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WO2004050100A1 - Method for treating a tumor using a thermo-gelling chitosan composition - Google Patents

Method for treating a tumor using a thermo-gelling chitosan composition Download PDF

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Publication number
WO2004050100A1
WO2004050100A1 PCT/CA2003/001880 CA0301880W WO2004050100A1 WO 2004050100 A1 WO2004050100 A1 WO 2004050100A1 CA 0301880 W CA0301880 W CA 0301880W WO 2004050100 A1 WO2004050100 A1 WO 2004050100A1
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Prior art keywords
salt
composition
glycerol
mono
chitosan
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PCT/CA2003/001880
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French (fr)
Inventor
Mohammed Berrada
Ajay Gupta
Abdellatif Chenite
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Bio Syntech Canada Inc.
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Priority to AU2003287812A priority Critical patent/AU2003287812A1/en
Publication of WO2004050100A1 publication Critical patent/WO2004050100A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/722—Chitin, chitosan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin

Definitions

  • the present invention relates to a new method for treating a tumor using as an active ingredient a thermo-gelling chitosan composition.
  • Polymeric interstitial chemotherapy increases survival of humans with recurrent malignant tumors such as gliomas and of animals with orthotopically- transplanted tumors in the various locations including brain.
  • Drug-loaded polymers implanted orthotopically such as intra-cranially have the advantage of bypassing the blood-brain barrier and releasing drug molecules locally in the brain over a long term sustained and safe fashion.
  • Malignant tumors such as gliomas are known to recur at the periphery of the tumor excision site due to the residual tumors left at the site of resection after surgery.
  • These resection beds can be filled with impiantabie matrices in conjunction with anti-tumor molecules such as camptothecin, cisplatin, taxol, carmustin etc.
  • non-injectable impiantabie matrices loaded with anti-tumor molecules requires invasive surgical implantation procedures and repeat dosing to maintain the desired anti-tumor effect. Furthermore, these types of drug loaded matrices may in some cases, depending on the drug used be difficult to manufacture and at times, require the use of organic solvents during the manufacturing,, traces of which can cause acute toxicity. [0004] It is highly desirable to be provided a simple injectable formulation that is readily impiantabie intratumorally or in the vicinity of tumors, to stay at the injection site and suppress the tumor growth.
  • One aim of the present invention is to provide a simple formulation that is readily impiantabie intratumorally or in the vicinity of a tumor, and that will stay at the injection site to suppress the tumor growth.
  • a method for treating a tumor in a patient comprising the step of administering to a patient in need thereof an effective amount of a chitosan- based thermogelling composition, said composition reducing the growth of the tumor in said patient.
  • the chitosan-based thermogelling composition is administered concurrently with an anti-tumor agent such as paclitaxel.
  • thermogelling composition for use in treating tumors.
  • chitosan based thermo-gelling composition is intended to mean a composition which comprises chitosan or a derivative thereof, and a salt of polyol or sugar, wherein said composition gels upon heating and is adapted to be formed and/or to gel in situ within a tissue, organ or cavities of an animal or a human. More preferably, the composition contains i) 0.1 to 5.0% by weight of chitosan or a chitosan derivative; and ii) 1.0 to 20% by weight of the salt of polyol or sugar.
  • the salt of polyol or sugar is preferably selected from the group consisting of mono-phosphate dibasic salt, mono-sulfate salt and mono-carboxylic acid salt of polyol or sugar.
  • the composition preferably turns into a gel at temperature above 20°C, and more preferably within a temperature range from 20 to 70°C.
  • the salt may be any of the following or in any of the following combination a) a mono-phosphate dibasic salt selected from the group consisting of glycerol, comprising glycerol-2-phosphate, sn-glycerol 3- phosphate and L-glycerol-3-phosphate salts, b) a mono-phosphate dibasic salt and said polyol is selected from the group consisting of histidinol, acetol, diethylstilbestrol, indole-glycerol, sorbitol, ribitol, xylitol, arabinitol, erythritol, inositol, mannitol, glucitol and a mixture thereof, c) a mono-phosphate dibasic salt and said sugar is selected from the group consisting of fructose
  • the chitosan based thermo-gelling composition contains chitosan- ⁇ -glycerophosphate, chitosan- ⁇ - glycerophosphate, chitosan-glucose-1 -glycerophosphate, and chitosan- fructose-6-glycerophosphate.
  • Self-gelling refers to the ability of the composition to turn into a gel under specific conditions such as the internal composition or/and the action of external stimuli. It comprises pH-triggered or pH-controlled gelling, thermogelling, ionic gelling, chemical cross linking and the like.
  • biocompatible refers herein to the quality of a solution that can be compatible with tissues, that is not toxic to tissues, and that is tolerated by the tissues.
  • treatment of tumors is intended to mean a reduction of the tumor growth and thus an amelioration of the condition of the patient treated.
  • FIG. 1A illustrates the growth of a mouse breast MCF-7 tumor implanted into a mammary fat pad (mfp), when treated with either the chitosan based thermogelling composition in accordance with the present invention, paclitaxel alone or a composition consisting of paclitaxel and the chitosan- based thermogelling composition implanted into mfp (in the vicinity of the tumor);
  • mfp mammary fat pad
  • FIG. 1 B illustrates the growth of a mouse breast MCF-7 tumor implanted subcutaneously (sc) when treated with either the chitosan based thermogelling composition in accordance with the present invention, paclitaxel alone or a composition consisting of paclitaxel and the chitosan-based thermogelling composition implanted into mfp;
  • FIG. 2 illustrates a histogram showing the survival of rats untreated or treated with a chitosan-based thermogelling composition in accordance with the present invention
  • Figs. 3A and 3B illustrate the effect of the method of the present invention on brain tumor of untreated rat (sacrificed on day 16, Fig. 3A) and treated rat (sacrificed on day 82, Fig. 3B);
  • FIG. 4 illustrates the growth of a mouse breast EMT-6 tumor when treated with either the chitosan based thermogelling composition administered intra-tumorally, paclitaxel alone (administered IV) or a composition consisting of paclitaxel and the chitosan-based thermogelling composition administered intratumorally; and
  • Fig. 5 illustrates body weights (ratio from initial) in each treatment group.
  • novel injectable thermogelling biocompatible and biodegradable biopolymer based pharmaceutical formulations for treating a cellular proliferative disease were found. These formulations contain as an active ingredient a chitosan-based thermogelling composition for inhibiting the tumor growth. In one embodiment, the formulations may contain a therapeutically effective amount of an anti-tumor drug and/or a biocompatible carrier that is an immunopotentiating agent.
  • formulations provide advantages, such as preferable distribution of the drug at the tumor site, favourable pharmacokinetics such as prolonged half-life (area under the curve - AUC), controlled and sustained long- term release of the active ingredient and reduction of systemic drug toxicity.
  • the present invention relates to the use of a chitosan based injectable, thermogelling, biocompatible and biodegradable formulation to inhibit tumor growth either alone or in conjunction with an anti-tumor drug such as camptothecin, cisplatin, paclitaxel etc., encapsulated or incorporated therein.
  • an anti-tumor drug such as camptothecin, cisplatin, paclitaxel etc.
  • thermogelling composition As described above, it has been found that random chitosans 81 % DDA (degree of deacetylation) with average molecular weights of 661 kDa with a viscosity of 57.8 mPa.s when formulated into a thermogelling composition as described above is effective in suppressing growth of tumor cell lines such as C-6, EMT-6, and MCF-7.
  • the sustained release of the encapsulated anti-tumor drug from the injectable thermogelling composition can be obtained by varying the properties of chitosan (degree of deacetylation, acetyl group distribution, molecular weight, concentration of chitosan, drug and other additives).
  • such controlled release formulation of an anti-tumor drug can be prepared by mixing the chitosan-based thermogelling composition with the active pharmaceutical ingredient (API) for producing a formulation that is injectable, stable, and homogeneous, that exhibits zero order release kinetics, i.e. no burst release, that is biocompatible, biodegradable, and reduces systemic drug toxicity, and that gives favourable pharmacokinetics including longer half life and larger area under the curve (AUC).
  • API active pharmaceutical ingredient
  • a C6 clonal line was developed from a rat glioblastoma chemically induced in the brain of a Wistar rat. Transplantation of C6 cells by stereotactic procedures produces intra-cerebral tumors presenting some of the characteristic features of spontaneous gliomas with good reproducibility.
  • camptothecin For the rat glioma model the drug used was camptothecin. This has been investigated in published studies of intra-tumoral drug release using an intra-cranial model (Weingart, J.D.; Thompson, R.C.; Tyler, B.; Calvin, O.M., Brem, H. Local delivery of the topoisomerase I inhibitor camptothecin sodium prolongs survival in the rat intracranial 9L gliosarcoma model. Int. J. Tumor, 1995; Sep. 4, 62(5): 605-9). The drug has been previously shown to have significant anti-neoplastic action but clinical use of it as a systemic agent is limited by severe toxicity. This makes it a particularly attractive agent for local delivery by sustained release vehicle.
  • the tumor is initiated by stereotactic injection of C6 cells (0.5-2.0 x 10 5 in 10 ⁇ L). 12-14 days after tumor implant the chitosan-based thermogelling composition was used. The composition is introduced by a stereotactic procedure through the same burr hole which was used for implantation of the cells.
  • the endpoint is dependent on tumor growth.
  • a brain tumor is not accessible for measurement of size tumor progress will be assessed on the basis of behavioral and neurological signs of tumor growth. Animals are sacrificed when simultaneous expression of several of these signs indicates that the tumor has grown sufficiently to cause these signs.
  • Results indicate that while both 20% and 50% discs significantly extended survival the effect of 50% was markedly greater than that of 20% (69 versus 25 days). On this basis, a one-dose level of 5mg/tumor, or a lower or a higher dose level (3 mg/kg or 40 mg/kg respectively) has been used. Results
  • thermogelling composition either alone or with paclitaxel on human breast tumor MCF-7 cell line implanted orthotopically into immuno-compromised SCID mice's mammary fat pad as well as into a distal subcutaneous location.
  • the composition is used concurrently with paclitaxel, the resulting mixture is referred to as pacligelTM or paclitaxel-gel.
  • a positive control taxol or paclitaxel alone was also used.
  • Pacligel doses ranging from 40 mg/kg to 320 mg/kg were implanted into the mammary fat pad of the mice and the tumor volumes were measured as a function of time. Compared to the free taxol administered intra-peritonially (i.p.), the pacligel didn't show any signs of systemic toxicity, no loss in the body weight of animals was observed and there were no fatalities or other adverse effects observed at either of the 40 mg/kg, 80 mg/kg or 320 mg/kg dose levels. However, free taxol when administered i.p. into the mice, showed an acute toxicity at 40 mg/kg and 80 mg/kg doses with an initial loss of body weights. The 160 mg/kg free taxol dose when administered i.p. into the mice, was found to be lethal.
  • the chitosan-based thermogelling composition by itself caused delay in tumor growth. There was a significant delay in the growth of subcutaneous tumors for the paclitaxel-gel groups giving a good indication that the free taxol was getting released from paclitaxel-gel and entering into the systemic circulation at a safe concentration i.e. low systemic exposure or low Area Under the Concentration vs. Time Curve (AUC).
  • AUC Area Under the Concentration vs. Time Curve
  • rat glioblastoma C-6 cells were implanted intracranially into Wistar rats and the chitosan-based thermogelling composition was injected intra-tumorally into the rats. The tumor growth was measured as a function of time by looking at any abnormal neurological signs.
  • Figs. 3A and 3B illustrate a brain of an untreated rat (sacrificed on day 16, Fig. 3A) and a treated rat (sacrificed on day 82, Fig. 3B). These results clearly illustrate the marked beneficial effect of the treatment of the present invention.
  • EMT-6 cells (2 X 10 5 ) were injected on the flank of female Balb/c mice. On day 6, 7, 8 or 9 of tumor growth, the mice were injected with the test formulation.
  • the test formulation were either saline IV at 0.2 mL/day X 4 days beginning at day 6, 8 or 9, or paclitaxel IV at a dose of 10 mg/kg/day X 4 days beginning at day 6, 7, 8 or 9, or the chitosan-based thermogelling composition IT at a dose of 10 ⁇ L intra-tumoral injected day 7, or pacligel IT at a dose of 10 ⁇ L of gel with 40m/kg of paclitaxel intra-tumoral injected day 7.
  • the tumor growth was measured as a function of time. Comparing the control group animals treated with saline alone, with the mice treated with either the chitosan-based thermogelling composition alone or with the pacligel, the chitosan-based thermogelling composition alone and the pacligel had reduced tumor growth rate.
  • the chitosan-based thermogelling composition without paclitaxel was found to be much more efficient in suppressing tumor growth compared to the free paclitaxel administered IV (Fig. 4).
  • the chitosan-based thermogelling composition caused no systemic toxicity initially compared to animals treated with free paclitaxel. There was an initial loss of body weight in animals treated with free paclitaxel for up to 10 days. No body weight loss was observed in the animals treated with the chitosan-based thermogelling composition with or without paclitaxel during the first 10 days (Fig. 5).
  • non-chitosan polymers that are inflammatory and produce an anti-tumor effect by non-specific pathways such as a tumoricidal cytokine production
  • the mechanism underlying the present invention is inflammation mediated and the chitosan-based thermogelling composition, while dispersed into and around the tumors generates inflammation mediated cytokine release and some of them including IL-6, IL-12 have been shown to have anti-tumor activity.
  • the chitosan-based thermogelling composition when turning into a gel stays as an implant in the brain and continues to produce mild inflammation over a long period of time. This could be seen as a potentially new mechanism for tumor chemotherapy, especially when implants like the gel excite selective production of the tumoricidal proteins such as cytokines mentioned above.

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Abstract

The present invention relates to a new method for treating tumor using as an active ingredient a thermo-gelling chitosan composition. The thermo-gelling chitosan composition preferably comprises i) 0.1 to 5.0% by weight of chitosan or a chitosan derivative; and ii) 1.0 to 20% by weight of a salt of polyol or sugar selected from the group consisting of mono-phosphate dibasic salt, mono-sulfate salt and a mono-carboxylic acid salt of polyol or sugar, wherein said composition has a final pH ranging from 5.8 and 7.4, and forms a stable, biocompatible, biodegradable gel under physiological conditions gels within a temperature range from 20 to 70°C, said composition reducing the growth of the tumor in said patient.

Description

METHOD FOR TREATING A TUMOR USING A THERMO- GELLING CHITOSAN COMPOSITION
TECHNICAL FIELD
[0001] The present invention relates to a new method for treating a tumor using as an active ingredient a thermo-gelling chitosan composition.
BACKGROUND OF THE INVENTION
[0002] Localized delivery of antitumor drugs directly to tumors using biocompatible and biodegradable polymeric or biopolymeric matrices maximizes the efficacy of the drugs while minimizing systemic exposure and toxicity (Brem, H. Polymers to treat brain tumors. Biomaterials, 1990; 11 : 699-701 ; Langer, R. New methods of drug delivery. Science, 1990; 249: 1527-1533; and Yapp, D.T.T.; Lloyd, D.K.; Zhu, J.; Lehnert, S., Tumor treatment by sustained intratumoral release of cisplatin. Effects of drug alone and combined with radiation. Int. J. Radiation Oncology Biol. Phys., 1997; vol. 39, no. 2, 497-504). Polymeric interstitial chemotherapy increases survival of humans with recurrent malignant tumors such as gliomas and of animals with orthotopically- transplanted tumors in the various locations including brain. Drug-loaded polymers implanted orthotopically such as intra-cranially have the advantage of bypassing the blood-brain barrier and releasing drug molecules locally in the brain over a long term sustained and safe fashion. Malignant tumors such as gliomas are known to recur at the periphery of the tumor excision site due to the residual tumors left at the site of resection after surgery. These resection beds can be filled with impiantabie matrices in conjunction with anti-tumor molecules such as camptothecin, cisplatin, taxol, carmustin etc.
[0003] The use of non-injectable impiantabie matrices loaded with anti-tumor molecules requires invasive surgical implantation procedures and repeat dosing to maintain the desired anti-tumor effect. Furthermore, these types of drug loaded matrices may in some cases, depending on the drug used be difficult to manufacture and at times, require the use of organic solvents during the manufacturing,, traces of which can cause acute toxicity. [0004] It is highly desirable to be provided a simple injectable formulation that is readily impiantabie intratumorally or in the vicinity of tumors, to stay at the injection site and suppress the tumor growth.
SUMMARY OF THE INVENTION
[0005] One aim of the present invention is to provide a simple formulation that is readily impiantabie intratumorally or in the vicinity of a tumor, and that will stay at the injection site to suppress the tumor growth.
[0006] In accordance with the present invention, it was found with much surprise that a chitosan based thermo-gelling composition as described in US patent 6,344,488, the entire content of which is incorporated herein by reference, could be used as matrices with anti-tumour properties. Much of the surprise arose when it was noted that the chitosan based thermo-gelling composition itself, without the addition of an anti-tumour drug, had anti-tumour properties. Of course, one skilled in the art may also want to use the chitosan based thermo-gelling composition for its anti-tumor properties, in conjunction with other anti-tumour drugs to enhance the treatment. In fact, the combined use of the chitosan based thermo-gelling composition with other anti-tumour drugs shows synergy amongst the drug and the tumoricidal carrier for suppressing tumor growth.
[0007] In accordance with the present invention there is provided a method for treating a tumor in a patient, said method comprising the step of administering to a patient in need thereof an effective amount of a chitosan- based thermogelling composition, said composition reducing the growth of the tumor in said patient.
[0008] In one embodiment, the chitosan-based thermogelling composition is administered concurrently with an anti-tumor agent such as paclitaxel.
[0009] In accordance with the present invention there is also provided a chitosan-based thermogelling composition for use in treating tumors. [0010] For the purpose of the present invention the following terms are defined below.
[0011] The term "chitosan based thermo-gelling composition" is intended to mean a composition which comprises chitosan or a derivative thereof, and a salt of polyol or sugar, wherein said composition gels upon heating and is adapted to be formed and/or to gel in situ within a tissue, organ or cavities of an animal or a human. More preferably, the composition contains i) 0.1 to 5.0% by weight of chitosan or a chitosan derivative; and ii) 1.0 to 20% by weight of the salt of polyol or sugar. The salt of polyol or sugar is preferably selected from the group consisting of mono-phosphate dibasic salt, mono-sulfate salt and mono-carboxylic acid salt of polyol or sugar. The composition preferably turns into a gel at temperature above 20°C, and more preferably within a temperature range from 20 to 70°C. The salt may be any of the following or in any of the following combination a) a mono-phosphate dibasic salt selected from the group consisting of glycerol, comprising glycerol-2-phosphate, sn-glycerol 3- phosphate and L-glycerol-3-phosphate salts, b) a mono-phosphate dibasic salt and said polyol is selected from the group consisting of histidinol, acetol, diethylstilbestrol, indole-glycerol, sorbitol, ribitol, xylitol, arabinitol, erythritol, inositol, mannitol, glucitol and a mixture thereof, c) a mono-phosphate dibasic salt and said sugar is selected from the group consisting of fructose, galactose, ribose, glucose, xylose, rhamnulose, sorbose, erythrulose, deoxy-ribose, ketose, mannose, arabinose, fuculose, fructopyranose, ketoglucose, sedoheptulose, trehalose, tagatose, sucrose, allose, threose, xylulose, hexose, methylthio-ribose, methylthio-deoxy-ribulose, and a mixture thereof, d) a mono- phosphate dibasic salt, said polyol is selected from the group consisting of palmitoyl-glycerol, linoleoyl-glycerol, oleoyl-glycerol, arachidonoyl-glycerol, and a mixture thereof; and e) a glycerophosphate salt selected from the group consisting of glycerophosphate disodium, glycerophosphate dipotassium, glycerophosphate calcium, glycerophosphate barium and glycerophosphate strontium.
[0012] In a preferred embodiment, the chitosan based thermo-gelling composition contains chitosan-α-glycerophosphate, chitosan-β- glycerophosphate, chitosan-glucose-1 -glycerophosphate, and chitosan- fructose-6-glycerophosphate.
[0013] "Self-gelling" refers to the ability of the composition to turn into a gel under specific conditions such as the internal composition or/and the action of external stimuli. It comprises pH-triggered or pH-controlled gelling, thermogelling, ionic gelling, chemical cross linking and the like.
[0014] The term "biocompatible" refers herein to the quality of a solution that can be compatible with tissues, that is not toxic to tissues, and that is tolerated by the tissues.
[0015] The term "treatment" of tumors is intended to mean a reduction of the tumor growth and thus an amelioration of the condition of the patient treated.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] Fig. 1A illustrates the growth of a mouse breast MCF-7 tumor implanted into a mammary fat pad (mfp), when treated with either the chitosan based thermogelling composition in accordance with the present invention, paclitaxel alone or a composition consisting of paclitaxel and the chitosan- based thermogelling composition implanted into mfp (in the vicinity of the tumor);
[0017] Fig. 1 B illustrates the growth of a mouse breast MCF-7 tumor implanted subcutaneously (sc) when treated with either the chitosan based thermogelling composition in accordance with the present invention, paclitaxel alone or a composition consisting of paclitaxel and the chitosan-based thermogelling composition implanted into mfp;
[0018] Fig. 2 illustrates a histogram showing the survival of rats untreated or treated with a chitosan-based thermogelling composition in accordance with the present invention; [0019] Figs. 3A and 3B illustrate the effect of the method of the present invention on brain tumor of untreated rat (sacrificed on day 16, Fig. 3A) and treated rat (sacrificed on day 82, Fig. 3B);
[0020] Fig. 4 illustrates the growth of a mouse breast EMT-6 tumor when treated with either the chitosan based thermogelling composition administered intra-tumorally, paclitaxel alone (administered IV) or a composition consisting of paclitaxel and the chitosan-based thermogelling composition administered intratumorally; and
[0021] Fig. 5 illustrates body weights (ratio from initial) in each treatment group.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0022] In the present invention, novel injectable thermogelling biocompatible and biodegradable biopolymer based pharmaceutical formulations for treating a cellular proliferative disease were found. These formulations contain as an active ingredient a chitosan-based thermogelling composition for inhibiting the tumor growth. In one embodiment, the formulations may contain a therapeutically effective amount of an anti-tumor drug and/or a biocompatible carrier that is an immunopotentiating agent.
[0023] These formulations provide advantages, such as preferable distribution of the drug at the tumor site, favourable pharmacokinetics such as prolonged half-life (area under the curve - AUC), controlled and sustained long- term release of the active ingredient and reduction of systemic drug toxicity.
[0024] In particular, the present invention relates to the use of a chitosan based injectable, thermogelling, biocompatible and biodegradable formulation to inhibit tumor growth either alone or in conjunction with an anti-tumor drug such as camptothecin, cisplatin, paclitaxel etc., encapsulated or incorporated therein.
[0025] In accordance with the present invention, it has been found that random chitosans 81 % DDA (degree of deacetylation) with average molecular weights of 661 kDa with a viscosity of 57.8 mPa.s when formulated into a thermogelling composition as described above is effective in suppressing growth of tumor cell lines such as C-6, EMT-6, and MCF-7.
[0026] When an anti-tumor drug is used in combination with the chitosan- based thermogelling composition for treating tumor, the sustained release of the encapsulated anti-tumor drug from the injectable thermogelling composition can be obtained by varying the properties of chitosan (degree of deacetylation, acetyl group distribution, molecular weight, concentration of chitosan, drug and other additives). In one embodiment, such controlled release formulation of an anti-tumor drug can be prepared by mixing the chitosan-based thermogelling composition with the active pharmaceutical ingredient (API) for producing a formulation that is injectable, stable, and homogeneous, that exhibits zero order release kinetics, i.e. no burst release, that is biocompatible, biodegradable, and reduces systemic drug toxicity, and that gives favourable pharmacokinetics including longer half life and larger area under the curve (AUC).
[0027] The present invention will be more readily understood by referring to the following example which is given to illustrate the invention rather than to limit its scope.
EXAMPLE I In-vivo Experiments on rat glioblastomas
[0028] A C6 clonal line was developed from a rat glioblastoma chemically induced in the brain of a Wistar rat. Transplantation of C6 cells by stereotactic procedures produces intra-cerebral tumors presenting some of the characteristic features of spontaneous gliomas with good reproducibility.
[0029] For the rat glioma model the drug used was camptothecin. This has been investigated in published studies of intra-tumoral drug release using an intra-cranial model (Weingart, J.D.; Thompson, R.C.; Tyler, B.; Calvin, O.M., Brem, H. Local delivery of the topoisomerase I inhibitor camptothecin sodium prolongs survival in the rat intracranial 9L gliosarcoma model. Int. J. Tumor, 1995; Sep. 4, 62(5): 605-9). The drug has been previously shown to have significant anti-neoplastic action but clinical use of it as a systemic agent is limited by severe toxicity. This makes it a particularly attractive agent for local delivery by sustained release vehicle.
[0030] The tumor is initiated by stereotactic injection of C6 cells (0.5-2.0 x 105 in 10 μL). 12-14 days after tumor implant the chitosan-based thermogelling composition was used. The composition is introduced by a stereotactic procedure through the same burr hole which was used for implantation of the cells.
[0031] For the C6 tumor, the endpoint is dependent on tumor growth. However, since a brain tumor is not accessible for measurement of size tumor progress will be assessed on the basis of behavioral and neurological signs of tumor growth. Animals are sacrificed when simultaneous expression of several of these signs indicates that the tumor has grown sufficiently to cause these signs.
[0032] For analysis of results survival will be plotted on a Kaplan Meier survival curve and statistical significance determined by Kruskal Wallis non- parametric analysis of variance.
Drug delivery and dosage
A paper by Storm et al (Storm, P.B.; Brem, H. The treatment of brain tumors with drug-impregnated biodegradable polymers. In: Kornblith, P.L.; Walker, M.D., eds. Advances in Neuro-Oncology II. Armonk, NY : Futura Publishing Co; 1997: 435-445) describes the implantation of discs (weight 10 mg) of the (p(CPP-SA) polymer containing 20% and 50% (w/w) of camptothecin in the 9L intra-cranial glioma with a corresponding intra-tumoral dose of 2 and 5 mg of camptothecin. Results indicate that while both 20% and 50% discs significantly extended survival the effect of 50% was markedly greater than that of 20% (69 versus 25 days). On this basis, a one-dose level of 5mg/tumor, or a lower or a higher dose level (3 mg/kg or 40 mg/kg respectively) has been used. Results
[0033] Pre-clinical efficacy studies were conducted using the chitosan-based thermogelling composition either alone or with paclitaxel on human breast tumor MCF-7 cell line implanted orthotopically into immuno-compromised SCID mice's mammary fat pad as well as into a distal subcutaneous location. When the composition is used concurrently with paclitaxel, the resulting mixture is referred to as pacligel™ or paclitaxel-gel. A positive control (taxol or paclitaxel alone) was also used.
[0034] Pacligel doses ranging from 40 mg/kg to 320 mg/kg were implanted into the mammary fat pad of the mice and the tumor volumes were measured as a function of time. Compared to the free taxol administered intra-peritonially (i.p.), the pacligel didn't show any signs of systemic toxicity, no loss in the body weight of animals was observed and there were no fatalities or other adverse effects observed at either of the 40 mg/kg, 80 mg/kg or 320 mg/kg dose levels. However, free taxol when administered i.p. into the mice, showed an acute toxicity at 40 mg/kg and 80 mg/kg doses with an initial loss of body weights. The 160 mg/kg free taxol dose when administered i.p. into the mice, was found to be lethal.
[0035] The tumors in animals treated with free taxol started to grow on a new and steeper growth curve from day 37 onwards compared to the ones treated with paclitaxel-gel (also referred to as gel-taxol) (see Figs. 1A and 1 B). This is explained by the fact that more than 99.99% of free paclitaxel is cleared from the systemic circulation in the body in about 3.5 days, taking into consideration the half-life of paclitaxel of about 6 hours.
[0036] The chitosan-based thermogelling composition by itself caused delay in tumor growth. There was a significant delay in the growth of subcutaneous tumors for the paclitaxel-gel groups giving a good indication that the free taxol was getting released from paclitaxel-gel and entering into the systemic circulation at a safe concentration i.e. low systemic exposure or low Area Under the Concentration vs. Time Curve (AUC). [0037] In a first study, rat glioblastoma C-6 cells were implanted intracranially into Wistar rats and the chitosan-based thermogelling composition was injected intra-tumorally into the rats. The tumor growth was measured as a function of time by looking at any abnormal neurological signs. In two different pilot studies, rats injected with the chitosan-based thermogelling composition alone survived for periods exceeding 100 days and 150 days, whereas, the untreated rats died between days 20 and 25 (See Fig. 2). Figs. 3A and 3B illustrate a brain of an untreated rat (sacrificed on day 16, Fig. 3A) and a treated rat (sacrificed on day 82, Fig. 3B). These results clearly illustrate the marked beneficial effect of the treatment of the present invention.
[0038] In another study conducted separately from the first one, efficacy of pacligel against mouse breast EMT-6 tumors in mice was evaluated by implanting the chitosan-based thermogelling composition or the pacligel intratumorally into the mouse breast tumors implanted subcutaneously into the female Balb/c mice.
Method for EMT-6 Study
[0039] EMT-6 cells (2 X 105) were injected on the flank of female Balb/c mice. On day 6, 7, 8 or 9 of tumor growth, the mice were injected with the test formulation. The test formulation were either saline IV at 0.2 mL/day X 4 days beginning at day 6, 8 or 9, or paclitaxel IV at a dose of 10 mg/kg/day X 4 days beginning at day 6, 7, 8 or 9, or the chitosan-based thermogelling composition IT at a dose of 10μL intra-tumoral injected day 7, or pacligel IT at a dose of 10μL of gel with 40m/kg of paclitaxel intra-tumoral injected day 7.
[0040] The tumor growth was measured as a function of time. Comparing the control group animals treated with saline alone, with the mice treated with either the chitosan-based thermogelling composition alone or with the pacligel, the chitosan-based thermogelling composition alone and the pacligel had reduced tumor growth rate. In particular, the chitosan-based thermogelling composition without paclitaxel was found to be much more efficient in suppressing tumor growth compared to the free paclitaxel administered IV (Fig. 4). At the same time, the chitosan-based thermogelling composition caused no systemic toxicity initially compared to animals treated with free paclitaxel. There was an initial loss of body weight in animals treated with free paclitaxel for up to 10 days. No body weight loss was observed in the animals treated with the chitosan-based thermogelling composition with or without paclitaxel during the first 10 days (Fig. 5).
[0041] In accordance with the present invention, other non-chitosan polymers that are inflammatory and produce an anti-tumor effect by non-specific pathways such as a tumoricidal cytokine production, may be used. One could implant synthetic polymers, block co-polymers, other biopolymers, polymer microspheres, metallic particles, beads, stents or catheters intratumorally to create similar anti-tumor activity. It was found that the mechanism underlying the present invention is inflammation mediated and the chitosan-based thermogelling composition, while dispersed into and around the tumors generates inflammation mediated cytokine release and some of them including IL-6, IL-12 have been shown to have anti-tumor activity. The chitosan-based thermogelling composition when turning into a gel stays as an implant in the brain and continues to produce mild inflammation over a long period of time. This could be seen as a potentially new mechanism for tumor chemotherapy, especially when implants like the gel excite selective production of the tumoricidal proteins such as cytokines mentioned above.
[0042] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims.

Claims

WHAT IS CLAIMED IS:
1. A method for treating a tumor in a patient, said method comprising the step of administering to a patient in need thereof an effective amount of a chitosan-based thermogelling composition, said composition reducing the growth of the tumor in said patient.
2. The method of claim 1 , wherein the composition comprises chitosan or a derivative thereof, and a salt of polyol or a salt of sugar, said composition gelling upon heating and being adapted to be formed and/or to gel in situ within a tissue, organ or cavities of an animal or a human.
3. The method of claim 2, wherein the composition contains i) 0.1 to 5.0% by weight of chitosan or a chitosan derivative; and ii) 1.0 to 20% by weight of the salt of polyol or the salt of sugar.
4. The method of claim 3, wherein the salt of polyol or the salt of sugar is preferably selected from the group consisting of mono-phosphate dibasic salt, mono-sulfate salt and mono-carboxylic acid salt of polyol or sugar.
5. The method of claim 2, 3 or 4, wherein the composition turns into a gel at temperature above 20°C.
6. The method of claim 5, wherein the composition turns into a gel at a temperature ranging from 20 to 70°C.
7. The method of claim 2, 3, 4, 5 or 6, wherein the salt is any of the following combination a) a mono-phosphate dibasic salt selected from the group consisting of glycerol, comprising glycerol-2-phosphate, sn- glycerol 3-phosphate and L-glycerol-3-phosphate salts, b) a mono- phosphate dibasic salt and said polyol is selected from the group consisting of histidinol, acetol, diethylstilbestrol, indole-glycerol, sorbitol, ribitol, xylitol, arabinitol, erythritol, inositol, mannitol, glucitol and a mixture thereof, c) a mono-phosphate dibasic salt and said sugar is selected from the group consisting of fructose, galactose, ribose, glucose, xylose, rhamnulose, sorbose, erythrulose, deoxy-ribose, ketose, mannose, arabinose, fuculose, fructopyranose, ketoglucose, sedoheptulose, trehalose, tagatose, sucrose, allose, threose, xylulose, hexose, methylthio-ribose, methylthio-deoxy-ribulose, and a mixture thereof, d) a mono-phosphate dibasic salt, said polyol is selected from the group consisting of palmitoyl-glycerol, linpleoyl-glycerol, oleoyl- glycerol, arachidonoyl-glycerol, and a mixture thereof; and e) a glycerophosphate salt selected from the group consisting of glycerophosphate disodium, glycerophosphate dipotassium, glycerophosphate calcium, glycerophosphate barium and glycerophosphate strontium.
8. The method of claim 2, 3, 4, 5, 6 or 7, wherein the chitosan has a degree of deacetylation of 81 % with an average molecular weight of 661 kDa and a viscosity of 57.8 mPa.s.
9. The method of claim 1 , 2, 3, 4, 5, 6, 7 or 8, wherein the chitosan-based thermogelling composition is administered concurrently with an anti- tumor agent.
10. The method of claim 9, wherein the anti-tumor agent is camptothecin, cisplatin or paclitaxel.
11. The method of claim 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10, wherein the tumor is a bulk tumor.
12. The method of claim 11 , wherein the bulk tumor is a glioblastoma.
13. A chitosan-based thermogelling composition for use in treating a tumor.
14. The composition of claim 13, wherein the composition comprises chitosan or a derivative thereof, and a salt of polyol or a salt of sugar, said composition gelling upon heating and being adapted to be formed and/or to gel in situ within a tissue, organ or cavities of an animal or a human.
15. The composition of claim 14, wherein the composition contains i) 0.1 to 5.0% by weight of chitosan or a chitosan derivative; and ii) 1.0 to 20% by weight of the salt of polyol or the salt of sugar.
16. The composition of claim 15, wherein the salt of polyol or the salt of sugar is preferably selected from the group consisting of mono- phosphate dibasic salt, mono-sulfate salt and mono-carboxylic acid salt of polyol or sugar.
17. The composition of claim 14, 15 or 16, wherein the composition turns into a gel at temperature above 20°C.
18. The composition of claim 17, wherein the composition turns into a gel at a temperature ranging from 20 to 70°C.
19. The composition of claim 14, 15, 16, 17 or 18, wherein the salt is any of the following combination a) a mono-phosphate dibasic salt selected from the group consisting of glycerol, comprising glycerol-2-phosphate, sn-glycerol 3-phosphate and L-gIycerol-3-phosphate salts, b) a mono- phosphate dibasic salt and said polyol is selected from the group consisting of histidinol, acetol, diethylstilbestrol, indole-glycerol, sorbitol, ribitol, xylitol, arabinitol, erythritol, inpsitol, mannitol, glucitol and a mixture thereof, c) a mono-phosphate dibasic salt and said sugar is selected from the group consisting of fructose, galactose, ribose, glucose, xylose, rhamnulose, sorbose, erythrulose, deoxy-ribose, ketose, mannose, arabinose, fuculose, fructopyranose, ketoglucose, sedoheptulose, trehalose, tagatose, sucrose, allose, threose, xylulose, hexose, methylthio-ribose, methylthio-deoxy-ribulose, and a mixture thereof, d) a mono-phosphate dibasic salt, said polyol is selected from the group consisting of palmitoyl-glycerol, linoleoyl-glycerol, oleoyl- glycerol, arachidonoyl-glycerol, and a mixture thereof; and e) a glycerophosphate salt selected from the group consisting of glycerophosphate disodiurh, glycerophosphate dipotassium, glycerophosphate calcium, glycerophosphate barium and glycerophosphate strontium.
20. The composition of claim 14, 15, 16, 17, 18 or 19, wherein the chitosan has a degree of deacetylation of 81 % with an average molecular weight of 661 kDa and a viscosity of 57.8 mPa.s.
21. The composition of claim 13, 14, 15, 16, 17, 18, 19 or 20, further comprising an anti-tumor agent.
22. The composition of claim 21 , wherein the anti-tumor agent is camptothecin, cisplatin or paclitaxel.
23. The composition of claim 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22, wherein the tumor is a bulk tumor.
24. The composition of claim 23, wherein the bulk tumor is a glioblastoma.
25. Use of a chitosan-based thermogelling composition for treating tumors.
26. The use of claim 25, wherein the composition comprises chitosan or a derivative thereof, and a salt of polyol or a salt of sugar, said composition gelling upon heating and being adapted to be formed and/or to gel in situ within a tissue, organ or cavities of an animal or a human.
27. The use of claim 26, wherein the composition contains i) 0.1 to 5.0% by weight of chitosan or a chitosan derivative; and ii) 1.0 to 20% by weight of the salt of polyol or the salt of sugar.
28. The use of claim 27, wherein the salt of polyol or the salt of sugar is preferably selected from the group consisting of mono-phosphate dibasic salt, mono-sulfate salt and mono-carboxylic acid salt of polyol or sugar.
29. The use of claim 26, 27 or 28, wherein the composition turns into a gel at temperature above 20°C.
30. The use of claim 29, wherein the composition turns into a gel at a temperature ranging from 20 to 70°C.
31. The use of claim 26, 27, 28, 29 or 30, wherein the salt is any of the following combination a) a mono-phosphate dibasic salt selected from the group consisting of glycerol, comprising glycerol-2-phosphate, sn- glycerol 3-phosphate and L-glycerol-3-phosphate salts, b) a mono- phosphate dibasic salt and said polyol is selected from the group consisting of histidinol, acetol, diethylstilbestrol, indole-glycerol, sorbitol, ribitol, xylitol, arabinitol, erythritol, inositol, mannitol, glucitol and a mixture thereof, c) a mono-phosphate dibasic salt and said sugar is selected from the group consisting of fructose, galactose, ribose, glucose, xylose, rhamnulose, sorbose, erythrulose, deoxy-ribose, ketose, mannose, arabinose, fuculose, fructopyranose, ketoglucose, sedoheptulose, trehalose, tagatose, sucrose, allose, threose, xylulose, hexose, methylthio-ribose, methylthio-deoxy-ribulose, and a mixture thereof, d) a mono-phosphate dibasic salt, said polyol is selected from the group consisting of palmitoyl-glycerol, linoleoyl-glycerol, oleoyl- glycerol, arachidonoyl-glycerol, and a mixture thereof; and e) a glycerophosphate salt selected from the group consisting of glycerophosphate disodium, glycerophosphate dipotassium, glycerophosphate calcium, glycerophosphate barium and glycerophosphate strontium.
32. The use of claim 26, 27, 28, 29, 30 or 31 , wherein the chitosan has a degree of deacetylation of 81 % with an average molecular weight of 661 kDa and a viscosity of 57.8 mPa.s.
33. The use of claim 25, 26, 27, 28, 29, 30, 31 or 32, further comprising an anti-tumor agent.
34. The use of claim 33, wherein the anti-tumor agent is paclitaxel.
35. The use of claim 25, 26, 27, 28, 29, 30, 31 , 32, 33 or 34, wherein the tumor is a bulk tumor.
36. The use of claim 35, wherein the bulk tumor is a glioblastoma.
PCT/CA2003/001880 2002-12-03 2003-12-03 Method for treating a tumor using a thermo-gelling chitosan composition WO2004050100A1 (en)

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