NZ754173B2 - Pharmaceutical composition of benzenesulfonamide derivatives for treatment of adenoid cystic carcinoma - Google Patents

Abstract

Provided is a use of a pharmaceutical composition including a benzenesulfonamide derivative, i.e. para-toluene sulfonamide, and pharmaceutically acceptable carriers in the manufacture of medicaments for treating adenoid cystic carcinoma.

Description

PHARMACEUTICAL COMPOSITION OF BENZENESULFONAMIDE TIVES FOR TREATMENT OFADENOID CYSTIC OMA BACKGROUND cal Field The present disclosure relates to a method for treating adenoid cystic oma (ACC), especially al adenoid cystic carcinoma (TACC), in a subject by a pharmaceutical composition containing the benzenesulfonamide derivatives. ption of Related Art d cystic carcinoma (ACC) is a rare form of adenocarcinoma, which is a broad term describing any cancer that begins in glandular tissues. ACC most commonly occurs in the salivary glands, but may also arise in a wide range of other locations (exocrine glands) including, for example, the breast, lacrimal gland, and in the cervix, vulva, skin (including ceruminal glands of the ear), prostate, and tracheobronchial tree. Due to the distinctive logy and histogenesis, ACC are completely different from other tumors which are mainly consisted of squamous cell carcinomas (SCC) in clinical presentation, clinical outcome, treatment, and response to treatment.

Ninety percent of tracheal cancer in adults is malignant. Among malignant tracheal tumor, squamous cell carcinoma represents the most frequent histology (44%-63%), while tracheal adenoid cystic oma (TACC) accounts for 7%-16% of the cases (Ann Otolaryngol Rhinol 2015, 321079). TACC originates from the submucosal glands of the airway, and ultimately one-third of TACC cause malignant airway obstruction (MAO) with associated symptoms (Adv Ther 2014, 31:512-538), which is a potential life-threatening condition.

Primary cancer of the trachea is a relatively rare and accounts for only 0.1%-0.4% of all newly diagnosed respiratory tract cancers, which ponds to 2.6 new cases per 1,000,000 individuals annually worldwide, and less than 2 per million persons per year in the United States (equivalent to 641 persons per year in 2015’s US population) (J Thorac Cardiovasc Surg 1996, 112:1522—1531). It is shown that the prevalence of TACC is less than 100 per year and therefore being designated as a rare disease.

According to previous epidemiology and health statistics, smoking remains the major risk factor of SCC, but it does not seem to affect the incidence of TACC. The delay in diagnosis of TACC often occurs because the pulmonary fields remain normal on a chest radiograph (Chest 1999, 116:803-807); and patients with TACC usually present with ms such as coughing, wheezing and dyspnea and are often treated for asthma for months to years before being correctly diagnosed (Mayo Clin Proc 1993, 68: 680—684).

TACC is generally considered to be a low grade malignancy, but it tends to metastasize to distant sites and often recurs after a long interval (Chang Gung Med J 2005, -363). The survival is frequently less than 2 years with distal metastasis (Cancer 1994, 73:1390-1397). ACC spreads most commonly by direct extension, submucosal or perineural invasion, or hematogenous metastasis. Pulmonary metastasis is the most common, and metastasis to the brain, bone, liver, kidney, abdomen, and hearts have been reported (J Thorac Cardiovasc Surg 1996, 111:808-913; Am J Surgery 1982, 143:697-699; Cancer 1970, 25:1448-1456).

In the early stage of the e, primary treatment includes y with optional postoperative radiotherapy (RT). With the combined therapy, the 5-year overall survival (OS) rate reaches up to 52% in TACC (Int J Radiat Oncol Biol Phys 2008, 72:410-414; Ann Thorac Surg 1990, 49:69-77). r, resection is often difficult if there is invasion of adjacent critical tissues especially in patients with distal tracheal involvement (Am J Otolaryngol 2012, 33:226-231; Cancer/Radiotherapie 2005, -231), or tumors are too large to permit y.

The complete resection rate is reported to 42%-57% (Ann Thorac Cardiovasc Surg 2002, 8:74-77). ve surgical margins are ult to obtain because of the relative inability to resect more than 6 cm of the trachea, and thus TACC are prone to local recurrence (Am J Otolaryngol 2012, 33:226-231). herapy (RT) is used as the primary modality in unresectable TACC. However, TACC exhibits a limited response to chemotherapy and RT (Ann Otolaryngol Rhinol 2015, 3:1079). ed to 52% of 5-year survival rate of resected patients, the unresectable patients (subjected to only radiotherapy) have a lower survival rate (33% in 5 years) (Ann Thorac Surg 2004, 78:1889-1897).

In general, current therapies do not possess sufficient tumor/normal tissue selectivity, and thus the efficacy is limited in infiltrative lesions commonly seen in TACC (Pan Afr Med J 2014, . On the other hand, the FDA-designated orphan drug for adenoid cystic carcinoma, Dovitinib, a targeted kinase inhibitor, shows modest antitumor activity in the treatment of TACC. However, a complete treatment cycle takes 8 weeks, and nearly 94% of the patients in the clinical study had stable disease outcome (Cancer 2015, 121:2612—2617), which would hardly be satisfactory in the life-threatening airway obstruction condition. Therefore, there is a need in TACC patients for a therapy to provide tumor clearance as ent as physical therapy/resection, and as specific as targeted therapy.

Toluene sulfonamide is known as an effective anti-fungal agent and used to treat plant and animal (e.g., human) tissues infected with a . US s No. 5,891,454 and No. 6,727,287 both disclose a sulfonamide—containing composition that exhibits ancer and anti-tumor necrotizing activity. However, there is still a need in the art for providing an injectable composition which provides sustained tration of toluene sulfonamide and long acting effects for treating cancers.

SUMMARY In one embodiment of the present disclosure, a pharmaceutical composition for treating cancer is provided. The pharmaceutical composition comprises a benzenesulfonamide derivative or a pharmaceutically acceptable salt thereof, and a ceutically able carrier.

The pharmaceutical composition of the present disclosure has a viscosity of from 20 to 200 CR In one embodiment of the present disclosure, the pharmaceutical composition has a viscosity of from 40 to 60 CF, such as from 47.2 to 48.4 CF.

In one embodiment of the present disclosure, the benzenesulfonamide derivative in the ceutical composition may be represented by formula (I): R2 R1 R 3? \ttttttttttt3 ttttttttgsg/ 3'"\\ {a g \R: mama: ? 9* R: R: or a pharmaceutically acceptable salt thereof, wherein R1 to R7 are independently selected from the group consisting of H, a C1-C6 linear or branched alkyl group, a C1—C6 linear or branched alkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloheteroalkyl group, an amino group, and a halo group, or R6 and R7 are linked to each other to form a ring, and wherein the alkyl, alkoxy, cycloalkyl, cycloheteroalkyl group and the ring are tituted or substituted with one or more substituents. In one embodiment of the present disclosure, the substituent may be selected from the group consisting of , halo, oxo, ether, yl, carboxyl, amino, sulfo and sulfonamide group.

In one embodiment of the present disclosure, the esulfonamide derivative or the pharmaceutically acceptable salt thereof may be at least one selected from the group consisting of para-toluene sulfonamide ), ortho—toluene sulfonamide, meta-toluene sulfonamide, N-ethyl ortho-toluene sulfonamide, N—ethyl para-toluene sulfonamide, N-cyclohexyl para-toluene sulfonamide, ,N N' W: m: NH2 .' I:s! 34’ 2 062% r Sr 01"sz F 61%;} 0"le , , ’ , [£0 H H 1N": ,NH; w" ox. "3‘ :fix ’3 K O ‘ o o O ‘0 , , , , , , , , and In one embodiment of the present disclosure, the pharmaceutically acceptable carrier may be selected from the group consisting of hylene glycol (PEG), alkylene glycol, sebacic acid, dimethyl sulfoxide (DMSO), alcohol and a combination thereof. In another embodiment of the present disclosure, the alkylene glycol may be at least one of 2-ethyl-1,3-hexandiol and propanediol.

In one ment of the t disclosure, the pharmaceutical composition comprises PEG-400, 2-ethyl-1,3-hexandiol, propanediol, sebacic acid, and DMSO.

In one embodiment of the present disclosure, the benzenesulfonamide derivative may be present in an amount of from 10% to 50% by weight. In another embodiment of the present disclosure, the esulfonamide derivative may be present in an amount of from 20% to 40% by weight.

In one embodiment of the present disclosure, the pharmaceutical ition comprises at least one of 20% to 50% by weight of PEG, 5% to 15% by weight of propanediol, 1% to 5% by weight of sebacic acid, 10% to 20% by weight of 2-ethyl-1,3-hexanediol, 5% to 10% by weight of dimethyl sulfoxide and more than 0% to 30% by weight of anhydrous ethanol.

In one embodiment of the present disclosure, the pharmaceutical composition comprises oluene sulfonamide (p-TSA) in an amount of 330 mg/mL, the PEG-400 in an amount of 335 mg/mL, the 2-ethyl-1,3-hexandiol in an amount of 164 mg/mL, the propanediol in an amount of 82 mg/mL, the sebacic acid in an amount of 37 mg/mL, and the DMSO in an amount of 67 mg/mL.

In one embodiment of the present sure, the pharmaceutical composition may be in a form suitable for injection.

In another embodiment of the present disclosure, the method for treating adenoid cystic carcinoma is provided. The method comprises administering a therapeutically effective amount of the ceutical composition comprising a benzenesulfonamide derivative or a ceutically acceptable salt f, and a pharmaceutically acceptable carrier to a subject in need thereof.

In one embodiment of the present disclosure, the pharmaceutical ition may be administered to the subject intratumorally, intravenously, subcutaneously, intradermally, intrathecally, eritoneally, intramuscularly, or intrapleuraly.

In one embodiment of the present disclosure, the method is for treating adenoid cystic carcinoma which may be tracheal adenoid cystic carcinoma.

BRIEF DESCRIPTIONS OF THE DRAWINGS shows a photo of the d injection site after 1 mL of Sample A is injected by an 18 cm with 18G (18 Gauge) needle needling instrument; shows an ultrasound image of the incised injection site after 1 mL of Sample A is injected by an 18 cm with 18G needle needling instrument; shows a photo of the incised injection site after 1 mL of Sample A is injected by an 18 cm with 22G needle needling instrument; shows an ultrasound image of the incised injection site after 1 mL of Sample A is injected by an 18 cm with 22G needle ng instrument; shows a photo of the incised injection site after 1 mL of Sample B is injected by an 18 cm with 18G needle needling instrument; shows an ultrasound image of the incised injection site after 1 mL of Sample B is injected by an 18 cm with 18G needle ng instrument; shows a photo of the incised injection site after 1 mL of Sample B is ed by an 18 cm with 22G needle needling instrument; and shows a result of determining viscosities of Formulations PTS-Taiwan and PTSChina (1 centipoise (cP) = 0.001 pascal second (Pa.S)).

DETAILED DESCRIPTION The following examples are used to exemplify the present disclosure. A person of ordinary skills in the art can understand the other advantages of the present disclosure, based on the disclosure of the specification of the present disclosure. The t disclosure can also be implemented or applied as bed in different specific examples. It is possible to modify and or alter the examples for ng out this disclosure without contravening its spirit and scope, for different aspects and applications.

It is further noted that, as used in this specification, the singular forms "a," "an," and "the" include plural nts unless expressly and unequivocally limited to one referent. The term "or" is used interchangeably with the term "and/or" unless the context y indicates otherwise.

The present disclosure provides a pharmaceutical composition or a drug product that has a viscosity of from 20 to 200 cP. Particularly, the present disclosure provides a pharmaceutical composition containing the benzenesulfonamide derivatives or pharmaceutically acceptable salts thereof and pharmaceutically able carriers that have viscosity of from 40 to 60 cP.

In an embodiment of the present disclosure, the pharmaceutical composition exhibits antitumor activity, and comprises the benzenesulfonamide tives or ceutically acceptable salts thereof and the pharmaceutically acceptable rs, wherein the benzenesulfonamide derivative is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 to R7 are independently selected from the group consisting of H, a C1-C6 linear or branched alkyl group, a C1-C6 linear or branched alkoxy group, a C3-C6 lkyl group, a C3- C6 cycloheteroalkyl group, an amin o group, and a halo group, or R 6 and R7 are linked to each other to form a ring.

In an embodiment of the present disclosure, the alkyl, alkoxy, cycloalkyl, cycloheteroalkyl and the ring in R1 to R7 are ndently unsubstituted or substituted with one or more substituents. In r embodiment of the present disclosure, the substituent is selected from the group consisting of phenyl, halo, oxo, ether, yl, carboxyl, amino, sulfo and sulfonamide group.

In an embodiment of the t disclosure, the pharmaceutically acceptable carriers are chosen from polyethylene glycol (PEG), alkylene glycol, sebacic acid, dimethyl sulfoxide (DMSO), alcohol and a combination thereof. The es of the alkylene glycol include, but are not limited to, l-1,3-hexandiol and propanediol. The example of the PEG includes, but is not d to, PEG-400.

In an embodiment of the present disclosure, the benzenesulfonamide derivatives are in an amount of 10% to 50% of the composition by weight. For example, an amount of the benzenesulfonamide derivative in the pharmaceutical composition has a lower limit chosen from %, 15%, 20%, and 25% of the composition by weight, and an upper limit chosen from 50%, 45%, 40% and 35% of the composition by weight.

In an embodiment of the present disclosure, the pharmaceutically acceptable carriers are chosen from at least one of 20%-50% by weight of PEG, 5%-15% by weight of propanediol, 1%- % by weight of sebacic acid, 10%-20% by weight of 2-ethyl-1,3-hexanediol, 5%-10% by weight of dimethyl sulfoxide and more than 0%-30% by weight of anhydrous ethanol.

In an embodiment of the present sure, the pharmaceutical composition comprises p-TSA in an amount of 330 mg/mL, PEG-400 in an amount of 335 mg/mL, 2-ethyl-1,3-hexandiol in an amount of 164 mg/mL, propanediol in an amount of 82 mg/mL, sebacic acid in an amount of 37 mg/mL, and DMSO in an amount of 67 mg/mL.

The present disclosure also provides a method of treating ACC or symptom due to ACC by intratumoral injection of said pharmaceutical ition. In an embodiment of the present disclosure, the ACC or the symptom due to ACC may be at least one ed from the group consisting of tracheal adenoid cystic carcinoma, and malignant airway obstruction.

In an embodiment of the t disclosure, the method comprises injecting the pharmaceutical ition into an injection site of the subject. In an embodiment of the present disclosure, the injection site is an intratumoral site which may be determinable by an ultrasonic imaging system or a oscopy.

In an embodiment of the present disclosure, the benzenesulfonamide derivatives in the pharmaceutical composition may be administered to the subject in a therapeutically effective amount of from about 1000 mg to about 3300 mg per day, such as 1650 mg per day, 1980 mg per day and 2640 mg per day.

In an embodiment of the present disclosure, the pharmaceutical composition may be administered to the t 1 to 4 times per week, such as 2 times per week and 3 times per week.

In an embodiment of the present disclosure, the pharmaceutical composition may be administered to the subject for a 1- to 3-weeks ent period, such as 2-weeks treatment period.

In an ment of the present disclosure, the method further comprises monitoring at least one condition resulting from the injection by using the ultrasonic imaging system or the bronchoscopy. In an embodiment of the present disclosure, the resulting condition is diffusion condition.

In an embodiment of the t disclosure, the ion condition may be determinable by observing the ion of the ceutical composition from the injection site to a peripheral site.

In an embodiment of the present disclosure, the pharmaceutical composition may be loaded in a needling instrument with an 18G needle before administering to the subject.

The present disclosure provides a method of providing a pharmaceutical composition into a tissue, comprising injecting, by a needling instrument, the pharmaceutical composition into an injection site in a tissue, wherein the pharmaceutical ition comprises a benzenesulfonamide derivative such as p—TSA and the pharmaceutically acceptable carriers, and has a Viscosity of from 20 to 200 01’. In an embodiment of the present disclosure, the pharmaceutical composition has a Viscosity of from 40 to 60 CF, such as from 47.2 to 48.4 CF, and the needling instrument comprises an 18G .

In an embodiment of the present disclosure, the pharmaceutical composition is injected to the subject at a rate of about 0.1 mL to 0.2 mL per second.

In an embodiment of the present disclosure, the injection of the pharmaceutical composition is monitored by an ultrasonic imaging system or a bronchoscopy.

The present disclosure also provides a method of diffusing a pharmaceutical composition in a tissue, comprising determining a tumor borderline and an intratumoral ion site by using an ultrasonic imaging system or a bronchoscopy, and ing, by a needling instrument, a ermined amount of a pharmaceutical composition into the intratumoral injection site.

In an embodiment of the present disclosure, the pharmaceutical composition comprises a benzenesulfonamide derivative such as p-TSA and the pharmaceutically acceptable carriers, and has a viscosity of from 20 to 200 CR In an embodiment of the present disclosure, the pharmaceutical composition has a viscosity of from 40 to 60 CF, such as from 47.2 to 48.4 CF, and the needling ment comprises an 18G needle.

The present disclosure also provides a method of accumulating a pharmaceutical ition in a local tumor to generate a clinically effective outcome, sing injecting, by a needling instrument, the pharmaceutical composition in an intratumoral injection site, wherein the pharmaceutical composition has a viscosity of from 20 to 200 CR the intratumoral ion site is determinable by using an ultrasonic g system or a bronchoscopy, and the needling instrument has an 18G .

In an embodiment of the present disclosure, the accumulation of the pharmaceutical composition is observable by an ultrasonic imaging system or a bronchoscopy.

The present sure also provides a method of monitoring a movement of a pharmaceutical composition in a tissue, comprising ing an image by using a transducer of an ultrasonic imaging system; determining an injection site by analyzing the image; ing the pharmaceutical composition in the ion site; and monitoring a change in the image.

The present disclosure also provides a method of accumulating a pharmaceutical composition in a local tumor and reducing injecting difficulty, comprises injecting, by a needling instrument, the pharmaceutical composition in an intratumoral injection site, wherein the needling ment has an 18G needle, and the pharmaceutical composition has a viscosity of from 20 CF to 200 CR and the intratumoral injection site is determinable by using an ultrasonic imaging system or a bronchoscopy.

In an embodiment of the present disclosure, the method further comprises elevating the visibility of the injection of the pharmaceutical composition under the ultrasonic imaging system or the bronchoscopy.

The present sure also provides a method of diffusing a pharmaceutical composition in a tissue of a subject to generate a clinically effective outcome. The method ses injecting, by a ng instrument, the pharmaceutical composition in an intratumoral injection site of the tissue, wherein the needling instrument has an 18G needle, the pharmaceutical composition has a viscosity of from 20 CF to 200 CR and the intratumoral injection site is determinable by using an ultrasonic imaging system or a bronchoscopy.

The present disclosure further provides a method of using an ultrasound machine to identify a desirable position or regions, mainly a tumor position in an organ, and simultaneously monitor the diffusion of a pharmaceutical composition in an intratumoral injection.

The t disclosure further relates to a method of using ultrasound machine to identify a desirable position or regions, mainly the tumor on in an organ and simultaneous monitor the ion of a p-TSA-containing composition in an umoral injection.

In an embodiment of the present disclosure, the ceutical ition is in a form suitable for injection. For e, the pharmaceutical composition can be formulated to be a clear, colorless, oily, e solution packaged in either 3- or 5-mL glass ampoule.

The following are specific embodiments further demonstrating the efficacy of the current disclosure, but not to limit the scope of the current disclosure.

EXAMPLES The present disclosure is r described by means of the following examples. However, these examples are only illustrative of the disclosure, and in no way limits the scope and meaning of the present disclosure. Indeed, many modifications and variations of the present disclosure will be apparent to those d in the art upon reading this specification, and can be made without departing from its spirit and scope.

Example 1: Viscosity of Toluene Sulfonamide-containing Pharmaceutical Composition (Samples A and B) Two different samples were used in this example. Sample A contained p-TSA in an amount of 330 mg, PEG-400 in an amount of 335 mg, 2-ethyl-1,3-hexandiol in an amount of 164 mg, propanediol in an amount of 82 mg, sebacic acid in an amount of 37 mg, and DMSO in an amount of 67 mg, and anhydrous ethanol was added to Sample A to form a final volume of 1 mL.

Sample B was a mixture of Sample A with extra anhydrous ethanol by volume at a ratio of 5 to 2 (Sample A : 99.5% Ethanol = 5 : 2, v : v).

The samples used in this example, especially Sample A, had been shelved for about three years before the subsequent experiments, and that a person having ordinary skill in the art would understand that such data derived from the samples might deviate from the fresh equivalent solution and that certain deviation from the data should be allowable.

The viscosity of Sample A was measured in order to determine which ity was suitable for liver cancer, liver tumor, and/or hepatoma treatment. The model used in such study was a Brookfield Digital Viscometer, Model HADV-1. The study was performed as instructed by the ion Instructions as indicated in the al Manual of the Device (No. M/92-0210O604).

The procedure of the study was herein briefly incorporated and described.

A 0.5 mL Sample A, and a 0.5 mL Sample B were used in the study. A spindle 0) was used as suggested to be compatible with a sample volume around 0.5 mL. The spindle was immersed in the samples respectively. The experiment was carried out under room ature, and the speed was set at 100 RPM. Multiple times of viscosity measurement were taken. All viscosity data were recorded before and when the resulting values stabilize and converge into a stable range.

As shown in Table 1, Sample A had a torque between 71.9% and 73.7%, and a viscosity of 40 to 60 cP (centipoise), or at a centralized value, 47.2 to 48.4 cP. Sample B had a torque between 28.6% and 35.5%, and a ity of 18.2 to 23.3 cP.

Table 1 Sample A Sample B Torque 71.9%-73.7% 28.6%-35.5% 40-60 cP 3.3 47.2-48.4 The present study intended to present two compositions differing in their viscosity and intended to establish the ces of different viscosity that might further affect the composition retention time, diffusion and accumulation condition when injected into tissues or organs. It was understandable to a person having ordinary skill in the art that different compositions with same preparing process, different compositions with ent preparing processes, and same composition with different preparing processes might results in the same or ent composition with same or different viscosity measures.

Example 2: Diffusion and Retention of Samples A and B in an Animal Model To evaluate the influence of different composition viscosity on a living tissue or organ (ex vivo study), an animal study was carried out under proper ethical and moral standards.

Particularly, the experiment intended to evaluate the condition when a medical operator is injecting a p-TSA-containing pharmaceutical ition using a needling instrument to a tissue or organ, particularly a liver, and ably a cancerous tissue in a liver. It has y been established that ultrasound can reveal the position of hepatocellular carcinoma and can identify the tumor borderline (See Eric K. Outwater, Imaging of the Liver for Hepatocellular Cancer, Cancer Control. Vol. 17, No. 2, April 2010). It was ed of this experiment to examine the capability of an ultrasound device in identifying a desirable position, region, site or area in a tissue or organ for injection and simultaneously monitor the injection s, condition, requirement and results.

The ment was carried out by trained researchers and doctors. The materials used herein were as follows: fresh pig livers stored in a portable low temperature chamber, 18 cm with 18G needles, 18 cm with 22G needles, 10mL syringes, Sample A as ted in Table 1, Sample B (Sample A : 99.5% Ethanol = 5 : 2, v : v), anhydrous ethanol (Sigma Aldrich ) and Toshiba Aplio 500-8500 ultrasound machine (an ultrasonic imaging system).

The experiment was performed by the following steps. 1. Ultrasound gel was d to parts of the pig liver surface evenly by a transducer. The transducer was then affixed at a position that allowed clear imaging and recording of a ermined injection site which was around 1 to 2 cm under the liver e. 2. A loaded needling instrument was epared by loading the sample of about 5 mL in an 18 cm with 18G needle needling instrument. 3. The needle part was inserted until the tip reached the injection site. After insertion, the sample was injected into the injection site at a rate of around 0.1 to 0.2 0.0. per second. The images of the distribution, diffusion and retention status were recorded. Visibility on whether the injection was identifiable by the ultrasound imaging system and the easibility/difficulty of the injection were provided by the doctors who performed the injection. Visibility was measured on a scoring system from S1 to S5, where Sl reflected Cleary Visible while S5 reflected Invisible.

Easibility/Difficulty was measured on a scoring system from A1 to A5, where A1 reflected Easy to inject while A5 reflected Uninjectable (cannot inject into the tissue). 4. After 1 mL of the sample was injected, the needle was removed and the leakage of the sample, mainly from the puncture ed from the needle insertion, was observed and recorded immediately.

. The s were allowed some time to react to the tissue until it was further observed. An incision was made on the injection site so that the ion and distribution of the sample were observed and recorded.

Same procedures were performed by using an 18 cm with 22G needle. The ment therefore provided four sets of data, i.e., 18G needle with Sample A, 18G needle with Sample B, 22G needle with Sample A, and 22G needle with Sample B. ing to the s of the experiment, in both and , there was shown the incised injection site after 1 mL of Sample A was injected by an 18 cm with 18G needle needling instrument. As shown in , an Injection Site 1 was indicated by a circle. The Injection Site 1 revealed a faded color Portion 2 which indicated n denaturation due to the interaction between Sample A and the tissue. Such protein denaturation was one of the clinical effects if the composition is injected into a tumor, which damages and necrotizes the cells. In , Diffusion Pattern 3 was indicated by a circle. Diffusion Pattern 3 showed that the sample was confined and accumulated at a region. As provided by the s, the level of lity/difficulty was A3, and the level of Visibility was 82. There was no identifiable leakage after the needle was removed from the tissue under this condition.

Further referring to and , there was shown the incised injection site after 1mL of Sample A was injected by an 18 cm with 22G needle needling instrument. As shown in , an Injection Site 4 was indicated by a circle. The Injection Site 4 revealed a faded color Portion 5 which ted protein denaturation due to the interaction between Sample A and the tissue. In , Diffusion Pattern 6 was indicated by a circle. Diffusion Pattern 6 shows that the sample was confined and accumulated at a region. As provided by the doctors, the level of easibility/difficulty was A4, and the level of Visibility was S3, which suggest that it was harder to use an 22G needle to inject than a 18G needle and less visible than a 18G needle injection under ultrasonic imaging. There was only minor leakage, in the experiment a small drop, which at first was identifiable but then was absorbed back into the tissue. ing to and there was shown the incised injection site after 1 mL of Sample B was injected by an 18 cm with 18G needle needling instrument. As shown in , an Injection Site 7 was indicated by a circle. The Injection Site 7 revealed a faded color Portion 8 which indicated protein denaturation due to the interaction between Sample B and the . Portion 8 also revealed that the color faded n had a less defined border between unreached s and the interacted tissues, which ted a stronger diffusion of the sample into the . In , Diffusion Pattern 9 was indicated by a circle. ion Pattern 9 showed that the sample was not well confined and a border between unreached tissue and interacted tissue was not clearly fiable. As provided by the doctors, the level of easibility/difficulty was A2 to A3, and the level of Visibility was S1. The Visibility difference might result from the different compositions. Under ultrasonic imaging, Sample B had a higher visibility and an increased diffusion pattern in the experiment than in Sample A. Such diffusion phenomenon leaded to inability to constrain, limit and confine the sample in a desirable region.

Leakage of the sample from the puncture caused by the needle was barely identifiable.

Referring now to there was shown the incised injection site after 1 mL of Sample B was injected by an 18 cm with 22G needle needling instrument. As shown in an Injection Site 10 was indicated by a circle. The Injection Site 10 ed a faded color Portion 11 which indicated protein denaturation due to the interaction between Sample B and the tissue. As provided by the doctors, the level of easibility/difficulty was A4, and the level of Visibility was S4. While Sample B is being injected, the doctor commented that it is difficult to push the sample into the tissue and it takes longer than previous experiments and thus provide more time for the sample to diffuse into the tissue. A wilder diffusion pattern also reflected the poor lity under ultrasonic imaging. In addition, during the injection, a certain amount of the sample was spread onto the surface due to a burst out caused by ressurizing the syringe. Again, the diffusion phenomenon leaded to inability to constrain, limit and confine the sample in a desirable region.

According to the doctor, the combination of 18 cm 18G needling instrument with Sample A was a preferred treatment setting in an intra-tissue injection.

The diffusion and ion experiment s were compiled in Table 2.

Table 2 Sample A + Sample A + Sample B + Sample B + 18G 22G 18G 22G Visibility S2 S3 S1 S4 Easibility/Difficulty A3 A4 A2-A3 A4 Diffusion Pattern Less diffusion Less diffusion Diffused Diffused Leaked due to e Not observed Limited e Not observed dislodged needle Combining data from viscosity measure of the samples and the data from the liver injection, the present disclosure demonstrates that in liver tissue, there is a desirable pharmaceutical composition viscosity for a desirable diffusion n or confinement condition or accumulation condition, which leads to desirable clinical s on the injection site. A desirable intratumoral injection of anticancer agents s on both the potency and efficacy d by the anticancer agents and the distribution of the anticancer agents after injection. A desirable distribution condition is that the anticancer agents are confined only inside the tumor for a desirable period of time. The diffusion of anticancer agents inside the tumorous tissues and from tumorous tissue to normal tissue might eventually lead to normal tissue damages. On the other hand, if the viscosity is too high and thus the distribution is too low, the agents would only accumulate at the targeted region and will reduce the clinical effects of the agents. The present disclosure demonstrates that when a pharmaceutical ition containing p-TSA has a viscosity of from 40 to 60 CR or from 47.2 to 48.4 CF, the injection of that particular agents has desirable distribution and diffusion features, including easy to observe, easy to inject, and leads to a diffusion pattern that helps to release the agents slowly, prolong the reaction period in the region, reduce potential metabolism of the agents by the tissue, and yet not to diffuse too quickly into peripheral tissues that are not the targeted region. The present disclosure also demonstrates that ultrasonic imaging is an auxiliary tool to help doctors to locate a desirable injection site and monitor the ion status of p-TSA—containing pharmaceutical composition in a liver umoral injection.

It is however tandable to a person having ordinary skill in the art that any pharmaceutical composition containing p—TSA that has a viscosity of from 20 to 200 CR such as from 40 to 60 cP and from 47.2 to 48.4 CF can exert the desirable distribution patterns in a liver intratumoral injection, and that Sample A is an illustrative example having the desirable viscosity.

The t disclosure r demonstrates that a combination of a pharmaceutical composition containing a benzenesulfonamide derivative with a viscosity of from 20 to 200 CR such as from 40 to 60 cP and from 47.2 to 48.4 CF and a needling instrument with an 18G needle exerts a desirable easibility/difficulty to inject the composition intratumorally. Herein incorporated is the definition of a needle with 18G. An 18G needle has a nominal outer diameter of 1.270 m i 0.013 mm, a nominal inner diameter of 0.838 mm 1 0.038 mm and a nominal wall ess of 0.216m i 0.013 mm.

The present disclosure shows that when the ity of the ition is from 40 to 60 cP and an 18G needle is used, the ional efficiency (visibility and easibility/difficulty) and the treatment features (mainly diffusion, accumulation and retention of the composition) achieve a desirable balance; whereas, when at 18.2-23.3 cP with a 186 needle, such desirable balance is broken. ingly, the threshold of a desirable balance between operational efficiency and treatment es is located between 23 cP and 40 CF, a ence of 17 CF. It is to be noted that the viscometer uses a calibration standard solution as 500 cP and pure water as 1 CF. The maximal measurement capability is 21800 cP and the minimal is 7 CF. Therefore, a difference of 17 cP is ely small and might not be further differentiated. Yet, such small difference results in significant difference in the process of injecting the composition to the tissue. Taken er, the present disclosure provides a pharmaceutical composition (P) containing a benzenesulfonamide derivative with a viscosity larger than any value between 23 CF to 40 cP (P2X, where 40cP ZXZ23CP) would exert a desirable balance between operational efficiency and treatment features.

Example 3: Viscosity of Toluene Sulfonamide—containing ceutical ition (Formulations PTS-Taiwan and PTS-China) Two different samples, PTS—Taiwan and PPS—China, were used in this e.

Formulation PTS-China contained 30% by weight of p-TSA (Sigma Aldrich), 30% by weight of PEG-400, 15% by weight of 2-ethy1-1,3-hexandiol, 8% by weight of propanediol, 4% by weight of sebacic acid, 5% by weight of DMSO, and 8% by weight of anhydrous ethanol. The constituents of the Formulation PTS—Taiwan were the same as that of Formulation PPS-China, except that p-TSA in the Formulation PTS—Taiwan was synthesized by the inventors. The process of preparing such two samples was described as follows. p-TSA, PEG-400 and 2-ethyl-l,3-hexandiol were mixed in a container and heated to 85°C to 95°C with stirring to form Solution A. c acid and propanediol were mixed in another ner and heated to 85°C to 95°C with stirring to form on B. Solution A and Solution B were then mixed and stirred at 85°C to 95°C. DMSO and a portion of anhydrous l were mixed and stirred uniformly in a container to form Solution C. The mixture of Solution A and Solution B was cooled to 60°C and then added with Solution C. The mixture solution was cooled to room temperature and then added with the remaining anhydrous ethanol, followed by being filtered through a membrane filter with the pore size of 0.45 um to obtain the sample to be tested.

For determining ity of Formulations PTS—Taiwan and ina, the samples to be tested were kept at 25°C in a water bath. The rheometer (HAAKE RS-l, Thermo Fisher Scientific Co. Ltd) was set at 25°C, with a shear rate of from 0 (Us) tolOOO (l/s) . After ter was calibrated, about 3 mL of the sample was loaded into the sample tank of the rheometer by pipette. The Viscosity of the sample was then determined at different shear rates. The sample tank was washed with alcohol and water when the determination was ed. The rheometer would be calibrated again before determining the different sample. The results of determining Viscosities of Formulations PTS-Taiwan and PTS-China were shown in Example 4: Properties of Pharmaceutical ition of Benzenesulfonamides (PTSlOO) The pharmaceutical composition PTSlOO for intratumoral injection administration was a clear, colorless, oily, sterile solution, containing the components as listed in Table 3, and that could be packaged in either 3- or 5-mL glass ampoules. PTSlOO contains 330 mg/mL of the active drug p-TSA.

Table 3 Unit Formula Unit Formula Unit Formula Ingred'ents1 (g per3 mL (g per5 mL (mg/mL) ampoule) ampoule) Sebacic acid Ethanol The properties of PPS 100 were determined and described as follows.

Light sensitivity After had being stored in room temperature and lighting level from 4500 to 5500 Lx environment for 0, 5, 10 days, all PTSlOO products yed no significant change in appearance, particular matter inspection, and p—TSA content analysis. It demonstrated that PTSlOO was insensitive to short-term light exposure.

The stability testing of PTSlOO was completed for 24 months at the ing storage conditions: 25i2°C, 60i5% relative ty (RH) and 40i2°C, 75i5% RH Example 5: Efficacy of TACC treatment by PTSIOO in clinical trials Patient population Selected patients were those with non-small cell lung severe malignant airway obstruction as determined based on the following criteria: age ranged between 18 and 83 years, diagnosed as lung cancer pathologically, over 2/3 occlusion in right or left bronchi, or over 1/2 occlusion in trachea, which is ed by either CT scan, bronchoscopy, MRI, or X-ray imaging.

Enrollment of the study The total number of subjects initially planned for inclusion in the study was 89 based on biostatistical validity. The enrollment began with a total of 90 subjects. The total number of TACC in the study was 8 cases.

Administration Method To patients with central air way non-small cell lung cancer (NSCLC) tumor severe obstruction, PTSlOO was administrated via bronchoscopic intratumoral injection. All subjects need to have an outpatient surgery for PTSIOO ent. For each injection, the vital functions of patients will be monitored during therapy and vital sign examination will be confirmed after surgery.

For stration method, 5 mL of PTSIOO was aspirated from glass e and mixed adequately with orized solvent. After mixing, PTSlOO was injected into the tumor slowly by puncture needle. Necrotized tissue was d by biopsy forceps before each injection. A treatment cycle of PTSlOO was 2 weeks, and the injection dose in a treatment cycle was 2 to 3 doses per week. The first treatment cycle must include 4 treatments or more.

The dose of PTSlOO/ethanol mixture could be 0.1-1.5 mL (equivalent to 0.07-1 mL PTSlOO), with the l dose of 7 mL (5 mL PTS 100), tailored to the size of tumor. Maximal cumulative dose of /ethanol mixture was 14 mL (10 mL PTSlOO) for any single day. It is to be noted that the number of injection could be based on the range of necrotized tumor, and should be determined to necrotize the whole tumor.

Study Design Open-label, single arm, non-randomized.

Study results This study enrolled 90 subjects; 88 ts (73 males and 15 females, median age was 57.5 years (range between 22 and 80 years)) were included in the full analysis set (FAS), with 72 subjects completed all study treatment and included in the per protocol set (PPS). Among the 88 cases, 75% was squamous-cell carcinoma, and 12.5% was adenocarcinoma. Out of the patients in the FAS, 52.3% were staged as IV, and 42% were staged as IIIB.

The primary endpoint for the evaluation of the efficacy was based on the objective resolution rate of target tumor, and the improvement of the airway occlusion, as determined by computed tomography (CT) in accordance with Response tion Criteria In Solid Tumors (RECIST) standards and WHO standards, and evaluated on the 7th day after the last dose ("concluding visit") and the 30th days after concluding visit ("follow-up visit"). The efficacy index of FAS and PPS were summarized in Tables 4 and 5.

Table 4. Efficacy analysis of PTSlOO injection in NSCLC patients with central airway Obstruction (in FAS) Concluding visit (the Follow-up visit Verification ' Efficacy Index 7‘h day after last (the 30th day after method dose) concluding visit) 59.09% 43.18% oscopy ‘ 48.86% 29.55% Objective Resolution Rate WHO 67.05% (CR+PR) standard Primary Bronchoscopy WHO 76.14% standard Improvement CT rate of intratracheal oscopy 64.77% Climcal 39.77% cial apa01tY Table 5. Efficacy analysis of PTS injection in NSCLC patient with central airway Obstruction (in PPS) ding visit (the Follow-up visit Vefification cy Index 7‘h day after last (the 30th day after method dose) concluding v1s1t). . . 680807 48617 RECIST ,,,,,,,,,,,,,,,,,,, col’y 56.94% 33.33% . . RECIST Resolution Rate WHO 77.78% 54.17% (CR+PR) . standard tandard Improvement rate of intratracheal ' Bronchoscopy obstructlon aseline dyspne Clinical cial apaCItflFVC Performance ECOG status CR: complete response. PR: partial response.

TACC population from NSCLC—severe MAO clinical trial Among the recruited participants, 8 patients were diagnosed and categorized as TACC.

The response rates of the TACC patients were listed in Table 6. The treatment had an over 70% reduction in airway obstruction rate both in 7 days and 30 days post treatment, and also an over 87.5% ive response rate according to se tion Criteria in Solid Tumor (RECIST) was achieved. In addition, 3-yers survival rate of these 8 patients was 100% (8/8 survived) and the 5-year survival rate was 60% (5/8 survived). In spite of the survival rate of these 8 patients is similar to current standard of care, PTSIOO injection provides a disease-free margin comparing to other physical treatments to avoid possibilities of future local recurrence and distal metastasis.

Table 6. Clinical response of PTSlOO treatment on TACC patients 7 days post treatment 30 days follow up Survival Patient Bronchosco Bronchosco CT CT Py Py Last AOR AOR AOR AOR $35.5; 33$ Days interview TNM reducti OR reducti OR reducti OR i OR status stage on R on R on R on R name 11 (%) (%) (%) (%) 81.9 PR 100.0 CR 93.1 PR 100.0 CR 619 Alive 033:2 ET 78.5 PR 56.7 PR 95.2 PR 68.5 PR 532 Alive LF LF 85.6 PR 100.0 CR LFU LFU 120 Alive U U 05321 Tara: 69.6 PR 84.8 PR 65.6 PR 71.5 PR 424 Alive ms "5.. 81.4 PR 100.0 CR 84.9 PR 100.0 CR 172 Alive 88.7 PR 51.1 SD 74.5 PR 18.0 PR 397 Alive 94.6 PR 93.8 PR 96.3 PR 87.3 PR 763 Alive 81.9 PR 53.8 PR 93.1 PR 59.1 PR 800 Alive 87. 100 100 OR (%) 72.5 1%0 80.0 72.8 72.0 457 All alive 0 .0 AOR: airway obstruction rate. LFU: lost in follow up. LMB: left main bronchus. ET: end of trachea. UST: upper section of trachea. RMB: right main bronchus. MST: middle section of trachea. LST: lower section of trachea. ORR: objective response (RECIST). CR: complete response. PR: partial response. SD: stable disease.

Among the 8 patients with TACC, two patients were lost follow-up at the last visit, so the efficacy of 6 TACC patients was listed in Table 7, for comparing with the efficacy of other patients ing from squamous carcinoma or adenocarcinoma.

Table 7. Tracheal d cystic carcinoma in PTSlOO Phase III clinical trial AOR by bronchoscopy Patient ogical sun—types Percentage (RECIST criteria) Number Tracheal Adenoid CR 2 33.3% Cystic Carcinoma PR 4 66.7% (n=6) CR+PR 6 100.0% CR 13 37.1% Squamous Carcinoma PR 15 42.9% (n=35) CR+PR 28 80.0% CR 5 71.4% Adenocarcinoma PR 0 0 (n=7) CR+PR 5 71.4% Note: RECIST criteria evaluation was based on the F1 ison of visit sequence 1 & 6 (screening & visit after day 30 of dosing).

The results showed that the pharmaceutical composition of the present disclosure exhibits different efficacies for the different types of tumor. In comparison to the treatment of us carcinoma or adenocarcinoma, the pharmaceutical ition of the present sure is more effective for the treatment of TACC. Therefore, the pharmaceutical composition of the present disclosure can treat cancer, especially TACC, and improve the life y and clinical symptoms such as MAO of the patients. No significant increase in adverse reactions was found.

The disclosure has been described using exemplary preferred embodiments. However, it is to be understood that the scope of the sure is not limited to the disclosed embodiments. On the ry, it is intended to cover various modifications and similar rearrangement. The scope of the claims therefore should be accorded the broadest interpretation so as to encompass all such modifications and similar arrangements.

The term "comprise" and variants of the term such as "comprises" or "comprising" are used herein to denote the inclusion of a stated integer or stated integers but not to exclude any other integer or any other integers, unless in the context or usage an exclusive interpretation of the term is required.

In a first , the invention relates to use of a pharmaceutical composition in the manufacture of a medicament for treating adenoid cystic carcinoma in a subject in need thereof, wherein the pharmaceutical composition comprises a benzenesulfonamide derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable r, and wherein the benzenesulfonamide tive is para-toluene sulfonamide.

Claims (16)

1. Use of a pharmaceutical composition in the manufacture of a medicament for treating adenoid cystic oma in a subject in need thereof, wherein the pharmaceutical ition comprises a benzenesulfonamide derivative or a ceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and wherein the benzenesulfonamide derivative is para-toluene sulfonamide.

2. The use of claim 1, wherein the pharmaceutical composition has a viscosity of from 20 to 200

3. The use of claim 2, wherein the pharmaceutical composition has the ity of from 40 to 60

4. The use of claim 3, wherein the pharmaceutical composition has the viscosity of from 47.2 to 48.4 cP.

5. The use of claim 1, wherein the pharmaceutically able carrier is selected from the group ting of polyethylene glycol (PEG), alkylene glycol, sebacic acid, dimethyl sulfoxide (DMSO), alcohol and a combination thereof.

6. The use of claim 5, wherein the alkylene glycol is at least one of 2-ethyl-1,3-hexandiol and propanediol.

7. The use of claim 1, n the benzenesulfonamide derivative is present in an amount of from 10% to 50% by weight.

8. The use of claim 7, wherein the benzenesulfonamide derivative is present in an amount of from 20% to 40% by weight.

9. The use of claim 7, wherein the pharmaceutical composition further comprises at least one of 20% to 50% by weight of PEG, 5% to 15% by weight of propanediol, 1% to 5% by weight of sebacic acid, 10% to 20% by weight of 2-ethyl-1,3-hexanediol, 5% to 10% by weight of dimethyl sulfoxide and anhydrous ethanol in a range of from 0%, not included, to 30% by weight.

10. The uses of claim 9, wherein the pharmaceutical composition comprises the benzenesulfonamide derivative in an amount of about 330 mg/mL, the PEG in an amount of about 335 mg/mL, the 2-ethyl-1,3-hexandiol in an amount of about 164 mg/mL, the propanediol in an amount of about 82 mg/mL, the sebacic acid in an amount of about 37 mg/mL, and the DMSO in an amount of about 67 mg/mL.

11. The use of claim 1, wherein the pharmaceutical composition is formulated for administration to the subject by intratumoral, intravenous, aneous, intradermal, intrathecal, intraperitoneal, intramuscular, or intrapleural injection.

12. The use of claim 11, wherein the pharmaceutical composition is formulated for administration to the subject by a needling instrument having an 18G .

13. The use of claim 1, wherein the adenoid cystic carcinoma is al adenoid cystic carcinoma.

14. The use of claim 1, wherein the benzenesulfonamide derivative in the pharmaceutical composition is ated for administration to the subject in a eutically effective amount of from about 1000 mg to about 3300 mg per day.

15. The use of claim 1, wherein the pharmaceutical composition is formulated for administration to the subject 1 to 4 times per week.

16. The use of claim 1, wherein the pharmaceutical composition is formulated for administration to the t for a 1- to 3-week treatment period.