Method for treating malignant peripheral nerve sheath tumors

Abstract

To provide a method for treating malignant peripheral nerve sheath tumors (MPNSTs).SOLUTION: A method for treating malignant peripheral nerve sheath tumors is provided, the method comprising a step of administering a therapeutically effective amount of a pharmaceutical composition to a subject in need thereof, wherein the pharmaceutical composition comprises a benzenesulfonamide derivative and a pharmaceutically acceptable carrier thereof.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present disclosure relates to methods of treating peripheral nerve sheath tumors (PNSTs), particularly methods of treating malignant peripheral nerve sheath tumors (MPNSTs).

Background Art

[0002] Peripheral nerve sheath tumors (PNSTs), endoneurial fibroblasts, and / or Schwann cells occur relatively rarely in animals other than dogs. It is classified as a benign and malignant tumor. Malignant PNST (MPNST) most commonly occurs from the peripheral nerves, spinal roots, and cranial nerves of dogs. MPNST occurs in middle-aged to elderly dogs, particularly medium to large-sized dogs, and is characterized by slow growth and rare metastasis.

[0003] Canine PNSTs are similar to malignant PNSTs in humans in both histological and behavioral aspects. Histologically, PNSTs are characterized by the interaction pattern of spindle cells. There are two histological patterns, including Antoni A and B types, which are regions with densely packed spindle cells and regions with fewer cells with more pleomorphic cells, respectively. This type of tumor spreads proximally and distally along the nerve and may eventually invade the spinal cord, causing compression and associated nerve damage. Although metastasis is rare, metastasis to the lung and uvea has been reported.

[0004] There are treatment options for MPNST, including surgical resection, radiation therapy, and chemotherapy. Early detection and correct diagnosis of the tumor are central to complete surgical resection of this tumor and local recurrence can be reduced by postoperative radiation therapy. The recommended chemotherapy is a combination of vincristine, doxorubicin, and cyclophosphamide. However, it has not yet been fully studied. Recently, a novel therapy called meltomics therapy has become one of the treatment options.

[0005] Nevertheless, the optimization of appropriate drugs, dosages, and schedules for the treatment of MPNSTs remains lacking. Considering the high incidence of MPNSTs with severe health threats, it is an urgent and unmet need to overcome current technological limitations and develop pharmaceutical compositions to meet the requirements for effective treatment of MPNSTs.

SUMMARY OF THE INVENTION

[0006] In view of the above, the present disclosure provides an effective and safe pharmaceutical composition that can be used for the treatment or adjuvant treatment of MPNSTs. The pharmaceutical composition includes a benzenesulfonamide derivative and a pharmaceutically acceptable carrier thereof. By administering the pharmaceutical composition provided in the present disclosure, the size of tumors in a subject can be reduced and the quality of its life can be improved.

BRIEF DESCRIPTION OF THE DRAWINGS

[0007] The patent or application file includes at least one drawing executed in color. Copies of this patent or patent application publication, which include color drawings, are provided by the Patent Office upon request and payment of the necessary fees.

[0008] The present disclosure can be more fully understood by reading the following description of embodiments with reference to the accompanying drawings.

[0009]

Figure 1

[0010]

Figure 2

[0011]

Figure 3

[0012]

Figure 4

Mode for Carrying Out the Invention

[0013] The following examples are used to illustrate the present disclosure. Those skilled in the art can understand other advantages of the present disclosure based on the description of the present disclosure. In addition, the present disclosure can be implemented or applied as described in different embodiments. To implement the present disclosure, the following examples can be modified and / or changed without departing from its scope for different aspects and applications.

[0014] It should be noted that when used in the present disclosure, the singular forms "a", "an", and "the" include plural referents unless explicitly and clearly limited to one referent. The term "or" is used in the same sense as the term "and / or" unless otherwise indicated explicitly in the context.

[0015] As used herein, the terms "comprising," "comprises," "include," "including," "have," "having," "contain," "containing," and any other variations thereof are intended to broadly cover non-exclusive inclusion. For example, when an object is described as "including" a limitation, it may further include other components, elements, components, structures, regions, parts, devices, systems, processes, or connections, etc., without excluding other limitations, unless otherwise specified.

[0016] As used herein, the phrases "at least one" and "one or more" have the same meaning and can include one, two, three, or more.

[0017] Throughout this disclosure, ordinal numbers (e.g., first, second, third, etc.) may be used as adjectives for elements (i.e., any noun in this application). The use of ordinal numbers does not imply or create an order of elements, nor does it limit any element to only a single element, unless explicitly indicated by the use of terms such as "before," "after," "single," and other such terms. Rather, the use of ordinal numbers is to distinguish elements. By way of example, a first element is different from a second element, and the first element can include a plurality of elements and can follow (or precede) the second element in the order of elements.

[0018] As used herein, the term "about" generally means within ±20%, ±10%, ±5%, ±1%, ±0.5%, or ±0.1% of a given value or range. Alternatively, the term "about" means within the standard error of the acceptable mean value when considered by one of ordinary skill in the art. Unless otherwise specified, all numerical ranges, amounts, values, and percentages such as amounts of materials, durations of periods, temperatures, operating conditions, ratios of amounts, etc. disclosed herein should be understood to be modified in all instances by the term "about". Such numerical variations can occur, for example, as a result of experimental error; typical errors in measurement or handling procedures in making compounds, compositions, concentrates, or formulations; differences in the sources, manufacture, or purity of starting materials or components used in the present disclosure; or similar considerations.

[0019] The numerical ranges used herein are inclusive and combinable, and any numerical value falling within the numerical ranges herein can be regarded as the maximum or minimum value for deriving sub-ranges therefrom. For example, it should be understood that the numerical range "1% to 50%" includes any sub-ranges between the minimum value of 1% and the maximum value of 50%, such as sub-ranges of 1% to 20%, 30% to 50%, and 15% to 45%. Note that multiple numerical values used herein can be arbitrarily selected as the maximum and minimum values for deriving numerical ranges. For example, numerical ranges of 10% to 25%, 10% to 50%, and 25% to 50% can be derived from the numerical values of 10%, 25%, and 50%.

[0020] As used herein, the terms "treat," "treating," or "treatment" include partially or completely preventing, ameliorating, reducing, and / or managing symptoms, disorders, or conditions associated with a disease. The terms "treat," "treating," or "treatment" as used herein refer to the application or administration of one or more therapeutic agents or surgeries to a subject having a symptom, disorder, or condition associated with a disease, with the aim of partially or completely reducing, ameliorating, alleviating, delaying the onset, suppressing the progression, reducing the severity, and / or decreasing the incidence of one or more symptoms, disorders, or conditions associated with the disease. Treatment may be administered to a subject exhibiting only the initial signs of such symptoms, disorders, and / or conditions for the purpose of reducing the risk of developing symptoms, disorders, and / or conditions associated with the disease.

[0021] As used herein, the terms "subject," "individual," and "patient" are interchangeable and refer to an animal, such as a mammal. For example, the term "subject" may refer to both genders, male and female, unless a particular gender is indicated. In at least one embodiment of the present disclosure, the subject is selected from the group consisting of rodents, mice, monkeys, guinea pigs, dogs, cats, cows, sheep, pigs, horses, rabbits, and humans. In some preferred embodiments, the subject is a dog or a cat. In some preferred embodiments, the subject is a human.

[0022] As used herein, the term "substituted," when used to describe a chemical structure or moiety, refers to a derivative of that structure or moiety in which one or more of its hydrogen atoms are replaced by one or more substituents. Unless otherwise indicated, a "substituted" structure or moiety has substituents at one or more substitutable positions of that structure or moiety, and when two or more positions of any given structure or moiety are substituted, the substituents may be the same or different at each position.

[0023] The present disclosure relates to a pharmaceutical composition for treating MPNST in a subject in need of treatment, comprising a therapeutically effective amount of a benzenesulfonamide derivative and a pharmaceutically acceptable carrier thereof. The present disclosure also relates to a method for treating MPNST in a subject, comprising administering to the subject in need of treatment a therapeutically effective amount of the pharmaceutical composition of the present disclosure.

[0024] In at least one embodiment of the present disclosure, the benzenesulfonamide derivative is represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[0025]

Chemical formula

[0026] In the formula, R 1 ~R 7 are independently selected from the group consisting of H, C 1 ~C 6 linear or branched alkyl groups, C 1 ~C 6 linear or branched alkoxy groups, C 3 ~C 6 cycloalkyl groups, C 3 ~C 6 cycloheteroalkyl groups, amino groups, and halo groups, or R 6 and R 7 are linked to each other to form a ring.

[0027] In at least one embodiment of the present disclosure, the alkyl groups, alkoxy groups, cycloalkyl groups, cycloheteroalkyl groups and rings in R 1 ~R 7 are independently unsubstituted or substituted with one or more substituents. In some embodiments of the present disclosure, the substituents are selected from the group consisting of phenyl groups, halo groups, oxo groups, ether groups, hydroxyl groups, carboxyl groups, amino groups, sulfo groups, and sulfonamide groups.

[0028] In at least one embodiment of the present disclosure, the benzenesulfonamide derivative may be, but is not limited to, para-toluenesulfonamide (p-TSA), ortho-toluenesulfonamide, meta-toluenesulfonamide, N-ethyl-ortho-toluenesulfonamide, N-ethyl-para-toluenesulfonamide, or N-cyclohexyl-para-toluenesulfonamide.

[0029] In at least one embodiment of the present disclosure, the benzenesulfonamide derivative is at least one of para-toluenesulfonamide, ortho-toluenesulfonamide, and meta-toluenesulfonamide. The monomer of the benzenesulfonamide derivative is in the form of white crystals. In some embodiments, the pharmaceutical composition comprises a combination of two or more different benzenesulfonamide derivatives in any ratio.

[0030] In at least one embodiment of the present disclosure, the pharmaceutically acceptable carrier comprised in the pharmaceutical composition of the present disclosure is at least one selected from the group consisting of fillers, binders, preservatives, disintegrants, lubricants, suspending agents, wetting agents, biocompatible solvents, penetration enhancers, surfactants, thickeners, acids, flavoring agents, complexing agents, and any combination thereof.

[0031] In at least one embodiment of the present disclosure, the pharmaceutically acceptable carrier comprised in the pharmaceutical composition of the present disclosure is at least one selected from the group consisting of alkylene glycols, sebacic acid, dimethyl sulfoxide, ethanol, and any combination thereof.

[0032] In at least one embodiment of the present disclosure, examples of binders include, but are not limited to, pastes, sorbitol, guar gum, polyvinylpyrrolidone, cellulose derivatives such as hydroxypropylmethylcellulose, carboxymethylcellulose, carbomers (commercially available as Carbopols), and any combination thereof.

[0033] In at least one embodiment of the present disclosure, examples of preservatives include, but are not limited to, sodium benzoate, methyl paraben, propyl paraben, cresol, and any combination thereof.

[0034] In at least one embodiment of the present disclosure, examples of lubricants include, but are not limited to, metal stearates (e.g., magnesium stearate, calcium stearate, sodium stearate), stearic acid, talc, polyethylene glycol, soluble salts (e.g., sodium chloride and sodium benzoate), and any combination thereof.

[0035] In at least one embodiment of the present disclosure, examples of wetting agents include, but are not limited to, glycerin, sorbitol, polypropylene glycol, and any combination thereof.

[0036] In at least one embodiment of the present disclosure, examples of flavoring agents include, but are not limited to, peppermint oil, menthol, lemon oil, orange oil, cinnamon oil, and any combination thereof.

[0037] In at least one embodiment of the present disclosure, the pharmaceutically acceptable carrier may be polyethylene glycol (PEG), alkylene glycol, propylene glycol, sebacic acid, dimethyl sulfoxide (DMSO), ethanol, or any combination thereof. In some embodiments, examples of alkylene glycols include, but are not limited to, polyethylene glycol, propylene glycol, hexylene glycol, and any combination thereof.

[0038] In at least one embodiment of the present disclosure, the benzenesulfonamide derivative is selected from at least one of 1 wt% to 50 wt% of polyethylene glycol 400, 1 wt% to 10 wt% of 1,2-propylene glycol, 1 wt% to 10 wt% of sebacic acid, 1 to 20 wt% of 2-ethyl-1,3-hexanediol, 0 to 20 wt% of dimethyl sulfoxide, and 0 to 20 wt% of ethanol.

[0039] In at least one embodiment of the present disclosure, the benzenesulfonamide derivative is present in an amount of 1 wt% to 60 wt% of the pharmaceutical composition, for example, about 1 wt%, 2 wt%, 5 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 33 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 53 wt%, 55 wt% and 60 wt%. In some embodiments, the amount of the benzenesulfonamide derivative in the pharmaceutical composition has a lower limit selected from about 1 wt%, 5 wt%, 10 wt%, 15 wt%, 20 wt%, and 25 wt% of the composition and an upper limit selected from about 60 wt%, 55 wt%, 50 wt%, 45 wt%, 40 wt%, and 35 wt% of the composition. In some embodiments, the benzenesulfonamide derivative is present in an amount of 20 wt% to 40 wt% of the composition.

[0040] In at least one embodiment of the present disclosure, the pharmaceutical composition GW-MP101 provided herein comprises 1 wt% to 50 wt% of paratoluenesulfonamide, 1 wt% to 50 wt% of PEG400, 1 wt% to 10 wt% of 1,2-propylene glycol, 1 wt% to 5 wt% of sebacic acid, 0 to 15 wt% of paratoluenesulfonic acid, 1 to 20 wt% of 2-ethyl-1,3-hexanediol, 0 to 10 wt% of dimethyl sulfoxide, and 0 to 20 wt% of ethanol.

[0041] In at least one embodiment of the present disclosure, the pharmaceutical composition comprises at least one of 10% to 40% by weight of polyethylene glycol 400, 1% to 10% by weight of 1,2 - propylene glycol, 1% to 5% by weight of sebacic acid, 10% to 20% by weight of 2 - ethyl - 1,3 - hexanediol, 0% to 40% by weight of dimethyl sulfoxide, and 0% to 20% by weight of ethanol.

[0042] The method for preparing an injection of GW - MP101 formulation can be carried out, for example, by adding an adjuvant and / or a solvent to adjust the mixture to isotonicity. Also, the filtration step in this method can be carried out, for example, using a microporous filter.

[0043] In at least one embodiment of the present disclosure, the pharmaceutical composition may be formulated in a form suitable for administration routes such as enteral administration, sublingual administration, subcutaneous administration, rectal administration, and parenteral administration (for example, subcutaneous injection, intramuscular injection, intravenous injection, intratumoral injection, intraperitoneal injection, intra - arterial injection, and intrathecal injection). In some embodiments of the present disclosure, the pharmaceutical composition may be in a form selected from the group consisting of injection formulations, dry powders, tablets, oral liquids, flakes, films, lozenges, capsules, granules, pills, gels, lotions, ointments, emulsions, pastes, creams, eye drops, and salves.

[0044] In at least one embodiment of the present disclosure, the pharmaceutical composition may be administered to a subject intratumorally, intravenously, subcutaneously, intradermally, orally, intrathecally, intraperitoneally, intranasally, intramuscularly, intrapleurally, locally, or through spraying.

[0045] In at least one embodiment of the present disclosure, the pharmaceutical composition may be used to treat canine MPNST by inducing the removal of MPNST. For example, the GW-MP101 formulation of the present disclosure for inducing the removal of canine MPNST tumors is in the form of an injectable formulation and may be administered to a subject by intratumoral injection. The intratumoral injection dosage for the removal of canine MPNST may be from 0.1 mL / injection to 5 mL / injection (about 33 mg to 1650 mg of para-toluenesulfonamide or other benzenesulfonamide derivatives).

[0046] As used herein, the phrase "therapeutically effective amount" refers to the amount of an active ingredient (e.g., a benzenesulfonamide derivative) necessary to impart a desired therapeutic effect (e.g., inducing the removal of canine MPNST) to a subject being treated. The effective dosage will vary depending upon the route of administration, the use of excipients, the possibility of combination with other therapeutic treatments, and the condition being treated, as will be recognized by those skilled in the art.

[0047] In at least one embodiment of the present disclosure, the benzenesulfonamide derivative may be administered to a subject in a therapeutically effective amount of from about 1 mg / day to about 2000 mg / day during a treatment period or treatment cycle, such as 10 mg / day to 450 mg / day, 30 mg / day to 200 mg / day, or 40 mg / day to 150 mg / day. As used herein, the term "treatment cycle" refers to a treatment period that is repeated on a regular schedule followed by a period of rest without treatment.

[0048] In some embodiments of the present disclosure, the injection dosage for treating canine MPNST may be p-toluenesulfonamide or other benzenesulfonamide derivatives in the range of about 0.5 mg / day to 950 mg / day, 1 mg / day to 900 mg / day, 3 mg / day to 800 mg / day, 5 mg / day to 750 mg / day, 8 mg / day to 700 mg / day, 10 mg / day to 650 mg / day, 15 mg / day to 600 mg / day, 25 mg / day to 550 mg / day, 35 mg / day to 500 mg / day, 45 mg / day to 450 mg / day, 50 mg / day to 400 mg / day, 55 mg / day to 350 mg / day, 60 mg / day to 300 mg / day, and 65 mg / day to 250 mg / day.

[0049] In some embodiments of the present disclosure, the dosage of intratumoral injection for the removal of MPNST is 19.4 mL to 50 mL, about 6,400 mg to 16,500 mg of p-toluenesulfonamide or other benzenesulfonamide derivatives.

[0050] In at least one embodiment of the present disclosure, the pharmaceutical composition may be administered to the subject once or twice a day, one to seven times a week, or one to fourteen times a month. In at least one embodiment of the present disclosure, the pharmaceutical composition may be administered to the subject over a treatment period or treatment cycle of one to four weeks or one to four months. In some embodiments, the pharmaceutical composition may be administered to the subject two to three times a week over a two-week treatment period. In some embodiments, the pharmaceutical composition is administered to the subject more than six times during the first treatment period.

[0051] In at least one embodiment of the present disclosure, the pharmaceutical composition may be directly injected into the MPNST or injected into the area surrounding the MPNST. In some embodiments of the present disclosure, the dosage can be proportionally increased or decreased according to the treatment situation. In at least one embodiment of the present disclosure, the administration can continue until the tumor shrinks by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% (by volume or weight), or until the tumor is completely eliminated.

[0052] The present disclosure also provides the use of the pharmaceutical composition in the manufacture of a medicament for treating canine MPNST, wherein the pharmaceutical composition comprises the benzenesulfonamide derivative of the present disclosure and a pharmaceutically acceptable carrier thereof.

[0053] The present disclosure also provides the use of the pharmaceutical composition in the manufacture of a medicament for treating MPNST, wherein the pharmaceutical composition comprises the above-mentioned benzenesulfonamide derivative and a pharmaceutically acceptable carrier thereof. The present disclosure further provides a pharmaceutical composition for use in the treatment of MPNST, wherein the pharmaceutical composition comprises the above-mentioned benzenesulfonamide derivative and a pharmaceutically acceptable carrier thereof.

[0054] The following embodiments further demonstrate the effectiveness of the present disclosure, but should not be used to limit the scope of the present disclosure.

Example

[0055] The present disclosure is further illustrated by the following examples. However, these examples are merely illustrative of the present disclosure and in no way limit the scope and meaning of the present disclosure. In fact, many modifications and variations of the present disclosure will be apparent to those skilled in the art upon reading this specification and can be made without departing from its scope.

[0056] Preparation Example The pharmaceutical composition GW-MP101 for intratumoral injection is a colorless and transparent oily sterile solution containing the components listed in Table 1 and can be packaged in 5 mL glass ampoules. GW-MP101 contains 330 mg / mL of the active drug p-TSA.

[0057]

Table 1

[0058] The preparation of the composition of the present disclosure includes the steps of adding and mixing a solvent and an adjuvant in a predetermined ratio, heating the mixture to 80°C to 110°C while stirring to form a transparent oily liquid, gradually adding a sulfonamide drug while stirring until completely dissolved, and filtering and cooling the mixture to obtain the composition of the present disclosure of GW-MP101 in the form of an oily liquid.

[0059] The preparation of GW-MP101 injection can be carried out by using some techniques known in the art, such as adding an adjuvant and / or a solvent to adjust the mixture to an isotonic state or filtering the mixture by using a microporous filter.

[0060] The present disclosure also provides the use of GW-MP101 as a medicament for promoting the removal of in vivo tumors of a subject.

[0061] The effectiveness of the tumors disclosed in the present disclosure was evaluated by the following veterinary clinical trials. The trials followed the ethical principles related to the standards of Good Clinical Practice for the conduct of veterinary clinical trials.

[0062] Example 1 This clinical trial case was conducted at Evergreen Animal Hospital in Taipei City, Taiwan from October to December 2021.

[0063] Dog breed: Corgi Gender: Male Age: 13 years old Weight: 11 kg - 12 kg Liver function: Normal Kidney function: Normal Pathology: Malignant peripheral nerve sheath tumor, grade 2 Medical history: Anemia

[0064] Inclusion criteria are as follows: (A) The dog is 1 year of age or older; (B) The dog is diagnosed with MPNST by cytology or histopathology; (C) The veterinarian in the clinical trial assesses that the dog is inappropriate for surgical tumor removal; (D) The dog has at least one measurable tumor larger than 1 cm in diameter; (E) The veterinarian in the clinical trial assesses that the dog's mean life expectancy exceeds 3 months; and (F) The owner is able to understand and comply with the experimental procedures and is willing to sign the informed consent form.

[0065] Exclusion criteria are as follows: (A) The dog has received systemic chemotherapy within 4 weeks prior to participating in the study; (B) The dog has received radiation therapy within 4 weeks prior to participating in the study; (C) The dog has received major surgery (e.g., thoracotomy is not permitted, but non-invasive surgeries such as biopsies are permitted) within 4 weeks prior to participating in the study; (D) The dog has been treated with any other experimental drug, biological agent, medical material, or other anti-tumor treatment (such as immunomodulators and radiation therapy) within 4 weeks prior to participating in this study or during the period of this study experiment; (E) The dog has abnormal values in the following blood tests prior to participating in the study: a. Hemoglobin < 6.0 g / dL, b. Absolute neutrophil count (ANC) < 1,500 / μL, c. Albumin < 1.5 g / dL, d. Total bilirubin < 2 mg / dL, e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 5 × upper normal limit (UNL), f. Chronic kidney disease (CKD), International Renal Interest Society (IRIS) > stage 3; (F) The dog has any other serious disease such as infectious diseases, uncontrolled diabetes, stage C of chronic degenerative valvular disease (CDVD, one of the heart diseases), gastric ulcers, severe autoimmune diseases, etc., and the veterinarian in the clinical trial restricts the animal from participating in this study after evaluation; (G) The dog is known or suspected to have an allergic reaction to the components contained in any p-toluenesulfonamide drug; (H) The veterinarian in the clinical trial diagnoses that the dog's tumor is blocked by important blood vessels, so it is difficult to perform intratumoral injection there; (I) The dog is pregnant; (J) The veterinarian in the clinical trial determines that the dog is inappropriate to participate in this study.

[0066] Any individual who meets at least one of the following criteria should be withdrawn from the clinical trial: (A) Withdrawing the informed consent form; (B) The dog is receiving treatment prohibited by this trial; (C) After evaluating any pathological features, clinical adverse events, or any changes in the animal's condition, the veterinarian in the clinical trial determines that it is not in the most favorable situation for the dog to continue participating in the trial; (D) The dog is pregnant during the treatment period or is suspected of being pregnant by its owner or the trial veterinarian; (E) The dog has an adverse event of grade 3 or higher according to the Veterinary Cooperative Oncology Group - Common Terminology Criteria for Adverse Events (VCOG-CTCAE), and cannot return to grade 1 within 7 days after the adverse event, or the adverse event of grade 3 or higher still occurs after two dose reductions in the dog; (F) Signs and symptoms of disease progression or deterioration (the evaluation of deterioration is based on the Veterinary Cooperative Oncology Group - Response Evaluation Criteria in Solid Tumors v1.0 (VCOG-RECISTv1.0)); (G) Death; (H) Loss of follow-up; (I) Protocol violation.

[0067] Treatment method The test dogs received intratumoral injections of 3.8 mL, 3.7 mL, 1 mL, 3.7 mL, 3.6 mL, and 3.6 mL of the GW-MP101 drug on days 1, 5, 8, 12, 15, 22, 33, and 47 (each time was approximately 1180 - 1250 mg of p-toluenesulfonamide). The injection was performed as a single, multi-point (2 - 10 points) intratumoral injection.

[0068] Response evaluation criteria Electronic caliper measurements were performed before each administration, and computed tomography (CT) scans were performed before the first administration and at the final follow-up visit. Complete remission (CR) was defined as the complete disappearance of measurable or evaluable tumors, with no new tumors appearing for more than 4 weeks. Partial remission (PR) was defined as a reduction of 30% or more in measurable or evaluable tumors, with no new tumors appearing for more than 4 weeks. Stable disease (SD) was defined as a reduction of 30% or less or an increase of 20% or less in measurable or evaluable tumors. Progressive disease (PD) was defined as an increase of 20% or more in measurable or evaluable tumors or the appearance of new tumors due to the progression of other tumors.

[0069] Safety evaluation When conducting safety evaluations during the clinical trial period, the relevant researchers of the trial are responsible for defining and summarizing adverse events in the protocol (the relevant evaluation method referred to the "Veterinary Cooperative Oncology Group-Common Terminology Criteria for Adverse Events" (VCOG-CTCAE)).

[0070] The treatment results of MPNST in Example 1 are shown below.

[0071] Tumor volume change (measured with an electronic caliper) For the tumor, the measurement range was located in the MPNST of the right limb of the dog. After 6 administrations of the GW-MP101 drug, the volume of the tumor changed. The volume of the tumor was 32.84 cm 3 before treatment, 22.37 cm 3 before the second administration, and 0.30 cm 3 at the evaluation visit (6 weeks after the second administration). Comparing the tumor volume before the first administration with the tumor volume at the evaluation visit, the measurable or evaluable tumor was reduced by 100%, and the result was complete remission (CR) (see Table 2 and Figure 1 below).

[0072]

Table 2

[0073] Body temperature change The change in body temperature before and after each treatment is within 2.5 degrees (see below Table 3 and Figure 2).

[0074]

Table 3

[0075] Body weight change The change in body weight before and after each treatment is within 4.5 kg (see below Table 4 and Figure 3).

[0076]

Table 4

[0077] Intermediate efficacy (appearance change) After administering the GW - MP101 drug 6 times, an obvious change from swelling to flatness was observed at the tumor site on the limb of the dog (Figure 4).

[0078] Adverse effects No common side effects such as pain, nausea, vomiting, or local redness and inflammation were observed. The functions of the liver and kidneys were stable and normal during and after treatment.

[0079] Summary of this example The pharmaceutical composition of the present disclosure can effectively reduce or remove tumors, thereby improving the quality of life and clinical symptoms of dogs with MPNST. Furthermore, a significant increase in adverse reactions was not observed in the clinical trial.

[0080] The present disclosure has been described using exemplary embodiments. However, it should be understood that the scope of the present disclosure is not limited to the disclosed embodiments. On the contrary, various modifications and similar rearrangements are intended to be included. Therefore, the claims should be given the broadest interpretation so as to encompass all such modifications and similar configurations.

Claims

1. A method for treating malignant peripheral nerve sheath, comprising the step of administering a therapeutically effective amount of a pharmaceutical composition to a subject in need thereof, wherein the pharmaceutical composition comprises a benzenesulfonamide derivative and a pharmaceutically acceptable carrier.

2. The benzenesulfonamide derivative is represented by the following general formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, R １ to R ７ are independently selected from the group consisting of H, C １ to C ６ linear or branched alkyl group, C １ to C ６ linear or branched alkoxy group, C ３ to C ６ cycloalkyl group, C ３ to C ６ cycloheteroalkyl group, amino group, and halo group, or R ６ and R ７ are linked to each other to form a ring, and R １ to R ７ The alkyl group, the alkoxy group, the cycloalkyl group, the cycloheteroalkyl group, and the ring in R are each independently unsubstituted or substituted with one or more substituents. The method according to claim 1. (Claim 2) The method according to claim 1, wherein the substituent is selected from the group consisting of a phenyl group, a halo group, an oxo group, an ether group, a hydroxyl group, a carboxyl group, an amino group, a sulfo group, and a sulfonamide group.

3. The method according to claim 1, wherein the benzenesulfonamide derivative is at least one selected from the group consisting of para-toluenesulfonamide, ortho-toluenesulfonamide, meta-toluenesulfonamide, N-ethyl-ortho-toluenesulfonamide, N-ethyl-para-toluenesulfonamide, N-cyclohexyl-para-toluenesulfonamide, and any combination thereof.

4. The method according to claim 1, wherein the benzenesulfonamide derivative is para-toluenesulfonamide.

5. The method according to claim 1, wherein the pharmaceutically acceptable carrier is at least one selected from the group consisting of a filler, a binder, a preservative, a disintegrant, a lubricant, a suspending agent, a wetting agent, a biocompatible solvent, a penetration enhancer, a surfactant, a thickening agent, an acid, a flavoring agent, a complexing agent, and any combination thereof.

6. The method according to claim 1, wherein the pharmaceutically acceptable carrier is at least one selected from the group consisting of an alkylene glycol, sebacic acid, dimethyl sulfoxide, ethanol, and any combination thereof.

7. The method according to claim 6, wherein the alkylene glycol is at least one selected from the group consisting of polyethylene glycol, propylene glycol, hexylene glycol, and any combination thereof.

8. The method according to claim 1, wherein the benzenesulfonamide derivative is present in an amount of 1% to 50% by weight of the pharmaceutical composition.

9. The method according to claim 8, wherein the benzenesulfonamide derivative is present in an amount of 20% to 40% by weight of the pharmaceutical composition.

10. The method according to claim 1, wherein the pharmaceutical composition further comprises at least one of 10% to 40% by weight of polyethylene glycol 400, 1% to 10% by weight of 1,2 - propylene glycol, 1% to 5% by weight of sebacic acid, 10% to 20% by weight of 2 - ethyl - 1,3 - hexanediol, 0% to 40% by weight of dimethyl sulfoxide, and 0% to 20% by weight of ethanol.

11. The method according to claim 1, wherein the administration causes ablation of the malignant peripheral nerve sheath in the subject.

12. The method according to claim 1, wherein the subject is selected from the group consisting of rodents, mice, monkeys, guinea pigs, dogs, cats, cows, sheep, pigs, horses, rabbits, and humans.

13. The method according to claim 12, wherein the subject is a dog or a cat.

14. The method according to claim 1, wherein the benzenesulfonamide derivative in the pharmaceutical composition is administered to the subject in a therapeutically effective amount of about 10 mg / kg to about 100 mg / kg.

15. The method according to claim 1, wherein the benzenesulfonamide derivative in the pharmaceutical composition is administered to the subject in a therapeutically effective amount of about 10 mg / kg to about 5000 mg / kg during a treatment period or treatment cycle.

16. The method according to claim 1, wherein the pharmaceutical composition is administered to the subject intratumorally, intravenously, subcutaneously, intradermally, orally, intrathecally, intraperitoneally, intranasally, intramuscularly, intrapleurally, topically, or by spraying.

17. The method according to claim 1, wherein the pharmaceutical composition is in a form selected from the group consisting of injection preparations, dry powders, tablets, oral liquids, flakes, films, lozenges, capsules, granules, pills, gels, lotions, ointments, emulsions, pastes, creams, eye drops, and salves.

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