based on the total weight of the core.

[0452] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity for at least 10 days after at least partial surgical resection of the brain tumor, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day, and wherein the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising

[0453] a) a core comprising:

[0454] 5-aminolevulinic acid and a core polymer,

[0455] wherein the core polymer is selected from the group consisting of poly(lactic acid) (PLA), poly(ethylene oxide) (PEO), polyethylene glycol) (PEG), and poly (lactic- co-glycolic acid) (PLGA); and

[0456] JLP-P04628WO13 Application (final) docx< ABK 58

[0457] b) a shell consisting of an upper membrane, a spacer, and a lower membrane, wherein the upper membrane, the spacer, and the lower membrane each comprise a shell polymer, wherein the shell polymer is selected from poly(lactic acid) (PLA);

[0458] characterized in that

[0459] the shell polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; and

[0460] when the core polymer is poly(lactic acid) (PLA), polyethylene glycol) (PEG) or poly(ethylene oxide) (PEG), the core contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the core polymer in a range from 75 wt.% to 55 wt.% based on the total weight of the core; or

[0461] when the core polymer is poly(lactic-co-glycolic acid) (PLGA), the core contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the core polymer in a range from 25 wt.% to 35 wt.% based on the total weight of the core.

[0462] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity for at least 20 days after at least partial surgical resection of the brain tumor, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day, and wherein the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising

[0463] a) a core comprising:

[0464] 5-aminolevulinic acid and a core polymer,

[0465] wherein the core polymer is selected from the group consisting of poly(lactic acid) (PLA), poly(ethylene oxide) (PEO), polyethylene glycol) (PEG), and poly (lactic- JLP-P04628WO13 Application (final) docx< ABK 59

[0466] co-glycolic acid) (PLGA); and

[0467] b) a shell consisting of an upper membrane, a spacer, and a lower membrane, wherein the upper membrane, the spacer, and the lower membrane each comprise a shell polymer, wherein the shell polymer is selected from poly(lactic acid) (PLA);

[0468] characterized in that

[0469] the shell polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; and

[0470] when the core polymer is poly(lactic acid) (PLA), polyethylene glycol) (PEG) or poly(ethylene oxide) (PEG), the core contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the core polymer in a range from 75 wt.% to 55 wt.% based on the total weight of the core; or

[0471] when the core polymer is poly(lactic-co-glycolic acid) (PLGA), the core contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the core polymer in a range from 25 wt.% to 35 wt.% based on the total weight of the core.

[0472] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity for at least 25 days after at least partial surgical resection of the brain tumor, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day, and wherein the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising

[0473] a) a core comprising:

[0474] 5-aminolevulinic acid and a core polymer,

[0475] wherein the core polymer is selected from the group consisting of poly(lactic acid) JLP-P04628WO13 Application (final) docx< ABK 60

[0476] (PLA), poly(ethylene oxide) (PEO), polyethylene glycol) (PEG), and poly (lactic- co-glycolic acid) (PLGA); and

[0477] b) a shell consisting of an upper membrane, a spacer, and a lower membrane, wherein the upper membrane, the spacer, and the lower membrane each comprise a shell polymer, wherein the shell polymer is selected from poly(lactic acid) (PLA);

[0478] characterized in that

[0479] the shell polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; and

[0480] when the core polymer is poly(lactic acid) (PLA), polyethylene glycol) (PEG) or poly(ethylene oxide) (PEO), the core contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the core polymer in a range from 75 wt.% to 55 wt.% based on the total weight of the core; or

[0481] when the core polymer is poly(lactic-co-glycolic acid) (PLGA), the core contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the core polymer in a range from 25 wt.% to 35 wt.% based on the total weight of the core.

[0482] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity for 15 to 30 days after at least partial surgical resection of the brain tumor, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day, and wherein the direct intracranial drug delivery system is an implantable system for constant release of 5-aminolevulinic acid comprising a) a core comprising:

[0483] 5-aminolevulinic acid and a core polymer,

[0484] wherein the core polymer is selected from the group consisting of poly(lactic acid) JLP-P04628WO13 Application (final) docx< ABK 61

[0485] (PLA), poly(ethylene oxide) (PEO), polyethylene glycol) (PEG), and poly (lactic- co-glycolic acid) (PLGA); and

[0486] b) a shell consisting of an upper membrane, a spacer, and a lower membrane, wherein the upper membrane, the spacer, and the lower membrane each comprise a shell polymer, wherein the shell polymer is selected from poly(lactic acid) (PLA);

[0487] characterized in that

[0488] the shell polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; and

[0489] when the core polymer is poly(lactic acid) (PLA), polyethylene glycol) (PEG) or poly(ethylene oxide) (PEO), the core contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the core polymer in a range from 75 wt.% to 55 wt.% based on the total weight of the core; or

[0490] when the core polymer is poly(lactic-co-glycolic acid) (PLGA), the core contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the core polymer in a range from 25 wt.% to 35 wt.% based on the total weight of the core.

[0491] As already stated above, the indicated release rate refers to the total amount of 5-aminolevulinic acid released by the direct intracranial drug delivery system. Where the system comprises more than one implant, the stated amount corresponds to the cumulative release of all implants used for the treatment of the brain tumor, including brain metastases.

[0492] In a particularly preferred embodiment, the direct intracranial drug delivery system comprises

[0493] a) a core comprising:

[0494] 5-aminolevulinic acid and a core polymer,

[0495] wherein the core polymer is selected from the group consisting of poly(lactic acid) (PLA), poly(ethylene oxide) (PEO), polyethylene glycol) (PEG), and poly (lactic- co-glycolic acid) (PLGA); and

[0496] b) a shell consisting of an upper membrane, a spacer, and a lower membrane, wherein the upper membrane, the spacer, and the lower membrane each comprise a shell polymer, wherein the shell polymer is selected from poly(lactic acid) (PLA);

[0497] characterized in that

[0498] the shell polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; and

[0499] when the core polymer is poly(lactic acid) (PLA), polyethylene glycol) (PEG) or poly(ethylene oxide) (PEO), the core contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the core polymer in a range from 75 wt.% to 55 wt.% based JLP-P04628WO13 Application (final) docx< ABK 62

[0500] on the total weight of the core; or

[0501] when the core polymer is poly(lactic-co-glycolic acid) (PLGA), the core contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the core polymer in a range from 25 wt.% to 35 wt.% based on the total weight of the core;

[0502] wherein the shell further comprises 5-aminolevulinic acid in a range from 1 wt.% to 25 wt.% based on the total weight of the shell.

[0503] Preferably, the shell further comprises 5-aminolevulinic acid in a range from 1 wt.% to 20 wt.% based on the total weight of the shell. More preferably, the shell further comprises 5-aminolevulinic acid in a range from 1 wt.% to 15 wt.% based on the total weight of the shell.

[0504] In one embodiment, the core and / or the shell of the direct intracranial drug delivery system comprises at least one excipient. In one embodiment, said at least one excipient is an antioxidant selected from ascorbic acid, acetylcysteine, cysteine, thioglycerol, sodium hydrogen sulfite (sodium bisulfite), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), a-tocopherol acetate (vitamin E acetate), methionine, citric acid, ethylenediaminetetraacetic acid (EDTA), tartaric acid, gallic acid and its esters, glutathione, uric acid, carotenoids, and polyphenols. Preferably, the antioxidant is selected from, but not limited to, ascorbic acid, acetylcysteine, cysteine, thioglycerol, sodium hydrogen sulfite, butyl-hydroxyanisole, butylhydroxytoluene, a-tocopherol acetate, methionine, and chelators. Further suitable excipients which could be present in the intracranial drug delivery system are organic acids selected from citric acid, fumaric acid, glycolic acid, lactic acid, malic acid, tartaric acid, maleic acid, succinic acid and mixtures of two or more of these organic acids.

[0505] In another embodiment, said at least one excipient is an organic acid. In a particularly preferred embodiment, the direct intracranial drug delivery system comprises a) a core comprising:

[0506] 5-aminolevulinic acid and a core polymer,

[0507] wherein the core polymer is selected from the group consisting of poly(lactic acid) (PLA), poly(ethylene oxide) (PEO), polyethylene glycol) (PEG), and poly (lactic- co-glycolic acid) (PLGA); and

[0508] b) a shell consisting of an upper membrane, a spacer, and a lower membrane, wherein the upper membrane, the spacer, and the lower membrane each comprise a shell polymer, wherein the shell polymer is selected from poly(lactic acid) (PLA);

[0509] characterized in that

[0510] JLP-P04628WO13 Application (final) docx< ABK 63

[0511] the shell polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; and

[0512] when the core polymer is poly(lactic acid) (PLA), polyethylene glycol) (PEG) or poly(ethylene oxide) (PEG), the core contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the core polymer in a range from 75 wt.% to 55 wt.% based on the total weight of the core; or

[0513] when the core polymer is poly(lactic-co-glycolic acid) (PLGA), the core contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the core polymer in a range from 25 wt.% to 35 wt.% based on the total weight of the core;

[0514] and the delivery system further comprising at least one excipient in the core, or in the shell, wherein

[0515] the at least one excipient in the core is at least one organic acid having a pKa value in the range of about 1.7 to 4.5, and / or

[0516] the at least one excipient in the shell is selected from polyethylene glycol) (PEG).

[0517] In a particularly preferred embodiment, the direct intracranial drug delivery system comprises

[0518] a) a core comprising:

[0519] 5-aminolevulinic acid and a core polymer,

[0520] wherein the core polymer is selected from the group consisting of poly(lactic acid) (PLA), poly(ethylene oxide) (PEO), poly(ethylene glycol) (PEG), and poly (lactic- co-glycolic acid) (PLGA); and

[0521] b) a shell consisting of an upper membrane, a spacer, and a lower membrane, wherein the upper membrane, the spacer, and the lower membrane each comprise a shell polymer, wherein the shell polymer is selected from poly(lactic acid) (PLA);

[0522] characterized in that

[0523] the shell polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; and

[0524] when the core polymer is poly(lactic acid) (PLA), polyethylene glycol) (PEG) or poly(ethylene oxide) (PEO), the core contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the core polymer in a range from 75 wt.% to 55 wt.% based on the total weight of the core; or

[0525] when the core polymer is poly(lactic-co-glycolic acid) (PLGA), the core contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the core polymer in a range from 25 wt.% to 35 wt.% based on the total weight of the core;

[0526] and the delivery system further comprising at least one excipient in the core, or in the shell, wherein

[0527] the at least one excipient in the core is selected from the group consisting of citric JLP-P04628WO13 Application (final) docx< ABK 64

[0528] acid, fumaric acid, glycolic acid, lactic acid, malic acid, tartaric acid, maleic acid, succinic acid and a mixture thereof; and / or

[0529] the at least one excipient in the shell is selected from polyethylene glycol) (PEG).

[0530] In a particularly preferred embodiment, the direct intracranial drug delivery system comprises

[0531] a) a core comprising:

[0532] 5-aminolevulinic acid and a core polymer,

[0533] wherein the core polymer is selected from the group consisting of poly(lactic acid) (PLA), poly(ethylene oxide) (PEG), poly(ethylene glycol) (PEG), and poly (lactic- co-glycolic acid) (PLGA); and

[0534] b) a shell consisting of an upper membrane, a spacer, and a lower membrane, wherein the upper membrane, the spacer, and the lower membrane each comprise a shell polymer, wherein the shell polymer is selected from poly(lactic acid) (PLA);

[0535] characterized in that

[0536] the shell polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; and

[0537] when the core polymer is poly(lactic acid) (PLA), polyethylene glycol) (PEG) or poly(ethylene oxide) (PEO), the core contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the core polymer in a range from 75 wt.% to 55 wt.% based on the total weight of the core; or

[0538] when the core polymer is poly(lactic-co-glycolic acid) (PLGA), the core contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the core polymer in a range from 25 wt.% to 35 wt.% based on the total weight of the core;

[0539] and the delivery system further comprising at least one excipient in the core, or in the shell, wherein

[0540] the at least one excipient in the core is selected from the group consisting of citric acid, fumaric acid, glycolic acid, lactic acid, malic acid, tartaric acid, maleic acid, succinic acid and a mixture thereof; and / or

[0541] the at least one excipient in the shell is selected from polyethylene glycol) (PEG), and wherein the shell further comprises 5-aminolevulinic acid in a range from 1 wt.% to 25 wt.%, preferably from 1 wt.% to 20 wt.%, more preferably from 1 wt.% to 15 wt.% based on the total weight of the shell.

[0542] In a particularly preferred embodiment, the direct intracranial drug delivery system comprises

[0543] a) a core comprising:

[0544] 5-aminolevulinic acid and a core polymer,

[0545] JLP-P04628WO13 Application (final) docx< ABK 65

[0546] wherein the core polymer is selected from the group consisting of poly(lactic acid) (PLA), poly(ethylene oxide) (PEO), polyethylene glycol) (PEG), and poly (lactic- co-glycolic acid) (PLGA); and

[0547] b) a shell consisting of an upper membrane, a spacer, and a lower membrane, wherein the upper membrane, the spacer, and the lower membrane each comprise a shell polymer, wherein the shell polymer is selected from poly(lactic acid) (PLA);

[0548] characterized in that

[0549] the shell polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; and

[0550] when the core polymer is poly(lactic acid) (PLA), polyethylene glycol) (PEG) or poly(ethylene oxide) (PEO), the core contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the core polymer in a range from 75 wt.% to 55 wt.% based on the total weight of the core; or

[0551] when the core polymer is poly(lactic-co-glycolic acid) (PLGA), the core contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the core polymer in a range from 25 wt.% to 35 wt.% based on the total weight of the core;

[0552] and the delivery system further comprising at least one excipient in the core, or in the shell, wherein

[0553] the at least one excipient in the core is selected from the group consisting of citric acid, fumaric acid, glycolic acid, lactic acid, malic acid, tartaric acid, maleic acid, succinic acid and a mixture thereof; and / or

[0554] the at least one excipient in the shell is selected from polyethylene glycol) (PEG); and

[0555] the excipient in the core is in a range from 5 wt.% to 15 wt.%, based on the total weight of the core.

[0556] In a particularly preferred embodiment, the direct intracranial drug delivery system comprises

[0557] a) a core comprising:

[0558] 5-aminolevulinic acid and a core polymer,

[0559] wherein the core polymer is selected from the group consisting of poly(lactic acid) (PLA), poly(ethylene oxide) (PEO), polyethylene glycol) (PEG), and poly (lactic- co-glycolic acid) (PLGA); and

[0560] b) a shell consisting of an upper membrane, a spacer, and a lower membrane, wherein the upper membrane, the spacer, and the lower membrane each comprise a shell polymer, wherein the shell polymer is selected from poly(lactic acid) (PLA);

[0561] characterized in that

[0562] JLP-P04628WO13 Application (final) docx< ABK 66

[0563] the shell polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; and

[0564] when the core polymer is poly(lactic acid) (PLA), polyethylene glycol) (PEG) or poly(ethylene oxide) (PEG), the core contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the core polymer in a range from 75 wt.% to 55 wt.% based on the total weight of the core; or

[0565] when the core polymer is poly(lactic-co-glycolic acid) (PLGA), the core contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the core polymer in a range from 25 wt.% to 35 wt.% based on the total weight of the core;

[0566] and the delivery system further comprising at least one excipient in the core, or in the shell, wherein

[0567] the at least one excipient in the core is selected from the group consisting of citric acid, fumaric acid, glycolic acid, lactic acid, malic acid, tartaric acid, maleic acid, succinic acid and a mixture thereof; and / or

[0568] the at least one excipient in the shell is selected from polyethylene glycol) (PEG); and

[0569] the excipient in the shell is in a range from 35 wt.% to 45 wt.%, based on the total weight of the shell.

[0570] In a particularly preferred embodiment, the direct intracranial drug delivery system comprises

[0571] a) a core comprising:

[0572] 5-aminolevulinic acid and a core polymer,

[0573] wherein the core polymer is selected from the group consisting of poly(lactic acid) (PLA), poly(ethylene oxide) (PEO), polyethylene glycol) (PEG), and poly (lactic- co-glycolic acid) (PLGA); and

[0574] b) a shell consisting of an upper membrane, a spacer, and a lower membrane, wherein the upper membrane, the spacer, and the lower membrane each comprise a shell polymer, wherein the shell polymer is selected from poly(lactic acid) (PLA);

[0575] characterized in that

[0576] the shell polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; and

[0577] when the core polymer is poly(lactic acid) (PLA), polyethylene glycol) (PEG) or poly(ethylene oxide) (PEO), the core contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the core polymer in a range from 75 wt.% to 55 wt.% based on the total weight of the core; or

[0578] when the core polymer is poly(lactic-co-glycolic acid) (PLGA), the core contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the core polymer in a JLP-P04628WO13 Application (final) docx< ABK 67

[0579] range from 25 wt.% to 35 wt.% based on the total weight of the core;

[0580] and the delivery system further comprising at least one excipient in the core, or in the shell, wherein

[0581] the at least one excipient in the core is selected from the group consisting of citric acid, fumaric acid, glycolic acid, lactic acid, malic acid, tartaric acid, maleic acid, succinic acid and a mixture thereof; and / or

[0582] the at least one excipient in the shell is selected from polyethylene glycol) (PEG); and

[0583] the excipient in the core is in a range from 5 wt.% to 15 wt.%, based on the total weight of the core, and

[0584] wherein the excipient in the shell is only contained in the upper membrane and / or the lower membrane of the shell.

[0585] In a particularly preferred embodiment, the direct intracranial drug delivery system comprises

[0586] a) a core comprising:

[0587] 5-aminolevulinic acid and a core polymer,

[0588] wherein the core polymer is selected from the group consisting of poly(lactic acid) (PLA), poly(ethylene oxide) (PEG), polyethylene glycol) (PEG), and poly (lactic- co-glycolic acid) (PLGA); and

[0589] b) a shell consisting of an upper membrane, a spacer, and a lower membrane, wherein the upper membrane, the spacer, and the lower membrane each comprise a shell polymer, wherein the shell polymer is selected from poly(lactic acid) (PLA);

[0590] characterized in that

[0591] the shell polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; and

[0592] when the core polymer is poly(lactic acid) (PLA), polyethylene glycol) (PEG) or poly(ethylene oxide) (PEO), the core contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the core polymer in a range from 75 wt.% to 55 wt.% based on the total weight of the core; or

[0593] when the core polymer is poly(lactic-co-glycolic acid) (PLGA), the core contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the core polymer in a range from 25 wt.% to 35 wt.% based on the total weight of the core;

[0594] and the delivery system further comprising at least one excipient in the core, or in the shell, wherein

[0595] the at least one excipient in the core is selected from the group consisting of citric acid, fumaric acid, glycolic acid, lactic acid, malic acid, tartaric acid, maleic acid, succinic acid and a mixture thereof; and / or

[0596] JLP-P04628WO13 Application (final) docx< ABK 68

[0597] the at least one excipient in the shell is selected from polyethylene glycol) (PEG); the excipient in the shell is in a range from 35 wt.% to 45 wt.%, based on the total weight of the shell, and

[0598] wherein the excipient in the shell is only contained in the upper membrane and / or the lower membrane of the shell.

[0599] In a particularly preferred embodiment, the direct intracranial drug delivery system comprises

[0600] a) a core comprising:

[0601] 5-aminolevulinic acid and a core polymer,

[0602] wherein the core polymer is selected from the group consisting of poly(lactic acid) (PLA), poly(ethylene oxide) (PEG), polyethylene glycol) (PEG), and poly (lactic- co-glycolic acid) (PLGA); and

[0603] b) a shell consisting of an upper membrane, a spacer, and a lower membrane, wherein the upper membrane, the spacer, and the lower membrane each comprise a shell polymer, wherein the shell polymer is selected from poly(lactic acid) (PLA);

[0604] characterized in that

[0605] the shell polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; and

[0606] when the core polymer is poly(lactic acid) (PLA), polyethylene glycol) (PEG) or poly(ethylene oxide) (PEO), the core contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the core polymer in a range from 75 wt.% to 55 wt.% based on the total weight of the core; or

[0607] when the core polymer is poly(lactic-co-glycolic acid) (PLGA), the core contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the core polymer in a range from 25 wt.% to 35 wt.% based on the total weight of the core;

[0608] and the delivery system further comprising at least one excipient in the core, or in the shell, wherein

[0609] the at least one excipient in the core is in a range from 5 wt.% to 15 wt.%, based on the total weight of the core selected from the group consisting of citric acid, fumaric acid, glycolic acid, lactic acid, malic acid, tartaric acid, maleic acid, succinic acid and a mixture thereof; and / or

[0610] the at least one excipient in the shell is polyethylene glycol) (PEG), and

[0611] wherein the core is in a range from 40 wt.% to 75 wt.%, preferably from 45 wt.% to 70 wt.% based on the total weight of the implantable system.

[0612] In a particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system consisting of:

[0613] JLP-P04628WO13 Application (final) docx< ABK 69

[0614] a) a core consisting of:

[0615] 5-aminolevulinic acid in a range from 25 wt.% to 75 wt.%,

[0616] the core polymer in a range from 75 wt.% to 25 wt.%, and

[0617] optionally the excipient in the core in a range of 5 wt.% to 15 wt.%, based on the total weight of the core,

[0618] wherein the excipient in the core is citric acid, fumaric acid or a mixture thereof; and

[0619] b) a shell consisting of:

[0620] an upper membrane, a spacer, and a lower membrane each comprising a shell polymer in a range from 55 wt.% to 100 wt.%, and

[0621] optionally, 5-aminolevulinic acid in a range from 1 wt.% to 15 wt.%, or optionally, the excipient in the shell in a range from 35 wt.% to 45 wt.% based on the total weight of the shell,

[0622] wherein the excipient in the shell is PEG 400.

[0623] In a particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system consisting of:

[0624] a) a core consisting of:

[0625] 65 wt.% to 75 wt.% of 5-aminolevulinic acid, and 25 wt.% to 35 wt.% of poly (lactic-co-glycolic acid) (PLGA), based on a total weight of the core; and b) a shell consisting of poly(lactic acid) (PLA);

[0626] wherein in the system poly(lactic acid) (PLA) is in a range from 40 wt.% to 50 wt.%, based on a total weight of the implantable system.

[0627] In a particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system consisting of:

[0628] a) a core consisting of:

[0629] 25 wt.% to 45 wt.% of 5-aminolevulinic acid and 55 wt.% to 75 wt.% of poly(lactic acid) (PLA), based on a total weight of the core; and

[0630] b) a shell consisting of poly(lactic acid) (PLA);

[0631] wherein in the system

[0632] poly(lactic acid) (PLA) is in a range from 75 wt.% to 85 wt.%, based on a total weight of the implantable system.

[0633] In a particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system consisting of:

[0634] a) a core consisting of:

[0635] 25 wt.% to 35 wt.% of 5-aminolevulinic acid and 65 wt.% to 75 wt.% of poly(ethylene oxide), based on a total weight of the core; and

[0636] JLP-P04628WO13 Application (final) docx< ABK 70

[0637] b) a shell consisting of poly(lactic acid) (PLA);

[0638] wherein in the system poly(lactic acid) (PLA) is in a range from 45 wt.% to 60 wt.%, preferably 50 wt.% to 55 wt.%, based on a total weight of the implantable system.

[0639] In a particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system consisting of:

[0640] a) a core consisting of:

[0641] 65 wt.% to 75 wt.% of 5-aminolevulinic acid and 25 wt.% to 35 wt.% of poly (lactic-co-glycolic acid) (PLGA), based on a total weight of the core; and b) a shell consisting of 5 wt.% to 15 wt.% of 5-aminolevulinic acid, and 95 wt.% to 85 wt.% of poly(lactic acid) (PLA) based on a total weight of the shell; wherein in the system poly(lactic acid) (PLA) is in a range from 35 wt.% to 45 wt.%, based on a total weight of the system.

[0642] In a particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system consisting of:

[0643] a) a core consisting of:

[0644] 25 wt.% to 30 wt.% of 5-aminolevulinic acid, 5 wt.% to 15 wt.% of citric acid or fumaric acid, and 60 wt.% to 70 wt.% of poly(lactic acid) (PLA), based on a total weight of the core; and

[0645] b) a shell consisting of poly(lactic acid) (PLA);

[0646] wherein in the system poly(lactic acid) (PLA) is in a range from 75 wt.% to 85 wt.% and preferably in a range from 65 wt.% to 70 wt.%, based on a total weight of the system.

[0647] In a particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system consisting of:

[0648] a) a core consisting of:

[0649] 65 wt.% to 75 wt.% of 5-aminolevulinic acid, and 25 wt.% to 35 wt.% of poly (lactic-co-glycolic acid) (PLGA) based on a total weight of the core; and b) a shell consisting of 35 wt.% to 45 wt.% of poly(ethylene glycol) 400, and 55 wt.% to 65 wt.% of poly(lactic acid) (PLA) based on a total weight of the shell wherein in the system poly(lactic acid) (PLA) is in a range from 25 wt.% to 35 wt.%, based on a total weight of the system.

[0650] In a particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system consisting of:

[0651] a) a core consisting of:

[0652] 25 wt.% to 45 wt.% of 5-aminolevulinic acid, and 75 wt.% to 55 wt.% of JLP-P04628WO13 Application (final) docx< ABK 71

[0653] poly(lactic acid) (PLA) or polyethylene glycol) (PEG) or poly(ethylene oxide) (PEG) based on the total weight of the core;

[0654] or

[0655] 65 wt.% to 75 wt.% of 5-aminolevulinic acid, and 25 wt.% to 35 wt.% poly(lactic- co-glycolic acid) (PLGA) based on the total weight of the core;

[0656] and

[0657] b) a shell consisting of poly(lactic acid) (PLA);

[0658] wherein in the system the shell is present in a range from 20 wt.% to 60 wt.%, based on a total weight of the system.

[0659] In a particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system in the form of a wafer comprising

[0660] a) a core comprising:

[0661] 5-aminolevulinic acid and a core polymer,

[0662] wherein the core polymer is selected from the group consisting of poly(lactic acid) (PLA), poly(ethylene oxide) (PEO), polyethylene glycol) (PEG), and poly (lactic- co-glycolic acid) (PLGA); and

[0663] b) a shell consisting of an upper membrane, a spacer, and a lower membrane, wherein the upper membrane, the spacer, and the lower membrane each comprise a shell polymer, wherein the shell polymer is selected from poly(lactic acid) (PLA);

[0664] characterized in that

[0665] the shell polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; and

[0666] when the core polymer is poly(lactic acid) (PLA), polyethylene glycol) (PEG) or poly(ethylene oxide) (PEO), the core contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the core polymer in a range from 75 wt.% to 55 wt.% based on the total weight of the core; or

[0667] when the core polymer is poly(lactic-co-glycolic acid) (PLGA), the core contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the core polymer in a range from 25 wt.% to 35 wt.% based on the total weight of the core and

[0668] the spacer has a thickness (t4) of at least 0.6 mm.

[0669] In all embodiments disclosed herein, the spacer has a thickness (t4) of at least 0.6 mm, and is preferably in a range from 0.6 mm to 2.5 mm, preferably 0.7 mm to 1.5 mm, and more preferably 1.0 mm to 2.0 mm.

[0670] In a particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system in the form of a wafer comprising

[0671] JLP-P04628WO13 Application (final) docx< ABK 72

[0672] a) a core comprising:

[0673] 5-aminolevulinic acid and a core polymer,

[0674] wherein the core polymer is selected from the group consisting of poly(lactic acid) (PLA), poly(ethylene oxide) (PEO), polyethylene glycol) (PEG), and poly (lactic- co-glycolic acid) (PLGA); and

[0675] b) a shell consisting of an upper membrane, a spacer, and a lower membrane, wherein the upper membrane, the spacer, and the lower membrane each comprise a shell polymer, wherein the shell polymer is selected from poly(lactic acid) (PLA);

[0676] characterized in that

[0677] the shell polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; and

[0678] when the core polymer is poly(lactic acid) (PLA), polyethylene glycol) (PEG) or poly(ethylene oxide) (PEO), the core contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the core polymer in a range from 75 wt.% to 55 wt.% based on the total weight of the core; or

[0679] when the core polymer is poly(lactic-co-glycolic acid) (PLGA), the core contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the core polymer in a range from 25 wt.% to 35 wt.% based on the total weight of the core,

[0680] the spacer has a thickness (t4) of at least 0.6 mm, and

[0681] the core has a height (h₁) a height (h₁) in a range from 1 mm to 3 mm.

[0682] In a particularly preferred embodiment, the direct intracranial drug delivery system is an implantable system in the form of a wafer comprising

[0683] a) a core comprising:

[0684] 5-aminolevulinic acid and a core polymer,

[0685] wherein the core polymer is selected from the group consisting of poly(lactic acid) (PLA), poly(ethylene oxide) (PEO), polyethylene glycol) (PEG), and poly (lactic- co-glycolic acid) (PLGA); and

[0686] b) a shell consisting of an upper membrane, a spacer, and a lower membrane, wherein the upper membrane, the spacer, and the lower membrane each comprise a shell polymer, wherein the shell polymer is selected from poly(lactic acid) (PLA);

[0687] characterized in that

[0688] the shell polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; and

[0689] when the core polymer is poly(lactic acid) (PLA), polyethylene glycol) (PEG) or poly(ethylene oxide) (PEO), the core contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the core polymer in a range from 75 wt.% to 55 wt.% based JLP-P04628WO13 Application (final) docx< ABK 73

[0690] on the total weight of the core; or

[0691] when the core polymer is poly(lactic-co-glycolic acid) (PLGA), the core contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the core polymer in a range from 25 wt.% to 35 wt.% based on the total weight of the core,

[0692] the spacer has a thickness (t₄) of at least 0.6 mm, the core has a height (h₁) a height (h₁) in a range from 1 mm to 3 mm;

[0693] the upper membrane has a height (h₂) in a range from 0.20 mm to 0.60 mm; and the lower membrane has a height (h₃) in a range from 0.20 mm to 0.60 mm.

[0694] In all embodiments of brain implants disclosed herein, the weight percentage (wt.%) of all components together have to add up to 100%.

[0695] The inventors have further found that oral co-administration of an artemisinin compound together with the controlled-release of the composition described herein by the direct intracranial drug delivery system effectively inhibits tumor growth (see Examples 2 to 4 and 6).

[0696] Thus, a further aspect of the present invention is directed to a composition for use in treating brain tumor in a subject as described herein in combination with a therapeutically effective amount of an artemisinin compound selected from 1a, 1b, 1c, 1 d, and 1e or a pharmaceutically acceptable salt thereof

[0697]

[0698] artemisinin (1a) arteminol (1b, dihydroarteminisin)

[0699]

[0700] artemether (1c) arteether (1d)

[0701] JLP-P04628WO13 Application (final) docx< ABK

[0702] 74

[0703]

[0704] artesunate (1e) (ARS),

[0705] wherein the artemisinin compound is administered systemically or intracranially.

[0706] Preferably, the artemisinin compound is administered orally or intravenously. More preferably, the artemisinin compound is administered orally and preferably daily to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system.

[0707] As used herein, and unless otherwise specified, the term “pharmaceutically acceptable salt(s) of artemisinin”, includes, but is not limited to, salts of acidic or basic moieties of compounds described herein. Basic moieties are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, e.g. salts containing pharmacologically acceptable anions. Suitable organic acids include, but are not limited to, maleic, fumaric, benzoic, ascorbic, succinic, acetic, formic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, oleic, tannic, aspartic, stearic, palmitic, glycolic, glutamic, gluconic, glucaronic, saccharic, isonicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, benzenesulfonic acids, or pamoic (e.g, 1,1’-methylene-bis-(2-hydroxy-3-naphthoate)) acids. Suitable inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, or nitric acids. Compounds that include an amine moiety can form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Chemical moieties that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts are alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, or iron salts.

[0708] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after JLP-P04628WO13 Application (final) docx< ABK 75

[0709] at least partial surgical resection of the brain tumor in combination with artesunate (1e)., wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the artesunate (1e) is daily administered orally or intravenously to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system.

[0710] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound selected from 1a, 1b, 1c, 1d, and 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is administered daily administered orally or intravenously to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system, and wherein the daily dose of the artemisinin compound is in a range of 0.5 mg artemisinin compound per kg body weight to 10 mg artemisinin compound per kg body weight.

[0711] Preferably, the daily dose of the artemisinin compound is between about 0.1 mg and 100 mg artemisinin compound per kg body weight, more preferably about 0.2 mg and 80 mg artemisinin compound per kg body weight, more preferably about 0.3 mg and 50 mg artemisinin compound per kg body weight, more preferably about 0.4 mg and 25 mg artemisinin compound per kg body weight, more preferably about 0.5 mg and 10 mg artemisinin compound per kg body weight, more preferably about 1 mg and 8 mg artemisinin compound per kg body weight, more preferably about 2 mg and 6 mg artemisinin compound per kg body weight, and most preferably about 3 mg artemisinin compound per kg body weight.

[0712] Preferably, the daily dose of the artemisinin compound is about 0.5 mg artemisinin compound per kg body weight, 0.6 mg artemisinin compound per kg body weight, 0.7 mg artemisinin compound per kg body weight, 0.8 mg artemisinin compound per kg body weight, 0.9 mg artemisinin compound per kg body weight, 1 mg artemisinin compound per kg body weight, 1.5 mg artemisinin compound per kg body weight, 2.0 mg artemisinin compound per kg body weight, 2.5 mg artemisinin compound per kg body weight, 3.0 mg artemisinin compound per kg body weight, 3.5 mg artemisinin compound per kg body weight, 4.0 mg artemisinin compound per kg body weight, 4.5 JLP-P04628WO13 Application (final) docx< ABK 76

[0713] mg artemisinin compound per kg body weight, 5 mg artemisinin compound per kg body weight, 6 mg artemisinin compound per kg body weight, 7 mg artemisinin compound per kg body weight, 8 mg artemisinin compound per kg body weight, and most preferably about 9 mg, and about 10 mg artemisinin compound per kg body weight.

[0714] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound selected from 1a, 1b, 1c, 1d, and 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is administered daily administered orally or intravenously to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system, and wherein the total daily dose of the artemisinin compound is in a range of 100 mg to 300 mg, preferably 150 mg to 250 mg, more preferably 180 mg to 220 mg, and most preferably about 200 mg.

[0715] Preferably, the total daily dose of the artemisinin compound is 100 mg, more preferably 105 mg, more preferably 110 mg, more preferably 115 mg, more preferably 120 mg, more preferably 125 mg, more preferably 130 mg, more preferably 135 mg, more preferably 140 mg, more preferably 145 mg, more preferably 150 mg, more preferably 155 mg, more preferably 160 mg, more preferably 165 mg, more preferably 170 mg, more preferably 175 mg, more preferably 180 mg, more preferably 185 mg, more preferably 190 mg, more preferably 195 mg, and most preferably 200 mg.

[0716] Preferably, the total daily dose of the artemisinin compound is 300 mg, more preferably 295 mg, more preferably 290 mg, more preferably 285 mg, more preferably 280 mg, more preferably 275 mg, more preferably 270 mg, more preferably 265 mg, more preferably 260 mg, more preferably 255 mg, more preferably 250 mg, more preferably 245 mg, more preferably 240 mg, more preferably 235 mg, more preferably 230 mg, more preferably 225 mg, more preferably 220 mg, more preferably 215 mg, more preferably 210 mg, more preferably 205 mg, and most preferably 200 mg.

[0717] JLP-P04628WO13 Application (final) docx< ABK 77

[0718] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound selected from 1a, 1b, 1c, 1d, and 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is administered daily administered orally or intravenously to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system, and wherein a dose of the artemisinin compound of 100 mg is administered twice daily to the subject (e.g. in the morning 100 mg artemisinin compound and in the evening 100 mg artemisinin compound).

[0719] In one embodiment, the composition is continuously released into the resection cavity over 1 to 50 days or 1 to 40 days or 1 to 30 days, more preferably over 2 to 30 days, more preferably over 3 to 30 days, more preferably over 4 to 30 days, and most preferably over 8 to 30 days together with a daily oral administration of the artemisinin compound.

[0720] In one embodiment, the composition is continuously released into the resection cavity over at least 5 days, more preferably at least 6 days, more preferably at least 7 days, more preferably at least 8 days, more preferably at least 9 days, more preferably at least 10 days, more preferably at least 11 days, more preferably at least 12 days, more preferably at least 13 days, more preferably at least 14 days, more preferably at least 15 days, more preferably at least 16 days, more preferably at least 17 days, more preferably at least 18 days, more preferably at least 19 days, more preferably at least 20 days, more preferably at least 21 days, more preferably at least 22 days, more preferably at least 23 days, more preferably at least 24 days, more preferably at least 25 days, more preferably at least 26 days, more preferably at least 27 days, more preferably at least 28 days, more preferably at least 29 days, and more preferably at least 30 days after at least partial surgical resection of the brain tumor together with a daily oral administration of the artemisinin compound.

[0721] In one embodiment, the composition is continuously released into the resection cavity between 4 days to 30 days, more preferably between 5 days and 30 days, more preferably between 10 days and 29 days, more preferably between 14 days and 28 days, and most preferably between 16 days and 27 days after at least partial surgical resection of the brain tumor together with a daily oral administration of the JLP-P04628WO13 Application (final) docx< ABK 78

[0722] artemisinin compound.

[0723] In another embodiment, the composition is continuously released into the resection cavity together with a daily oral administration of the artemisinin compound between 3 days to 15 days, more preferably between 4 days and 14 days, more preferably between 5 days and 13 days, more preferably between 6 days and 12 days, and most preferably between 7 days and 11 days after at least partial surgical resection of the brain tumor.

[0724] In another embodiment, the composition is continuously released into the resection cavity together with a daily oral administration of the artemisinin compound between 8 days to 20 days, more preferably between 9 days and 19 days, more preferably between 10 days and 18 days, more preferably between 11 days and 17 days, and most preferably between 12 days and 16 days after at least partial surgical resection of the brain tumor.

[0725] In another embodiment, the composition is continuously released into the resection cavity together with a daily oral administration of the artemisinin compound between 13 days to 25 days, more preferably between 14 days and 24 days, more preferably between 15 days and 23 days, more preferably between 16 days and 22 days, and most preferably between 17 days and 21 days after at least partial surgical resection of the brain tumor.

[0726] In another embodiment, the composition is continuously released into the resection cavity together with a daily oral administration of the artemisinin compound between 18 days to 30 days, more preferably between 19 days and 29 days, more preferably between 20 days and 28 days, more preferably between 21 days and 27 days, and most preferably between 22 days and 26 days after at least partial surgical resection of the brain tumor.

[0727] In another embodiment, the composition is continuously released into the resection cavity together with a daily oral administration of the artemisinin compound between 23 days to 35 days, more preferably between 24 days and 34 days, more preferably between 25 days and 33 days, more preferably between 26 days and 32 days, and most preferably between 27 days and 30 days after at least partial surgical resection of the brain tumor.

[0728] JLP-P04628WO13 Application (final) docx< ABK 79

[0729] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously for at least 3 days to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system, and wherein the daily dose of the artemisinin compound is about 0.5 mg artemisinin compound per kg body weight, 0.6 mg artemisinin compound per kg body weight, 0.7 mg artemisinin compound per kg body weight, 0.8 mg artemisinin compound per kg body weight, 0.9 mg artemisinin compound per kg body weight, 1 mg artemisinin compound per kg body weight, 1.5 mg artemisinin compound per kg body weight, 2.0 mg artemisinin compound per kg body weight, 2.5 mg artemisinin compound per kg body weight, 3.0 mg artemisinin compound per kg body weight, 3.5 mg artemisinin compound per kg body weight, 4.0 mg artemisinin compound per kg body weight, 4.5 mg artemisinin compound per kg body weight, 5 mg artemisinin compound per kg body weight, 6 mg artemisinin compound per kg body weight, 7 mg artemisinin compound per kg body weight, 8 mg artemisinin compound per kg body weight, and most preferably about 9 mg, and about 10 mg artemisinin compound per kg body weight.

[0730] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously for at least 10 days to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system, and wherein the daily dose of the artemisinin compound is about 0.5 mg artemisinin compound per kg body weight, 0.6 mg artemisinin compound per kg body weight, 0.7 mg artemisinin compound per kg body weight, 0.8 mg artemisinin compound per kg body weight, 0.9 mg artemisinin compound per kg body weight, 1 mg artemisinin compound per kg body weight, 1.5 mg artemisinin compound per kg body weight, 2.0 JLP-P04628WO13 Application (final) docx< ABK 80

[0731] mg artemisinin compound per kg body weight, 2.5 mg artemisinin compound per kg body weight, 3.0 mg artemisinin compound per kg body weight, 3.5 mg artemisinin compound per kg body weight, 4.0 mg artemisinin compound per kg body weight, 4.5 mg artemisinin compound per kg body weight, 5 mg artemisinin compound per kg body weight, 6 mg artemisinin compound per kg body weight, 7 mg artemisinin compound per kg body weight, 8 mg artemisinin compound per kg body weight, and most preferably about 9 mg, and about 10 mg artemisinin compound per kg body weight.

[0732] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously for at least 15 days to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system, and wherein the daily dose of the artemisinin compound is about 0.5 mg artemisinin compound per kg body weight, 0.6 mg artemisinin compound per kg body weight, 0.7 mg artemisinin compound per kg body weight, 0.8 mg artemisinin compound per kg body weight, 0.9 mg artemisinin compound per kg body weight, 1 mg artemisinin compound per kg body weight, 1.5 mg artemisinin compound per kg body weight, 2.0 mg artemisinin compound per kg body weight, 2.5 mg artemisinin compound per kg body weight, 3.0 mg artemisinin compound per kg body weight, 3.5 mg artemisinin compound per kg body weight, 4.0 mg artemisinin compound per kg body weight, 4.5 mg artemisinin compound per kg body weight, 5 mg artemisinin compound per kg body weight, 6 mg artemisinin compound per kg body weight, 7 mg artemisinin compound per kg body weight, 8 mg artemisinin compound per kg body weight, and most preferably about 9 mg, and about 10 mg artemisinin compound per kg body weight.

[0733] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the JLP-P04628WO13 Application (final) docx< ABK 81

[0734] composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously for at least 20 days to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system, and wherein the daily dose of the artemisinin compound is about 0.5 mg artemisinin compound per kg body weight, 0.6 mg artemisinin compound per kg body weight, 0.7 mg artemisinin compound per kg body weight, 0.8 mg artemisinin compound per kg body weight, 0.9 mg artemisinin compound per kg body weight, 1 mg artemisinin compound per kg body weight, 1.5 mg artemisinin compound per kg body weight, 2.0 mg artemisinin compound per kg body weight, 2.5 mg artemisinin compound per kg body weight, 3.0 mg artemisinin compound per kg body weight, 3.5 mg artemisinin compound per kg body weight, 4.0 mg artemisinin compound per kg body weight, 4.5 mg artemisinin compound per kg body weight, 5 mg artemisinin compound per kg body weight, 6 mg artemisinin compound per kg body weight, 7 mg artemisinin compound per kg body weight, 8 mg artemisinin compound per kg body weight, and most preferably about 9 mg, and about 10 mg artemisinin compound per kg body weight.

[0735] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously for at least 25 days to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system, and wherein the daily dose of the artemisinin compound is about 0.5 mg artemisinin compound per kg body weight, 0.6 mg artemisinin compound per kg body weight, 0.7 mg artemisinin compound per kg body weight, 0.8 mg artemisinin compound per kg body weight, 0.9 mg artemisinin compound per kg body weight, 1 mg artemisinin compound per kg body weight, 1.5 mg artemisinin compound per kg body weight, 2.0 mg artemisinin compound per kg body weight, 2.5 mg artemisinin compound per kg body weight, 3.0 mg artemisinin compound per kg body weight, 3.5 mg artemisinin compound per kg body weight, 4.0 mg artemisinin compound per kg body weight, 4.5 mg artemisinin compound per kg body weight, 5 mg artemisinin compound per kg body weight, 6 mg artemisinin compound per kg body weight, 7 mg artemisinin compound per kg body weight, 8 mg artemisinin compound per kg body weight, and JLP-P04628WO13 Application (final) docx< ABK 82

[0736] most preferably about 9 mg, and about 10 mg artemisinin compound per kg body weight.

[0737] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously for at least 30 days to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system, and wherein the daily dose of the artemisinin compound is about 0.5 mg artemisinin compound per kg body weight, 0.6 mg artemisinin compound per kg body weight, 0.7 mg artemisinin compound per kg body weight, 0.8 mg artemisinin compound per kg body weight, 0.9 mg artemisinin compound per kg body weight, 1 mg artemisinin compound per kg body weight, 1.5 mg artemisinin compound per kg body weight, 2.0 mg artemisinin compound per kg body weight, 2.5 mg artemisinin compound per kg body weight, 3.0 mg artemisinin compound per kg body weight, 3.5 mg artemisinin compound per kg body weight, 4.0 mg artemisinin compound per kg body weight, 4.5 mg artemisinin compound per kg body weight, 5 mg artemisinin compound per kg body weight, 6 mg artemisinin compound per kg body weight, 7 mg artemisinin compound per kg body weight, 8 mg artemisinin compound per kg body weight, and most preferably about 9 mg, and about 10 mg artemisinin compound per kg body weight.

[0738] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously and simultaneously with the controlled release of the composition into the resection cavity for at least 3 days, wherein the daily dose of the artemisinin compound is about 0.5 mg artemisinin compound per kg body weight, 0.6 mg artemisinin compound per kg body weight, 0.7 mg artemisinin compound per kg body weight, 0.8 mg artemisinin JLP-P04628WO13 Application (final) docx< ABK 83

[0739] compound per kg body weight, 0.9 mg artemisinin compound per kg body weight, 1 mg artemisinin compound per kg body weight, 1.5 mg artemisinin compound per kg body weight, 2.0 mg artemisinin compound per kg body weight, 2.5 mg artemisinin compound per kg body weight, 3.0 mg artemisinin compound per kg body weight, 3.5 mg artemisinin compound per kg body weight, 4.0 mg artemisinin compound per kg body weight, 4.5 mg artemisinin compound per kg body weight, 5 mg artemisinin compound per kg body weight, 6 mg artemisinin compound per kg body weight, 7 mg artemisinin compound per kg body weight, 8 mg artemisinin compound per kg body weight, and most preferably about 9 mg, and about 10 mg artemisinin compound per kg body weight, and wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day.

[0740] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously and simultaneously with the controlled release of the composition into the resection cavity for at least 10 days, wherein the daily dose of the artemisinin compound is about 0.5 mg artemisinin compound per kg body weight, 0.6 mg artemisinin compound per kg body weight, 0.7 mg artemisinin compound per kg body weight, 0.8 mg artemisinin compound per kg body weight, 0.9 mg artemisinin compound per kg body weight, 1 mg artemisinin compound per kg body weight, 1.5 mg artemisinin compound per kg body weight, 2.0 mg artemisinin compound per kg body weight, 2.5 mg artemisinin compound per kg body weight, 3.0 mg artemisinin compound per kg body weight, 3.5 mg artemisinin compound per kg body weight, 4.0 mg artemisinin compound per kg body weight, 4.5 mg artemisinin compound per kg body weight, 5 mg artemisinin JLP-P04628WO13 Application (final) docx< ABK 84

[0741] compound per kg body weight, 6 mg artemisinin compound per kg body weight, 7 mg artemisinin compound per kg body weight, 8 mg artemisinin compound per kg body weight, and most preferably about 9 mg, and about 10 mg artemisinin compound per kg body weight, and wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day.

[0742] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously and simultaneously with the controlled release of the composition into the resection cavity for at least 15 days, wherein the daily dose of the artemisinin compound is about 0.5 mg artemisinin compound per kg body weight, 0.6 mg artemisinin compound per kg body weight, 0.7 mg artemisinin compound per kg body weight, 0.8 mg artemisinin compound per kg body weight, 0.9 mg artemisinin compound per kg body weight, 1 mg artemisinin compound per kg body weight, 1.5 mg artemisinin compound per kg body weight, 2.0 mg artemisinin compound per kg body weight, 2.5 mg artemisinin compound per kg body weight, 3.0 mg artemisinin compound per kg body weight, 3.5 mg artemisinin compound per kg body weight, 4.0 mg artemisinin compound per kg body weight, 4.5 mg artemisinin compound per kg body weight, 5 mg artemisinin compound per kg body weight, 6 mg artemisinin compound per kg body weight, 7 mg artemisinin compound per kg body weight, 8 mg artemisinin compound per kg body weight, and most preferably about 9 mg, and about 10 mg artemisinin compound per kg body weight, and wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a JLP-P04628WO13 Application (final) docx< ABK 85

[0743] constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day.

[0744] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously and simultaneously with the controlled release of the composition into the resection cavity for at least 20 days, wherein the daily dose of the artemisinin compound is about 0.5 mg artemisinin compound per kg body weight, 0.6 mg artemisinin compound per kg body weight, 0.7 mg artemisinin compound per kg body weight, 0.8 mg artemisinin compound per kg body weight, 0.9 mg artemisinin compound per kg body weight, 1 mg artemisinin compound per kg body weight, 1.5 mg artemisinin compound per kg body weight, 2.0 mg artemisinin compound per kg body weight, 2.5 mg artemisinin compound per kg body weight, 3.0 mg artemisinin compound per kg body weight, 3.5 mg artemisinin compound per kg body weight, 4.0 mg artemisinin compound per kg body weight, 4.5 mg artemisinin compound per kg body weight, 5 mg artemisinin compound per kg body weight, 6 mg artemisinin compound per kg body weight, 7 mg artemisinin compound per kg body weight, 8 mg artemisinin compound per kg body weight, and most preferably about 9 mg, and about 10 mg artemisinin compound per kg body weight, and wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 JLP-P04628WO13 Application (final) docx< ABK 86

[0745] mg - 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day.

[0746] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously and simultaneously with the controlled release of the composition into the resection cavity for at least 25 days, wherein the daily dose of the artemisinin compound is about 0.5 mg artemisinin compound per kg body weight, 0.6 mg artemisinin compound per kg body weight, 0.7 mg artemisinin compound per kg body weight, 0.8 mg artemisinin compound per kg body weight, 0.9 mg artemisinin compound per kg body weight, 1 mg artemisinin compound per kg body weight, 1.5 mg artemisinin compound per kg body weight, 2.0 mg artemisinin compound per kg body weight, 2.5 mg artemisinin compound per kg body weight, 3.0 mg artemisinin compound per kg body weight, 3.5 mg artemisinin compound per kg body weight, 4.0 mg artemisinin compound per kg body weight, 4.5 mg artemisinin compound per kg body weight, 5 mg artemisinin compound per kg body weight, 6 mg artemisinin compound per kg body weight, 7 mg artemisinin compound per kg body weight, 8 mg artemisinin compound per kg body weight, and most preferably about 9 mg, and about 10 mg artemisinin compound per kg body weight, and wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day.

[0747] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after JLP-P04628WO13 Application (final) docx< ABK 87

[0748] at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously and simultaneously with the controlled release of the composition into the resection cavity for at least 30 days, wherein the daily dose of the artemisinin compound is about 0.5 mg artemisinin compound per kg body weight, 0.6 mg artemisinin compound per kg body weight, 0.7 mg artemisinin compound per kg body weight, 0.8 mg artemisinin compound per kg body weight, 0.9 mg artemisinin compound per kg body weight, 1 mg artemisinin compound per kg body weight, 1.5 mg artemisinin compound per kg body weight, 2.0 mg artemisinin compound per kg body weight, 2.5 mg artemisinin compound per kg body weight, 3.0 mg artemisinin compound per kg body weight, 3.5 mg artemisinin compound per kg body weight, 4.0 mg artemisinin compound per kg body weight, 4.5 mg artemisinin compound per kg body weight, 5 mg artemisinin compound per kg body weight, 6 mg artemisinin compound per kg body weight, 7 mg artemisinin compound per kg body weight, 8 mg artemisinin compound per kg body weight, and most preferably about 9 mg, and about 10 mg artemisinin compound per kg body weight, and wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day.

[0749] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously and simultaneously with the controlled release of the composition into the resection cavity JLP-P04628WO13 Application (final) docx< ABK 88

[0750] for at least 3 days, and wherein the mass ratio of administered 5-ALA to the artemisinin compound 1e is between 1:1 and 1:3000, preferably between 1:2 and 1:2000, more preferably between 1:3 and 1:1000, more preferably between 1:5 and 1:500, more preferably between 1:6 and 1:400, more preferably between 1:7 and 1:300, more preferably between 1:8 and 1:200, more.preferably between 1:9 and 1: 150, and most preferably between 1:10 and 1: 100.

[0751] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously and simultaneously with the controlled release of the composition into the resection cavity for at least 10 days, and wherein the mass ratio of administered 5-ALA to the artemisinin compound 1e is between 1:1 and 1:3000, preferably between 1:2 and 1:2000, more preferably between 1:3 and 1:1000, more preferably between 1:5 and 1:500, more preferably between 1:6 and 1:400, more preferably between 1:7 and 1:300, more preferably between 1:8 and 1:200, more.preferably between 1:9 and 1: 150, and most preferably between 1:10 and 1: 100.

[0752] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously and simultaneously with the controlled release of the composition into the resection cavity for at least 15 days, and wherein the mass ratio of administered 5-ALA to the artemisinin compound 1e is between 1:1 and 1:3000, preferably between 1:2 and 1:2000, more preferably between 1:3 and 1:1000, more preferably between 1:5 and 1:500, more preferably between 1:6 and 1:400, more preferably between 1:7 and 1:300, more preferably between 1:8 and 1:200, more.preferably between 1:9 and 1: 150, and most preferably between 1:10 and 1: 100.

[0753] JLP-P04628WO13 Application (final) docx< ABK 89

[0754] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously and simultaneously with the controlled release of the composition into the resection cavity for at least 20 days, and wherein the mass ratio of administered 5-ALA to the artemisinin compound 1e is between 1:1 and 1:3000, preferably between 1:2 and 1:2000, more preferably between 1:3 and 1:1000, more preferably between 1:5 and 1:500, more preferably between 1:6 and 1:400, more preferably between 1:7 and 1:300, more preferably between 1:8 and 1:200, more.preferably between 1:9 and 1: 150, and most preferably between 1:10 and 1: 100.

[0755] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously and simultaneously with the controlled release of the composition into the resection cavity for at least 25 days, and wherein the mass ratio of administered 5-ALA to the artemisinin compound 1e is between 1:1 and 1:3000, preferably between 1:2 and 1:2000, more preferably between 1:3 and 1:1000, more preferably between 1:5 and 1:500, more preferably between 1:6 and 1:400, more preferably between 1:7 and 1:300, more preferably between 1:8 and 1:200, more.preferably between 1:9 and 1: 150, and most preferably between 1:10 and 1: 100.

[0756] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the JLP-P04628WO13 Application (final) docx< ABK 90

[0757] artemisinin compound is daily administered orally or intravenously and simultaneously with the controlled release of the composition into the resection cavity for at least 30 days, and wherein the mass ratio of administered 5-ALA to the artemisinin compound 1e is between 1:1 and 1:3000, preferably between 1:2 and 1:2000, more preferably between 1:3 and 1:1000, more preferably between 1:5 and 1:500, more preferably between 1:6 and 1:400, more preferably between 1:7 and 1:300, more preferably between 1:8 and 1:200, more.preferably between 1:9 and 1: 150, and most preferably between 1:10 and 1: 100.

[0758] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously and simultaneously with the controlled release of the composition into the resection cavity for at least 7 days, wherein the daily dose of the artemisinin compound is about 0.5 mg artemisinin compound per kg body weight, 0.6 mg artemisinin compound per kg body weight, 0.7 mg artemisinin compound per kg body weight, 0.8 mg artemisinin compound per kg body weight, 0.9 mg artemisinin compound per kg body weight, 1 mg artemisinin compound per kg body weight, 1.5 mg artemisinin compound per kg body weight, 2.0 mg artemisinin compound per kg body weight, 2.5 mg artemisinin compound per kg body weight, 3.0 mg artemisinin compound per kg body weight, 3.5 mg artemisinin compound per kg body weight, 4.0 mg artemisinin compound per kg body weight, 4.5 mg artemisinin compound per kg body weight, 5 mg artemisinin compound per kg body weight, 6 mg artemisinin compound per kg body weight, 7 mg artemisinin compound per kg body weight, 8 mg artemisinin compound per kg body weight, and most preferably about 9 mg, and about 10 mg artemisinin compound per kg body weight, and wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 5 mg per day.

[0759] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the JLP-P04628WO13 Application (final) docx< ABK 91

[0760] composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously and simultaneously with the controlled release of the composition into the resection cavity for at least 7 days, wherein the daily dose of the artemisinin compound is about 3 mg artemisinin compound per kg body weight, and wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day.

[0761] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously and simultaneously with the controlled release of the composition into the resection cavity for at least 7 days, wherein the daily dose of the artemisinin compound is about 3 mg artemisinin compound per kg body weight, and wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 1 mg per day.

[0762] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously and simultaneously with the controlled release of the composition into the resection cavity for at least 7 days, wherein the daily dose of the artemisinin compound is about 3 mg JLP-P04628WO13 Application (final) docx< ABK 92

[0763] artemisinin compound per kg body weight, and wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 2 mg per day.

[0764] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously and simultaneously with the controlled release of the composition into the resection cavity for at least 7 days, wherein the daily dose of the artemisinin compound is about 3 mg artemisinin compound per kg body weight, and wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 3 mg per day.

[0765] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously and simultaneously with the controlled release of the composition into the resection cavity for at least 7 days, wherein the daily dose of the artemisinin compound is about 3 mg artemisinin compound per kg body weight, and wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 4 mg per day.

[0766] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously and simultaneously with the controlled release of the composition into the resection cavity for at least 7 days, wherein the daily dose of the artemisinin compound is about 3 mg JLP-P04628WO13 Application (final) docx< ABK 93

[0767] artemisinin compound per kg body weight, and wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 5 mg per day.

[0768] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously and simultaneously with the controlled release of the composition into the resection cavity for at least 7 days, wherein the daily dose of the artemisinin compound is about 3 mg artemisinin compound per kg body weight, and wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 10 mg per day.

[0769] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously and simultaneously with the controlled release of the composition into the resection cavity for at least 7 days, wherein the daily dose of the artemisinin compound is about 3 mg artemisinin compound per kg body weight, and wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 15 mg per day.

[0770] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with an artemisinin compound 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously and simultaneously with the controlled release of the composition into the resection cavity for at least 7 days, wherein the daily dose of the artemisinin compound is about 3 mg JLP-P04628WO13 Application (final) docx< ABK 94

[0771] artemisinin compound per kg body weight, and wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 20 mg per day.

[0772] The artemisinin compound will typically be administered together with a suitable acceptable carrier selected with respect to the intended form of administration, i.e. for oral administration in the form of tablets, capsules (either solid filled, semi-solid filled or liquid filled), powders for constitution, gels, elixirs, dispersable granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices and could also be administered together with a carrier promoting crossing the blood brain barrier such as virus like particles, neurotropic viruses, exosomes, and nanoparticles. For example, for oral administration in the form of tablets or capsules, the artemisinin compound may be combined with any oral non-toxic pharmaceutically acceptable carrier, preferably with an inert carrier like lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid filled capsules) and the like. Moreover, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the tablet or capsule. Powders and tablets may contain about 5 to about 95-weight % of the artemisinin compound or the respective pharmaceutically active salt as active ingredient.

[0773] Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, poly(ethylene glycol) and waxes. Among suitable lubricants there may be mentioned boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like. Suitable disintegrants include starch, methylcellulose, guar gum, and the like. Sweetening and flavoring agents as well as preservatives may also be included, where appropriate. The disintegrants, diluents, lubricants, binders etc. are discussed in more detail below.

[0774] Moreover, the artemisinin compound may be formulated in sustained release formulation to provide the rate controlled release of the artemisinin compound to optimise the therapeutic effect(s), e.g. anti-cancer activity or activity against cancer metastases and the like. Suitable dosage forms for sustained release include tablets having layers of varying disintegration rates or controlled release, polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.

[0775] Liquid form preparations include solutions, suspensions, and emulsions. As an example, there may be mentioned water or water / propylene glycol solutions for JLP-P04628WO13 Application (final) docx< ABK 95

[0776] parenteral injections or addition of sweeteners and opacifiers for oral solutions, suspensions, and emulsions. Liquid form preparations may also include solutions for intranasal administration.

[0777] Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be present in combination with a pharmaceutically acceptable carrier such as an inert, compressed gas, e.g. nitrogen.

[0778] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides like cocoa butter is melted first, and the active ingredient is then dispersed homogeneously therein e.g. by stirring. The molten, homogeneous mixture is then poured into conveniently sized moulds, allowed to cool, and thereby solidified.

[0779] Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions.

[0780] The term capsule as recited herein refers to a specific container or enclosure made e.g. of methylcellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredient(s). Capsules with hard shells are typically made of blended of relatively high gel strength gelatins from bones or pork skin. The capsule itself may contain small amounts of dyes, opaquing agents, plasticisers and / or preservatives.

[0781] Under tablet a compressed or moulded solid dosage form is understood which comprises the active ingredients with suitable diluents. The tablet may be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation, or by compaction well known to a person of ordinary skill in the art.

[0782] Oral gels refer to the active ingredients dispersed or solubilised in a hydrophilic semisolid matrix.

[0783] Powders for constitution refers to powder blends containing the active ingredients and suitable diluents which can be suspended e.g. in water or in juice.

[0784] Suitable diluents are substances that usually make up the major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol, and sorbitol, starches derived from wheat, corn, rice, and potato, and celluloses such as microcrystalline cellulose. The amount of diluent in the JLP-P04628WO13 Application (final) docx< ABK 96

[0785] composition can range from about 5 to about 95 % by weight of the total composition, preferably from about 25 to about 75 weight%, and more preferably from about 30 to about 60 weight%.

[0786] The term disintegrants refers to materials added to the composition to support break apart (disintegrate) and release the artemisinin compound. Suitable disintegrants include starches, “cold water soluble” modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline celluloses, and cross-linked microcrystalline celluloses such as sodium croscaramellose, alginates such as alginic acid and sodium alginate, clays such as bentonites, and effervescent mixtures. The amount of disintegrant in the composition may range from about 2 to about 20 weight% of the composition, more preferably from about 5 to about 10 weight%.

[0787] Binders are substances which bind or “glue” together powder particles and make them cohesive by forming granules, thus serving as the “adhesive” in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose, starches derived from wheat, corn, rice and potato, natural gums such as acacia, gelatin and tragacanth, derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate, cellulose materials such as methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose, polyvinylpyrrolidone, and inorganic compounds such as magnesium aluminum silicate. The amount of binder in the composition may range from about 2 to about 20 weight% of the composition, preferably from about 3 to about 10 weight %, and more preferably from about 3 to about 6 weight%.

[0788] Lubricants refer to a class of substances which are added to the dosage form to enable the tablet granules etc. after being compressed to release from the mould by reducing friction or wear. Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate, or potassium stearate, stearic acid, high melting point waxes, and other water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycol)s and D, L-leucine. Lubricants are usually added at the very last step before compression, since they must be present at the surface of the granules. The amount of lubricant in the composition may range from about 0.2 to about 5 weight % of the composition, preferably from about 0.5 to about 2 weight %, and more preferably from about 0.3 to about 1.5 weight % of the composition.

[0789] JLP-P04628WO13 Application (final) docx< ABK 97

[0790] Glidents are materials that prevent caking of the components of the pharmaceutical composition and improve the flow characteristics of granulate so that flow is smooth and uniform. Suitable glidents include silicon dioxide and talc. The amount of glident in the composition may range from about 0.1 to about 5 weight% of the final composition, preferably from about 0.5 to about 2 weight%.

[0791] Coloring agents are excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide. The amount of the coloring agent may vary from about 0.1 to about 5 weight% of the composition, preferably from about 0.1 to 1 weight %.

[0792] Chemotherapeutic agents

[0793] The composition for use in treating brain tumor described herein may be further combined with systemic administration of anti-glioblastoma drug to effectively inhibit postoperative tumor growth.

[0794] Therefore, another aspect of the present invention is directed to a composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with a therapeutically effective amount of at least one antiglioblastoma drug, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the therapeutically effective amount of at least one anti-glioblastoma drug is administered systemically to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system.

[0795] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided in an direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with a therapeutically effective amount of at least one anti-glioblastoma drug, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the at least one anti-glioblastoma drug selected from the group consisting of temozolomide, dexamethasone, lomustine, methotrexate, everolimus, carmustine, JLP-P04628WO13 Application (final) docx< ABK 98

[0796] cyclophosphamide, cisplatin, carboplatin, 5-fluorouracil, triptolide, homoharringtonin, dactinomycin, doxorubicin, epirubicin, idarubicin, ribavirin, topotecan, flubendazole, itraconazole, vindesine sulfate, cerivastatin, vincristine, vinorebine, nisoldipine, deoxyadenosine, chloro-2’-deoxyadenosine, 5-nonyloxytryptamine, 2(1 H)-pyrimidinone, pitavastatin, sertraline, irinotecan, clofazimine, tovorafenib, and docetaxel, and wherein the therapeutically effective amount of at least one antiglioblastoma drug is administered systemically to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system.

[0797] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided in an direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with a therapeutically effective amount of at least one anti-glioblastoma drug, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the at least one anti-glioblastoma drug selected from the group consisting of temozolomide, lomustine, cisplatin, and 5 fluorouracil, and wherein the therapeutically effective amount of at least one anti-glioblastoma drug is administered systemically to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system.

[0798] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided in an direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with a therapeutically effective amount of temozolomide, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the therapeutically effective amount of temozolomide is administered systemically to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system.

[0799] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided in an direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with a JLP-P04628WO13 Application (final) docx< ABK 99

[0800] therapeutically effective amount of at least one anti-glioblastoma drug, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the therapeutically effective amount of at least one anti-glioblastoma drug is administered systemically to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system in a range of 0.1 to 100 mg / kg per body weight per day.

[0801] Preferred, the dose of the anti-glioblastoma drug is administered orally daily is at least 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5 or 15.0 mg / kg anti-glioblastoma drug per body weight per day.

[0802] In a preferred embodiment the composition for use in treating brain tumor in a subject comprises 5-aminolevulinic acid, wherein, in use, the composition is provided in an direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with a therapeutically effective amount of an artemisinin compound selected from 1a, 1b, 1c, 1 d, and 1e or a pharmaceutically acceptable salt thereof, and at least one anti-glioblastoma drug, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system, and wherein the therapeutically effective amount of at least one anti-glioblastoma drug is administered systemically to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system.

[0803] In a preferred embodiment the composition for use in treating brain tumor in a subject comprises 5-aminolevulinic acid, wherein, in use, the composition is provided in an direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with a therapeutically effective amount of an artemisinin compound selected from 1a, 1b, 1c, 1 d, and 1e or a pharmaceutically acceptable salt thereof, and at least one anti-glioblastoma drug selected from the group consisting of temozolomide, dexamethasone, lomustine, methotrexate, everolimus, carmustine, cyclophosphamide, cisplatin, carboplatin, 5-fluorouracil, JLP-P04628WO13 Application (final) docx< ABK 100

[0804] triptolide, homoharringtonin, dactinomycin, doxorubicin, epirubicin, idarubicin, ribavirin, topotecan, flubendazole, itraconazole, vindesine sulfate, cerivastatin, vincristine, vinorebine, nisoldipine, deoxyadenosine, chloro-2’-deoxyadenosine, 5-nonyloxytryptamine, 2(1 H)-pyrimidinone, pitavastatin, sertraline, irinotecan, clofazimine, tovorafenib, and docetaxel, wherein the artemisinin compound is daily administered orally or intravenously to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system, and wherein the therapeutically effective amount of at least one anti-glioblastoma drug is administered systemically to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system.

[0805] In a preferred embodiment the composition for use in treating brain tumor in a subject comprises 5-aminolevulinic acid, wherein, in use, the composition is provided in an direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with a therapeutically effective amount of an artemisinin compound selected from 1a, 1b, 1c, 1 d, and 1e or a pharmaceutically acceptable salt thereof, and at least one anti-glioblastoma drug selected from the group consisting of temozolomide, lomustine, cisplatin, and 5 fluorouracil, wherein the artemisinin compound is daily administered orally or intravenously to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system, and wherein the therapeutically effective amount of at least one anti-glioblastoma drug is administered systemically to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system.

[0806] In a preferred embodiment the composition for use in treating brain tumor in a subject comprises 5-aminolevulinic acid, wherein, in use, the composition is provided in an direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with a therapeutically effective amount of an artemisinin compound selected from 1a, 1b, 1c, 1 d, and 1e or a pharmaceutically acceptable salt thereof, and at least one anti-glioblastoma drug, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is daily administered orally or intravenously to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system, and wherein the therapeutically effective amount of at least one anti-glioblastoma drug is administered JLP-P04628WO13 Application (final) docx< ABK 101

[0807] systemically to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system in a range of 0.1 to 100 mg / kg per body weight per day.

[0808] Preferred, the dose of the anti-glioblastoma drug is administered orally daily is at least 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5 or 15.0 mg / kg anti-glioblastoma drug per body weight per day.

[0809] Another aspect of the present invention is directed to the composition for use in treating brain tumor as described herein in combination with a radiotherapy, photodynamic therapy, an immunotherapy, an electromagnetic field therapy, hyperthermia therapy, chemotherapy, cancer immunotherapy and / or a cellular therapy such as Car-T and TIL. Preferred is a combination with chemotherapy, radiotherapy, and photodynamic therapy.

[0810] Reworded, in a preferred embodiment, the composition for use in treating brain tumor in a subject in combination with a radiotherapy, photodynamic therapy, immunotherapy, electromagnetic field therapy, hyperthermia therapy, chemotherapy, cancer immunotherapy, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided in an direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the composition is continuously released into the resection cavity over 1 to 50 days after at least partial surgical resection of the brain tumor, and wherein the brain tumor is a glioblastoma multiforme.

[0811] In another embodiment, the composition is continuously released into the resection cavity over 1 to 50 days or 1 to 40 days or 1 to 30 days, more preferably over 2 to 30 days, more preferably over 3 to 30 days, more preferably over 4 to 30 days, more preferably over 5 to 30 days, and most preferably over 8 to 30 days.

[0812] Preferably, the composition is continuously released into the resection cavity over at least 4 days, more preferably at least 5 days, more preferably at least 6 days, more preferably at least 7 days, more preferably at least 8 days, more preferably at least 9 days, more preferably at least 10 days, more preferably at least 11 days, more JLP-P04628WO13 Application (final) docx< ABK 102

[0813] preferably at least 12 days, more preferably at least 13 days, more preferably at least 14 days, more preferably at least 15 days, more preferably at least 16 days, more preferably at least 17 days, more preferably at least 18 days, more preferably at least 19 days, more preferably at least 20 days, more preferably at least 21 days, more preferably at least 22 days, more preferably at least 23 days, more preferably at least 24 days, more preferably at least 25 days, more preferably at least 26 days, more preferably at least 27 days, more preferably at least 28 days, more preferably at least 29 days, and most preferably at least 30 days after at least partial surgical resection of the brain tumor.

[0814] In another embodiment, the composition is continuously released into the resection cavity between 4 days to 30 days, more preferably between 5 days and 30 days, more preferably between 10 days and 30 days, more preferably between 15 days and 30 days, and most preferably between 20 days and 30 days after at least partial surgical resection of the brain tumor.

[0815] In another embodiment, the composition is continuously released into the resection cavity between 3 days to 15 days, more preferably between 4 days and 14 days, more preferably between 5 days and 13 days, more preferably between 6 days and 12 days, and most preferably between 7 days and 11 days after at least partial surgical resection of the brain tumor.

[0816] In another embodiment, the composition is continuously released into the resection cavity between 8 days to 20 days, more preferably between 9 days and 19 days, more preferably between 10 days and 18 days, more preferably between 11 days and 17 days, and most preferably between 12 days and 16 days after at least partial surgical resection of the brain tumor.

[0817] In another embodiment, the composition is continuously released into the resection cavity between 13 days to 25 days, more preferably between 14 days and 24 days, more preferably between 15 days and 23 days, more preferably between 16 days and 22 days, and most preferably between 17 days and 21 days after at least partial surgical resection of the brain tumor.

[0818] In another embodiment, the composition is continuously released into the resection cavity between 18 days to 30 days, more preferably between 19 days and 29 days, more preferably between 20 days and 28 days, more preferably between 21 days and 27 days, and most preferably between 22 days and 26 days after at least partial surgical resection of the brain tumor.

[0819] JLP-P04628WO13 Application (final) docx< ABK 103

[0820] In another embodiment, the composition is continuously released into the resection cavity between 23 days to 35 days, more preferably between 24 days and 34 days, more preferably between 25 days and 33 days, more preferably between 26 days and 32 days, and most preferably between 27 days and 30 days after at least partial surgical resection of the brain tumor.

[0821] In a preferred embodiment, the composition for use in treating brain tumor in a subject in combination with a radiotherapy, photodynamic therapy, immunotherapy, electromagnetic field therapy, hyperthermia therapy, chemotherapy, cancer immunotherapy, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided in an direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of 0.1 mg – 100 mg per day, and wherein the brain tumor is a glioblastoma multiforme.

[0822] Preferably, the 5-aminolevulinic acid in the composition is continuously released at a constant rate of 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day.

[0823] Preferably, the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg per day; more preferably at a constant rate of about 0.2 mg per day; more preferably at a constant rate of about 0.3 mg per day; more preferably at a constant rate of about 0.4 mg per day; more preferably at a constant rate of about 0.5 mg per day; more preferably at a constant rate of about 0.6 mg per day; more preferably at a constant rate of about 0.7 mg per day; more preferably at a constant rate of about 0.8 mg per day; more preferably at a constant rate of about 0.9 mg per day; more preferably at a constant rate of about 1.0 mg per day; more preferably at a constant rate of about 1.1 mg per day; more preferably at a constant rate of about 1.2 mg per day; more preferably at a constant rate of about 1.3 mg per day; more preferably at a constant rate of about 1.4 mg per day; more preferably at a JLP-P04628WO13 Application (final) docx< ABK 104

[0824] constant rate of about 1.5 mg per day; more preferably at a constant rate of about 1.6 mg per day; more preferably at a constant rate of about 1.7 mg per day; more preferably at a constant rate of about 1.8 mg per day; more preferably at a constant rate of about 1.9 mg per day; more preferably at a constant rate of about 2.0 mg per day; more preferably at a constant rate of about 2.1 mg per day; more preferably at a constant rate of about 2.2 mg per day; more preferably at a constant rate of about 2.3 mg per day; more preferably at a constant rate of about 2.4 mg per day; more preferably at a constant rate of about 2.5 mg per day; more preferably at a constant rate of about 2.6 mg per day; more preferably at a constant rate of about 2.7 mg per day; more preferably at a constant rate of about 2.8 mg per day; more preferably at a constant rate of about 2.9 mg per day; more preferably at a constant rate of about 3.0 mg per day; more preferably at a constant rate of about 3.1 mg per day; more preferably at a constant rate of about 3.2 mg per day; more preferably at a constant rate of about 3.3 mg per day; more preferably at a constant rate of about 3.4 mg per day; more preferably at a constant rate of about 3.5 mg per day; more preferably at a constant rate of about 3.6 mg per day; more preferably at a constant rate of about 3.7 mg per day; more preferably at a constant rate of about 3.8 mg per day; more preferably at a constant rate of about 3.9 mg per day; more preferably at a constant rate of about 4.0 mg per day; more preferably at a constant rate of about 4.1 mg per day; more preferably at a constant rate of about 4.2 mg per day; more preferably at a constant rate of about 4.3 mg per day; more preferably at a constant rate of about 4.4 mg per day; more preferably at a constant rate of about 4.5 mg per day; more preferably at a constant rate of about 4.6 mg per day; more preferably at a constant rate of about 4.7 mg per day; more preferably at a constant rate of about 4.8 mg per day; more preferably at a constant rate of about 4.9 mg per day; more preferably at a constant rate of about 5.0 mg per day; more preferably at a constant rate of about 5.1 mg per day; more preferably at a constant rate of about 5.2 mg per day; more preferably at a constant rate of about 5.3 mg per day; more preferably at a constant rate of about 5.4 mg per day; more preferably at a constant rate of about 5.5 mg per day; more preferably at a constant rate of about 5.6 mg per day; more preferably at a constant rate of about 5.7 mg per day; more preferably at a constant rate of about 5.8 mg per day; more preferably at a constant rate of about 5.9 mg per day; more preferably at a constant rate of about 6.0 mg per day; more preferably at a constant rate of about 6.1 mg per day; more preferably at a constant rate of about 6.2 mg per day; more preferably at a constant rate of about 6.3 mg per day; more preferably at a constant rate of about 6.4 mg per day; more preferably at a constant rate of about 6.5 mg per day; more preferably at a constant rate of about 6.6 mg per day; more preferably at a constant rate of about 6.7 mg per day; more preferably at a constant rate of about 6.8 mg per day; more preferably at a constant rate of about 6.9 mg per JLP-P04628WO13 Application (final) docx< ABK 105

[0825] day; more preferably at a constant rate of about 7.0 mg per day; more preferably at a constant rate of about 7.1 mg per day; more preferably at a constant rate of about 7.2 mg per day; more preferably at a constant rate of about 7.3 mg per day; more preferably at a constant rate of about 7.4 mg per day; more preferably at a constant rate of about 7.5 mg per day; more preferably at a constant rate of about 7.6 mg per day; more preferably at a constant rate of about 7.7 mg per day; more preferably at a constant rate of about 7.8 mg per day; more preferably at a constant rate of about 7.9 mg per day; more preferably at a constant rate of about 8.0 mg per day; more preferably at a constant rate of about 8.1 mg per day; more preferably at a constant rate of about 8.2 mg per day; more preferably at a constant rate of about 8.3 mg per day; more preferably at a constant rate of about 8.4 mg per day; more preferably at a constant rate of about 8.5 mg per day; more preferably at a constant rate of about 8.6 mg per day; more preferably at a constant rate of about 8.7 mg per day; more preferably at a constant rate of about 8.8 mg per day; more preferably at a constant rate of about 8.9 mg per day; more preferably at a constant rate of about 9.0 mg per day; more preferably at a constant rate of about 9.1 mg per day; more preferably at a constant rate of about 9.2 mg per day; more preferably at a constant rate of about 9.3 mg per day; more preferably at a constant rate of about 9.4 mg per day; more preferably at a constant rate of about 9.5 mg per day; more preferably at a constant rate of about 9.6 mg per day; more preferably at a constant rate of about 9.7 mg per day; more preferably at a constant rate of about 9.8 mg per day; more preferably at a constant rate of about 9.9 mg per day; and most preferably at a constant rate of about 10.0 mg per day.

[0826] In a preferred embodiment, the composition for use in treating brain tumor in a subject in combination with a radiotherapy, photodynamic therapy, immunotherapy, electromagnetic field therapy, hyperthermia therapy, chemotherapy, cancer immunotherapy, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided in an direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity over 1 to 30 days, preferably 7 to 30 days, more preferably 12 to 29 days, more preferably 14 to 28 days after at least partial surgical resection of the brain tumor, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a JLP-P04628WO13 Application (final) docx< ABK 106

[0827] constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day, and wherein the brain tumor is a glioblastoma multiforme.

[0828] In a preferred embodiment, the composition for use in treating brain tumor in a subject in combination with a radiotherapy, photodynamic therapy, immunotherapy, electromagnetic field therapy, hyperthermia therapy, chemotherapy, cancer immunotherapy, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided in an direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity for at least 3 days after at least partial surgical resection of the brain tumor, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day, and wherein the brain tumor is a glioblastoma multiforme.

[0829] In a preferred embodiment, the composition for use in treating brain tumor in a subject in combination with a radiotherapy, photodynamic therapy, immunotherapy, electromagnetic field therapy, hyperthermia therapy, chemotherapy, cancer immunotherapy, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided in an direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity for at least 10 days after at least partial surgical resection of the brain tumor, wherein the JLP-P04628WO13 Application (final) docx< ABK 107

[0830] 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a rate of 1.0 mg – 3.0 mg per day, and wherein the brain tumor is a glioblastoma multiforme. The release is in relation to one single implant. Of course, more than one composition can be used for the treatment of the brain tumor including brain metastases.

[0831] In a preferred embodiment, the composition for use in treating brain tumor in a subject in combination with a radiotherapy, photodynamic therapy, immunotherapy, electromagnetic field therapy, hyperthermia therapy, chemotherapy, cancer immunotherapy, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided in an direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity for at least 20 days after at least partial surgical resection of the brain tumor, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day, and wherein the brain tumor is a glioblastoma multiforme.

[0832] In a preferred embodiment, the composition for use in treating brain tumor in a subject in combination with a radiotherapy, photodynamic therapy, immunotherapy, electromagnetic field therapy, hyperthermia therapy, chemotherapy, cancer JLP-P04628WO13 Application (final) docx< ABK 108

[0833] immunotherapy, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided in an direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity for at least 25 days after at least partial surgical resection of the brain tumor, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day, and wherein the brain tumor is a glioblastoma multiforme.

[0834] In a preferred embodiment, the composition for use in treating brain tumor in a subject in combination with a radiotherapy, photodynamic therapy, immunotherapy, electromagnetic field therapy, hyperthermia therapy, chemotherapy, cancer immunotherapy, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided in an direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the composition is continuously released into the resection cavity for at least 30 days after at least partial surgical resection of the brain tumor, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of about 0.1 mg – 100 mg per day, more preferably at a constant rate of 0.15 mg – 90 mg per day, more preferably at a constant rate of 0.2 mg – 80 mg per day, more preferably at a constant rate of 0.25 mg – 70 mg per day, more preferably at a constant rate of 0.3 mg – 60 mg per day, more preferably at a constant rate of 0.35 mg – 50 mg per day, more preferably at a constant rate of 0.4 mg – 40 mg per day, more preferably at a constant rate of 0.42 mg – 30 mg per day, more preferably at a constant rate of 0.45 mg – 20 mg per day, more preferably at a constant rate of 0.5 mg – 10 mg per day, more preferably 0.8 mg – 5.0 mg per day, and most preferably at a constant rate of 1.0 mg – 3.0 mg per day, and wherein the brain tumor is a JLP-P04628WO13 Application (final) docx< ABK 109

[0835] glioblastoma multiforme.

[0836] Preferably, the composition for use in treating brain tumor in a subject as described herein is combined with a radiotherapy or photodynamic therapy.

[0837] Thus, a further aspect of the present invention is directed to a composition for use in treating brain tumor in a subject as described herein in combination with a radiotherapy or photodynamic therapy and with a therapeutically effective amount of an artemisinin compound selected from 1a, 1b, 1c, 1 d, and 1e or a pharmaceutically acceptable salt thereof, wherein the artemisinin compound is daily administered orally or intravenously to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system.

[0838] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with a radiotherapy or photodynamic therapy and with artesunate (1e)., wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, and wherein the artesunate (1e) is daily administered orally or intravenously to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system.

[0839] In a preferred embodiment, the composition for use in treating brain tumor in a subject, the composition comprises 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor in combination with a radiotherapy or photodynamic therapy and with an artemisinin compound selected from 1a, 1b, 1c, 1d, and 1e or a pharmaceutically acceptable salt thereof, wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner, wherein the artemisinin compound is administered daily administered orally or intravenously to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system, and wherein the daily dose of the artemisinin compound is in a range of 0.5 mg artemisinin compound per kg body weight to 10 mg artemisinin compound per kg body weight.

[0840] JLP-P04628WO13 Application (final) docx< ABK 110

[0841] Preferably, the daily dose of the artemisinin compound is between about 0.1 mg and 100 mg artemisinin compound per kg body weight, more preferably about 0.2 mg and 80 mg artemisinin compound per kg body weight, more preferably about 0.3 mg and 50 mg artemisinin compound per kg body weight, more preferably about 0.4 mg and 25 mg artemisinin compound per kg body weight, more preferably about 0.5 mg and 10 mg artemisinin compound per kg body weight, more preferably about 1 mg and 8 mg artemisinin compound per kg body weight, more preferably about 2 mg and 6 mg artemisinin compound per kg body weight, and most preferably about 3 mg artemisinin compound per kg body weight.

[0842] Preferably, the daily dose of the artemisinin compound is about 0.5 mg artemisinin compound per kg body weight, 0.6 mg artemisinin compound per kg body weight, 0.7 mg artemisinin compound per kg body weight, 0.8 mg artemisinin compound per kg body weight, 0.9 mg artemisinin compound per kg body weight, 1 mg artemisinin...

Claims

-ABK 128Claims1. A composition for use in treating brain tumor in a subject, the composition comprising 5-aminolevulinic acid, wherein, in use, the composition is provided by a direct intracranial drug delivery system to a subject after at least partial surgical resection of the brain tumor, and wherein the direct intracranial drug delivery system releases a therapeutically effective amount of the composition into a resection cavity in a controlled-release manner.

2. The composition for use according to claim 1, wherein the composition is continuously released into the resection cavity over 4 to 30 days.

3. The composition for use according to claim 1 or 2, wherein the 5-aminolevulinic acid in the composition is continuously released at a constant rate of 0.1 mg – 100 mg per day.

4. The composition for use according to any one of claims 1 to 3, wherein the brain tumor is a glioma, preferably a glioblastoma multiforme.

5. The composition for use according to any one of claims 1 to 4, wherein the direct intracranial drug delivery system is an implantable system comprising a) a core comprising 5-aminolevulinic acid and a first biodegradable polymer, andb) a shell comprising a second biodegradable polymer;wherein the shell encloses the core.

6. The composition for use according to claim 5, wherein the shell consists of an upper membrane, a lower membrane, and a spacer arranged between the upper membrane and the lower membrane, wherein the upper membrane, the lower membrane, and the spacer each comprise the second biodegradable polymer.

7. The composition for use according to claim 5 or claim 6, wherein the first biodegradable polymer and the second biodegradable polymer are identical.

8. The composition for use according to claim 5, wherein the shell consists of an upper membrane, a lower membrane, and a spacer, wherein the spacer and theJLP-P04628WO13 Application (final) docx< ABK 129lower membrane together define a vessel, the vessel comprising a cavity configured to receive the core; orwherein the shell consists of an upper shell portion and a lower shell portion, each defining a cavity portion, the cavity portions together forming a cavity configured to receive the core.

9. The composition for use according to any one of claims 5 to 8, wherein the first biodegradable polymer is selected from the group consisting of poly(lactic acid), poly(ethylene oxide), polyethylene glycol), and poly (lactic-co-glycolic acid); andthe second biodegradable polymer is selected from poly(lactic acid);the implantable system characterized in thatthe second biodegradable polymer is in a range from 20 wt.% to 60 wt.% based on the total weight of the implantable system; andwhen the first biodegradable polymer is poly(lactic acid), polyethylene glycol), or poly(ethylene oxide), the core contains 5-aminolevulinic acid in a range from 25 wt.% to 45 wt.%, and the first biodegradable polymer in a range from 75 wt.% to 55 wt.% based on the total weight of the core; orwhen the first biodegradable polymer is poly(lactic-co-glycolic acid), the core contains 5-aminolevulinic acid in a range from 65 wt.% to 75 wt.% and the first biodegradable polymer in a range from 25 wt.% to 35 wt.% based on the total weight of the core.

10. The composition for use according to any one of claims 5 to 9, wherein the system comprisesa) a core consisting of:65 wt.% to 75 wt.% of 5-aminolevulinic acid, and 35 wt.% to 25 wt.% of poly(lactic-co-glycolic acid), based on a total weight of the core; and b) a shell consisting of poly(lactic acid);wherein in the system poly(lactic acid) is in a range from 40 wt.% to 50 wt.%, based on a total weight of the implantable system;ora) a core consisting of:25 wt.% to 45 wt.% of 5-aminolevulinic acid and 75 wt.% to 55 wt.% of poly(lactic acid), based on a total weight of the core; andb) a shell consisting of poly(lactic acid);wherein in the system poly(lactic acid) is in a range from 75 wt.% to 85 wt.%, based on a total weight of the implantable system;JLP-P04628WO13 Application (final) docx< ABK 130ora) a core consisting of:25 wt.% to 35 wt.% of 5-aminolevulinic acid and 75 wt.% to 65 wt.% of poly(ethylene oxide), based on a total weight of the core; andb) a shell consisting of poly(lactic acid);wherein in the system poly(lactic acid) is in a range from 45 wt.% to 60 wt.%, preferably 50 wt.% to 55 wt.%, based on a total weight of the implantable system;ora) a core consisting of:65 wt.% to 75 wt.% of 5-aminolevulinic acid and 35 wt.% to 25 wt.% of poly(lactic-co-glycolic acid), based on a total weight of the core; and b) a shell consisting of 5 wt.% to 15 wt.% of 5-aminolevulinic acid, and 95 wt.% to 85 wt.% of poly(lactic acid) based on a total weight of the shell; wherein in the system poly(lactic acid) is in a range from 35 wt.% to 45 wt.%, based on a total weight of the system;ora) a core consisting of:25 wt.% to 30 wt.% of 5-aminolevulinic acid, 5 wt.% to 15 wt.% of citric acid or fumaric acid, and 60 wt.% to 70 wt.% of poly(lactic acid), based on a total weight of the core; andb) a shell consisting of poly(lactic acid);wherein in the system poly(lactic acid) is in a range from 75 wt.% to 85 wt.% and preferably in the range from 65 wt.% to 70 wt.%, based on a total weight of the system;ora) a core consisting of:65 wt.% to 75 wt.% of 5-aminolevulinic acid, and 35 wt.% to 25 wt.% of poly (lactic-co-glycolic acid) based on a total weight of the core; andb) a shell consisting of 35 wt.% to 45 wt.% of polyethylene glycol) 400, and 55 wt.% to 65 wt.% of poly(lactic acid), based on a total weight of the shell wherein in the system poly(lactic acid) is in a range from 25 wt.% to 35 wt.%, based on a total weight of the system.ora) a core consisting of:25 wt.% to 45 wt.% of 5-aminolevulinic acid, and 75 wt.% to 55 wt.% of JLP-P04628WO13 Application (final) docx< ABK 131poly(lactic acid) or polyethylene glycol) or poly(ethylene oxide) based on the total weight of the core;or65 wt.% to 75 wt.% of 5-aminolevulinic acid, and 25 wt.% to 35 wt.% poly(lactic-co-glycolic acid) based on the total weight of the core; andb) a shell consisting of poly(lactic acid);wherein in the system the shell is present in a range from 20 wt.% to 60 wt.%, based on a total weight of the system.

11. The composition for use according to claim 6, wherein the first biodegradable polymer is poly(lactic acid) or polyethylene oxide) and the second biodegradable polymer is poly(lactic acid);characterized in thatthe core contains 5-aminolevulinic acid in a range from 20 wt.% to 50 wt.%, and the first biodegradable polymer in a range from 80 wt.% to 50 wt.% based on the total weight of the core;the core has a diameter (d1) in a range of 9 mm to 12 mm and a height (h1) in a range from 1 mm to 3 mm;the second biodegradable polymer is in a range from 30 wt.% to 60 wt.% based on the total weight of the system;the upper membrane has a diameter (d2) in a range of 10 mm to 15 mm and a height (h2) in a range from 0.20 mm to 0.60 mm; andthe lower membrane has a diameter (d3) in a range of 10 mm to 15 mm and a height (h3) in a range from 0.20 mm to 0.60 mm.

12. The composition for use according to any one of claims 5 to 11, wherein the second biodegradable polymer is poly(D, L-lactide) having carboxyl end groups and a weight-average molecular weight (Mw) of 18,000–24,000 g / mol, as determined by gel permeation chromatography.

13. The composition for use according to any one of claims 5 to 12, wherein the second biodegradable polymer is poly(D, L-lactide) having ester end groups and a weight-average molecular weight (Mw) of 10,000–18,000 g / mol, as determined by gel permeation chromatography.

14. The composition for use according to any one of claims 5 to 13, wherein the first biodegradable polymer is poly(D, L-lactide) having carboxyl end groups and aJLP-P04628WO13 Application (final) docx< ABK 132weight-average molecular weight (Mw) of 18,000–24,000 g / mol, as determined by gel permeation chromatography.

15. The composition for use according to any one of claims 5 to 13, wherein the first biodegradable polymer is polyethylene oxide).

16. The composition for use according to any one of claims 5 to 15, wherein the implantable system has a total height of 1.5 mm to 4.0 mm.

17. The composition for use according to any one of claims 5 to 16, wherein the core has a diameter (d₁) of about 10 mm and a height (h₁) in a range from 1.4 mm to 3.0 mm.

18. The composition for use according to any one of claims 5 to 17, wherein the shell is free of 5-aminolevulinic acid.

19. The composition for use according to claim 6, wherein the core consists of 5-aminolevulinic acid and poly(D, L-lactide),the core contains 5-aminolevulinic acid in a range from 35 wt.% to 45 wt.%, and the poly(D, L-lactide) in a range from 55 wt.% to 65 wt.% based on the total weight of the core;the core has a diameter (di) in the range of 9 mm to 11 mm and a height (hi) in a range from 1.2 mm to 1.8 mm;the shell consists of poly(D, L-lactide) and is in a range from 40 wt.% to 50 wt.% based on the total weight of the system;the upper membrane has a diameter (d2) in a range of 11 mm to 13 mm and a height (h2) in a range from 0.20 mm to 0.30 mm;the lower membrane has a diameter (d3) in a range of 11 mm to 13 mm and a height (h3) in a range from 0.20 mm to 0.30 mm;orthe core consists of 5-aminolevulinic acid and poly(D, L-lactide),the core contains 5-aminolevulinic acid in a range from 35 wt.% to 45 wt.%, and the poly(D, L-lactide) in a range from 55 wt.% to 65 wt.% based on the total weight of the core;the core has a diameter (d1) in the range of 9 mm to 11 mm and a height (h1) in a range from 1.2 mm to 1.8 mm;the shell consists of poly(D, L-lactide) and is in a range from 45 wt.% to 55 wt.% JLP-P04628WO13 Application (final) docx< ABK 133based on the total weight of the system;the upper membrane has a diameter (d2) in a range of 11 mm to 13 mm and a height (h2) in a range from 0.30 mm to 0.40 mm;the lower membrane has a diameter (d3) in a range of 11 mm to 13 mm and a height (h3) in a range from 0.30 mm to 0.40 mm;orthe core consists of 5-aminolevulinic acid and poly(D, L-lactide),the core contains 5-aminolevulinic acid in a range from 25 wt.% to 35 wt.%, and the poly(D, L-lactide) in a range from 65 wt.% to 75 wt.% based on the total weight of the core;the core has a diameter (d1) in the range of 9 mm to 11 mm and a height (h1) in a range from 2.0 mm to 3.0 mm;the shell consists of poly(D, L-lactide) and is in a range from 40 wt.% to 50 wt.% based on the total weight of the system;the upper membrane has a diameter (d2) in a range of 11 mm to 13 mm and a height (h2) in a range from 0.30 mm to 0.40 mm;the lower membrane has a diameter (d3) in a range of 11 mm to 13 mm and a height (h3) in a range from 0.30 mm to 0.40 mm;orthe core consists of 5-aminolevulinic acid and poly(ethylene oxide),the core contains 5-aminolevulinic acid in a range from 25 wt.% to 35 wt.%, and the poly(ethylene oxide) in a range from 65 wt.% to 75 wt.% based on the total weight of the core;the core has a diameter (d1) in the range of 9 mm to 11 mm and a height (h1) in a range from 1.2 mm to 1.8 mm;the shell consists of poly(D, L-lactide) and is in a range from 45 wt.% to 55 wt.% based on the total weight of the system;the upper membrane has a diameter (d2) in a range of 11 mm to 13 mm and a height (h2) in a range from 0.30 mm to 0.40 mm;the lower membrane has a diameter (d3) in a range of 11 mm to 13 mm and a height (h3) in a range from 0.30 mm to 0.40 mm;orthe core consists of 5-aminolevulinic acid and poly(ethylene oxide),JLP-P04628WO13 Application (final) docx< ABK 134the core contains 5-aminolevulinic acid in a range from 25 wt.% to 35 wt.%, and the polyethylene oxide) in a range from 65 wt.% to 75 wt.% based on the total weight of the core;the core has a diameter (d1 ) in the range of 9 mm to 11 mm and a height (hi ) in a range from 1.2 mm to 1.8 mm;the shell consists of poly(D, L-lactide) and is in a range from 50 wt.% to 60 wt.% based on the total weight of the system;the upper membrane has a diameter (d2) in a range of 11 mm to 13 mm and a height (h2) in a range from 0.45 mm to 0.55 mm;the lower membrane has a diameter (d3) in a range of 11 mm to 13 mm and a height (h3) in a range from 0.45 mm to 0.55 mm;orthe core consists of 5-aminolevulinic acid and poly(D, L-lactide),the core contains 5-aminolevulinic acid in a range from 25 wt.% to 35 wt.%, and the poly(D, L-lactide) in a range from 65 wt.% to 75 wt.% based on the total weight of the core;the core has a diameter (d1 ) in the range of 9 mm to 11 mm and a height (hi ) in a range from 2.0 mm to 3.0 mm;the shell consists of poly(D, L-lactide) and is in a range from 30 wt.% to 45 wt.% based on the total weight of the system;the upper membrane has a diameter (d2) in a range of 11 mm to 13 mm and a height (h2) in a range from 0.20 mm to 0.30 mm;the lower membrane has a diameter (d3) in a range of 11 mm to 13 mm and a height (h3) in a range from 0.20 mm to 0.30 mm.

20. The composition for use according to any one of claims 1 to 19, the composition further comprising an antioxidant selected from ascorbic acid, acetylcysteine, cysteine, thioglycerol, sodium hydrogen sulfite, butylated hydroxyanisole, butylated hydroxytoluene, a-tocopherol acetate, methionine, citric acid, ethylenediaminetetraacetic acid, tartaric acid, gallic acid and its esters, glutathione, uric acid, carotenoids, and polyphenols and / or an organic acid selected from citric acid, fumaric acid, glycolic acid, lactic acid, malic acid, tartaric acid, maleic acid, succinic acid and a mixture of two or more of these organic acids.

21. The composition for use according to any one of claims 1 to 20, wherein the direct intracranial drug delivery system is a pump, preferably an osmotic pump. JLP-P04628WO13 Application (final) docx-ABK22. The composition for use according to any one of claims 1 to 21 further in combination with a therapeutically effective amount of an artemisinin compound selected from 1a, 1b, 1c, 1 d, and 1e or a pharmaceutically acceptable salt thereofartemisinin (1a) arteminol (1b,dihydroarteminisin)arteether (1d)artesunate (1e),wherein the artemisinin compound is administered systemically or intracranially.

23. The composition for use according to claim 22, wherein the artemisinin compound is daily administered orally or intravenously to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system.JLP-P04628WO13 Application (final) docx< ABK 13624 The composition for use according to claim 22 or 23, wherein the artemisinin compound is artesunate (1e).

25. The composition for use according to claim 23 or 24, wherein the daily dose of the artemisinin compound is in a range of 0.5 mg artemisinin compound per kg body weight to 10 mg artemisinin compound per kg body weight.

26. The composition for use according to any one of claims 1 to 25 further in combination with a therapeutically effective amount of at least one antiglioblastoma drug selected from the group consisting of temozolomide, dexamethasone, lomustine, methotrexate, everolimus, carmustine, cyclophosphamide, cisplatin, carboplatin, 5-fluorouracil, triptolide, homoharringtonin, dactinomycin, doxorubicin, epirubicin, idarubicin, ribavirin, topotecan, flubendazole, itraconazole, vindesine sulfate, cerivastatin, vincristine, vinorebine, nisoldipine, deoxyadenosine, chloro-2’-deoxyadenosine, 5-nonyloxytryptamine, 2(1 H)-pyrimidinone, pitavastatin, sertraline, irinotecan, clofazimine, tovorafenib, and docetaxel, wherein the therapeutically effective amount of at least one anti-glioblastoma drug is administered systemically daily to the subject during the release of the therapeutically effective amount of the composition into the resection cavity by the direct intracranial drug delivery system.

27. The composition for use according to claim 26, wherein the at least one antiglioblastoma drug is selected from temozolomide, lomustine, cisplatin, and 5-fluorouracil.

28. The composition for use according to any one of claims 1 to 27 further in combination with a radiotherapy, photodynamic therapy, immunotherapy, electromagnetic field therapy, hyperthermia therapy, chemotherapy, cancer immunotherapy, cellular therapy such as Car-T and TIL.JLP-P04628WO13 Application (final) docx

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