AU2023285788A1

AU2023285788A1 - Method for treating peripheral nerve sheath tumor

Info

Publication number: AU2023285788A1
Application number: AU2023285788A
Authority: AU
Inventors: Mao-yuan LIN; Chuan-Ching Yang; Nan-shan ZHONG
Original assignee: Gongwin Biopharm Co Ltd
Current assignee: Gongwin Biopharm Co Ltd
Priority date: 2023-12-20
Filing date: 2023-12-20
Publication date: 2025-07-10
Anticipated expiration: 2043-12-20
Also published as: AU2023285788B2

Abstract

#$%^&*AU2023285788A120250710.pdf##### ABSTRACT Provided is a pharmaceutical composition for treating malignant peripheral nerve sheath (MPNST), including a benzenesulfonamide derivative and a pharmaceutically acceptable carrier. Also provided is a method for treating canine MPNST by administering 5 the pharmaceutical composition to a subject in need thereof. ABSTRACT Provided is a pharmaceutical composition for treating malignant peripheral nerve sheath (MPNST), including a benzenesulfonamide derivative and a pharmaceutically 5 acceptable carrier. Also provided is a method for treating canine MPNST by administering the pharmaceutical composition to a subject in need thereof. 20 23 28 57 88 20 D ec 2 02 3 A B S T R A C T 2 0 2 3 2 8 5 7 8 8 2 0 D e c 2 0 2 3 P r o v i d e d i s a p h a r m a c e u t i c a l c o m p o s i t i o n f o r t r e a t i n g m a l i g n a n t p e r i p h e r a l n e r v e s h e a t h ( M P N S T ) , i n c l u d i n g a b e n z e n e s u l f o n a m i d e d e r i v a t i v e a n d a p h a r m a c e u t i c a l l y 5 a c c e p t a b l e c a r r i e r . A l s o p r o v i d e d i s a m e t h o d f o r t r e a t i n g c a n i n e M P N S T b y a d m i n i s t e r i n g t h e p h a r m a c e u t i c a l c o m p o s i t i o n t o a s u b j e c t i n n e e d t h e r e o f .

Description

METHODFOR METHOD FORTREATING TREATINGPERIPHERAL PERIPHERALNERVE NERVESHEATH SHEATHTUMOR TUMOR

BACKGROUND BACKGROUND 1. 1. Technical Field Technical Field

5 5 The present disclosure relates to methods for treating peripheral nerve sheath tumor The present disclosure relates to methods for treating peripheral nerve sheath tumor 2023285788

(PNST), and particularly to methods for treating malignant peripheral nerve sheath tumor (PNST), and particularly to methods for treating malignant peripheral nerve sheath tumor

(MPNST). (MPNST).

2. Description of Related Art 2. Description of Related Art

10 10 Peripheral nerve sheath tumor (PNST), endoneurial fibroblasts, and/or Schwann cells Peripheral nerve sheath tumor (PNST), endoneurial fibroblasts, and/or Schwann cells

occurs relatively occurs relatively infrequently infrequently in in animals animals except dog. It except dog. It is is classified classified as as aa benign and benign and

malignant tumor. malignant tumor.Malignant MalignantPNSTs PNSTs (MPNSTs) (MPNSTs) arise commonly arise most most commonly from peripheral from peripheral

nerves, spinal nerves, spinal roots, roots,and andcranial cranialnerves inindogs. nerves MPNSTs dogs. occur in MPNSTs occur in middle-aged middle-agedtotoolder older

dogs, particularly in medium- to large-breeds and are characterized by slow growth and rare dogs, particularly in medium- to large-breeds and are characterized by slow growth and rare

15 15 metastasis. metastasis.

Canine PNSTs Canine PNSTs resemble resemble malignant malignant PNSTs PNSTs in humans, in humans, regarding regarding both both histology histology and and

behavior. Histologically, the PNST is characterized by interacting patterns of spindle cells. behavior. Histologically, the PNST is characterized by interacting patterns of spindle cells.

There are two histological patterns including Antoni types A and B, which are dense areas There are two histological patterns including Antoni types A and B, which are dense areas

of spindle-shaped cells and less cellular areas with more pleomorphic cells, respectively. of spindle-shaped cells and less cellular areas with more pleomorphic cells, respectively.

20 20 This kind This kind of of tumor tumorspreads spreadsproximally proximallyand anddistally distally along along the the nerve nerve and andmay mayultimately ultimately

involve the spinal cord, causing compression and associated neurological deficits. Despite involve the spinal cord, causing compression and associated neurological deficits. Despite

metastases being rare, lung and uveal metastases have been reported. metastases being rare, lung and uveal metastases have been reported.

There are therapeutic options for MPNST including surgical resection, radiotherapy, There are therapeutic options for MPNST including surgical resection, radiotherapy,

and chemotherapy. Early detection of the mass and correct diagnosis is the core of this tumor and chemotherapy. Early detection of the mass and correct diagnosis is the core of this tumor

25 25 for complete surgical resection and postsurgical radiotherapy could reduce local recurrences. for complete surgical resection and postsurgical radiotherapy could reduce local recurrences.

Recommended Recommended chemotherapeutic chemotherapeutic method method is a is a combination combination of vincristine,doxorubicin, of vincristine, doxorubicin,and and

cyclophosphamide. However, it has not yet been sufficiently researched. The novel therapy cyclophosphamide. However, it has not yet been sufficiently researched. The novel therapy

of metronomic therapy has recently become one of the therapeutic options. of metronomic therapy has recently become one of the therapeutic options.

Nevertheless, there is still lacking optimization of proper drugs, doses, and schedules Nevertheless, there is still lacking optimization of proper drugs, doses, and schedules

for the for thetreatment treatmentofofMPNST. In view MPNST. In view of of the the high high incidence incidence of ofMPNST withserious MPNST with serioushealth health

5 5 threats, it is an urgent and unmet need to develop pharmaceutical compositions to break threats, it is an urgent and unmet need to develop pharmaceutical compositions to break 2023285788

through the current technical limitations and meet demands in the effective treatment of through the current technical limitations and meet demands in the effective treatment of

MPNST. MPNST.

BRIEF SUMMARY BRIEF SUMMARY In view In viewofofthethe foregoing, foregoing, the the present present disclosure disclosure provides provides effective effective and and safe safe

10 10 pharmaceutical compositions that can be used for the treatment or adjuvant treatment of pharmaceutical compositions that can be used for the treatment or adjuvant treatment of

MPNST. MPNST. The The pharmaceutical pharmaceutical composition composition comprises comprises a benzenesulfonamide a benzenesulfonamide derivative derivative and and

a pharmaceutically a pharmaceutically acceptable acceptable carrier carrier thereof. thereof. By administration of By administration of the the pharmaceutical pharmaceutical

composition provided in the present disclosure, the size of tumor in the subject is reduced composition provided in the present disclosure, the size of tumor in the subject is reduced

and the life quality thereof can be improved. and the life quality thereof can be improved.

15 15

BRIEF DESCRIPTION BRIEF DESCRIPTION OF OFTHE THEDRAWINGS DRAWINGS

The patent or application file contains at least one drawing executed in color. Copies The patent or application file contains at least one drawing executed in color. Copies

of this patent or patent application publication with color drawing(s) will be provided by the of this patent or patent application publication with color drawing(s) will be provided by the

Office upon request and payment of the necessary fee. Office upon request and payment of the necessary fee.

20 20 The present The presentdisclosure disclosurecan canbebemore more fully fully understood understood by reading by reading the following the following

descriptions ofofthe descriptions embodiments, the embodiments, with with reference referencemade made to tothe theaccompanying accompanying drawings. drawings.

FIG. 11 shows FIG. showsthe the volume volumechange changeofofMPNSTs MPNSTs in the in the tumor tumor of the of the dog dog (Case (Case No. No. 01- 01-

S10-E10)treated S10-E10) treated with with the theGW-MP101 drug, GW-MP101 drug, wherein wherein thedosage the dosageofofPTS PTSininthe theGW-MP101 GW-MP101

drug is 100 mg/kg/dog. PTS: para-toluene sulfonamide; i.t: intratumoral administration. drug is 100 mg/kg/dog. PTS: para-toluene sulfonamide; i.t: intratumoral administration.

2

FIG. 22 shows FIG. showsthe the body bodytemperature temperaturechange changeofofthe the dog dog (Case (Case No. No.01-S10-E10) 01-S10-E10)treated treated

with the with theGW-MP101 drug,wherein GW-MP101 drug, wherein the the dosage dosage of PTS in of PTS inthe theGW-MP101 drug is GW-MP101 drug is 100 100

mg/kg/dog. PTS: para-toluene sulfonamide; i.t: intratumoral administration. mg/kg/dog. PTS: para-toluene sulfonamide; i.t: intratumoral administration.

FIG. 33 shows FIG. the body shows the bodyweight weightchange changeofofthe the dog dog (Case (Case No. No.01-S10-E10) 01-S10-E10)treated treatedwith with

5 5 the GW-MP101 the drug, GW-MP101 drug, wherein wherein thethe dosage dosage of of PTS in in PTS theGW-MP101 the GW-MP101drug drug is 100 is 100 mg/kg/dog. mg/kg/dog. 2023285788

PTS: para-toluene sulfonamide; i.t: intratumoral administration. PTS: para-toluene sulfonamide; i.t: intratumoral administration.

FIG. 44 shows FIG. the representative shows the representative clinical clinicalphotographs ofof photographs canine MPNSTs canine in the MPNSTs in the tumor tumor

of the of the dog dog (Case (Case No. 01-S10-E10)before No. 01-S10-E10) beforeand andafter after the the administration administration of ofthe theGW-MP101 GW-MP101

drug. D: Day; T1 to T6: the 1st to 6th administration of the GW-MP101 drug; SV: Subject drug. D: Day; T1 to T6: the 1st to 6th administration of the GW-MP101 drug; SV: Subject

10 10 Visit; RV: Visit; RV: Random Visit; CV: Random Visit; CV:Conclusion ConclusionVisit. Visit.

DETAILEDDESCRIPTION DETAILED DESCRIPTION

Thefollowing The followingexamples examplesareareused usedtotoexemplify exemplify thethe presentdisclosure. present disclosure.AAperson personofof

ordinary skill in the art can understand the other advantages of the present disclosure, based ordinary skill in the art can understand the other advantages of the present disclosure, based

15 15 on the on the specification specification ofof the thepresent presentdisclosure. disclosure.The The present present disclosure disclosure can can also also be be

implemented or applied as described in different examples. It is possible to modify and/or implemented or applied as described in different examples. It is possible to modify and/or

alter the following examples for carrying out this disclosure without contravening its scope alter the following examples for carrying out this disclosure without contravening its scope

for different aspects and applications. for different aspects and applications.

It is noted that, as used in this disclosure, the singular forms “a,” “an,” and “the” include It is noted that, as used in this disclosure, the singular forms "a," "an," and "the" include

20 20 plural referents unless expressly and unequivocally limited to one referent. The term “or” is plural referents unless expressly and unequivocally limited to one referent. The term "or" is

used interchangeably with the term “and/or” unless the context clearly indicates otherwise. used interchangeably with the term "and/or" unless the context clearly indicates otherwise.

As used herein, the term “comprise,” “comprising,” “include,” “including,” “have,” As used herein, the term "comprise," "comprising," "include," "including," "have,"

“having,” “contain,”"containing," "having," "contain," “containing,” and and any other any other variations variations thereof thereof are intended are intended toacover a to cover

non-exclusive inclusion. For example, when describing an object “comprises” a limitation, non-exclusive inclusion. For example, when describing an object "comprises" a limitation,

25 25 unless otherwise unless otherwise specified, specified, itit may mayadditionally additionallyinclude includeother other ingredients,elements, ingredients, elements,

3

components, structures, regions, parts, devices, systems, steps, or connections, etc., and components, structures, regions, parts, devices, systems, steps, or connections, etc., and

should not exclude other limitations. should not exclude other limitations.

As used herein, the terms “at least one” and “one or more” may have the same meaning As used herein, the terms "at least one" and "one or more" may have the same meaning

and include one, two, three, or more. and include one, two, three, or more.

5 5 Throughout this disclosure, ordinal numbers (e.g., first, second, third, etc.) may be used as Throughout this disclosure, ordinal numbers (e.g., first, second, third, etc.) may be used as 2023285788

an adjective for an element (i.e., any noun in the application). The use of ordinal numbers is not an adjective for an element (i.e., any noun in the application). The use of ordinal numbers is not

to imply or create an ordering of the elements nor to limit any element to being only a single to imply or create an ordering of the elements nor to limit any element to being only a single

element unless expressly indicated, such as by the use of the terms “before,” “after,” “single,” element unless expressly indicated, such as by the use of the terms "before," "after," "single,"

and other such terminology. Rather, the use of ordinal numbers is to distinguish between the and other such terminology. Rather, the use of ordinal numbers is to distinguish between the

10 10 elements. By way of an example, a first element is distinct from a second element, and the first elements. By way of an example, a first element is distinct from a second element, and the first

element may encompass more than one element and succeed (or precede) the second element in element may encompass more than one element and succeed (or precede) the second element in

an ordering of elements. an ordering of elements.

As used herein, the term “about” generally means within ±20%, ±10%, ±5%, ±1% ±0.5%, As used herein, the term "about" generally means within +20%, +10%, +5%, 11% +0.5%,

and ±0.1% of a given value or range. Alternatively, the term “about” means within an acceptable and 0.1% of a given value or range. Alternatively, the term "about" means within an acceptable

15 15 standard error of the mean when considered by one of ordinary skill in the art. Unless otherwise standard error of the mean when considered by one of ordinary skill in the art. Unless otherwise

expressly specified, all of the numerical ranges, amounts, values and percentages such as those expressly specified, all of the numerical ranges, amounts, values and percentages such as those

for quantities of materials, durations of time periods, temperatures, operating conditions, ratios for quantities of materials, durations of time periods, temperatures, operating conditions, ratios

of amounts, and the likes disclosed herein should be understood as modified in all instances by of amounts, and the likes disclosed herein should be understood as modified in all instances by

the term “about.” Such variations in the numerical value may occur by, e.g., the experimental the term "about." Such variations in the numerical value may occur by, e.g., the experimental

20 20 error, the typical error in measuring or handling procedure for making compounds, compositions, error, the typical error in measuring or handling procedure for making compounds, compositions,

concentrates, or formulations, the differences in the source, manufacture, or purity of starting concentrates, or formulations, the differences in the source, manufacture, or purity of starting

materials or ingredients used in the present disclosure, or like considerations. materials or ingredients used in the present disclosure, or like considerations.

The numeral ranges used herein are inclusive and combinable, any numeral value that falls The numeral ranges used herein are inclusive and combinable, any numeral value that falls

within the numeral scope herein could be taken as a maximum or minimum value to derive the within the numeral scope herein could be taken as a maximum or minimum value to derive the

25 25 sub-ranges therefrom. For example, it should be understood that the numeral range “1% to 50%” sub-ranges therefrom. For example, it should be understood that the numeral range "1% to 50%"

comprises any comprises any sub-ranges sub-ranges between between the the minimum value of minimum value of 1% to the 1% to the maximum valueofof50%, maximum value 50%,

4

such as the sub-ranges from 1% to 20%, from 30% to 50%, and from 15% to 45%. In addition, such as the sub-ranges from 1% to 20%, from 30% to 50%, and from 15% to 45%. In addition,

a plurality of numeral values used herein can be optionally selected as maximum and minimum a plurality of numeral values used herein can be optionally selected as maximum and minimum

values to derive numerical ranges. For instance, the numerical ranges of 10% to 25%, 10% to values to derive numerical ranges. For instance, the numerical ranges of 10% to 25%, 10% to

50%, and 25% to 50% can be derived from the numeral values of 10%, 25%, and 50%. 50%, and 25% to 50% can be derived from the numeral values of 10%, 25%, and 50%.

5 5 As used herein, the term “treat,” “treating” or “treatment” encompasses partially or As used herein, the term "treat," "treating" or "treatment" encompasses partially or 2023285788

completely preventing, ameliorating, mitigating and/or managing a symptom, a disorder or a completely preventing, ameliorating, mitigating and/or managing a symptom, a disorder or a

condition associated with a disease. The term “treat,” “treating” or “treatment” as used herein condition associated with a disease. The term "treat," "treating" or "treatment" as used herein

refers to application or administration of one or more therapeutic agent or surgery to a subject, refers to application or administration of one or more therapeutic agent or surgery to a subject,

who has a symptom, a disorder or a condition associated with a disease, with the purpose to who has a symptom, a disorder or a condition associated with a disease, with the purpose to

10 10 partially or completely alleviate, ameliorate, relieve, delay onset of, inhibit progression of, reduce partially or completely alleviate, ameliorate, relieve, delay onset of, inhibit progression of, reduce

severity of, and/or reduce incidence of one or more symptoms, disorders or conditions associated severity of, and/or reduce incidence of one or more symptoms, disorders or conditions associated

with the disease. Treatment may be administered to a subject who exhibits only an early sign of with the disease. Treatment may be administered to a subject who exhibits only an early sign of

such symptoms, disorders, and/or conditions for the purpose of decreasing the risk of developing such symptoms, disorders, and/or conditions for the purpose of decreasing the risk of developing

the symptoms, disorders, and/or conditions associated with a disease. the symptoms, disorders, and/or conditions associated with a disease.

15 15 As used herein, the terms “subject,” “individual” and “patient” may be interchangeable and As used herein, the terms "subject," "individual" and "patient" may be interchangeable and

refer to an animal, e.g., a mammal. The term “subject” is intended to refer to both the male and refer to an animal, e.g., a mammal. The term "subject" is intended to refer to both the male and

female gender unless one gender is specifically indicated. At least one embodiment of the present female gender unless one gender is specifically indicated. At least one embodiment of the present

disclosure, the subject is selected from the group consisting of a rodent, a murine, a monkey, a disclosure, the subject is selected from the group consisting of a rodent, a murine, a monkey, a

guinea pig, a dog, a cat, a cow, a sheep, a pig, a horse, a rabbit, and a human. In some guinea pig, a dog, a cat, a cow, a sheep, a pig, a horse, a rabbit, and a human. In some

20 20 embodiments, the subject is a dog or a cat. In other embodiments, the subject is a human. embodiments, the subject is a dog or a cat. In other embodiments, the subject is a human.

As used herein, the term “substituted,” when used to describe a chemical structure or moiety, As used herein, the term "substituted," when used to describe a chemical structure or moiety,

refers to a derivative of that structure or moiety, wherein one or more of its hydrogen atoms is/are refers to a derivative of that structure or moiety, wherein one or more of its hydrogen atoms is/are

substituted with one or more substituent(s). Unless otherwise indicated, a “substituted” structure substituted with one or more substituent(s). Unless otherwise indicated, a "substituted" structure

or moiety has a substituent at one or more substitutable positions of the structure or moiety, and or moiety has a substituent at one or more substitutable positions of the structure or moiety, and

25 25 when more than one position in any given structure or moiety is substituted, the substituent is when more than one position in any given structure or moiety is substituted, the substituent is

either the same or different at each position. either the same or different at each position.

5

The present disclosure is directed to a pharmaceutical composition for treating MPNST The present disclosure is directed to a pharmaceutical composition for treating MPNST

in a subject in need thereof, comprising a benzenesulfonamide derivative in a therapeutically in a subject in need thereof, comprising a benzenesulfonamide derivative in a therapeutically

effective amount and a pharmaceutically acceptable carrier thereof. The present disclosure effective amount and a pharmaceutically acceptable carrier thereof. The present disclosure

is further is further directed directed to method to a amethod for for treating treating MPNST, MPNST, comprising comprising administering administering a a

5 5 therapeutically effective amount of the pharmaceutical composition of the present disclosure therapeutically effective amount of the pharmaceutical composition of the present disclosure 2023285788

to the subject in need thereof. to the subject in need thereof.

In at In at least least one one embodiment embodiment of the of the present present disclosure, disclosure, the the benzenesulfonamide benzenesulfonamide

derivative is represented by formula (I) below: derivative is represented by formula (I) below:

R2 R1 o R6 R3 R7 o R4 R5 (I), (I),

10 10 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof,

wherein R to R are independently selected from the group consisting of H, a C -C linear wherein R1 1 to R7 7are independently selected from the group consisting of H, a C1-C61 linear 6

or branched alkyl group, a C -C linear or branched alkoxy group, a C -C cycloalkyl group, a 1 linear or branched alkyl group, a C1-C6 6 or branched alkoxy group, a C3-C63 cycloalkyl 6 group, a

C -C cycloheteroalkyl group, an amino group, and a halo group, or R and R are linked to 3 6cycloheteroalkyl group, an amino group, and a halo group, or R6 and R7 6are linked C3-C6 7 to

each other to form a ring. each other to form a ring.

15 15 In at least one embodiment of the present disclosure, the alkyl group, the alkoxy group, the In at least one embodiment of the present disclosure, the alkyl group, the alkoxy group, the

cycloalkyl group, the cycloheteroalkyl group, and the ring in R to R are independently cycloalkyl group, the cycloheteroalkyl group, and the ring in R1 to R7 1are independently 7

unsubstituted or substituted with one or more substituents. In some embodiments of the present unsubstituted or substituted with one or more substituents. In some embodiments of the present

disclosure, the substituent is selected from the group consisting of phenyl, halo, oxo, ether, disclosure, the substituent is selected from the group consisting of phenyl, halo, oxo, ether,

hydroxyl, carboxyl, amino, sulfo, and sulfonamide group. hydroxyl, carboxyl, amino, sulfo, and sulfonamide group.

20 20 In at least one embodiment of the present disclosure, the benzenesulfonamide derivative In at least one embodiment of the present disclosure, the benzenesulfonamide derivative

may be, but not limited to, para-toluene sulfonamide (p-TSA), ortho-toluene sulfonamide, may be, but not limited to, para-toluene sulfonamide (p-TSA), ortho-toluene sulfonamide,

meta-toluene sulfonamide, meta-toluene sulfonamide,N-ethyl-ortho-toluene N-ethyl-ortho-toluene sulfonamide, sulfonamide, N-ethyl-para-toluene N-ethyl-para-toluene

sulfonamide, or sulfonamide, or N-cyclohexyl-para-toluene sulfonamide. N-cyclohexyl-para-toluene sulfonamide.

In at least one embodiment of the present disclosure, the benzenesulfonamide derivative In at least one embodiment of the present disclosure, the benzenesulfonamide derivative

6

is at least one of para-toluene sulfonamide, ortho-toluene sulfonamide, and meta-toluene is at least one of para-toluene sulfonamide, ortho-toluene sulfonamide, and meta-toluene

sulfonamide. The monomer sulfonamide. The monomerof of thethe benzenesulfonamide benzenesulfonamide derivative derivative is is ininthe theform formofofwhite white

crystal. In some embodiments, the pharmaceutical composition comprises a combination of crystal. In some embodiments, the pharmaceutical composition comprises a combination of

two or more different benzenesulfonamide derivatives in any ratio. two or more different benzenesulfonamide derivatives in any ratio.

5 5 In at least one embodiment of the present disclosure, the pharmaceutically acceptable In at least one embodiment of the present disclosure, the pharmaceutically acceptable 2023285788

carrier contained in the pharmaceutical composition of the present disclosure may be at least carrier contained in the pharmaceutical composition of the present disclosure may be at least

one selected from the group consisting of a filler, a binder, a preservative, a disintegrating one selected from the group consisting of a filler, a binder, a preservative, a disintegrating

agent, aa lubricant, agent, lubricant, aa suspending suspendingagent, agent,a awetting wettingagent, agent,a biocompatible a biocompatible solvent, solvent, a a

penetration enhancer, penetration enhancer, aa surfactant, surfactant, aa thickening thickening agent, agent, ananacid, acid,a aflavoring flavoringagent, agent,a a

10 10 complexingagent, complexing agent, and and any any combination combinationthereof. thereof.

In at least one embodiment of the present disclosure, the pharmaceutically acceptable In at least one embodiment of the present disclosure, the pharmaceutically acceptable

one selected from the group consisting of alkylene glycol, sebacic acid, dimethyl sulfoxide, one selected from the group consisting of alkylene glycol, sebacic acid, dimethyl sulfoxide,

ethanol, and any combination thereof. ethanol, and any combination thereof.

15 15 In at least one embodiment of the present disclosure, the examples of the binder include, In at least one embodiment of the present disclosure, the examples of the binder include,

but are not limited to, paste, sorbitol, guar gum, polyvinyl pyrrolidone, cellulose derivatives, but are not limited to, paste, sorbitol, guar gum, polyvinyl pyrrolidone, cellulose derivatives,

such as such as hydroxypropyl methylcellulose, carboxymethyl hydroxypropyl methylcellulose, cellulose, carbomer carboxymethyl cellulose, carbomer (commercially (commercially

available as Carbopols), and any combination thereof. available as Carbopols), and any combination thereof.

In at least one embodiment of the present disclosure, the examples of the preservative In at least one embodiment of the present disclosure, the examples of the preservative

20 20 include, but are not limited to, sodium benzoate, methyl paraben, propyl paraben, cresol, include, but are not limited to, sodium benzoate, methyl paraben, propyl paraben, cresol,

and any combination thereof. and any combination thereof.

In at least one embodiment of the present disclosure, the examples of the lubricant include, In at least one embodiment of the present disclosure, the examples of the lubricant include,

but are not limited to, metal stearates (such as magnesium stearate, calcium stearate, and but are not limited to, metal stearates (such as magnesium stearate, calcium stearate, and

sodium stearate), stearic acid, talc, polyethylene glycol, soluble salts (such as sodium sodium stearate), stearic acid, talc, polyethylene glycol, soluble salts (such as sodium

25 25 chloride and sodium benzoate), and any combination thereof. chloride and sodium benzoate), and any combination thereof.

7

In at least one embodiment of the present disclosure, the examples of the wetting agent In at least one embodiment of the present disclosure, the examples of the wetting agent

include, but are not limited to, glycerin, sorbitol, polypropylene glycol, and any combination include, but are not limited to, glycerin, sorbitol, polypropylene glycol, and any combination

thereof. thereof.

In at least one embodiment of the present disclosure, the examples of the flavoring agent In at least one embodiment of the present disclosure, the examples of the flavoring agent

5 5 include, but are not limited to, peppermint oil, menthol, lemon oil, orange oil, cinnamon oil, include, but are not limited to, peppermint oil, menthol, lemon oil, orange oil, cinnamon oil, 2023285788

and any combination thereof. and any combination thereof.

carrier may be polyethylene glycol (PEG), alkylene glycol, propylene glycol, sebacic acid, carrier may be polyethylene glycol (PEG), alkylene glycol, propylene glycol, sebacic acid,

dimethyl sulfoxide dimethyl sulfoxide (DMSO), ethanol,ororany (DMSO), ethanol, anycombination combination thereof.InInsome thereof. embodiments, someembodiments,

10 10 the examples of the alkylene glycol include, but are not limited to, polyethylene glycol, the examples of the alkylene glycol include. but are not limited to, polyethylene glycol,

propylene glycol, hexylene glycol, and any combination thereof. propylene glycol, hexylene glycol, and any combination thereof.

carrier is chosen from at least one of 1% to 50% by weight of polyethylene glycol 400, 1% carrier is chosen from at least one of 1% to 50% by weight of polyethylene glycol 400, 1%

to 10% by weight of 1,2-propylene glycol, 1% to 10% by weight of sebacic acid, 1% to 20% to 10% by weight of 1,2-propylene glycol, 1% to 10% by weight of sebacic acid, 1% to 20%

15 15 by weight by weight of of 2-ethyl-1,3-hexanediol, 2-ethyl-1,3-hexanediol,0% 0% to to 20% by weight 20% by weight of of dimethyl dimethyl sulfoxide, sulfoxide, and and 0% 0%

to 20% by weight of ethanol. to 20% by weight of ethanol.

In at least one embodiment of the present disclosure, the benzenesulfonamide derivative is In at least one embodiment of the present disclosure, the benzenesulfonamide derivative is

present in an amount of from 1% to 60% of the pharmaceutical composition by weight, such present in an amount of from 1% to 60% of the pharmaceutical composition by weight, such

as about as about 1%, 1%, 2%, 5%, 10%, 2%, 5%, 10%,15%, 15%,20%, 20%, 25%, 25%, 30%, 30%, 33%, 33%, 35%,35%, 40%, 40%, 45%, 45%, 50%,55% 50%, 53%, 53%, 55%

20 20 and 60%. and 60%.InInsome some embodiments, embodiments, an amount an amount of benzenesulfonamide of the the benzenesulfonamide derivative derivative in in the the

pharmaceutical composition pharmaceutical compositionhas has aa lower lower limit limitchosen chosenfrom from about about1%, 1%, 5%, 5%, 10%, 15%,20%, 10%, 15%, 20%,

and 25% of the composition by weight, and an upper limit chosen from about 60%, 55%, 50%, and 25% of the composition by weight, and an upper limit chosen from about 60%, 55%, 50%,

45%, 40%, 45%, 40%,andand35%35% of composition of the the composition by weight. by weight. In some In some embodiments, embodiments, the the

benzenesulfonamidederivative benzenesulfonamide is present derivative is present in in an an amount amountof of from from 20% 20% to 40%toof40% the of the

25 25 compositionby composition by weight. weight.

In at least one embodiment of the present disclosure, the pharmaceutical composition In at least one embodiment of the present disclosure, the pharmaceutical composition

GW-MP101 GW-MP101 provided provided herein herein comprises comprises 1%50% 1% to to 50% by weight by weight of para-toluene of para-toluene sulfonamide, sulfonamide,

1% to 40% 1% to byweight 40% by weightof of PEG 400,4%4%toto10% PEG400, 10%byby weight weight ofof1,2-propylene 1,2-propyleneglycol, glycol, 1% 1%5%to 5%

by weight of sebacic acid, 0% to 15% by weight of para-toluene sulfonic acid, 1% to 20% by weight of sebacic acid, 0% to 15% by weight of para-toluene sulfonic acid, 1% to 20%

5 5 by weight by weight of of 2-ethyl-1,3-hexanediol, 2-ethyl-1,3-hexanediol,0% 0% to to 10% by weight 10% by weight of of dimethyl dimethyl sulfoxide, sulfoxide, and and 0% 0% 2023285788

to 20% by weight of ethanol. to 20% by weight of ethanol.

comprises at least one of 10% to 40% by weight of polyethylene glycol 400, 1% to 10% by 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 weight of 1,2-propylene glycol, 1% to 5% by weight of sebacic acid, 10% to 20% by weight of

10 10 2-ethyl-1,3-hexanediol, 0% to 40% by weight of dimethyl sulfoxide, and 0% to 20% by weight 2-ethyl-1,3-hexanediol, 0% to 40% by weight of dimethyl sulfoxide, and 0% to 20% by weight

of ethanol of ethanol

The process for preparing an injection formulation of the GW-MP101 preparation can The process for preparing an injection formulation of the GW-MP101 preparation can

be carried out by, for example, adding an adjuvant and/or a solvent to adjust the mixture to be carried out by, for example, adding an adjuvant and/or a solvent to adjust the mixture to

be isotonic. Further, the step of filtering in the process can be carried out by, for example, be isotonic. Further, the step of filtering in the process can be carried out by, for example,

15 15 using a microporous filter. using a microporous filter.

may be formulated into a form suitable for the following administration routes: enteral may be formulated into a form suitable for the following administration routes: enteral

administration, sublingual administration, sublingualadministration, administration, subcutaneous subcutaneous administration, administration, rectal rectal

administration, and parenteral administration, such as subcutaneous injection, intramuscular administration, and parenteral administration, such as subcutaneous injection, intramuscular

20 20 injection, intravenous injection, intratumoral injection, abdominal injection, intraarterial injection, intravenous injection, intratumoral injection, abdominal injection, intraarterial

injection, and subarachnoid injection. In some embodiments of the present disclosure, the injection, and subarachnoid injection. In some embodiments of the present disclosure, the

pharmaceutical composition pharmaceutical may compositionmay be be in in a form a form selected selected from from thethe group group consisting consisting of of an an

injection formulation, a dry powder, a tablet, an oral liquid, a flake, a film, a lozenge, a injection formulation, a dry powder, a tablet, an oral liquid, a flake, a film, a lozenge, a

capsule, a granule, a pill, a gel, a lotion, an ointment, an emulsifier, a paste, a cream, an eye capsule, a granule, a pill, a gel, a lotion, an ointment, an emulsifier, a paste, a cream, an eye

25 25 drop, and a salve. drop, and a salve.

9

maybe be may administered administered to subject to the the subject intratumorally, intratumorally, intravenously, intravenously, subcutaneously, subcutaneously,

intradermally, orally, intrathecally, intraperitoneally, intranasally, intramuscularly, intrapleurally, intradermally, orally, intrathecally, intraperitoneally, intranasally, intramuscularly, intrapleurally,

topically, or through nebulization. topically, or through nebulization.

5 5 In at least one embodiment of the present disclosure, the pharmaceutical composition In at least one embodiment of the present disclosure, the pharmaceutical composition 2023285788

maybebeused may usedtoto treat treat aacanine MPNST bybytriggering canineMPNST triggering ablation ablation of of the theMPNST. Forexample, MPNST. For example,

the GW-MP101 preparation of the present disclosure for triggering ablation of the canine the GW-MP101 preparation of the present disclosure for triggering ablation of the canine

MPNST may be in the form of an injection formulation and administered to the subject by MPNST may be in the form of an injection formulation and administered to the subject by

intratumoral injection. The intratumoral injection dose for canine MPNST ablation may be intratumoral injection. The intratumoral injection dose for canine MPNST ablation may be

10 10 from 0.1 from 0.1mL/injection mL/injectiontoto5 5mL/injection mL/injection (about (about 33 33 mg1650 mg to to 1650 mg of mg of para-toluene para-toluene

sulfonamide or other benzenesulfonamide derivatives). sulfonamide or other benzenesulfonamide derivatives).

As used herein, the phrase “a therapeutically effective amount” refers to the amount of As used herein, the phrase "a therapeutically effective amount" refers to the amount of

an active ingredient (e.g., the benzenesulfonamide derivative) that is required to confer a an active ingredient (e.g., the benzenesulfonamide derivative) that is required to confer a

desired therapeutic effect (e.g., triggering ablation of a canine MPNST) on the treated desired therapeutic effect (e.g., triggering ablation of a canine MPNST) on the treated

15 15 subject. Effective doses will vary, as recognized by one of ordinary skill in the art, depending subject. Effective doses will vary, as recognized by one of ordinary skill in the art, depending

on routes on routes ofofadministration, administration, excipient excipient usage, usage,the thepossibility possibility ofofco-usage co-usagewith with other other

therapeutic treatment, and the condition to be treated. therapeutic treatment, and the condition to be treated.

may be administered to the subject in a therapeutically effective amount of from about 1 may be administered to the subject in a therapeutically effective amount of from about 1

20 20 mg/daytotoabout mg/day about2000 2000mg/day mg/day during during a treatmentperiod a treatment periodorora atreatment treatmentcycle, cycle, such such as as 10 10

mg/daytoto 450 mg/day 450mg/day, mg/day,3030mg/day mg/day to to 200mg/day, 200mg/day, or mg/day or 40 40 mg/day to 150 to 150 mg/day. mg/day. As As used used

herein, the term “treatment cycle” refers to a treatment period followed by a rest period herein, the term "treatment cycle" refers to a treatment period followed by a rest period

without treatment that is repeated on a regular schedule. without treatment that is repeated on a regular schedule.

In some embodiments of the present disclosure, the injection dosage for treating canine In some embodiments of the present disclosure, the injection dosage for treating canine

25 25 MPNST MPNST maymay be ainrange be in a range of of from from about about 0.5mg/day 0.5 mg/dayto to 950mg/day, 950 mg/day, from from 1 mg/day 1 mg/day to to 900900

mg/day, from mg/day, from33mg/day mg/daytoto800 800mg/day, mg/day, from from 5 mg/day 5 mg/day to 750 to 750 mg/day, mg/day, fromfrom 8 mg/day 8 mg/day to to

10

700 mg/day, 700 mg/day,from from1010mg/day mg/day to 650 to 650 mg/day, mg/day, fromfrom 15 mg/day 15 mg/day to 600tomg/day, 600 mg/day, from 25from 25

mg/daytoto550 mg/day 550mg/day, mg/day,from from3535 mg/day mg/day to 500 to 500 mg/day, mg/day, fromfrom 45 mg/day 45 mg/day tomg/day, to 450 450 mg/day,

from 50 from 50mg/day mg/daytoto400mg/day, 400mg/day, from from 55 55 mg/day mg/day to 350 to 350 mg/day, mg/day, from from 60 mg/day 60 mg/day to 300 to 300

mg/day, and mg/day, and from from6565mg/day mg/day to 250 to 250 mg/day mg/day of p-toluenesulfonamide of p-toluenesulfonamide or other or other

5 5 benzenesulfonamide derivatives. benzenesulfonamide derivatives. 2023285788

In some embodiment of the present disclosure, the dosage of intratumoral injection for In some embodiment of the present disclosure, the dosage of intratumoral injection for

the ablation the ablationofofMPNST is 19.4 MPNST is 19.4 mL to 50 mL to 50 mL mLabout about6,400 6,400mgmg to to16,500 16,500mgmg of of p- p-

toluenesulfonamide or other benzenesulfonamide derivatives. toluenesulfonamide or other benzenesulfonamide derivatives.

10 10 may be administered to the subject 1 to 2 times per day, 1 to 7 times per week, or 1 to 14 may be administered to the subject 1 to 2 times per day, 1 to 7 times per week, or 1 to 14

times per month. In at least one embodiment of the present disclosure, the pharmaceutical times per month. In at least one embodiment of the present disclosure, the pharmaceutical

composition may be administered to the subject for a 1- to 4-week or 1- to 4-month treatment composition may be administered to the subject for a 1- to 4-week or 1- to 4-month treatment

period or period or treatment cycle.InIn treatmentcycle. some some embodiments, the pharmaceutical embodiments, the pharmaceutical composition maybebe composition may

administered to the subject 2 to 3 times per week for a 2-week treatment period. In some administered to the subject 2 to 3 times per week for a 2-week treatment period. In some

15 15 embodiments, the pharmaceutical composition is administered to the subject equal to or more embodiments, the pharmaceutical composition is administered to the subject equal to or more

than 6 times in the first treatment period. than 6 times in the first treatment period.

can be directly injected into MPNST or injected into the area surrounding the MPNST. In can be directly injected into MPNST or injected into the area surrounding the MPNST. In

some embodiments of the present disclosure, the dosage can be proportionally increased or some embodiments of the present disclosure, the dosage can be proportionally increased or

20 20 decreased according to a therapeutic situation. In at least one embodiment of the present decreased according to a therapeutic situation. In at least one embodiment of the present

disclosure, the administration may continue until the tumor shrinks about 5%, 10%, 15%, disclosure, the administration may continue until the tumor shrinks about 5%, 10%, 15%,

20%, 25%, 20%, 25%, 30%, 30%, 35%, 35%, 40%, 40%, 45%, 45%, 50%, 50%, 55%, 55%, 60%, 60%, 65%, 65%, 70%, 70%, 75%, 75%, 80%, 80%, 85%, 85%, 90%, 90%, or or

95% (by volume or weight), or until the tumor is fully eliminated. 95% (by volume or weight), or until the tumor is fully eliminated.

The present The present disclosure disclosure also also provides a use provides a of aa pharmaceutical use of compositionininthe pharmaceutical composition the

25 25 manufactureofof aa medicament manufacture medicament fortreating for treating aa canine canine MPNST, MPNST, wherein wherein the the pharmaceutical pharmaceutical

11

compositioncomprises composition comprisesa abenzenesulfonamide benzenesulfonamide derivative derivative of of thepresent the presentdisclosure disclosureand anda a

pharmaceutically acceptable carrier thereof. pharmaceutically acceptable carrier thereof.

manufactureofofaa medicament manufacture medicamentforfor treatingMPNST, treating MPNST,and and the the pharmaceutical pharmaceutical composition composition

5 5 comprises the benzenesulfonamide derivative and the pharmaceutically acceptable carrier comprises the benzenesulfonamide derivative and the pharmaceutically acceptable carrier 2023285788

thereof as thereof as mentioned above.The mentioned above. Thepresent presentdisclosure disclosure further further provides provides the the pharmaceutical pharmaceutical

compositionfor composition for use useinin the the treatment treatmentofofMPNST, MPNST,and and the pharmaceutical the pharmaceutical composition composition

comprises the benzenesulfonamide derivative and the pharmaceutically acceptable carrier comprises the benzenesulfonamide derivative and the pharmaceutically acceptable carrier

thereof as mentioned above. thereof as mentioned above.

10 10 The following embodiments further demonstrate the efficacy of the current disclosure, but The following embodiments further demonstrate the efficacy of the current disclosure, but

should not be used to limit the scope of the present disclosure. should not be used to limit the scope of the present disclosure.

EXAMPLES EXAMPLES 15 15 The present The present disclosure disclosure is is further further described by means described by meansofofthethefollowing followingexamples. examples.

However, these examples are only illustrative of the disclosure, and in no way limit the However, these examples are only illustrative of the disclosure, and in no way limit the

scope and meaning of the present disclosure. Indeed, many modifications and variations of scope and meaning of the present disclosure. Indeed, many modifications and variations of

the present the present disclosure disclosure will will be be apparent apparent totothose thoseskilled skilled inin the theart art upon uponreading readingthis this

specification, and can be made without departing from its scope. specification, and can be made without departing from its scope.

20 20

Preparation Example Preparation Example

The pharmaceutical The pharmaceuticalcomposition compositionGW-MP101 GW-MP101 for intratumoral for intratumoral injectioninjection

administration was a clear, colorless, oily, sterile solution, containing the components as administration was a clear, colorless, oily, sterile solution, containing the components as

listed in Table 1, and that could be packaged in 5 mL glass ampoules. GW-MP101 contains listed in Table 1, and that could be packaged in 5 mL glass ampoules. GW-MP101 contains

25 25 330 mg/mL 330 mg/mL ofof theactive the active drug drug p-TSA. p-TSA.

12

Table 11 Table

p-Toluenesulfonamide p-Toluenesulfonamide 1%-60% 1%-60%

PEG-400 PEG-400 10%-40% 10%-40%

1,2-Propylene glycol 1,2-Propylene glycol 1%-10% 1%-10%

Sebacic acid Sebacic acid 1%-5% 1%-5% 2023285788

p-Toluenesulfonic acid p-Toluenesulfonic acid 0%-5% 0%-5%

2-Ethyl-1,3-hexanediol 2-Ethyl-1,3-hexanediol 10%-20% 10%-20%

Dimethyl sulfoxide Dimethyl sulfoxide 0-40% 0-40%

Ethanol Ethanol 0-20% 0-20%

Preparation of the composition of the present disclosure includes the process of: adding Preparation of the composition of the present disclosure includes the process of: adding

and mixing the solvents and adjuvants in a given ratio; heating the mixture to 80°C to 110°C and mixing the solvents and adjuvants in a given ratio; heating the mixture to 80°C to 110°C

with stirring to form a clear oily liquid; gradually adding the sulfa drug with stirring until with stirring to form a clear oily liquid; gradually adding the sulfa drug with stirring until

5 5 completely dissolved; filtering and cooling the mixture to obtain the composition of the completely dissolved; filtering and cooling the mixture to obtain the composition of the

present disclosure present disclosureininanan oily liquid oily formform liquid GW-MP101. GW-MP101.

The preparation The preparation of of the the GW-MP101 injection GW-MP101 injection maymay be conducted be conducted by some by some techniques techniques

known in the art, e.g., adding an adjuvant and/or solvent to adjust the mixture to an isotonic known in the art, e.g., adding an adjuvant and/or solvent to adjust the mixture to an isotonic

state, or filtering the mixture by using a microporous filter. state, or filtering the mixture by using a microporous filter.

10 10 The present The present disclosure disclosure also also provides provides the the use use of of GW-MP101 GW-MP101 as a as a medicament medicament for for

promoting tumor ablation in the body of the subject. promoting tumor ablation in the body of the subject.

The efficacy The efficacy of of the the tumor tumordisclosed disclosed in in the the present present disclosure disclosure was assessed by was assessed bythe the

following veterinary clinical trials. The trials followed the relevant ethical principles of following veterinary clinical trials. The trials followed the relevant ethical principles of

Veterinary Good Clinical Practice. Veterinary Good Clinical Practice.

15 15

EMBODIMENT EMBODIMENT 11

The case in the clinical trial was carried out at Evergreen animal hospital in Taipei City, The case in the clinical trial was carried out at Evergreen animal hospital in Taipei City,

Taiwanfrom Taiwan fromOctober OctobertotoDecember December 2021. 2021.

13

Dogbreed: Dog breed: Corgi Corgi

Gender: Male Gender: Male

Age: 13 years old Age: 13 years old

Weight: 11 Weight: 11 kg kg to to 12 12 kg kg

5 5 Liver function: normal Liver function: normal 2023285788

Kidney function: normal Kidney function: normal

Pathology: Malignant peripheral nerve sheath tumor, grade 2 Pathology: Malignant peripheral nerve sheath tumor, grade 2

Medicalhistory: Medical history: Anemia Anemia

The inclusion criteria are: (A) the dog is greater than or equal to 1-year-old; (B) the The inclusion criteria are: (A) the dog is greater than or equal to 1-year-old; (B) the

10 10 dog is dog is diagnosed diagnosed with with MPNST MPNST by cytology by cytology or histopathology; or histopathology; (C) (C) the the trial trial veterinarian veterinarian

assesses that the dog is unsuitable for removal of the tumor by surgery; (D) the dog has at assesses that the dog is unsuitable for removal of the tumor by surgery; (D) the dog has at

least one measurable tumor that is larger than 1 cm in diameter; (E) the trial veterinarian least one measurable tumor that is larger than 1 cm in diameter; (E) the trial veterinarian

assesses the assesses the life life expectancy of the expectancy of the dog dogtotoexceed exceed3 months; 3 months; and and (F) (F) the owner the owner can can

understand and understand and abide abidebybythe theexperimental experimentalprocedure procedureand andisiswilling willingtotosign sign an aninformed informed

15 15 consent form. consent form.

The exclusion criteria are: (A) the dog has received systemic chemotherapy within 4 The exclusion criteria are: (A) the dog has received systemic chemotherapy within 4

weeks before weeks before entering entering thethe trial;(B) trial; (B)the thedog doghashasreceived received radiotherapy radiotherapy within within 4 weeks 4 weeks beforebefore

entering the trial; (C) the dog has undergone a major operation (for example, thoracotomy entering the trial; (C) the dog has undergone a major operation (for example, thoracotomy

is not allowed, but the non-invasive operation, such as biopsy, is allowed) within 4 weeks is not allowed, but the non-invasive operation, such as biopsy, is allowed) within 4 weeks

20 20 before entering the trial; (D) the dog is treated by any other experimental drugs, biological before entering the trial; (D) the dog is treated by any other experimental drugs, biological

formulations, medical materials, or other anti-tumor treatments (such as immunomodulators formulations, medical materials, or other anti-tumor treatments (such as immunomodulators

and radiotherapy) within 4 weeks before entering this trial or during the period of this trial and radiotherapy) within 4 weeks before entering this trial or during the period of this trial

experiment; (E) the dog has the following abnormal value of blood tests before entering the experiment; (E) the dog has the following abnormal value of blood tests before entering the

trial: a. hemoglobin < 6.0 g/dL; b. absolute neutrophil count (ANC) < 1,500/μL; c. albumin trial: a. hemoglobin < 6.0 g/dL; b. absolute neutrophil count (ANC) < 1,500/ u L; C. albumin

25 25 < 1.5 g/dL; d. total bilirubin < 2mg/dL; e. alanine aminotransferase (ALT) and aspartate < 1.5 g/dL; d. total bilirubin < 2mg/dL; e. alanine aminotransferase (ALT) and aspartate

aminotransferase aminotransferase (AST) (AST) >> 5x 5× upper uppernormal normallimit limit(UNL); (UNL);f.f. chronic chronic kidney kidney disease disease (CKD), (CKD),

14

the International Renal Interest Society (IRIS) > stage 3; (F) the dog suffers from any other the International Renal Interest Society (IRIS) > stage 3; (F) the dog suffers from any other

serious diseases such as infection, uncontrolled diabetes, stage C of chronic degenerative serious diseases such as infection, uncontrolled diabetes, stage C of chronic degenerative

valve disease (CDVD, one of the heart diseases), gastric ulcer, severe autoimmune disease, valve disease (CDVD, one of the heart diseases), gastric ulcer, severe autoimmune disease,

and the trial veterinarian restricts the animal from participating in this trial after the and the trial veterinarian restricts the animal from participating in this trial after the

5 5 assessment; (G) the dog is known or suspected of having allergic reactions to the ingredients assessment; (G) the dog is known or suspected of having allergic reactions to the ingredients 2023285788

contained in any p-toluenesulfonamide drugs; (H) the trial veterinarian diagnoses that the contained in any p-toluenesulfonamide drugs; (H) the trial veterinarian diagnoses that the

dog’s tumor dog's tumorwaswas blocked blocked by important by important blood blood vessels, vessels, SO it so it is difficult is difficult to perform to perform

intratumoral injection therein; (I) the dog is pregnant; and (J) the trial veterinarian intratumoral injection therein; (I) the dog is pregnant; and (J) the trial veterinarian

determines that the dog is unsuitable for participating in this trial. determines that the dog is unsuitable for participating in this trial.

10 10 Those who met at least one of the following criteria should be withdrawn from clinical Those who met at least one of the following criteria should be withdrawn from clinical

trials: (A) trials: (A)the theinformed informed consent consent form is withdrawn; form is (B) the withdrawn; (B) the dog dogreceives receives the the treatment treatment

prohibited by this trial; (C) after assessing any pathological characteristics, clinical adverse prohibited by this trial; (C) after assessing any pathological characteristics, clinical adverse

events, or any changes in the condition of the animal, the trial veterinarian determines that events, or any changes in the condition of the animal, the trial veterinarian determines that

it is not the most advantageous situation to allow the dog to continue participating in the it is not the most advantageous situation to allow the dog to continue participating in the

15 15 trial; (D) the dog is pregnant during the treatment period or is suspected of being pregnant 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 above by its owner or the trial veterinarian; (E) the dog has an adverse event of grade 3 or above

according to international adverse events of oncology organization (Veterinary Cooperative according to international adverse events of oncology organization (Veterinary Cooperative

Oncology Group Oncology Group -- Common TerminologyCriteria Common Terminology Criteria for forAdverse AdverseEvents, Events,VCOG-CTCAE) VCOG-CTCAE)

and cannot return to grade 1 within 7 days after the adverse event, or the grade 3 or above and cannot return to grade 1 within 7 days after the adverse event, or the grade 3 or above

20 20 adverse event still occurs after 2 dose reductions in the dog; (F) signs and symptoms of adverse event still occurs after 2 dose reductions in the dog; (F) signs and symptoms of

disease progression or deterioration (assessment of deterioration was based on Veterinary disease progression or deterioration (assessment of deterioration was based on Veterinary

Cooperative Oncology Cooperative Oncology Group Group - Response - Response Evaluation Evaluation Criteria Criteria in Tumors in Solid Solid Tumors v1.0 v1.0

(VCOG-RECIST v1.0)); (G) death; (H) loss of follow-up tracking; and (I) violation of the (VCOG-RECIST v1.0)); (G) death; (H) loss of follow-up tracking; and (I) violation of the

plan. plan.

25 25 Treatmentmethod: Treatment method:

The test dog was given intratumoral injections of 3.8, 3.7, 1, 3.7, 3.6, 3.6 mL of the The test dog was given intratumoral injections of 3.8, 3.7, 1, 3.7, 3.6, 3.6 mL of the

15

GW-MP101 drug on Day 1, 5, 8, 12, 15, 22, 33, 47 (each time about 1180 to 1250 mg of p- GW-MP101 drug on Day 1, 5, 8, 12, 15, 22, 33, 47 (each time about 1180 to 1250 mg of p-

toluenesulfonamide). The injections were carried out in single, multi-point (2 to 10 points) toluenesulfonamide). The injections were carried out in single, multi-point (2 to 10 points)

intratumoral injections. intratumoral injections.

Response assessment criteria: Response assessment criteria:

5 5 The electronic vernier caliper measurement was performed before each administration, The electronic vernier caliper measurement was performed before each administration, 2023285788

and the computed tomography (CT) scan was performed before the first administration and and the computed tomography (CT) scan was performed before the first administration and

at the conclusion visit. Complete response (CR) means that a measurable or evaluable tumor at the conclusion visit. Complete response (CR) means that a measurable or evaluable tumor

disappears completely, disappears completely, and andnononewnew tumors tumors appear appear for more for more than weeks. than four four weeks. PartialPartial

response (PR) response (PR) means meansthat that aa measurable measurableoror evaluable evaluable tumor tumorshrinks shrinks by by more morethan thanoror equal equal

10 10 to 30%, to and no 30%, and nonew newtumors tumorsappear appearforformore more thanfour than fourweeks. weeks.Stable Stabledisease disease(SD) (SD)means means

that a measurable or evaluable tumor shrinks by less than or equal to 30% or enlarges by that a measurable or evaluable tumor shrinks by less than or equal to 30% or enlarges by

less than or equal to 20%. Disease progression (PD) means that a measurable or evaluable less than or equal to 20%. Disease progression (PD) means that a measurable or evaluable

tumor enlarges by more than or equal to 20%, or other tumors deteriorate, and new tumors tumor enlarges by more than or equal to 20%, or other tumors deteriorate, and new tumors

appear. appear.

15 15 Safety assessment: Safety assessment:

When conducting safety assessment during the trial period, the relevant researchers of When conducting safety assessment during the trial period, the relevant researchers of

the trial were responsible for defining and compiling the adverse events in the protocol (the the trial were responsible for defining and compiling the adverse events in the protocol (the

methodfor method forassessment waswas assessment referred referred to “Veterinary to "Veterinary Cooperative Cooperative Oncology Oncology Group - Group -

Common Common TerminologyCriteria Terminology Criteria for forAdverse AdverseEvents (VCOG Events -CTCAE).” (VCOG-CTCAE)."

20 20

The treatment The treatment results results ofofMPNST inEmbodiment MPNST in Embodiment 1 areshown 1 are shown below. below.

Tumor volume change (measured with the electronic vernier caliper): Tumor volume change (measured with the electronic vernier caliper):

Regarding the tumor, the measurement range thereof was located in the MPNST of the Regarding the tumor, the measurement range thereof was located in the MPNST of the

25 25 right limb of the dog. After 6 times administrations of the GW-MP101 drug, the volume of right limb of the dog. After 6 times administrations of the GW-MP101 drug, the volume of

3 the tumor the changed. The tumor changed. Thevolume volumeofofthe thetumor tumorwas was 32.84 32.84 cm³cm before before treatment,22.37 treatment, 22.37 cm3 cm³

16

3 assessment visit (6 weeks after the 2nd before the 2nd administration, and 0.30 cm at the assessment visit (6 weeks after the 2nd before the 2nd administration, and 0.30 cm³ at the

administration). Comparing the volume of the tumor before the first administration with administration). Comparing the volume of the tumor before the first administration with

that at the assessment visit, the measurable or assessable tumor shrinks by 100%, and the that at the assessment visit, the measurable or assessable tumor shrinks by 100%, and the

result was a complete response (CR) (referring to Table 1 below and FIG. 1). result was a complete response (CR) (referring to Table 1 below and FIG. 1).

5 5 2023285788

Table 11 Table

D1 D1 D5 D5 D8 D8 D12 D12 D15 D15 D22 D22 D33 D33 D47 D47

T1 T1 T2 T2 RV RV T3 T3 T4 T4 T5 T5 T6 T6 CV CV

a a 3.89 3.89 3.45 3.45 3.65 3.65 3.20 3.20 2.59 2.59 2.07 2.07 1.38 1.38 0.59 0.59

b b 4.47 4.47 4.09 4.09 4.20 4.20 3.74 3.74 2.70 2.70 2.39 2.39 1.13 1.13 0.52 0.52

c C 3.78 3.78 3.17 3.17 3.65 3.65 3.71 3.71 0.73 0.73 -- -- -- -- -- --

Volume 32.84 Volume 32.84 22.37 22.37 27.88 27.88 22.23 22.23 2.53 2.53 4.60 4.60 1.56 1.56 0.30 0.30

Volume (cm ) = a (cm) × b (cm) × c (cm) × 1/2 Volume (cm³) =3 a (cm) X b (cm) XC (cm) X 1/2

D: Day; T1 to T6: the 1st to 6th administration of treatment; RV: Random Visit; CV: Conclusion Visit D: Day; T1 to T6: the 1st to 6th administration of treatment; RV: Random Visit; CV: Conclusion Visit

10 10 Bodytemperature Body temperaturechange: change:

The variation of the body temperature before and after each treatment is within 2.5 The variation of the body temperature before and after each treatment is within 2.5

degree. (referring to Table 2 below and FIG. 2). degree. (referring to Table 2 below and FIG. 2).

Table 22 Table

D1 D1 D5 D5 D8 D8 D12 D12 D15 D15 D22 D22 D33 D33 D47 D47

T1 T1 T2 T2 RV RV T3 T3 T4 T4 T5 T5 T6 T6 CV CV

Bodytemperature Body temperature 38.20 37.60 38.20 37.60 38.10 38.10 37.40 37.40 37.80 37.80 38.30 38.30 37.30 37.30 --- ---

Before treatment Before treatment

Bodytemperature Body temperature 37.90 37.00 37.90 37.00 -- -- 37.7 37.7 37.5 38.10 37.5 38.10 38.10 38.10 -- --

After treatment After treatment

17

Changein Change in body body -0.79 -1.60 -0.79 -1.60 -- 0.80 0.80 -0.79 -0.52 -0.79 -0.52 2.14 2.14 -- temperature temperature

Bodyweight Body weightchange: change: 2023285788

The variation The variation of of the the body bodyweight weight before before andand after after each each treatment treatment is within is within 4.5 4.5

5 5 kilograms. (referring to Table 3 below and FIG. 3). kilograms. (referring to Table 3 below and FIG. 3).

Table 33 Table

D1 D1 D5 D5 D8 D8 D12 D12 D15 D15 D22 D22 D33 D33 D47 D47

T1 T1 T2 T2 RV RV T3 T3 T4 T4 T5 T5 T6 T6 CV CV

Bodyweight Body weight 12.45 12.45 12.10 12.10 11.90 11.90 12.15 12.15 12.05 12.05 12.10 12.10 12.10 12.10 -- --

Weight change Weight change 0.00 0.00 -2.81 -2.81 4.42 -2.41 4.42 -2.41 -3.21 -3.21 -2.81 -2.81 -2.81 -2.81 -- --

Interim efficacy (appearance change): Interim efficacy (appearance change):

10 10 After 6 administrations of the GW-MP101 drug, an obvious change in the limb of the After 6 administrations of the GW-MP101 drug, an obvious change in the limb of the

dog was observed, from being swollen to being flat at the tumor site (FIG. 4). dog was observed, from being swollen to being flat at the tumor site (FIG. 4).

Adverse effects: Adverse effects:

Nocommon No commonside side effects effects suchsuch as pain, as pain, nausea, nausea, vomiting vomiting or redness or local local redness and and

inflammation hadbeen inflammation had beenobserved. observed.The The functionsofofthe functions theliver liver and andkidney kidneywere werestable stableand and

15 15 normal during and after the treatment. normal during and after the treatment.

Conclusionof Conclusion of this this embodiment: embodiment:

The pharmaceutical composition of the present disclosure can effectively reduce or The pharmaceutical composition of the present disclosure can effectively reduce or

ablate tumor and thereby improve the quality of life and clinical symptoms of dogs with ablate tumor and thereby improve the quality of life and clinical symptoms of dogs with

20 20 MPNST. Furthermore, no significant increase in adverse reactions has been observed in the MPNST. Furthermore, no significant increase in adverse reactions has been observed in the

18

clinical trials. clinical trials.

The disclosure has been described using exemplary embodiments. However, it is to be The disclosure has been described using exemplary embodiments. However, it is to be

5 5 understood that the scope of the disclosure is not limited to the disclosed embodiments. On understood that the scope of the disclosure is not limited to the disclosed embodiments. On 2023285788

the contrary, it is intended to cover various modifications and similar rearrangement. The the contrary, it is intended to cover various modifications and similar rearrangement. The

scope of scope of the the claims claimstherefore therefore should shouldbebeaccorded accorded thethe broadest broadest interpretationSOsoasastoto interpretation

encompass all such modifications and similar arrangements. encompass all such modifications and similar arrangements.

19

Claims

CLAIMS CLAIMS What is claimed is: What is claimed is:

1. 1. A A method method for for treating treating a malignant a malignant peripheral peripheral nerve sheath, nerve sheath, comprising comprising administering administering a a

therapeutically effective amount of a pharmaceutical composition to a subject in need therapeutically effective amount of a pharmaceutical composition to a subject in need

5 5 thereof, wherein thereof, the pharmaceutical wherein the pharmaceuticalcomposition compositioncomprises comprises a benzenesulfonamide a benzenesulfonamide

derivative and a pharmaceutically acceptable carrier thereof. derivative and a pharmaceutically acceptable carrier thereof. 2023285788

Themethod 2. The 2. methodof of claim claim 1, 1, wherein wherein thethe benzenesulfonamide benzenesulfonamide isisrepresented derivative derivative representedbyby

formula (I) below: formula (I) below:

R2 R1 o R6 R3 R7 o R4 R5 (I), (I),

wherein R to R are independently selected from the group consisting of H, a C -C linear wherein R1 1 to R7 7are independently selected from the group consisting of H, a C1-C6 1linear 6

each other to form a ring, and each other to form a ring, and

15 15 wherein the alkyl group, the alkoxy group, the cycloalkyl group, the cycloheteroalkyl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the cycloheteroalkyl group,

and the ring in R to R are independently unsubstituted or substituted with one or more 1 R7 are and the ring in R1 to 7 independently unsubstituted or substituted with one or more

substituents. substituents.

2. The method of claim 1, wherein the substituent is selected from the group consisting of 2. The method of claim 1, wherein the substituent is selected from the group consisting of

20 20 phenyl, halo, oxo, ether, hydroxyl, carboxyl, amino, sulfo, and sulfonamide groups. phenyl, halo, oxo, ether, hydroxyl, carboxyl, amino, sulfo, and sulfonamide groups.

3. The 3. method The method of of claim claim 1, 1, wherein wherein the benzenesulfonamide the benzenesulfonamide derivative derivative is at one is at least leastselected one selected

from the group consisting of para-toluene sulfonamide, ortho-toluene sulfonamide, meta- from the group consisting of para-toluene sulfonamide, ortho-toluene sulfonamide, meta-

20

toluene sulfonamide, toluene sulfonamide, N-ethyl-ortho-toluene N-ethyl-ortho-toluene sulfonamide, sulfonamide,N-ethyl-para-toluene N-ethyl-para-toluene

sulfonamide, N-cyclohexyl-para-toluene sulfonamide, N-cyclohexyl-para-toluenesulfonamide, sulfonamide,and andany anycombination combinationthereof. thereof.

4. The method 4. The methodof of claim claim 1, 1, wherein wherein the the benzenesulfonamide benzenesulfonamide derivative derivative is para-toluene is para-toluene

5 5 sulfonamide. sulfonamide. 2023285788

5. The method of claim 1, wherein the pharmaceutically acceptable carrier is at least one 5. The method of claim 1, wherein the pharmaceutically acceptable carrier is at least one

selected from the group consisting of a filler, a binder, a preservative, a disintegrating agent, selected from the group consisting of a filler, a binder, a preservative, a disintegrating agent,

a lubricant, a suspending agent, a wetting agent, a biocompatible solvent, a penetration a lubricant, a suspending agent, a wetting agent, a biocompatible solvent, a penetration

10 10 enhancer, a surfactant, a thickening agent, an acid, a flavoring agent, a complexing agent, enhancer, a surfactant, a thickening agent, an acid, a flavoring agent, a complexing agent,

and any combination thereof. and any combination thereof.

6. The method of claim 1, wherein the pharmaceutically acceptable carrier is at least one 6. The method of claim 1, wherein the pharmaceutically acceptable carrier is at least one

selected from the group consisting of alkylene glycol, sebacic acid, dimethyl sulfoxide, selected from the group consisting of alkylene glycol, sebacic acid, dimethyl sulfoxide,

15 15 ethanol, and any combination thereof. ethanol, and any combination thereof.

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

thereof. thereof.

20 20

8. The method of claim 1, wherein the benzenesulfonamide derivative is present in an amount 8. The method of claim 1, wherein the benzenesulfonamide derivative is present in an amount

of from of from 1% to 50% 1% to 50%bybyweight weightofofthe the pharmaceutical pharmaceutical composition. composition.

9. The method of claim 8, wherein the benzenesulfonamide derivative is present in an amount 9. The method of claim 8, wherein the benzenesulfonamide derivative is present in an amount

25 25 of from of from 20% to 40% 20% to 40%bybyweight weightofofthe the pharmaceutical pharmaceuticalcomposition. composition.

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10. The 10. method The method ofof claim claim 1, 1, wherein wherein the the pharmaceutical pharmaceutical composition composition furtherfurther at leastat least comprises comprises

one of one of 10% 10%toto40% 40%by by weight weight of of polyethylene polyethylene 400,1%1% glycol400, glycol to to 10%10% by weight by weight of 1,2- of 1,2-

propylene glycol, propylene glycol, 1% to 5% 1% to byweight 5% by weightofofsebacic sebacic acid, acid, 10% to 20% 10% to 20%bybyweight weightofof2-ethyl- 2-ethyl-

1,3-hexanediol, 1,3-hexanediol, 0% to 40% 0% to byweight 40% by weightofofdimethyl dimethylsulfoxide, sulfoxide, and and 0% to 20% 0% to 20%bybyweight weightofof

5 5 ethanol. ethanol. 2023285788

11. 11. The methodofofclaim The method claim1,1,wherein wherein thethe causesablation administeringcauses administering ablationofofthe themalignant malignant

peripheral nerve sheath in the subject. peripheral nerve sheath in the subject.

10 10 12.

12. The method The method of claim of claim 1, wherein 1, wherein the subject the subject is selected is selected from from the theconsisting group group consisting of a of a

rodent, a murine, a monkey, a guinea pig, a dog, a cat, a cow, a sheep, a pig, a horse, a rabbit, rodent, a murine, a monkey, a guinea pig, a dog, a cat, a cow, a sheep, a pig, a horse, a rabbit,

and aa human. and human.

13. 13. The method The method of of claim claim 12, 12, wherein wherein the subject the subject is aordog is a dog or cat. cat.

15 15

14. The 14. method The method of of claim claim 1, 1, wherein wherein the the benzenesulfonamide benzenesulfonamide in the in derivative derivative the pharmaceutical pharmaceutical

composition is administered to the subject in the therapeutically effective amount of from composition is administered to the subject in the therapeutically effective amount of from

about 10 about 10 mg/kg to about mg/kg to about 100 mg/kg. 100 mg/kg.

20 20

15. The 15. method The method of of claim claim 1, 1, wherein wherein the the benzenesulfonamide benzenesulfonamide in the in derivative derivative the pharmaceutical pharmaceutical

about 10 mg/kg to about 5000 mg/kg during a treatment period or a treatment cycle. about 10 mg/kg to about 5000 mg/kg during a treatment period or a treatment cycle.

16. Themethod 16. The methodof of claim claim 1, wherein 1, wherein the pharmaceutical the pharmaceutical composition composition is administered is administered to the to the

25 25 subject intratumorally, intravenously, subcutaneously, intradermally, orally, intrathecally, subject intratumorally, intravenously, subcutaneously, intradermally, orally, intrathecally,

intraperitoneally, intranasally, intramuscularly, intrapleurally, topically, or through nebulization. intraperitoneally, intranasally, intramuscularly, intrapleurally, topically, or through nebulization.

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17. Themethod 17. The methodof of claim claim 1, wherein 1, wherein the pharmaceutical the pharmaceutical composition composition is in is in a form a form selected selected

from the group consisting of an injection formulation, a dry powder, a tablet, an oral liquid, from the group consisting of an injection formulation, a dry powder, a tablet, an oral liquid,

a flake, a film, a lozenge, a capsule, a granule, a pill, a gel, a lotion, an ointment, an a flake, a film, a lozenge, a capsule, a granule, a pill, a gel, a lotion, an ointment, an

5 5 emulsifier, a paste, a cream, an eye drop, and a salve. emulsifier, a paste, a cream, an eye drop, and a salve. 2023285788

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