WO2021256427A1 - 抗がん療法の増感剤 - Google Patents
抗がん療法の増感剤 Download PDFInfo
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- WO2021256427A1 WO2021256427A1 PCT/JP2021/022520 JP2021022520W WO2021256427A1 WO 2021256427 A1 WO2021256427 A1 WO 2021256427A1 JP 2021022520 W JP2021022520 W JP 2021022520W WO 2021256427 A1 WO2021256427 A1 WO 2021256427A1
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- tumor
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- hyaluronic acid
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- anticancer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0038—Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy
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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
- A61K33/40—Peroxides
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- 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
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
- A61N2005/1092—Details
- A61N2005/1098—Enhancing the effect of the particle by an injected agent or implanted device
Definitions
- the present invention relates to a sensitizer for anti-cancer therapy such as radiation therapy or anti-cancer chemotherapy, and in particular, to a sensitizer for anti-cancer therapy containing hydrogen peroxide and hyaluronic acid or a salt thereof. be.
- Non-Patent Documents 1 and 2 Overcoming breast cancer is a global challenge, but it is estimated that 2 million people worldwide will develop breast cancer, 80% of which are said to be locally progressive diseases (Non-Patent Documents 1 and 2). .. In the UK, of the 55,000 new cases, only a minority (7 to 13%) of women have locally progressive lesions, and the lifetime prevalence of locally progressive disease is significant (Non-Patent Document 3). From 6). Frail and the elderly who are unsuitable for or refuse surgery are difficult to treat, and such patients receive RT and / or endocrine therapy to relieve breast ulcers, bleeding, and pain. Often the most appropriate option.
- Non-Patent Documents 7 and 8 Cell-level interactions between H 2 O 2 and ionizing radiation (IR) were first reported in osteosarcoma (HS-Os-1) and prostate cancer (PC-3) cell lines, and H 2 Extreme resistance was shown with either O 2 or 30 Gy alone (Non-Patent Documents 7 and 8).
- the addition of 0.1 mM H 2 O 2 prior to IR resulted in improved cytotoxicity without causing double-strand breaks in DNA that mediate classical cell death (non-patent literature). 9, 10). It was speculated that the new mechanism involves the rupture of the lysosomal membrane associated with the release of a strong oxidant containing heavy metal ions that permeate mitochondria and activate apoptosis (Non-Patent Document 11).
- sensitizers for effective anticancer therapy for tumors and the schedule of anticancer therapies such as effective radiation therapy and anticancer chemotherapy after administration of the sensitizer are still unclear. No.
- the present invention is a specific amount of a sensitizer for anticancer therapy prepared by combining H 2 O 2 in a specific concentration range with hyaluronic acid or a salt thereof in a specific concentration range.
- a sensitizer for anticancer therapy prepared by combining H 2 O 2 in a specific concentration range with hyaluronic acid or a salt thereof in a specific concentration range.
- the present invention provides the following aspects in order to solve the above-mentioned problems:
- Anti-cancer therapy sensitizer containing (a) 0.01-3.5% (w / v) hydrogen peroxide and (b) 0.1-10% (w / v) hyaluronic acid or a salt thereof.
- the dose of the sensitizer to the tumor is selected from 1.2 mL to 15.0 mL depending on the size of the tumor.
- the sensitizer [2] The sensitizer according to [1], wherein the sensitizer contains 0.5% (w / v) of hydrogen peroxide.
- the dose is (1) For the tumor having a maximum diameter of less than 3.0 cm, 1.2 mL or more and less than 3.0 mL, (2) For the tumor having a maximum diameter of 3.0 cm or more and less than 6.0 cm, 2.4 mL or more and less than 6.0 mL, (3) For the tumor having a maximum diameter of 6.0 cm or more and less than 10.0 cm, 3.6 mL or more and less than 9.0 mL, (4) The sensitizer according to [1] or [2], wherein the maximum diameter of the tumor mass is in the range of 3.6 or more and 15.0 mL or less for a tumor having a size of 10.0 cm or more.
- the sensitizer is characterized by having a pain-reducing effect, a skin toxicity-reducing effect, or both a pain-reducing effect and a skin-toxicity-reducing effect, in addition to an anticancer effect [1]. -The sensitizer according to any one of [3]. [5] The sensitizer according to any one of [1] to [4], wherein the anticancer therapy is radiotherapy or anticancer chemotherapy. [6] The sensitizer according to any one of [1] to [5], which comprises injecting the sensitizer into the tumor 1 to 3 times a week during the treatment period of the tumor. ..
- the sensitizer according to [8], wherein the anticancer therapy is performed once, two or three times a week.
- the radiosensitizer according to [11], wherein the dose per dose in the anticancer radiotherapy is 5 to 7 Gy.
- the dose and usage of the sensitizer for the anticancer therapy of the present invention can improve the effect of the anticancer therapy (radiotherapy and anticancer chemotherapy) and effectively treat the tumor. More specifically, the sensitizer of the present invention has a pain-reducing effect, a skin toxicity-reducing effect, or a pain-reducing effect and a skin-toxicity-reducing effect, in addition to the main anticancer effect. It has become clear that it may have both effects.
- FIG. 1 is a diagram showing an outline of a non-randomized controlled trial design.
- FIG. 2 is a diagram showing the EQD2 equation used to compare the equivalent RT doses in 2 Gy fractionated irradiation resulting in the same logarithmic cell death on a predetermined schedule.
- FIG. 3 shows a series of ultrasound images of breast tumors showing H 2 O 2 administration.
- FIG. 3A shows an ultrasound image showing needle penetration (arrow) under ultrasound guidance.
- FIG. 3B shows an ultrasound image showing an intratumoral injection of a H 2 O 2 + sodium hyaluronate gel mixture.
- FIG. 3C shows an ultrasound image showing the degradation (arrows) of H 2 O 2 with the formation of oxygen microbubbles (arrows) that generate sound waves in the tumor.
- FIG. 3A shows an ultrasound image showing needle penetration (arrow) under ultrasound guidance.
- FIG. 3B shows an ultrasound image showing an intratumoral injection of a H 2 O 2 + sodium hyaluronate gel mixture.
- FIG. 4 is a diagram showing a subject self-reported tumor pain scale.
- tumor pain refers to the pain experienced at the target tumor site during radiation therapy with or without H 2 O 2 injection.
- FIG. 5A is a diagram showing changes in tumor volume in treated human subjects.
- FIG. 5A shows a box plot showing a cumulative multiple reduction (log2 conversion) for the tumor volume of all 12 subjects.
- FIG. 5B shows a waterfall plot showing the rate of tumor volume change up to 12 months after RT, normalized to baseline tumor measurements. The data show tumor measurements 9 and 12 months after RT for 3 and 8 subjects, respectively.
- FIG. 6 is a diagram showing a clinical photograph of the patient with subject number 10 in Example 6 (6-2). In this figure, FIG.
- FIG. 6A is a clinical photograph showing the left breast (baseline) of subject number 10 having a fungal tumor.
- FIG. 6B is a clinical photograph showing the left breast of subject number 10 12 months after treatment with H 2 O 2 + RT.
- FIG. 7 is a diagram showing an 18 F-FDG PET scan image of the subject No. 8 in Example 6 (6-2). In this figure, FIG. 7A shows high tracer uptake of the left breast tumor at baseline, and FIG. 7B shows complete metabolic remission at 12 months post-treatment.
- the anti-cancer therapy sensitizer of the present invention comprises 0.01 to 3.5 (v / v)% component (a) hydrogen peroxide and 0.1 to 10 (v / v)% component (b) hyaluronic acid or a component thereof.
- the dose of the sensitizer to the tumor is selected from 1.2 mL to 15.0 mL depending on the size of the tumor.
- the sensitizer for anti-cancer therapy as used in the present invention is a formulation composition that is used directly inside the tumor-affected area in advance or at the same time as the anti-cancer therapy for the tumor, and is an anti-cancer therapy for the tumor-affected area. It is possible to enhance the effect of.
- anti-cancer therapy in the present invention can be used as a treatment method for anti-cancer such as radiation therapy (irradiation) and anti-cancer chemotherapy.
- radiation therapy refers to a treatment method in which radiation is applied to an affected part of a tumor to damage the DNA of the tumor cells and cause cell death in the cancer cells. It may be performed in combination with the anticancer chemotherapy described later.
- radiation that can be used in radiotherapy X-rays, electron beams, proton beams, heavy particle beams, ⁇ (alpha) rays, ⁇ (beta) rays, ⁇ (gamma) rays and the like can be used.
- Radiation therapy methods include an external irradiation method that irradiates radiation from outside the body, and a sealed brachytherapy method in which a radiation source is directly inserted into a body tissue or a cavity such as the esophagus or uterus for treatment.
- an external irradiation method that irradiates radiation from outside the body
- a sealed brachytherapy method in which a radiation source is directly inserted into a body tissue or a cavity such as the esophagus or uterus for treatment.
- external irradiation method or brachytherapy may be used, or external irradiation and brachytherapy may be combined.
- anti-cancer chemotherapy means all cancer treatments with anti-cancer agents (anti-cancer agents). In the present invention, it may be carried out in combination with the above-mentioned radiation therapy.
- the effect of radiotherapy with a linear accelerator on cancer cells depends on about 70% of the production of active oxygen such as hydroxyl radical.
- active oxygen such as hydroxyl radical.
- hypoxia in tumor tissue affects the production of reactive oxygen species. Due to these characteristics, hypoxia elimination is effective for both radiation therapy and chemotherapy. Therefore, a substance that sensitizes the therapeutic effect of radiation also sensitizes the effect of anticancer chemotherapy.
- the "tumor" to which the sensitizer of the present invention is used may be any tumor (solid tumor) that forms a tumor mass other than a tumor of the blood system, for example. It may be benign or malignant, epithelial or non-epithelial. Among such tumors, malignant tumors are mainly assumed as the tumors to which the sensitizer of the present invention is administered. In addition, although there is no limitation on the susceptibility of tumors to anticancer therapy, the sensitizer of the present invention is used for tumors that have been treated with radiation therapy and / or anticancer chemotherapy in the past but are resistant to them. Can also be used.
- the "tumor affected area” refers to a tumor tissue formed mainly by tumor cells, and the tumor tissue includes a mixture of tumor cells and normal cells and / or normal tissues.
- the ratio of the volume or the number of cells occupied by the tumor cells to the normal cells and / or the normal tissues is not particularly limited.
- the therapeutic effect of anticancer therapy with or without the sensitizer of the present invention is a general evaluation method for tumor treatment such as tumor tissue shrinkage rate, patient survival rate, recurrence rate after treatment, etc. Can be evaluated by.
- the sensitizer of the present invention is a composition composed of a combination of the component (a) and the component (b).
- “combined” means that the sensitizer targeted by the present invention is defined as “combined”.
- the condition (combination agent) contains both the ingredient (a) and the ingredient (b) from the beginning.
- the preparation containing the component (a) and the preparation containing the component (b) exist in separate packaging forms and are sold as a combination (kit), or.
- (iii) Includes the case where the preparation containing the component (a) and the preparation containing the component (b) are present in the market in separate packaging forms and in separate distribution channels, and are used in combination at the time of use. It is used in the sense of
- the sensitizer for anticancer therapy "combined” in the present invention is a component in the sensitizer for anticancer therapy at the time of final use (in the present invention, this is referred to as “final preparation”). It means that both (a) and the component (b) need to be contained, and the form at the distribution stage including sales is not particularly questioned.
- the sensitizer of the present invention is characterized by containing 0.01 to 3.5% (w / v) of the component (a) hydrogen peroxide as an active ingredient.
- hydrogen peroxide used in the present invention represents hydrogen peroxide molecule (H 2 O 2 ; molecular weight 34) itself.
- hydroxide solution refers to hydrogen peroxide dissolved in distilled water from the Japanese Bureau.
- % (w / v) represents a weight / volume percent concentration.
- the sensitizer of the present invention is characterized by containing 0.1 to 10% (w / v) of the component (b) hyaluronic acid or a salt thereof as an auxiliary component.
- concentration of the component (b) is not limited, but is preferably in the range of 0.1 to 5% (w / v), more preferably in the range of 0.1 to 3% (w / v), and further preferably in the range of 0.3. It can be used in the range of ⁇ 1% (w / v).
- the hyaluronic acid used in the present invention may be one extracted from animal tissue or one produced by a fermentation method, and its origin is not questioned. It is preferably produced by a fermentation method because of its safety and stability of production.
- the strain used in the fermentation method is not particularly limited, for example, in addition to hyaluronic acid-producing microorganisms belonging to the genus Streptococcus isolated from the natural world, Streptococcus Equi FM-100 described in JP-A-63-123392.
- Hyaluronic acid-producing microorganisms such as Streptococcus Equi FM-300 (Streptococcus bacillus No. 2319) described in JP-A-2-234689 can be used arbitrarily. can.
- hyaluronic acid As hyaluronic acid, hyaluronic acid having various molecular weights has been conventionally known. Although not limited, in the present invention, for example, hyaluronic acid having a molecular weight of usually about 500,000 to 10 million, preferably about 500,000 to 8 million, more preferably about 500,000 to 5 million is used as the mass average molecular weight. Can be done.
- the mass average molecular weight of hyaluronic acid can be measured by the SEC-MALLS method using a multi-angle light scattering detector (MALLS) as a detector in the size exclusion chromatogram (SEC) (for example, C. Yomota, See Bull. Natl. Inst. Health Sci., 121, 030-033 (2003), etc.).
- MALLS multi-angle light scattering detector
- SEC size exclusion chromatogram
- the hyaluronic acid targeted by the present invention may be crosslinked hyaluronic acid.
- the crosslinked hyaluronic acid is a polymer having a three-dimensional network structure, and is in the form of a gel in a state of being swollen in a medium. That is, the crosslinked hyaluronic acid swells in a physiologically acceptable medium and has the form of a hydrogel.
- cross-linked hyaluronic acid As an example of cross-linked hyaluronic acid, there can be mentioned cross-linked hyaluronic acid formed from hyaluronic acid having a mass average primary molecular weight of more than 800,000.
- the crosslinked hyaluronic acid is characterized in that when the crosslinked point of the crosslinked hyaluronic acid is cleaved, a linear hyaluronic acid having a mass average molecular weight of more than 800,000 is produced.
- a differential refractometer and a multi-angle laser light scattering detector (MALLS) are used as detectors in the gel permission chromatogram (GPC). It can be easily measured by GPC-MALLS (multi-angle light scattering).
- the crosslinked hyaluronic acid used in the present invention may have a hydrolyzable crosslink point.
- the cross-linking point is hydrolyzable means that the cross-linking point is decomposed under physiological conditions, for example, at 37 ° C., pH 7.4, and physiological saline, in preference to the decomposition of the main chain of hyaluronic acid. It means having a property.
- Examples of the crosslinked structure having better hydrolyzability than the main chain decomposition of hyaluronic acid include a carbamate bond, a hydrazone bond, a hydrazide bond and a phosphate ester bond, and the most typical structure is an ester bond.
- the crosslinked hyaluronic acid having an ester bond in the crosslinked structure includes an ester of a carboxyl group of polyhydric alcohol and hyaluronic acid, an ester of a hydroxyl group of polyvalent carboxylic acid and hyaluronic acid, and an ester of a polyvalent epoxy compound and a carboxyl group of hyaluronic acid. And so on.
- Such crosslinked hyaluronic acid includes crosslinked hyaluronic acid in which the carboxyl group of hyaluronic acid and the hydroxyl group are directly ester-bonded (this is referred to as "crosslinked ester having a self-crosslinked ester bond" or "self-crosslinked ester-bonded hyaluronic acid”). ..
- the self-crosslinked ester-bonded hyaluronic acid can be produced by a conventionally known method.
- a self-crosslinked ester-bonded hyaluronic acid in which some or all of the carboxyl groups are esterified with the same polysaccharide chain or the alcohol group of another polysaccharide chain can be prepared as described in EP0341745B1 and also in WO99 / 10385.
- a method for preparing self-crosslinked ester-bonded hyaluronic acid by adjusting the aqueous solution of hyaluronic acid to an acidic acid, freezing the aqueous solution, and then thawing at least once, and WO01 / 57093 without freezing.
- a method for preparing a self-crosslinked ester-bonded hyaluronic acid by mixing an acidic solution with hyaluronic acid so as to have a concentration of 5% or more and maintaining the coexistence state is described.
- Such self-crosslinked ester-bound hyaluronic acid is considered to be safer than the cross-linked hyaluronic acid produced by another cross-linking reaction because the natural hyaluronic acid released by hydrolysis is metabolized by a physiological metabolic pathway. ..
- hyaluronic acid in which the carboxyl group of hyaluronic acid is crosslinked to the hydroxyl group of the same hyaluronic acid molecule and / or to the hydroxyl group of another hyaluronic acid molecule by an ester bond can be mentioned (for example). See JP-A-2003-252905).
- the degree of cross-linking of the cross-linked hyaluronic acid for example, the amount of intermolecular ester bond to be introduced can be arbitrarily controlled according to the purpose of use and the required characteristics of the cross-linked hyaluronic acid.
- the amount of ester bond can be defined as a ratio to the total number of carboxyl groups in hyaluronic acid.
- hyaluronic acid is preferably used as an aqueous solution or a water-swelling gel.
- hyaluronic acid When hyaluronic acid is used in the state of an aqueous solution, it is not limited, but it is preferable to use crosslinked hyaluronic acid having an intermolecular ester bond amount of less than 0.5%. When hyaluronic acid is used in the state of a water-swelling gel, it is preferable to use crosslinked hyaluronic acid having an intermolecular ester bond amount of about 0.5% to 1%, although it is not limited.
- the molecular structure of crosslinked hyaluronic acid can be confirmed by NMR (Carbohydr. Res. Vol245, p113-128, 1993, Macromolecules Vol29, p2894-2902, 1996).
- Cross-linked hyaluronic acid can be prepared, for example, by adjusting the aqueous hyaluronic acid solution to acidity and converting the dissociated carboxyl group into an acid type.
- the acid treatment of the aqueous hyaluronic acid solution causes a deacetylation reaction of N-acetyl-D-glucosamine units under high temperature conditions and competes with the cross-linking reaction (see JP-A 1-266102), so the reaction temperature is lowered. It is preferable to do so.
- the reaction temperature for which crosslink formation is prioritized is preferably room temperature or lower, and a more preferable reaction temperature is 10 ° C. or lower.
- the hyaluronic acid concentration in the reaction solution is preferably 5% by mass or more, more preferably 10% by mass or more.
- a substance that catalyzes the dehydration condensation reaction can be added to the reaction system.
- an acidic catalyst is generally used, and sulfuric acid, hydrochloric acid, aromatic sulfonic acid derivatives and the like can be used.
- crosslinked hyaluronic acid When forming crosslinked hyaluronic acid, a material having excellent biocompatibility similar to hyaluronic acid, for example, chondroitin sulfate, carboxymethyl cellulose and the like may be mixed and complexed to form crosslinked hyaluronic acid. Further, when forming crosslinked hyaluronic acid, a pharmaceutically or physiologically active substance can be added to form crosslinked hyaluronic acid containing these substances.
- the crosslinked hyaluronic acid thus obtained can then be subjected to an operation of removing the acid component used for adjusting the acidity.
- the operation for removing the acid component include washing with an aqueous solvent or dialysis.
- the aqueous solvent is not particularly limited as long as it does not impair the function of the crosslinked hyaluronic acid, and for example, water, physiological saline, phosphate buffer, etc. are used, but physiological saline is preferable. Phosphate buffer or the like can be used.
- the acid-type carboxyl group remains in the washed crosslinked hyaluronic acid, it can be in the form of a salt such as sodium-type (chloride).
- the chloride method is not limited, but examples thereof include a method of adjusting the pH of the crosslinked hyaluronic acid aqueous solution to about 7 with an aqueous sodium hydroxide solution, or a method of immersing the crosslinked hyaluronic acid in a physiological saline solution or a phosphate buffered physiological saline solution. can do.
- the crosslinked hyaluronic acid thus prepared is a sensitizer for the anticancer therapy of the present invention in a solution state, a state of being immersed in a solvent, or a state of being moistened with a solvent, depending on the purpose of use. , These can be collectively used as a material for "sensitizer").
- Cross-linked hyaluronic acid swells in a physiologically acceptable medium to form a gel. Therefore, when the sensitizer of the present invention has the form of an injectable agent, cross-linked hyaluronic acid (gel) is used as a suspension in order to inject it into the tumor affected area to be irradiated or anticancer chemotherapy through an injection needle. It needs to be dispersed in a physiologically acceptable medium.
- the suspension can be prepared by disrupting the crosslinked hyaluronic acid at any stage of its manufacturing or purification steps using a crusher such as a mixer or homogenizer.
- the particle size of the crosslinked hyaluronic acid hydrogel particles can be adjusted arbitrarily, but when the crosslinked hyaluronic acid is dispersed in a physiologically acceptable medium and then treated with a homogenizer, the dispersed particle size is usually about 0.05 to 2 ⁇ m. Can be easily adjusted.
- the equilibrium swelling ratio of the crosslinked hyaluronic acid gel can be arbitrarily adjusted by the degree of crosslinking of the crosslinked hyaluronic acid. For example, if the equilibrium swelling ratio is 100 times, the concentration of hyaluronic acid in the physiologically acceptable medium will be 1%. When the equilibrium swelling ratio is 10 times, the concentration of hyaluronic acid in the physiologically acceptable medium is 10%.
- the hyaluronic acid may be either ordinary hyaluronic acid (non-crosslinked type) or crosslinked hyaluronic acid (crosslinked hyaluronic acid) as described above, and any of these may be used. It can also be used in combination with. Further, it may be used in a single form or a single molecular weight, or a mixture of different crosslinked hyaluronic acids or hyaluronic acids having different molecular weights may be used.
- hyaluronic acid (used in the concept including crosslinked hyaluronic acid) can also be used in the form of a salt.
- the salt of hyaluronic acid is not limited, but alkali metal salts such as sodium, potassium, and lithium can be preferably exemplified.
- a sodium salt of hyaluronic acid is preferred.
- the sensitizer of the present invention includes a pharmaceutically acceptable physiological saline solution, a phosphate buffer solution, etc. (for example, sodium chloride, phosphorus). Sodium hydrogen phosphate, sodium dihydrogen phosphate, etc.) can be included.
- the sensitizer of the present invention does not particularly limit the liquid property as long as it is compatible with the human body, but it is preferably adjusted to the pH range of 6 to 8.5. More preferably, the pH is in the range of 6.8 to 7.8.
- the dosage form of the sensitizer of the present invention may contain an tonicity agent, a pH adjuster and a buffer solution.
- the tonicity agent include sodium chloride, glycerin, glucose, polyethylene glycol, propylene glycol, D-mannitol, fructose, xylitol, sodium dihydrogen phosphate, sodium phosphate and the like, and sodium chloride is preferably used.
- the pH adjuster include hydrochloric acid, sodium hydroxide and the like, and the pH is adjusted in the range of 6 to 8.5, preferably pH 6.8 to 7.8 as described above.
- the buffer solution used for maintaining the pH include a phosphate buffer solution, a Tris buffer solution, and an acetate buffer solution. A phosphate buffer is preferably used.
- the sensitizer of the present invention has a liquid (including a lysate, an emulsion and a suspension) or a gel, and is used as an injection. Therefore, the sensitizer of the present invention can be administered as it is by using a syringe or the like to the tumor affected area to be treated with anticancer therapy, or by a method of injecting through an angiographic catheter.
- a syringe or catheter pump For injection, specifically, while checking the penetration status of the sensitizer into the tissue under the guidance of ultrasonography, use a syringe or catheter pump to adjust the injection amount while adjusting the injection needle. It is preferable to use it.
- the sensitizer can be widely spread to the tumor tissue by changing the depth and direction of the injection needle with the ultrasonic guide.
- the form of the sensitizer for the anticancer therapy of the present invention is the form of an injectable agent.
- an aqueous solution is prepared using water for injection (distilled water for injection, sterile water for injection, etc.), isotonic agent, pH adjuster, buffer solution, etc., and the aqueous solution contains components (a) and components (b). ) Can be added and blended in a ratio within the above range, filled in a container, sealed, and then sterilized by high-pressure steam sterility, hot water immersion sterility, or the like.
- the preparation containing the component (a) and the preparation containing the component (b) at the time of use are mixed and mixed using water for injection (distilled water for injection, sterile water for injection, etc.) as necessary. It can also be prepared (prepared before use).
- the sensitizer of the present invention when used in clinical practice, for example, as component (a), 0.4 ml of 3% H 2 O 2 encapsulated in a syringe (eg, 2.0 ml supplied by Stockport Pharmaceuticals (UK)). 20 mg hyaluronic acid or a salt thereof (eg, 2.0 ml sodium hyaluronate provided by AAH Pharmaceuticals (UK), OSTENIL (eg, OSTENIL), loaded in a 2.0 ml syringe as ingredient (b). Registered trademark)) can be used, and the sensitizer of the present invention can be prepared at the time of use by mixing them.
- a syringe eg, 2.0 ml supplied by Stockport Pharmaceuticals (UK)
- 20 mg hyaluronic acid or a salt thereof eg, 2.0 ml sodium hyaluronate provided by AAH Pharmaceuticals (UK)
- OSTENIL eg, OSTENIL
- a syringe filled with hydrogen peroxide solution and a syringe loaded with a solution of hyaluronic acid or a salt thereof are connected via a 2-way tap, and the syringes are alternately pumped under sterile conditions.
- Ingredient (a) (2.0 ml 3% H 2 O 2 sterile ampoule supplied by Stockport Pharmaceuticals (UK)) and ingredient (b) (2.0 ml sodium hyaluronate provided by AAH Pharmaceuticals (UK)) exemplified above.
- OSTENIL® can be mixed to prepare 2.4 ml of sensitizer containing 0.5% H 2 O 2.
- the prepared 2.4 ml sensitizer is evenly divided into two syringes, with 1.2 ml of the sensitizer containing 0.5% H 2 O 2 as the minimum dosing unit. be able to.
- Dosage and administration of the sensitizer of the present invention can be appropriately determined according to the condition of the tumor to be treated, for example, 1 to 3 times a week during the treatment period of the tumor. , Preferably twice a week, infused into the tumor.
- the sensitizer is also infused into the tumor a total of 2 to 8 times, preferably a total of 4 to 6 times, during the treatment period of the tumor.
- the dose of the sensitizer to the affected area of the tumor may range from 1.2 mL to 15.0 mL, depending on the condition of the tumor to be treated.
- the dose of the sensitizer to the affected area of the tumor is a sensitizer containing 0.5% H 2 O 2 prepared according to the above-mentioned time-of-use preparation example, depending on the size of the tumor. It can be used for 0.5 to 5 preparations. For example, when using a sensitizer containing 2.4 ml of 0.5% H 2 O 2 in one preparation, 1.2 ml of 0.5 preparation to 12.0 ml of 5 preparation, which is the smallest dosing unit at the time of 1 preparation.
- the minimum dosing unit at the time of one preparation is 1.5 ml for 0.5 preparation to 15.0 ml for 5 preparations. Can be administered up to.
- the dose of the sensitizer to the tumor can be adjusted in consideration of the size of the tumor mass, the hardness of the tumor mass, the clarity of the tumor boundary, the type of tumor cell to be treated, and the like, for example, a tumor.
- a tumor As for the relationship between mass size and dose, (1) For the tumor having a maximum diameter of less than 3.0 cm, 1.2 mL or more and less than 3.0 mL (corresponding to 0.5 preparation to 1 preparation), (2) For tumors with a maximum diameter of 3.0 cm or more and less than 6.0 cm, 2.4 mL or more and less than 6.0 mL (1 to 2 preparations), (3) For tumors with a maximum diameter of 6.0 cm or more and less than 10.0 cm, 3.6 mL or more and less than 9.0 mL (1.5 to 3 preparations), and (4) Maximum diameter of tumor mass For tumors with a length of 10.0 cm or more, the range may be 3.6 mL or more and 15.0 mL or less (1.5 to 5 preparations). Tumor size can be
- the sensitizer of the present invention was originally developed to enhance the anti-cancer effect of anti-cancer therapy, and was known to have an anti-cancer effect.
- the sensitizer of the present invention showed a tumor size reducing effect, and as a result of this main effect, pain was secondary. It has been clarified that it may have a reducing effect, a skin toxicity reducing effect, or both a pain reducing effect and a skin toxicity reducing effect.
- the sensitizer of the present invention enhances the anticancer effect of anticancer therapies such as radiation therapy or anticancer chemotherapy and greatly reduces the size of the tumor cell mass, resulting in pain caused by the tumor cell mass.
- the action of reducing the amount of cancer can be obtained.
- the sensitizer of the present invention in anti-cancer therapy, it is possible to reduce the intensity of anti-cancer therapy for obtaining the same effect as when only anti-cancer therapy is performed.
- the radiation dose can be reduced by using the sensitizer of the present invention, and as a result, the skin toxicity generated by irradiation can be reduced. Is considered to be obtained.
- Anti-cancer therapy combined with the sensitizer of the present invention is not used alone, but in combination with anti-cancer therapy used in clinical practice such as radiation therapy or anti-cancer chemotherapy. It is intended to be used.
- the sensitizer of the present invention is used as a sensitizer for radiation therapy, it is used for the affected part of the tumor to be irradiated prior to irradiation during radiation therapy. Preferably, it can be used for radiotherapy for radiation-resistant tumors.
- examples of radiation-resistant tumors include tumors in which hypoxic tumor cells are abundant and tumors in which antioxidant enzymes are abundant.
- the greatest challenge in cancer radiotherapy based on linear accelerators, which are currently widely used, is the existence of radiation-resistant cancer cells.
- Such radioresistant tumor tissues are abundant in hypoxic sites and are resistant to radiation therapy.
- the resistance of these cells to radiation does not cause fixation by oxygen to radiation-induced DNA damage in a low oxygen state, and further, it resists reactive oxygen species produced in tumor cells by radiation. It is said that it is difficult to induce apoptosis because the oxidative enzyme is eliminated.
- radiation-resistant tumors include various sarcomas such as malignant melanoma, malignant glioblastoma, and osteosarcoma, and almost all locally advanced cancers that have grown to several centimeters or more. can.
- the radiotherapy is performed by applying the sensitizer of the present invention to the affected area of the target tumor and then irradiating the affected area with X-rays or electron beams.
- the dosage and administration of radiation therapy depends on factors such as the type of radiation, the physical condition of the patient to be treated, and the condition of the tumor to be treated, for example, daily, once every two days, once every three days, one. It can be decided as appropriate, such as once a week or once every 10 days.
- the dose per dose in radiation therapy can be appropriately selected from the range of 1.75 to 3.75 Gy.
- the total dose can be appropriately selected from the range of 31.5-67.5 Gy.
- radiation therapy can be appropriately selected from the range of 16 to 20 days.
- the dose per dose in radiation therapy can be appropriately selected from the range of 5.0 to 7.0 Gy.
- the total dose per week can be appropriately selected from the range of 5.0 to 21.0 Gy.
- the total number of radiation treatments can be appropriately selected from the range of 4 to 8 times, preferably 6 times. Radiation therapy is performed within 24 hours, preferably within 12 hours, more preferably within 6 hours, even more preferably within 2 hours after injection of the sensitizer into the tumor.
- the sensitizer of the present invention is used as a sensitizer for anticancer chemotherapy, it is used for the tumor affected area to be treated prior to the anticancer chemotherapy (administration of the anticancer agent). Infusion administration is preferable).
- it can be used for tumors for which anticancer chemotherapy is ineffective as well as relatively large tumors.
- many solid tumors such as gastric cancer, non-small cell lung cancer, colon / rectal cancer, liver cancer, pancreatic cancer, uterine cancer, esophageal cancer, and breast cancer are resistant to anticancer chemotherapy.
- anti-cancer chemotherapy can be performed within 24 hours, preferably within 12 hours, more preferably within 6 hours, even more preferably within 2 hours after injection of anti-cancer chemotherapy.
- the anticancer chemotherapy is performed in parallel with the administration of the anticancer agent (before, after or at the same time as the administration of the anticancer agent). , It can be carried out by applying the sensitizer of the present invention to the target tumor affected area.
- the dosage and administration of anticancer chemotherapy can be appropriately determined depending on factors such as the type of anticancer drug, the physical condition of the patient to be treated, and the condition of the tumor to be treated.
- the method of applying the sensitizer in this case can be carried out by injecting the sensitizer into the tumor affected area, preferably using an injection needle or a catheter under the guidance of an ultrasonic examination.
- the conditions for injecting the sensitizer vary depending on the degree and size of the tumor, but a method of injecting 1 ml to 5 ml, preferably 3 ml at a time can be mentioned.
- the dosing schedule may be the same as the radiation therapy schedule.
- a tumor treatment method using a combination of radiation therapy or anticancer chemotherapy and the sensitizer of the present invention is also provided.
- the therapeutic method of the present invention comprises the step of administering the sensitizer of the present invention to the tumor, and the step of performing radiation therapy or anticancer chemotherapy.
- Example 1 Study Design In this example, a systematic study was conducted in which intratumoral H 2 O 2 injection combined with RT for locally advanced breast cancer was tested.
- the main purpose of this experiment was to evaluate the safety and permissibility of H 2 O 2 injection with moderate fractionated RT. Secondary endpoints also included a percentage of subjects requiring additional pain medication, an incidence of grade 3 or higher skin toxicity, and an assessment of tumor response.
- This non-randomized trial targeted subjects with locally advanced or locally recurrent breast cancer, with or without metastasis, who were indicated for RT for disease management in the local area.
- the subjects were either inoperable due to the degree of co-morbidity or local disease, or unsuitable for primary breast surgery due to the presence of metastatic disease.
- Figure 1 shows a study of intratumoral administration of H 2 O 2 in a sodium hyaluronate gel in combination with two radiotherapy divided dose schedules and a corresponding follow-up schedule in subjects with locally advanced breast cancer. It outlines the non-randomized trial design of the trial.
- # indicates radiation therapy divided irradiation
- US indicates ultrasound
- RT indicates radiation therapy.
- Target subjects are 18 years of age or older, with breast cancer histologically confirmed, requiring breast RT for local control and / or relief of local area symptoms, and injectable superficial sites.
- the subject had at least one breast tumor with a diameter of 3 cm or more. Any combination of estrogen receptor (ER), progesterone receptor (PR), and HER2 expression was tolerated.
- Exclusion criteria included a history of RT to the breast and a combination of biotherapies other than trastuzumab, pertuzumab, and denosumab.
- female subjects of childbearing age were excluded. Subjects whose anatomical location of the breast tumor interfered with safe access to intratumoral injection, such as close proximity to blood vessels and brachial plexus, were excluded.
- tumor lysis syndrome (mild) has been reported in a total of 139 breast cancer subjects in the Japanese literature. Based on this finding on the safety of H 2 O 2 + RT, 12 subjects were recruited in this study. Subjects who received split doses of RT daily and twice a week were analyzed as a single layer, the study was enrolled, and all subjects who received at least one intratumoral H 2 O 2 were defined as the study population. did. Tumor volume was calculated using 3D measurements obtained from US scans.
- Example 2 Pharmaceutical formulation This example describes the pharmaceutical formulation used in the test.
- the 0.5% H 2 O 2 solution used as the sensitizer of the present invention is 0.4 ml of 3% H 2 O 2 (2.0 ml sterile ampoule supplied by Stockport Pharmaceuticals (UK)) and 2.0 ml of OSTENIL®. ) (20 mg sodium hyaluronate loaded in a 2.0 ml syringe provided by AAH Pharmaceuticals (UK)).
- the low molecular weight of H 2 O 2 (34 g / mol) can ensure rapid drug equilibration within the gel.
- the mixture was a colorless viscous solution (pH 6.8 to 7.8), stored at room temperature and stable for 2 hours after preparation by viscosity measurement (conducted by Stockport Pharmaceuticals (UK)).
- the gel allows the release of H 2 O 2 for at least 24 hours, a feature of which is twice weekly during RT. It is a strong basis for administration.
- each syringe contains a total of 2.4 ml of 0.5% H 2 O 2 , and the content of both syringes is the amount required for a tumor, typically measured as 30-60 mm in diameter. ..
- Example 3 Radiation therapy This example describes the content of radiation therapy to be performed on each subject.
- the RT schedule was selected according to the performance status of the subject and comorbidity, and the daily treatment schedule was selected for the suitable subject.
- RTs were irradiated using a linear accelerator with 6 to 10 MV photons, 3D planning with scan data from treatment planning CT, and a standard tangential facing field.
- the subject was simulated and treated in a supine position on a breastboard with both arms abducted.
- Clinical target volume (CTV) included the entire ipsilateral breast, including the deep fascia, but the underlying muscles and covering skin were excluded if they were not involved in the disease.
- the RT irradiation dose was specified as 100% equal dose so that the target volume was within the equal dose of 95% to 107%.
- Boost irradiation of the tumor bed increased EQD2 to 36 Gy with 6 fractionated doses, comparable to the dose intensity already reported in previous subject cohorts with the same drug. rice field.
- Table 1 summarizes the demographics of the subjects, tumor characteristics, pretreatment and RT target amount.
- H 2 O 2 injection Compliance with H 2 O 2 injection was 100% in all subjects, including one case of needle phobia. All of the subject, the subject has received a RT 1 after receiving H 2 O 2 injection of a predetermined within 2 hours, which has received the mistake once RT divided irradiation prior to H 2 O 2 injection All subjects received RT, with one exception. Results are reported with a minimum of 12 months follow-up for all surviving subjects at the time of reporting (range 2-24 months). Eleven subjects completed a 12-month follow-up, and subject number 12 died of progressive metastatic disease just two months after RT.
- Example 4 The intratumoral injection embodiment of H 2 O 2 in sodium hyaluronate gel, subjected to intratumoral injection of H 2 O 2 to the subject, and confirmed the results.
- the reason for starting KORTUC in the second week is that it allows the tumor stromal pressure to be reduced at the RT in the first week, which makes the injection technically easier and more acceptable to the subject. It was to do so.
- Injections were made with a 23 gauge needle by a trained radiologist or radiologist under ultrasound (US) guidance after injecting 0.5% lignokine to anesthetize the skin.
- US ultrasound
- For tumors 30-60 mm in size two syringes (4.8 ml) of 0.5% H 2 O 2 were injected at each time point in a sodium hyaluronate gel. Tumors larger than 60 mm required 3 syringes (7.2 ml).
- the number of needle marks in the tumor and the point of entry into the skin were determined by the radiologist during the ultrasound scan and were guided by the extent and distribution of oxygen microbubbles during the injection procedure. If the gel returned to the skin surface when the needle was pulled out, it was immediately wiped off with sterile gauze. If the subject has one or more distinct tumors in the breast / axilla, the clinician / should clearly document the lesion (usually the largest) in which the injection was made to help assess the response. I requested a radiologist. RT was performed within 1-2 hours after H 2 O 2 injection.
- Treatment monitoring in each RT group defines a minimum weekly interval between the first subject and subject number 2 in the tumor.
- Acute toxicity data related to injections were reviewed by the Independent Data Monitoring Committee (IDMC).
- Example 5 Primary endpoint
- the target endpoints (primary endpoint, primary endpoint) were achieved in the clinical trials of each subject.
- the primary endpoint was to relate to the timing, severity and duration of post-injection pain recorded via a self-reported questionnaire completed by the subject at home. Severity and duration were recorded on an 11-point numerical scale ranging from 0 (“no pain”) to 10 (“worst possible pain”) before and 24 hours after each H 2 O 2 injection ( Figure 4). reference). The scores reported by the subjects were used to calculate i) the proportion of subjects with a pain score above baseline by 5 points or more after any intratumoral injection, and ii) the required amount of additional analgesics.
- Example 6 Secondary endpoint
- achievement of items (secondary endpoint) for evaluating effects other than the main endpoint (primary endpoint) of the clinical trial was confirmed.
- the secondary endpoints in this example were acute skin toxicity and tumor reaction due to RT.
- the highest grade of skin toxicity reported was Grade 3 in 5 of the 12 subjects, Grade 2 in 4 subjects, Grade 1 and 2 in 1 subject.
- the subject was grade 0 (Tables 2 and 4). All five subjects who experienced grade 3 skin toxicity were treated with a bolus during radiation therapy (due to tumor skin infiltration). No enhancement of erythema due to local leakage of H 2 O 2 was suggested.
- the acute radiation dermatitis observed in this study was similar to that expected with standard RT monotherapy, including subjects with cancer infiltrating the skin. There were no cases of tumor lysis syndrome.
- Tumor response was assessed 3, 6 and 12 months after treatment. Three-dimensional US measurements were performed at each time point and the tumor volume was calculated assuming that the breast tumor had a semi-elliptical shape as previously demonstrated. It is believed that the maximum size of the tumor alone cannot accurately represent the reaction of the tumor, especially if the tumor is "flattened” after radiation therapy. Tumor volume was compared to pretreatment measurements by applying a principle similar to RECIST. Complete remission (CR) was defined as the disappearance of the target lesion, partial remission (PR) was defined as a tumor volume reduction of at least 30%, and stable state (SD) was defined as a tumor volume reduction of less than 30% or an increase of less than 20%. ..
- CR Complete remission
- PR partial remission
- SD stable state
- Figures 5A and 5 show details of the tumor response based on US measurements at consecutive time points after treatment.
- the tumor volume reduction rate was 50 to 100%. All subjects evaluated in this study maintained local region control in irradiated target lesions at final clinical follow-up (median 12 levies, range 2 to 24 months). Subject number 12 died of metastatic disease 6 weeks after RT and could not be evaluated at the 3-month endpoint of tumor response.
- FIG. 6 shows, as an exemplary example, the spread of tumors in subject number 10 before RT treatment and 12 months after treatment (subjects maintain CR for 18 months). Only 1/12 subjects had one or more distinct tumor lesions within the RT treatment dose. In this subject, only the tumor injected with H 2 O 2 maintained PR after 12 months, whereas the two lesions that received the same RT alone were stable (the lesions that were not injected were internal. It acted as a control). Regarding the evaluation of tumor response, there was a discrepancy between the US measurement and the evaluation of clinical response between the two subjects (Table 5). Subject No. 9 showed increased tumor size on US measurements for 6 to 12 months, although clinical tests showed partially superior response.
- Acute skin toxicity was no different from what was expected with the same RT alone.
- grade 3 radiation dermatitis occurred only in subjects with skin infiltration (due to the 5 mm layer of wax "blanket", not about 70% of the prescribed dose for subjects without skin infiltration. When 100% of the prescribed dose was surely applied to the skin).
- Grade 3 desquamation was controlled with standard support measures such as barrier creams and dressings, and symptoms disappeared completely in all cases.
- the dose and usage of the sensitizer for the anticancer therapy of the present invention can improve the effect of the anticancer therapy (radiotherapy or anticancer chemotherapy) and effectively treat the tumor. More specifically, the sensitizer of the present invention has a pain-reducing effect, a skin toxicity-reducing effect, or a pain-reducing effect and a skin-toxicity-reducing effect, in addition to the main anticancer effect. It has become clear that it may have both effects.
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Abstract
Description
[1] (a)0.01~3.5%(w/v)の過酸化水素、及び(b)0.1~10%(w/v)のヒアルロン酸又はその塩、を含む抗がん療法の増感剤であって、
腫瘍への前記増感剤の投与量が、腫瘍のサイズに応じて1.2 mL~15.0 mLから選択されることを特徴とする、
前記増感剤。
[2] 前記増感剤が、0.5%(w/v)の過酸化水素を含む、[1]に記載の増感剤。
[3] 前記投与量が、
(1)腫瘍塊の最大径の長さが3.0 cm未満のサイズの前記腫瘍に対しては、1.2 mL以上3.0 mL未満、
(2)腫瘍塊の最大径の長さが3.0 cm以上6.0 cm未満のサイズの前記腫瘍に対しては、2.4 mL以上6.0 mL未満、
(3)腫瘍塊の最大径の長さが6.0 cm以上10.0 cm未満のサイズの前記腫瘍に対しては、3.6 mL以上9.0 mL未満、
及び
(4)腫瘍塊の最大径の長さが10.0 cm以上のサイズの腫瘍に対しては、3.6以上15.0 mL以下
の範囲である、[1]又は[2]に記載の増感剤。
[4] 前記増感剤が、抗がん作用に加えて、疼痛低減作用、皮膚毒性低減作用、または疼痛低減作用と皮膚毒性低減作用の両方の作用を有することを特徴とする、[1]~[3]のいずれかに記載の増感剤。
[5] 抗がん療法が、放射線療法または抗がん化学療法である、[1]~[4]のいずれかに記載の増感剤。
[6] 前記増感剤を、前記腫瘍の治療期間中、週に1から3回、前記腫瘍に注入することを特徴とする、[1]~[5]のいずれかに記載の増感剤。
[7] 前記増感剤を、前記腫瘍の治療期間中、合計2から8回、前記腫瘍に注入することを特徴とする、[1]~[6]のいずれかに記載の増感剤。
[8] 前記腫瘍への前記増感剤の注射後24時間以内に抗がん療法が実施されることを特徴とする、[1]~[7]のいずれかに記載の増感剤。
[9] 前記抗がん療法が、毎日実施されることを特徴とする、[8]に記載の増感剤。
[10] 前記抗がん放射線療法における1回あたりの線量が、1.75から3.75 Gyである、[8]又は[9]に記載の放射線増感剤。
[11] 前記抗がん療法が、週に1、2又は3回実施されることを特徴とする、[8]に記載の増感剤。
[12] 前記抗がん放射線療法における1回あたりの線量が、5から7 Gyである、[11]に記載の放射線増感剤。
便宜上、本願で使用される特定の用語は、ここに集めている。別途規定されない限り、本願で使用される全ての技術用語及び科学用語は、本発明が属する技術分野の当業者が一般的に理解するのと同じ意味を有する。文脈で別途明記されない限り、単数形「a」、「an」及び「the」は複数の言及を含む。
(i) 最初から成分(a)と成分(b)の両方が含まれている状態(配合剤)である場合、
(ii)成分(a)を含有する製剤と成分(b)を含有する製剤とがおのおの別個の包装形態で存在し、組み合わせ物(キット)として販売される場合、または
(iii)成分(a)を含有する製剤と成分(b)を含有する製剤とがおのおの別個の包装形態で、また別個の流通経路で市場に存在し、使用時に組み合わせて使用される場合
を包含する意味で用いられる。
本発明の増感剤は、有効成分として0.01~3.5%(w/v)の成分(a)過酸化水素を含むことを特徴とする。
本発明の増感剤は、補助成分として、0.1~10%(w/v)の成分(b)ヒアルロン酸またはその塩を含むことを特徴とする。成分(b)の濃度としては、限定されるものではないが、好ましくは0.1~5%(w/v)の範囲、より好ましくは0.1~3%(w/v)の範囲、更に好ましくは0.3~1%(w/v)の範囲で使用することができる。
更に、本発明の増感剤は、上記成分(a)および成分(b)に加えて、医薬的に許容し得る生理的食塩水やリン酸緩衝液等(例えば、塩化ナトリウム、リン酸水素ナトリウム、リン酸二水素ナトリウムなど)を含むことができる。本発明の増感剤は、人体に適合性があればその液性を特に制限するものではないが、好ましくはpH6~8.5の範囲に調整されていることが好ましい。より好ましくはpH6.8~7.8の範囲である。
本発明の増感剤は、液状(溶解液、乳濁液、懸濁液を含む)またはゲル状を有し、注入剤として使用するものである。したがって、本発明の増感剤は、抗がん療法を行う対象の腫瘍患部に注射器などを用いてそのまま注入するか、または血管造影のカテーテルを介して注入する方法により投与することができる。注入は、具体的には超音波検査でのガイド下にて増感剤の組織への浸透状況を確認しながら、注射器やカテーテルポンプなどでを使用して注入量を調節しながら、注射針を用いて行なうことが好ましい。この場合、超音波ガイドで注入針の深さや方向を変えることにより、増感剤を腫瘍組織に広くいきわたらすことができる。
本発明の増感剤の投与回数は、治療対象の腫瘍の状況に応じて適宜定めることができ、例えば、腫瘍の治療期間中、週に1~3回、好ましくは週2回、腫瘍に注入される。また、増感剤は、腫瘍の治療期間中、合計2から8回、好ましくは合計4から6回、腫瘍に注入される。
(1)腫瘍塊の最大径の長さが3.0 cm未満のサイズの前記腫瘍に対しては、1.2 mL以上3.0 mL未満(0.5調製~1調製に対応)、
(2)腫瘍塊の最大径の長さが3.0 cm以上6.0 cm未満のサイズの腫瘍に対しては、2.4 mL以上6.0 mL未満(1調製~2調製)、
(3)腫瘍塊の最大径の長さが6.0 cm以上10.0 cm未満のサイズの腫瘍に対しては、3.6 mL以上9.0 mL未満(1.5調製~3調製)、及び
(4)腫瘍塊の最大径の長さが10.0 cm以上のサイズの腫瘍に対しては、3.6 mL以上15.0 mL以下(1.5調製~5調製)の範囲
であってもよい。腫瘍サイズは、RECIST(Response Evaluation Criteria in Solid Tumors)ガイドラインに従って測定することができる。
本発明の増感剤は、単独で使用するのではなく、放射線療法あるいは抗がん化学療法などの臨床現場で使用される抗がん療法と組み合わせて使用するものである。
本発明の別の実施態様として、放射線療法又は抗がん化学療法と本発明の増感剤とを組みあわせて用いる腫瘍治療方法も提供される。本発明の治療方法は、腫瘍に本発明の増感剤を投与するステップ、および放射線療法または抗がん化学療法を行うステップを含む。
本実施例においては、局所進行性乳がんに対するRTを併用した腫瘍内H2O2注射を試験した系統的に実施された研究を行った 。
本実施例は、試験において使用する医薬品の製剤化を説明する。
本実施例は、各被検体に実施する放射線治療の内容を説明する。
本実施例では、被検体に対してH2O2の腫瘍内注射を行い、その結果を確認した。
本実施例においては、各被検体における臨床試験において目的とする評価項目(主要評価項目、プライマリエンドポイント)の達成を確認した。
本実施例においては、治験の主要な評価項目(プライマリエンドポイント)以外の効果を評価するための項目(セカンダリエンドポイント)の達成を確認した。
皮膚毒性は、RT期間中及びRTの4週間後、すべての被検体について、臨床チームのメンバーによって毎週評価した。標準化されたプロフォーマは、乳房の皮膚の紅斑と落屑の程度を記録した。各RT群において、最初の3人の被検体のうち、RTの6週間後にグレード3以上の持続性CTCAE(v4.02)皮膚毒性が1人も認められなかった場合、独立データモニタリング委員会(IDMC)は、そのRTスケジュール内で更に3人の被検体の募集を継続することを許可した。湿潤性落屑が皮膚のひだを越えて認められた場合、重症度がグレード1以下に減少するまで評価を毎週継続した。これらの症例では、RT開始からRTの4週間後までの間にグレード3以上の皮膚毒性を示した被検体の割合及びRT開始からRTの4週間後までに報告された最悪のグレードの皮膚毒性が記録された。しかしながら、がんが皮膚に浸潤している場合、通常、RTのみでグレード3以上の皮膚毒性を被検体が経験することが認識されている。
腫瘍の反応は、治療後3、6、12ヶ月目に評価した。各時点で3次元のUS測定を行い、以前に実証されたように乳房腫瘍は半楕円形をしていると仮定して腫瘍体積を計算した。腫瘍の最大寸法だけでは、特に放射線治療後に腫瘍が「平坦化」した場合には、腫瘍の反応を正確に表すことはできないと考えられている。腫瘍体積は、RECISTに類似した原則を適用して治療前の測定値と比較した。完全寛解(CR)は標的病変の消失、部分寛解(PR)は腫瘍体積が少なくとも30%減少したもの、安定状態(SD)は腫瘍体積が30%未満減少又は20%未満増加したものと定義した。
Claims (12)
- (a)0.01~3.5%(w/v)の過酸化水素、及び(b)0.1~10%(w/v)のヒアルロン酸又はその塩、を含む抗がん療法の増感剤であって、
腫瘍への前記増感剤の投与量が、腫瘍のサイズに応じて1.2 mL~15.0 mLから選択されることを特徴とする、
前記増感剤。 - 前記増感剤が、0.5%(w/v)の過酸化水素を含む、請求項1に記載の増感剤。
- 前記投与量が、
(1)腫瘍塊の最大径の長さが3.0 cm未満のサイズの前記腫瘍に対しては、1.2 mL以上3.0 mL未満、
(2)腫瘍塊の最大径の長さが3.0 cm以上6.0 cm未満のサイズの前記腫瘍に対しては、2.4 mL以上6.0 mL未満、
(3)腫瘍塊の最大径の長さが6.0 cm以上10.0 cm未満のサイズの前記腫瘍に対しては、3.6 mL以上9.0 mL未満、
及び
(4)腫瘍塊の最大径の長さが10.0 cm以上のサイズの腫瘍に対しては、3.6以上15.0 mL以下
の範囲である、請求項1又は2に記載の増感剤。 - 前記増感剤が、抗がん作用に加えて、疼痛低減作用、皮膚毒性低減作用、または疼痛低減作用と皮膚毒性低減作用の両方の作用を有することを特徴とする、請求項1~3のいずれかに記載の増感剤。
- 抗がん療法が、放射線療法または抗がん化学療法である、請求項1~4のいずれかに記載の増感剤。
- 前記増感剤を、前記腫瘍の治療期間中、週に1から3回、前記腫瘍に注入することを特徴とする、請求項1~5のいずれかに記載の増感剤。
- 前記増感剤を、前記腫瘍の治療期間中、合計2から8回、前記腫瘍に注入することを特徴とする、請求項1~6のいずれかに記載の増感剤。
- 前記腫瘍への前記増感剤の注射後24時間以内に抗がん療法が実施されることを特徴とする、請求項1~7のいずれかに記載の増感剤。
- 前記抗がん療法が、毎日実施されることを特徴とする、請求項8に記載の増感剤。
- 前記抗がん放射線療法における1回あたりの線量が、1.75から3.75 Gyである、請求項8又は9に記載の放射線増感剤。
- 前記抗がん療法が、週に1、2又は3回実施されることを特徴とする、請求項8に記載の増感剤。
- 前記抗がん放射線療法における1回あたりの線量が、5から7 Gyである、請求項11に記載の放射線増感剤。
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