JP2009067771A - Therapeutic method for neurological disease - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method whereby a dispersion system containing a therapeutic agent can effectively be administered from the lumber vertebra, even when a primary lesion of a neurological disease is a cranial area such as the vicinity of the cerebral ventricle. <P>SOLUTION: The method of treating a human neurological disease, which is chronic and is particularly hard in achieving a clinical effect, comprises the followings. The therapeutic agent which is contained in the lipid-containing synthetic membrane vesicle dispersion system, is administered to the area of a neurological disease, particularly, to a cerebrospinal fluid (CSF), enabling an effective amount of the drug to exist continuously for a long time. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a method for treating neurological diseases using sustained-release excipients in delivering therapeutic agents to human cerebrospinal fluid (CSF).

  Neurological diseases belong to diseases that are particularly difficult to treat. A major factor complicating the treatment of these diseases is that many drugs cannot cross the vascular brain barrier when administered systemically. The inability of conventional drug delivery to meet these needs is particularly problematic in chronic neurological diseases such as benign or malignant cell growth or diseases caused by various viral pathogens.

  One of the most difficult chronic neurological diseases to treat is a disease caused by metastatic infiltration, such as meningitis. Neoplastic meningitis is caused by metastatic infiltration of the leptomeninges by cancer and is often a complication of acute leukemia, lymphoma, or breast and lung cancer. Autopsy studies have shown that 5-8% of patients with solid tumors have metastasized to the leptomeninges during the course of the disease. There is a specific indication that neoplastic meningitis is likely to have increased due to increased survival with effective systemic treatment (Bleyer, Curr. Probl. Cancer, 12: 184, 1988).

Standard treatments for neoplastic meningitis include chemotherapy, in which the drugs are administered alone or in combination in the sheath, and radiation therapy. Radiation therapy that irradiates the entire cerebrospinal stem often results in severe myelosuppression and is insufficient to control active leptomeningitis disease, except in cases of leukemic meningitis ( Kogan, in Principle and Practice of Radiation Oncology, Perez, et al. Eds., Lippincott, Philadelphia, PA, pp. 1280-1281, 1987). Similarly, systemic chemotherapy is not generally effective in active meningococcal malignancies because of poor drug blood-brain barrier permeability (Blasberg, et al., Can Treat. Rep., 61: 633, 1977; Shapiro, et al., New Eng. J. Med., 293: 161, 1975). Cytarabine, one of the three most commonly used chemotherapeutic agents for endothecal treatment of neoplastic meningitis, is a cell cycle specific drug that kills cells only during DNA synthesis .
Bleyer, Curr. Probl. Cancer, 12: 184, 1988 Kogan, in Principle and Practice of Radiation Oncology, Perez, et al. Eds., Lippincott, Philadelphia, PA, pp. 1280-1281, 1987 Blasberg, et al., Can. Treat. Rep., 61: 633, 1977; Shapiro, et al., New Eng. J. Med., 293: 161, 1975

  Therefore, for optimal tumor killing with drugs such as cytarabine, the drug is continuously administered intravenously or frequently injected daily to maintain a therapeutically effective amount in the cerebrospinal fluid over time There is a need. Such a procedure is uncomfortable for the patient, time consuming for the physician, and may increase the risk of infectious meningitis. Therefore, there is a need for a sustained release depot formulation that allows therapeutic agents to continue to contact neurological diseases and exert a mitigating effect. The present invention addresses these needs.

  The present invention is based on the important discovery that when a therapeutic agent is administered as part of a dispersion system, the clinical effectiveness of the therapeutic agent in treating various human neurological diseases can be greatly improved. It is a departure. This approach in treatment allows the drug to be maintained at an effective dose level for a relatively long period of time so that the neurological disease is constantly exposed to the drug. Surprisingly, it is possible to effectively administer a dispersion containing a therapeutic agent from the lumbar spine even if the primary lesion of the neurological disease is in the cranial region, eg near the ventricle.

  The present invention relates to a method of administering a therapeutic agent to cerebrospinal fluid (CSF) in alleviating neurological diseases. The surprising effect of therapeutic agents in reducing neurological disease is that the therapeutic agent is present in the disperse system so that the therapeutic agent is sustained in the ventricular cavity. This is because it can exist. With the method of the present invention, the therapeutic agent can be made to persist in the area of neurological disease, so it is particularly effective in treating such diseases that are chronic and difficult to achieve clinical effects. Can be obtained.

  The term “neurological disorder” refers to any disorder that occurs in the brain, spinal column, and related tissues, such as the meninges, that is susceptible to an appropriate therapeutic agent. Various neurological diseases for which the method of the present invention is effective include diseases associated with cell proliferative diseases. The term “cell proliferative disorder” encompasses malignant as well as non-malignant cell populations that often differ in morphological appearance from the surrounding tissue. Therefore, the cell proliferative disease may be a disease caused by a benign tumor or a malignant tumor. In the latter case, malignant tumors can be further characterized as primary tumors or metastatic tumors, ie tumors that have spread from different parts of the body. Primary tumors include glial cells (astrocytoma, deficient glioma, glioblastoma), ventricular ependymocytes (ventricular ependymoma), and supporting tissues (meningiomas, Schwann cell tumors, choroid plexus) May arise from papilloma). In children, tumors typically arise from primitive cells (medulloblastoma, neuroblastoma, chordoma), whereas in adults, astrocytomas and Glioblastoma is the most common. However, the most common central nervous system tumors are generally metastatic, especially those that invade the leptomeninges. Tumors that commonly infiltrate the meninges by metastasis include non-Hodgkin lymphoma, leukemia, melanoma, and adenocarcinoma of breast, lung, and gastrointestinal origin.

  The methods of the present invention are also useful in reducing neurological diseases that occur as a result of infectious diseases. Aseptic meningitis as well as encephalitis are diseases of the central nervous system caused by viruses. Viral infections that can best enjoy the ability of the method of the present invention to enable the sustained presence of therapeutic agents include viral diseases caused by late or retroviruses. Of particular importance as retroviruses are lentiviruses, which include HTLV-I, HTLV-II, HIV-1 and HIV-2.

  According to the method of the present invention, neurological diseases caused by infectious diseases caused by prokaryotes can also be treated. In general, prokaryotic pathogens include bacteria such as Haemophilus influenzae, Neisseria meningitidis, Streptococcus pneumonia, Pseudomonas aeruginosa (Pseudomonas aeruginosa), Escherichia coli (E. coli), Klebsiella enterobacter , Proteus species, Mycobacterium tuberculosis, Staphylococcus aureus, and Listeria monocytogenes. Infectious diseases may also be caused by eukaryotic organisms such as fungi. Important fungi that can be treated with the method of the present invention include Cryptococcus, Coccidioides imimitis, Histoplasma, Candida, Nocardia, and Blast myces.

  The therapeutic agents used in the methods of the present invention include delivery systems such as macromolecular complexes, nanocapsules, microspheres, or synthetic or natural polymers in the form of beads, and lipid-containing systems such as oil-in-water emulsions, It is contained in micelles, mixed micelles, synthetic membrane vesicles, and resealed erythrocytes and administered to cerebrospinal fluid. These systems are collectively known as distributed systems. The particles constituting such a system usually have a particle size of about 20 nm-50 μm. When the particle size is within such a range, the particles can be suspended in the formulation buffer and injected into the cerebrospinal fluid using a syringe. The particles can be administered from the ventricle, but are preferably administered intrathecally. Particularly suitable is particle injection by lumbar puncture.

  The materials used in preparing the dispersion are usually sterilized by filter sterilization, non-toxic and biodegradable. For example, albumin, ethyl cellulose, casein, gelatin, lecithin, phospholipids and soybean oil are used in this way. Can be used. The polymer dispersion can be prepared in a manner similar to microencapsulation coacervation. In some cases, the density of the dispersion can be changed by changing the specific gravity, so that the density of the dispersion can be made higher or lower than the cerebrospinal fluid. For example, the specific gravity of the dispersed material can be increased by adding biocompatible molecules having a high specific gravity such as iohexol, iodixanol, metrizamide, sucrose, trehalose and glucose.

  One type of dispersion that can be used in the present invention is a dispersion of a therapeutic agent in a polymer matrix. The therapeutic agent is released as the polymer matrix is degraded or biodegraded, and the degraded or biodegraded polymer matrix becomes a soluble product and is discharged outside the body. For these purposes, several groups of synthetic polymers such as polyesters (Pitt, et al., In Controlled Release of Bioactive Materials, R. Baker, Ed. Academic Press, New York, 1980), polyamides (Sidman, et al. al., Journal of Membrane Science, 7: 227, 1979), polyurethane (Maser, et al., Journal of Polymer Science, Polymer Symposium, 66: 259, 1979), polyorthoester (Heller, et al., Polymer Engineering) Science, 21: 727, 1981), polyanhydrides (Leong, et al., Biomaterials, 7: 364, 1986) have been studied. Numerous studies have already been made on PLA and PLA / PGA polyesters. Of course, this kind of research has been done in consideration of convenience and safety. These polymers are readily available as they are already used as biodegradable sutures and degrade to non-toxic lactic and glycolic acids (see US Pat. No. 4,578,384, US Pat. No. 4,765,973). Are incorporated herein by reference).

  Solid polymer dispersions can be synthesized by using polymerization methods such as bulk polymerization, interfacial polymerization, solution polymerization, and ring opening polymerization (Odian, G., Principles of Polymerization, 2nd ed., John Wiley & Sons, New York, 1981). By using any of these methods, various different synthetic polymers with a wide range of mechanical, chemical and biodegradable properties can be obtained. It can be controlled by changing parameters such as temperature, concentration of reactants, type of solvent, and reaction time. In some cases, the solid polymer dispersion is first formed as a large lump, and then subjected to treatment such as pulverization to make the particles sufficiently small to maintain dispersion in an appropriate physiological buffer. (See US 4,452,025, US 4,389,330, US 4,696,258, which are hereby incorporated by reference).

  The mechanism by which therapeutic drugs are released from biodegradable plates, cylinders, and spheres is described in Hopfenberg (in Controlled Release Polymeric Formulations, pp. 26-32, Paul, DR and Harris, FW, Eds., American Chemical Society, Washington , DC, 1976). The release of additives from such devices whose release is primarily controlled by matrix collapse is represented by the following simple equation:

M _t / M _∞ = 1− [1-k ₀ t / C ₀ a] ⁿ
N in the formula is 3 for a sphere, 2 for a cylinder, and 1 for a plate. The symbol a represents the radius of a sphere or cylinder, or the half thickness of a plate. M _t and M _∞ are the released drug masses after time t and infinite time, respectively.

  Synthetic membrane vesicles are most suitable as the dispersion system of the present invention. The term “synthetic membrane vesicle” refers to a structure commonly known as a liposome having one or more concentric spaces, as well as a plurality of non-concentric spaces defined by a single bilayer membrane. It is called.

  When phospholipids are dispersed in an aqueous solvent, the phospholipids swell and hydrate, and the aqueous medium spontaneously forms multilamellar concentric bilayer vesicles separating the lipid bilayers. Such systems are commonly referred to as multilamellar liposomes or multilamellar vesicles (MLV) and have a diameter in the range of about 100 nm to about 4 μm. Sonication of the MLV produces small unilamellar vesicles (SUVs) with a diameter in the range of about 20 nm to about 50 nm, which contains an aqueous solution in its central part.

  The composition of synthetic membrane vesicles is usually a combination of phospholipids, especially phospholipids with a high phase transition temperature, and steroids, especially cholesterol. Other phospholipids or lipids can also be used.

  Examples of lipids useful in producing synthetic membrane vesicles include phosphatidyl compounds such as phosphatidylglycerol, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, sphingolipids, cerebrosides, and gangliosides. Particularly useful are diacylphosphatidylglycerols in which the lipid moiety contains 14-18 carbon atoms, in particular 16-18 carbon atoms and is saturated. Specific examples of phospholipids include egg phosphatidylcholine, dipalmitoyl phosphatidylcholine, and distearoyl phosphatidylcholine.

  In preparing vesicles containing therapeutic agents, drug encapsulation efficiency, drug instability, homogeneity and particle size of the resulting vesicles, drug to lipid ratio, formulation permeability instability, As well as pharmacological tolerance of the formulation should be considered (Szoka, et al., Annual Reviews of Biophysics and Bioengineering, 9: 467, 1980; Deamer, et al., In Liposomes, Marcel Dekker , New York, 1983, 27; Hope, et al., Chem. Phys. Lipids, 40: 89, 1986).

  In some cases, it is also possible to produce synthetic membrane vesicles having various degrees of target specificity. Vesicle targeting is classified based on anatomical and mechanistic factors. Anatomical classification is based on the level of selectivity, eg, organ-specific, cell-specific, or organelle-specific. Mechanistic targeting can be further distinguished based on whether the targeting is passive or active. Passive targeting takes advantage of the natural tendency of vesicles to be transported to cells of the reticuloendothelial system (RES) of organs that contain sinusoidal capillaries. Active targeting, on the other hand, modifies vesicles by coupling vesicles with specific ligands, such as monoclonal antibodies, sugars, glycolipids, or proteins, or by changing the vesicle composition or particle size. To target organs and cell types other than those where natural localization occurs. Vesicles may also be physically localized in the capillary bed.

  In the present invention, resealed red blood cells can also be used as the dispersion system. When erythrocytes are suspended in a hypotonic solvent, swelling occurs and the cell membrane breaks. As a result, pores with a diameter of about 200-500 angstroms are formed, resulting in an equilibrium between the intracellular environment and the extracellular environment. The ionic strength of the surrounding solvent is then adjusted to isotonic conditions and the cells are incubated at 37 ° C., closing the pores and resealing the red blood cells. Using this technique, the therapeutic agent can be encapsulated inside the resealed red blood cells.

  The surface of the dispersion can be modified by various methods. Non-lipid substances can also be attached via a linking group to one or more hydrophobic groups, for example alkyl chains consisting of about 12-20 carbon atoms. In the case of a synthetic membrane vesicle delivery system, lipid groups can be incorporated into the lipid bilayer to maintain a stable association between the compound and the membrane bilayer. In that case, various linking groups can be used in binding the lipid chain to the compound.

  Whether in the case of a ligand or a receptor, the number of molecules that bind to a synthetic membrane vesicle depends on the size of the vesicle, the size of the binding molecule, the binding affinity of the molecule for the receptor or ligand of the target cell, etc. Depending on the situation. In most cases, the binding molecules will be from about 0.05 to about 2 mole percent, preferably from about 0.1 to about 1 mole, based on the percentage of binding molecules relative to the total number of molecules in the bilayer of the outer membrane of the vesicle. % Are present on the vesicles.

In general, the various compounds that bind to the surface of the targeted delivery system are ligands and receptors that allow the dispersion to actively “home in” to the desired tissue. The ligand can be any desired compound that specifically binds to another compound, referred to as a receptor, to form a homologous pair of ligand and receptor. Compounds bound to the surface of the dispersion system can be from small haptens with a molecular weight of about 125-200 to much larger, with molecular weights of about 6000 or more, but generally less than 1 million. It can be as diverse as antibodies. Of particular importance are proteinaceous ligands and receptors. In general, surface membrane proteins that bind to specific effector molecules are called receptors. However, most of the receptors used in the present invention are antibodies. These antibodies may be monoclonal antibodies or polyclonal antibodies, and may be fragments capable of binding to epitope determinants, such as Fab, F (ab ′) ₂ , and Fv. Techniques for conjugating proteins such as antibodies to synthetic membrane vesicles are well known (see US Pat. No. 4,806,466, US Pat. No. 4,857,735, which are hereby incorporated by reference).

  The term “therapeutic agent” as used herein with respect to the compositions of the invention includes, but is not limited to, drugs, radioisotopes, and immunomodulators. One of ordinary skill in the art will be aware of or can readily identify other similar materials. Of course, there can be a combination of a therapeutic agent and a predetermined type of dispersion, such that the combination is more compatible than the other combinations. For example, a method for producing a solid polymer dispersion may not be compatible with the sustained biological activity of proteinaceous therapeutics. However, conditions that result in an incompatible combination of a specific therapeutic substance and a specific dispersion are well known and can be easily identified, thus avoiding the possibility of such problems. It is a daily work.

  Examples of drugs that can be contained in the dispersion include non-protein drugs and protein drugs. The term “non-proteinaceous drug” encompasses compounds that have been classically called drugs, such as mitomycin C, daunorubicin, vinblastine, AZT, and various hormones. Of particular importance are anti-tumor cell cycle specific drugs such as cytarabine, methotrexate, 5-fluorouracil (5-FU), furoxyuridine (FUDR), bleomycin, 6-mercapto-purine, 6-thioguanine, fludarabine phosphate , Vincristine, and vinblastine. Other similar materials that can be used in the present invention should be well known to those skilled in the art.

  Examples of proteinaceous drugs that can be contained in the dispersion system include biological response modifiers including immunomodulators and antibiotics. The term “biological response modifier” is intended to encompass substances that are involved in modulating the immune response in a way that enhances certain desired therapeutic effects, eg, destruction of tumor cells. Examples of immune response modifiers include compounds such as lymphokines. Examples of lymphokines include tumor necrosis factor, interleukin, lymphotoxin, macrophage activating factor, migration inhibitory factor, colony stimulating factor, and interferon. Examples of interferons that can be contained in the dispersion include α-interferon, β-interferon, γ-interferon, and subtypes thereof. It is also possible to contain a peptide or polysaccharide fragment derived from such a proteinaceous drug or derived independently from it. One skilled in the art will also be aware of or can readily identify other substances that can act as proteinaceous drugs.

When using radioisotopes in the treatment of cell proliferative disorders, such as tumors, certain radioisotopes may be more dependent on factors such as tumor distribution and size and isotope stability and radioactivity. In some cases, it may be preferred over another radioisotope. Depending on the type of malignant tumor that is present, one type of emitter may be preferred over another. In general, radioisotopes that emit alpha and beta particles are preferred for immunotherapy. For example, if the patient has a solid tumor focus, a high energy beta emitter, such as ⁹⁰ Y, that can penetrate several millimeters of tissue would be suitable. On the other hand, if the malignant disease is composed of a single target cell such as leukemia, a high energy α emitter, such as ²¹² Bi, over a short distance would be suitable. Examples of radioisotopes that can be included in the dispersion for therapeutic purposes include ¹²⁵ I, ¹³¹ I, ⁹⁰ Y, ⁶⁷ Cu, ²¹² Bi, ²¹¹ At, ²¹² Pb, ⁴⁷ Sc, ¹⁰⁹ Pd, and ¹⁸⁸ Re. is there. Other radioisotopes that can be included in the dispersion should also be well known to those skilled in the art. When an antibody is contained in the dispersion, the antibody may be a monoclonal antibody, a polyclonal antibody, or may be labeled with a therapeutic agent. The term “antibody” or “immunoglobulin” as used herein refers to an epitope present on the pathogen of a cell proliferative or infectious neurological disease as well as a complete molecule. Also encompassed are fragments capable of binding determinants such as Fab, F (ab) ₂ , and Fv. When bound to the antibody, the therapeutic agent can be bound directly or indirectly. An example of indirect coupling is the use of a spacer portion. Such spacer moieties can be soluble or insoluble (Diener, et al., Science, 231: 148, 1986) and can be selected such that the drug is released from the antibody molecule at the target site. it can. Examples of therapeutic agents that can be conjugated to antibodies during immunotherapy include the aforementioned agents and radioisotopes, as well as lectins and toxins.

  Lectins are proteins that are normally isolated from plant material and bind to specific sugar moieties. Many lectins can also aggregate cells and stimulate lymphocytes. However, ricin is a toxic lectin and has been used in immunotherapy. In that case, it is preferable to realize the site-specific delivery of the toxic effect by binding the α peptide chain of lysine (the part causing the toxicity of ricin) to the antibody molecule.

  Toxins are toxic substances produced by plants, animals, or microorganisms that can often be lethal when doses are high enough. Diphtheria toxin is a substance produced by Corynebacterium diphtheria and can be used for therapy. This toxin is composed of α and β subunits, which can be separated under appropriate conditions. Toxic alpha components can be conjugated to antibodies and used for site-specific delivery to target cells for which the antibody has specificity. Other therapeutic agents that can be combined with monoclonal antibodies are also known and can be readily ascertained by those skilled in the art.

  Labeled or unlabeled antibodies can also be used in combination with various therapeutic agents such as those described herein. Particularly preferred is a combination therapy of a monoclonal antibody and an immunomodulator or other biological response modifier. As an example, monoclonal antibodies can be used in combination with α-interferon. This therapy enhances the targeting of monoclonal antibodies to tumors by increasing the expression of antigens reactive to monoclonal antibodies by tumor cells (Greiner, et al., Science, 235: 895). , 1987). A dispersion system using synthetic membrane vesicles having a plurality of non-concentric spaces is particularly useful in combination therapy because various therapeutic agents can be enclosed in each of the non-concentric spaces. A person skilled in the art should be able to select an appropriate one from various biological response modifiers and create a desired effector function that enhances the efficacy of the monoclonal antibody or other therapeutic agent used in combination.

  When the monoclonal antibody of the present invention is used in combination with various therapeutic agents, for example, the therapeutic agents described herein, the administration of the monoclonal antibody and the therapeutic agent is usually substantially simultaneously. Will be done. The term “substantially contemporaneous” means that the monoclonal antibody and the therapeutic agent are administered simultaneously in close proximity in time. In general, it is preferred to administer the therapeutic agent followed by the monoclonal antibody. For example, the therapeutic agent can be administered 1-6 days before the monoclonal antibody is administered. Administration of the therapeutic agent can be performed daily or at any interval, depending on factors such as the nature of the neurological disease, the condition of the patient, and the half-life of the agent.

  As used in reference to the compositions of the present invention, the term “therapeutically effective” means that the therapeutic agent is present at a concentration sufficient to achieve the particular medical effect for which the therapeutic agent is intended. Means that. Desired medical effects that can be achieved include, but are not limited to, chemotherapy, antibiotic therapy, and metabolic regulation. The exact dose depends on factors such as the type of the particular therapeutic agent and the desired effect, as well as patient factors such as age, gender and general condition. One of ordinary skill in the art should be able to easily set a therapeutically effective concentration in view of and using these various factors without undue experimentation.

  The above description is for illustrating the present invention, and the scope of the present invention is not limited by these descriptions. Indeed, one of ordinary skill in the art would be able to easily devise and manufacture additional embodiments based on the teachings herein without undue experimentation.

Example 1
Production of Depot / ARA-C (DTC101) This example describes the production of synthetic membrane vesicles defined by a single bilayer membrane and having a plurality of non-concentric spaces containing ara-C.

  Dioleyl lecithin (8.3 g), dipalmitoylphosphatidylglycerol (1.66 g), cholesterol (6.15 g), and triolein (13 g) in a 13 liter glass homogenizer vessel equipped with a 2 inch stirring blade. 1.73 g) was mixed with 800 ml of chloroform (lipid phase). Next, cytosine arabinoside (33 mg / ml) was dissolved in 0.151 N HCl (final volume, 1.2 liters) and added to the homogenizer vessel. The mixing blade was rotated at 800 rpm for 10 minutes to form a water-in-oil emulsion.

  Low ionic strength aqueous components including free base lysine (40 mM) and glucose (3.2%) were added to the homogenizer to form chloroform globules and the mixing blade was rotated at 3500 rpm for 90 seconds. To remove the chloroform, nitrogen gas was blown into the mixture at 62 liters / minute for 30 minutes, while the vessel was heated to 35 ° C. The resulting product was purified and concentrated by diafiltration using polysulfone hollow fibers (pore size 0.1 μ, surface area 8 square feet).

Example 2
Treatment by intrathecal and intraventricular administration using depot / ARA-C inclusions

芽球クリーゼ状態の慢性髄膜炎性白血病の患者１名以外の全患者の右側脳室に、オマヤレザバーを載置した。治療としては、２−３週に１回、保存剤を含有しない０．９％ＮａＣｌ溶液へ懸濁させたＤＴＣ１０１を、脳室あるいは腰椎鞘経由で、一回の注射で投与した。レザバーは、ＤＴＣ１０１の投与後ならびに脳脊髄液をサンプリングするごとに、自己由来の脳脊髄液で洗浄した。 A. Patients and Methods Twelve patients with histological diagnosis of cancer and radiological or cytological results of neoplastic meningitis were treated. This human study was conducted with the approval of the UCSD Human Subjects Committee. There was no requirement for the implementation status, and it was said that chemotherapy by intracerebral spinal fluid administration may be performed before the study. Patients were given a total of 47 doses of DTC101. Four patients suffered from hematological malignancies and eight patients suffered from solid tumors (Table 1). Five patients received concurrent treatment with systemic chemotherapy.

Omaya reservoir was placed in the right ventricle of all patients except one patient with chronic meningitis leukemia with blast crisis. As a treatment, once every 2-3 weeks, DTC101 suspended in a 0.9% NaCl solution containing no preservative was administered as a single injection via the ventricle or lumbar sheath. The reservoir was washed with autologous cerebrospinal fluid after administration of DTC101 and every time cerebrospinal fluid was sampled.

B. Treatment The two patients who were able to evaluate were given 32.5 cycles or more before increasing the initial dose of 12.5 mg (25, 37.5, 50, 125 mg). Treatment continued until the disease progressed or the maximum dose of 7 was reached. The first series of tests included a history and physical examination and a complete neurological examination, complete blood count (CBC) and platelet count, cerebrospinal fluid samples for cytological examination, serum chemistry, appropriate imaging CT or MR scans with or without agents, indium-DTPA cerebrospinal fluid flow studies were performed (Chamberlain, et al., Neurol., 40: 435-438, 1990; Chamberlain, et al., Neurol., 41: 1765-1769, 1991). Prior to each cycle of DTC101, a neurological history was examined and examined, blood counts and chemical properties were examined, and cerebrospinal fluid samples for cytological examination were collected. If a cerebrospinal fluid cytological test performed twice consecutively at intervals of 1 week or more is negative, it is defined that a complete cytological response has occurred and does not show a complete response. It was determined that there was no response. A progressive disease was determined when the cytological findings changed from negative to positive. Changes in parenchymal central nervous system lesions or lesions outside the central nervous system are not considered to be affected by treatment within the CSR and were not used in response determination. The various toxic symptoms resulting from the treatment were evaluated on the "Common Toxicity Scale" of the National Cancer Institute.

  FIG. 1 shows the pharmacokinetics of cytarabine in cerebrospinal fluid after administration of various doses of DTC101 ranging from 12.5 to 125 mg into the ventricle. It was collected from the same ventricle where DTC101 was administered. Figure A: Total concentration of cytarabine. Figure B: Free cytarabine concentration. Each point of the data is an average value obtained from three or more courses, and an error bar indicates the standard error of the average. After administration of the maximum tolerated dose (75 mg) into the ventricle, the concentration of free cytarabine in the ventricle (cytarabine released from the DepoFoam particles into the cerebrospinal fluid) has an average initial (α) half-life of 9. 4 ± 1.6 hours (SEM) and terminal (β) half-life decreased exponentially at 14.1 ± 23 hours (SEM). The total ventricular concentration (free cytarabine + encapsulated cytarabine) decreased exponentially as well.

Pharmacokinetic study Cerebrospinal fluid and blood samples from the ventricle were collected immediately before administration, 1 hour after administration, and 1, 2, 4, 7, 14, 21 days after administration. In some patients, a sample of lumbar cerebrospinal fluid was collected at one of the above collection points as part of the assessment of the cytological properties of lumbar cerebrospinal fluid. For intralumbar administration, a lumbar sac sample was taken 3 minutes after administration instead of the 1 hour sample. The collected cerebrospinal fluid and blood samples were collected in a test tube containing 40 μM tetrahydrouridine at a final concentration, and cytarabine was catalyzed in vitro by cytidine deaminase to produce uracil arabinoside (ara-U). ). Blood samples with heparin added were immediately placed on ice and plasma was isolated from blood cells by centrifugation. Cerebrospinal fluid samples were centrifuged at 600 × g for 5 minutes to separate the depoform particles from the free cytarabine fraction (supernatant). Depot foam pellets were dissolved by sequentially stirring in 200 μl methanol and distilled water. The free cytarabine fraction of cerebrospinal fluid was analyzed without further processing. Plasma was ultrafiltered (YMT membrane, No. 4104; Danvers, Mass., USA, Amicon Corp.). Cerebrospinal fluid and plasma samples are cryopreserved at −20 ° C. prior to the previously described method (Kaplan, JG, et al., J. Neuro-Onc., 9: 225-229, 1990). ) Was analyzed by a modified method. Sample analysis was performed using a high performance liquid chromatography apparatus (Milford, Mass., USA, Waters Associates), a 254 mm and 280 mm UV detector, two Pecosphere C-series connected in series. 18 reverse phase column (3 × 3C cartridge, Norwalk, Conn., USA, Perkin-Elmer) and 6.7 mM potassium phosphate / By using with 3.3 mM phosphoric acid mixture (pH 2.8). The retention time of cytarabine was 6 minutes, and the retention time of ara-U, which is the main metabolite, was 7 minutes. There were no peaks that interfered with each other.

The pharmacokinetic curve ^fits the exponential function C (t) = Ae ^−αt + BE ^βt , where C (t) is the concentration at time 5, A and B are constants, and α and β are initial The rate constant and the terminal rate constant. Curves were fitted by iterative nonlinear regression using the RSTRIP program (MicroMath Scientific Software, Salt Lake City, UT, USA). The area under the concentration-time curve (AUC) was determined to the last measured concentration by the linear trapezoidal formula and extrapolated to infinity. The clearance of cytarabine from the CSR was determined by dividing the cytarabine dose by the AUC. The initial distribution volume (V _d ) of cytarabine in the cerebrospinal fluid was calculated by dividing the dose of cytarabine by the concentration measured at the 1 hour time point.

Table 2 gives details of the pharmacokinetic parameters as a function of dose. Increasing the dose from 12.5 mg to 125 mg did not significantly alter half-life (T _1/2 ), volume of distribution (V _d ), and clearance (Cl).

  FIG. 2 shows the maximum ventricular cytarabine concentration (Figure A) measured 1 hour after administration of DTC101, and cerebrospinal fluid drug exposure (AUC, Figure B) as a function of the dose administered to the ventricle. Show. White circles and black circles indicate total cytarabine concentration and free cytarabine concentration, respectively. Each point of the data is an average value obtained from three or more courses, and an error bar indicates the standard error of the average. There was a linear relationship between these pharmacokinetic parameters and the dose, suggesting that the clearance process would not saturate at the dose range studied. The total AUC of ara-U averaged 3.7 ± 0.9% (SEM) of the total AUC of cytarabine in cerebrospinal fluid. In plasma, neither cytarabine nor ara-U was detected at any time point (detection limit for cytarabine and ara-U = 0.25 μg / ml).

  Cerebrospinal fluid samples of the lumbar spine were collected during 5 courses in 2 patients after the maximum tolerated dose (75 mg) of DTC101 was administered to the ventricle. In FIG. 3, the drug concentration in the ventricle and the number of DTC101 particles are compared with the values of the lumbar subarachnoid space. The figure shows a comparison of cytarabine concentrations in the ventricles (black circles) and lumbar vertebrae (white circles) (Figs. A and B are the total cytarabine concentration and free cytarabine concentration, respectively) and the number of particles of DTC101 (Fig. C). , As a function of the time elapsed since the administration of DTC101 into the ventricle. The initial intracerebroventricular free cytarabine concentration decreased exponentially with a half-life of 6.8 hours, and cytarabine was detectable in lumbar cerebrospinal fluid after 1.25 hours, and increased rapidly with a doubling time of 0.53 hours. Subsequently, the lumbar and ventricular free and total cytarabine concentrations decreased in parallel, and the lumbar drug concentration remained similar to the ventricular drug concentration throughout the late phase of the decay curve.

  Cerebrospinal fluid samples in the ventricle and lumbar spine were collected from 4 patients who received DTC101 intrathecally by lumbar puncture. FIG. 4 shows that the therapeutically effective concentration of free cytarabine (> 0.1 μg / ml) in the cerebrospinal fluid of the ventricles was maintained for 3-6 days after intrathecal administration by lumbar puncture and for 14 days after intralumbar administration It has been shown that significant total cytarabine concentrations were detected in the cerebrospinal fluid of the ventricles. Ventricular cerebrospinal fluid cytarabine concentration (solid line) as a function of time elapsed since DTC101 was administered to the lumbar spine (3) and cytarabine concentration (dashed line) of lumbar cerebrospinal fluid after 3 days and 14 days White squares and white circles indicate the total cytarabine concentration, and black squares and black circles indicate the free cytarabine concentration. After administration into the lumbar spine, a therapeutically effective concentration of free cytarabine was maintained in the lumbar subarachnoid space for over 14 days.

Table 3 shows the toxicity due to DTC101 as a function of dose. Toxicity was transient and treatment with DTC101 given below did not delay treatment due to drug-related toxicity. There was one death due to toxic brain injury that developed 36 hours after the administration of 125 mg of DTC101 into the ventricle. This patient also received irradiation of the entire brain (20 Gy divided into 5 times) to partially block the flow of cerebrospinal fluid at the base of the brain. Except for one patient who had undergone autologous bone marrow transplant 2 months prior to the administration of DTC101, no hematological toxicity was observed due to DTC101. The maximum tolerated dose for DTC101 was 75 mg, and dose limiting toxicity occurred at a dose of 125 mg, at which excessive vomiting and brain damage were observed.

Table 4 shows that oral administration of dexamethasone at a dose of 2-4 mg twice daily had a significant effect in alleviating the toxicity associated with DTC101. Fever, headache, nausea / vomiting were all suppressed. Three patients received DTC101 while orally administering dexamethasone, and the same amount of DTC101 was administered without oral administration of dexamethasone. All three patients were toxic when dexamethasone was not administered, and toxicity was almost completely suppressed when dexamethasone was administered simultaneously.

  Four patients were treated with DTC101 administered into the lumbar sheath. Toxicity was similar to that observed after DTC101 was administered intraventricularly, except grade 1-2 light back pain was observed in 4 out of 9 cycles.

Nine of the 12 patients were positive for cerebrospinal fluid cytology immediately prior to treatment. In 7 of these 9 patients capable of performing cytological evaluation, treatment with DTC101 eliminated malignant cells in the cerebrospinal fluid (Table 5). The duration of response ranged from 2-26 weeks with a median of 16 weeks. One of the patients who did not respond was afflicted with AIDS-related non-Hodgkin lymphoma and the other was afflicted with a primary brain tumor. Survival for all patients studied ranged from 3 to 64 weeks (median: 21 weeks).

  Three of the 12 patients showed signs of neoplastic meningitis when examined by CT or MRI scans, but had negative cerebrospinal fluid cytological findings prior to treatment. The pharmacological response could not be evaluated. However, none of these three patients showed a positive cytological finding of cerebrospinal fluid during treatment.

  Surprisingly, a cytological response was observed at all dose levels and was not limited to higher doses. One patient with multiple myeloma relapsed after first cytological response at the 25 mg dose level of DTC101, and responded again with increasing doses of DTC101 (37.5 mg). Of the 5 patients with headache, 3 responded to treatment with DTC101. There were no clinical improvements in patients who had focal neurological deficits (eye muscle palsy or paraparesis) or diffuse neurological deficits (acute confusion) at the start of treatment.

  Several embodiments of the invention have been described. However, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, it is to be understood that the invention is not limited by the specific embodiments shown but only by the appended claims.

FIG. 1A shows the pharmacokinetics in the ventricular cerebrospinal fluid of DTC101 administered intraventricularly as a function of dose in the range of 12.5-125 mg. FIG. 1B shows the pharmacokinetics in the ventricular cerebrospinal fluid of DTC101 administered intraventricularly as a function of dose in the range of 12.5-125 mg. FIG. 2 shows the maximum cerebrospinal fluid cytarabine concentration (FIG. 2a) as well as AUC (FIG. 2B) as a function of dose. FIG. 3 shows a comparison of the cytarabine concentration in the ventricle (black circle) and the lumbar cytarabine concentration (white circle) [FIGS. A and B are the total cytarabine concentration and free cytarabine concentration, respectively] Is shown as a function of elapsed time after intraventricular administration of DTC101. FIG. 4 shows cerebral spinal fluid cytarabine concentration as a function of elapsed time after administration of DTC101 (solid line) and cytarabine concentration in lumbar cerebrospinal fluid after 3 minutes and 14 days ( (Broken line).

Claims (20)

  Contains therapeutic agents contained in biodegradable lipid-containing synthetic membrane vesicle dispersions and is sufficient to reduce disease when administered to human cerebrospinal fluid (CSF) with disease A pharmaceutical composition for alleviating neurological disease, characterized in that the drug can continue to be present in the ventricular cavity over time.   The pharmaceutical composition according to claim 1, wherein the neurological disease is a cell proliferative disease.   The pharmaceutical composition according to claim 1, wherein the neurological disease is neoplastic meningitis.   The pharmaceutical composition according to claim 1, wherein the neurological disease is an infectious disease.   The pharmaceutical composition according to claim 4, wherein the infectious disease is caused by a lentivirus.   The pharmaceutical composition according to claim 4, wherein the infectious disease is caused by a prokaryotic organism.   The pharmaceutical composition according to claim 4, wherein the infectious disease is caused by a eukaryote.   The pharmaceutical composition according to claim 1, wherein the neurological disease is caused by metabolic failure.   The pharmaceutical composition according to claim 1, wherein the therapeutic agent is selected from the group consisting of an antitumor agent, an antibacterial agent, and an antiviral agent.   The pharmaceutical composition according to claim 9, wherein the antitumor drug is cytarabine.   The pharmaceutical composition according to claim 1, wherein the synthetic membrane vesicle is a liposome.   The pharmaceutical composition according to claim 11, wherein the liposome has a plurality of concentric spaces.   The pharmaceutical composition according to claim 1, wherein the synthetic membrane vesicle has a plurality of non-concentric spaces.   The pharmaceutical composition according to claim 1, wherein the dispersion system has a higher specific gravity than cerebrospinal fluid.   15. The pharmaceutical composition according to claim 14, wherein the dispersion system is one in which the specific gravity of the dispersion liquid is made higher than that of the cerebrospinal fluid by enclosing molecules having a higher specific gravity than cerebrospinal fluid.   The pharmaceutical composition according to claim 15, wherein the molecule having a higher specific gravity than cerebrospinal fluid is a carbohydrate.   The pharmaceutical composition according to claim 16, wherein the carbohydrate is selected from the group consisting of sucrose, trehalose, and glucose.   The pharmaceutical composition according to claim 1, wherein the dispersion system has a specific gravity lower than that of cerebrospinal fluid.   2. A pharmaceutical composition according to claim 1 wherein the dispersion is target specific.   The pharmaceutical composition according to claim 19, wherein the dispersion system is actively targeted by coupling with a moiety selected from the group consisting of sugar, glycolipid and protein.

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