FIELD OF THE INVENTION

The present invention generally relates to treatment of epithelial cystic neoplasms (cysts).

BACKGROUND

A cystic neoplasm (cyst) is an abnormal sac in the body that may be filled with a liquid or semisolid substance. A cyst can form in any part of the body, including bones, organs and soft tissues. Generally, cysts are noncancerous (benign), however, a benign cyst can be precancerous and change into a malignant growth. Epithelial cysts are cysts which have an inner epithelial lining. Examples of epithelial cysts include gastrointestinal cysts such as hepatic cysts, pancreatic cysts, splenic cysts, colon cysts; urologic cysts such as renal cysts, epididymal cysts, prostatic cysts; gynecological cysts such as ovarian cysts and vaginal cysts; head and neck cysts such as thyroid cysts, parathyroid cysts, and other head and neck cysts; as well as other cysts such as Baker's cysts, lung cysts, lymphatic cysts, and pericardial cysts.

Pancreatic cystic neoplasms are being detected with increasing frequency due to improved cross-sectional imaging and routine examination (Pitman 2010). Mucinous pancreatic cystic neoplasms represent approximately 75% of all pancreatic cystic neoplasms and are divided into two categories: intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs). Both types of mucinous pancreatic neoplasms may present with symptoms such as abdominal pair, pancreatitis, jaundice, weight loss, malabsorption, nausea, vomiting, and palpable abdominal mass (Tanaka 2005; Muthusamy 2016). Oftentimes, the cysts do not present any symptoms at all and are detected by chance because of the improved imaging when patients are being examined for other reasons.

Mucinous pancreatic cystic neoplasms have malignant potential, thus each patient diagnosed is at risk for developing pancreatic cancer (Farrell 2015; Sarr 2000). In a study of 401 patients with pancreatic cysts, 11% of resected cysts contained invasive cancer (Ferrone 2009). Patients diagnosed with IPMN have a 40% chance of invasive cancer and 58% have underlying malignant features, while those with MCN have a malignancy risk that varies between 10% and 50% (Greer 2016; Allen 2007). To avoid progression to pancreatic cancer, an aggressive and rapidly fatal disease, all patients with mucinous pancreatic cysts should be carefully evaluated and offered treatment (National Cancer Institute 2016, Fernández-del Castillo 1995).

An emerging treatment for mucinous pancreatic cysts is cyst fluid aspiration by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) followed by endoscopic ultrasound-guided (EUS-guided) ethanol lavage as an ablative agent in order to induce cell death by membrane lysis, protein denaturation, and vascular occlusion (Jani 2011; DeWitt 2009). However, studies examining cyst volume response to ethanol injection failed to standardize their techniques and ethanol concentration/volume, and a ten-year study conducted by Gómez 2016 demonstrated that only 9% of patients experienced complete cyst resolution (Gomez 2016; Kirtane 2016). There has been some controversy regarding the current treatment methods and practices for pancreatic cysts (Farrell 2013, Tanaka 2016, McGrath 2017).

Current methods for determining malignancy within mucinous cysts provide unreliable results. It is difficult to identify cyst histology without resection. Approximately 25% of non-operative histologic diagnoses are inaccurate. Physicians compensate for this deficit by recommending that patients with cysts with features such as symptoms, positive cytology, mural nodules, or greater than 3 cm undergo surgical resection (Pitman 2010). Due to the concerns of mucin leakage, pancreatic fistulae, and recurrence, the standard surgical treatment for invasive and non-invasive MCNs and IPMNs is pancreatectomy with lymph node dissection, rather than focal non-anatomic resections or resections without lymphadenectomy or splenectomy (Tanaka 2012). In a study of 37 high-volume centers (2694 patients), the pancreatectomy mortality rate was reported to be 1.3%, increasing to 3.0% in patients 80 years of age and over, with overall complication rates ranging from 20.0% to 72.2% (Tamirisa 2016). In patients that can be diagnosed with a malignancy rate of less than 3%, the risk of death from pancreatectomy is higher than that of malignancy (Allen 2007). Even after surgery, the recurrence rates of cysts can be as high as 20% (Tanaka 2012). Untreated cysts, however, may progress to malignant disease while under observation (Allen 2007).

SUMMARY OF THE INVENTION

The present invention provides solutions to the aforementioned limitations and deficiencies in the art relating to treatment of cystic neoplasms (cysts), particularly to treatment of epithelial cysts including pancreatic cysts, by injection of antineoplastic particles, such as taxane particles, directly into the cysts (intracystic injection). When a composition of antineoplastic particles, such as taxane particles (e.g., paclitaxel particles or docetaxel particles), are injected into a cyst, the antineoplastic particles will persist in the cyst for a longer time than a solution of antineoplastic agent injected into the cyst because solutions are more easily and quickly cleared from the cysts by the body. Although not bound by theory, it is hypothesized that the use of antineoplastic particles result in increased efficacy and decreased toxicity as compared with solutions of antineoplastic agents, at least in part, due to the slow release of the antineoplastic agent from the suspended particle. It also is hypothesized that because of the physical characteristics of the antineoplastic particles, they can embed within or on the inner epithelial lining of the cyst resulting in a longer residence time than with solutions or with albumin coated particles. Instillation of a suspension of antineoplastic particles directly into the pancreatic cyst creates a depot effect where the antineoplastic agent is slowly released from the particles into tire cyst, resulting in prolonged local exposure of the antineoplastic agent. Clearance from the pancreas is reduced, with lower systemic levels of antineoplastic agent, further limiting systemic toxicity. In a preferred embodiment, the antineoplastic particles are taxane particles such as paclitaxel particles or docetaxel particles.

In one aspect of the invention, disclosed are methods for treating epithelial cysts, the methods comprise injecting a composition comprising an effective amount of antineoplastic particles directly into the cyst (intracystic injection) thereby treating the epithelial cyst, wherein the particles have a mean particles size (number) of from 0.1 microns to 5 microns. In preferred embodiments, the antineoplastic particles are taxane particles. In some embodiments, the particles of the antineoplastic agent have a mean particle size (number) of from 0.1 microns to 1.5 microns. In some embodiments, the taxane particles are paclitaxel particles. In some embodiments, the composition and taxane particles exclude albumin. In other embodiments, the taxane particles are docetaxel particles. In some embodiments, the epithelial cyst is a pancreatic cyst such as a mucinous pancreatic cyst. In some embodiments, the epithelial cyst is reduced in volume/size, has reduced growth rate, is eliminated, or is ablated alter treatment by injection of the composition. In some embodiments, the pain associated with an epithelial cyst is reduced after injection of the composition.

In another aspect of the invention, disclosed are kits comprising: (a) a first vial comprising taxane particles; (b) a second vial comprising a pharmaceutically acceptable aqueous carrier and a surfactant; and (c) instructions for reconstituting the antineoplastic particles into a suspension useful for intracystic injection by: combining the contents of the first vial and the second vial to form the suspension and optionally diluting the suspension with a diluent. In some embodiments, the taxane particles have a mean particle size (number) of from 0.1 microns to 1.5 microns. In some embodiments, the surfactant is a polysorbate. In some embodiments, the taxane particles are paclitaxel particles. In other embodiments, the taxane particles are docetaxel particles.

Also, disclosed in the context of the present invention are the following embodiments 1 to 39:Embodiment 1 is a method for treating an epithelial cyst, the method comprising injecting a composition comprising an effective amount of antineoplastic particles directly into the cyst, thereby treating the epithelial cyst, wherein the particles have a mean particle size (number) of from 0.1 microns to 5 microns.Embodiment 2 is the method of embodiment 1, wherein the composition further comprises a liquid carrier, and wherein the composition comprises a suspension of the antineoplastic particles dispersed in the carrier.Embodiment 3 is the method of embodiment 2, wherein the carrier is an aqueous carrier.Embodiment 4 is the method of embodiment 3, wherein the aqueous carrier comprises 0.9% saline solution.Embodiment 5 is the method of any one of embodiments 3 or 4, wherein the aqueous carrier comprises a surfactant.Embodiment 6 is the method of embodiment 5, wherein the surfactant is a polysorbate.Embodiment 7 is the method of embodiment 6, wherein the polysorbate is polysorbate 80, and wherein the polysorbate 80 is present in the aqueous carrier at a concentration of between about 0.01% v/v and about 1% v/v.Embodiment 8 is the method of any one of embodiments 3 to 7, wherein the composition further comprises a diluent, wherein the carrier and the diluent form a mixture, and wherein the composition is a suspension of the antineoplastic particles dispersed in the carrier/diluent mixture.Embodiment 9 is the method of embodiment 8, wherein the diluent is a 0.9% saline solution.Embodiment10is the method of any one of embodiment 1 to 9, wherein the antineoplastic particles are taxane particles.Embodiment 11 is the method of embodiment 10, wherein the taxane particles comprise at least 95% of the taxane, wherein the taxane particles have a mean particle size (number) of from 0.1 microns to 1.5 microns, and wherein the composition and taxane particles exclude albumin.Embodiment 12 is the method of any one of embodiments 10 to 11, wherein the concentration of taxane particles in the composition is between about 6 mg/mL and about 15 mg/mL.Embodiment 13 is the method of any one of embodiments 10 to 12, wherein the taxane particles are paclitaxel particles.Embodiment 14 is the method of embodiment 13, wherein the paclitaxel particles have a specific surface area (SSA) of at least 18 m2/g, 20 m2/g, 25 m2/g, 30 m2/g, 32 m2/g, 34 m2/g, or 35 m2/g; or from about 18 m2/g to about 50 m2/g.Embodiment 15 is the method of any one of embodiments 13 to 14, wherein the paclitaxel particles have a bulk density (not-tapped) of 0.05 g/cm3to 0.15 g/cm3.Embodiment 16 is the method of any one of embodiments 10 to 12, wherein the taxane particles are docetaxel particles.Embodiment 17 is the method of embodiment 16, wherein the docetaxel particles have a specific surface area (SSA) of at least 18 m2/g, 20 m2/g, 25 m2/g, 30 m2/g, 35 m2/g, 40 m2/g, or 42 m2/g; or from about 18 m2/g and about 60 m2/g.Embodiment 18 is the method of any one of embodiments 16 to 17, wherein the docetaxel particles have a bulk density (not-tapped) of 0.05 g/cm3to 0.15 g/cm3.Embodiment 19 is the method of any one of embodiments 1 to 18, wherein the cyst fluid is withdrawn from the cyst prior to injecting the composition.Embodiment 20 is the method of embodiment 19, wherein the volume of the composition injected into the cyst is equal to the volume of cyst fluid removed from the cyst.Embodiment 21 is the method of any one of embodiments 1 to 20, wherein the epithelial cyst is a pancreatic cyst.Embodiment 22 is the method of embodiment 21, wherein the pancreatic cyst is a mucinous pancreatic cyst.Embodiment 23 is the method of any one of embodiments 1 to 22, wherein the injection of the composition is conducted by endoscopic ultrasound-guided line needle injection (EUS-FNI).Embodiment 24 is the method of any one of embodiments 1 to 25, wherein the epithelial cyst is reduced in volume/size, has reduced growth rate, is eliminated, or is ablated after injection of the composition, and/or wherein the pain associated with the cyst is reduced.Embodiment 25 is the method of any one of embodiments 1 to 24, wherein the epithelial cyst is benign.Embodiment 26 is a kit comprising:(a) a first vial comprising taxane particles;(b) a second vial comprising a pharmaceutically acceptable aqueous carrier and a surfactant; and(c) instructions for reconstituting the taxane particles into a suspension useful for intracystic injection by: combining the contents of the first vial and the second vial to form the suspension and optionally diluting the suspension with a diluent.Embodiment 27 is the kit of embodiment 26, wherein the aqueous carrier is 0.9% saline solution, wherein the surfactant is a polysorbate, and wherein the polysorbate is at a concentration of between about 0.01% v/v and about 1% v/v.Embodiment 28 is the kit of any one of embodiments 26 to 27, wherein the diluent is 0.9% saline solution.Embodiment 29 is the kit of any one of embodiments 26 to 28, wherein the taxane particles comprise at least 95% of the taxane, wherein the taxane particles have a mean particle size (number) of from 0.1 microns to 1.5 microns, and wherein the taxane particles exclude albumin.Embodiment 30 is the kit of any one of embodiments 26 to 29, wherein the taxane particles are solid, uncoated (neat) individual particles; wherein the taxane particles are not bound to any substance; wherein no substances are absorbed or adsorbed onto the surface of the taxane particles; wherein the taxane particles are not encapsulated, contained, enclosed or embedded within any substance; wherein the taxane particles are not coated with any substance; wherein the taxane particles are not microemulsions, nanoemulsions, microspheres, or liposomes; wherein the taxane particles are not bound to, encapsulated in, or coated with a monomer, a polymer (or biocompatible polymer), a protein a surfactant, or albumin; and/or wherein a monomer, a polymer (or biocompatible polymer), a protein, a surfactant, or albumin is not absorbed or adsorbed onto the surface of the taxane particles.Embodiment 31 is the kit of any one of embodiments 26 to 30, wherein the taxane particles are paclitaxel particles.Embodiment 32 is the kit of embodiment 31, wherein the paclitaxel particles have a specific surface area (SSA) of at least 18 m2/g, 20 m2/g, 25 m2/g, 30 m2/g, 32 m2/g, 34 m2/g, or 35 m2/g; or from about 18 m2/g to about 50 m2/g.Embodiment 33 is the kit of any one of embodiments 31 to 32, wherein the paclitaxel particles have a bulk density (not-tapped) of 0.05 g/cm3to 0.15 g/cm3.Embodiment 34 is the kit of any one of embodiments 26 to 30, wherein the taxane particles are docetaxel particles.Embodiment 35 is the kit of embodiment 34, wherein the docetaxel particles have a specific surface area (SSA) of at least 18 m2/g, 20 m2/g, 25 m2/g, 30 m2/g, 35 m2/g, 40 m2/g, or 42 m2/g; or from about 18 m2/g and about 60 m2/g.Embodiment 36 is the kit of any one of embodiments 34 to 35, wherein the docetaxel particles have a bulk density (not-tapped) of 0.05 g/cm3to 0.15 g/cm3.Embodiment 37 is a method of administering a composition comprising antineoplastic particles to an epithelial cyst of a subject, the method comprising injecting the composition into the cyst using endoscopic ultrasound guided-fine needle injection, wherein the antineoplastic particles have a mean particle size (number) of from 0.1 microns to 5 microns, and wherein the antineoplastic particles are crystalline particles.Embodiment 38 is the method of embodiment 37, wherein the antineoplastic particles have a mean particle size (number) of from 0.3 microns to 5 microns.Embodiment 39 is the method of any one of embodiments 37 to 38, wherein the antineoplastic particles are taxane particles.

The term “antineoplastic agents” as used herein are drugs used to treat neoplasms including non-cancerous neoplasms and malignant neoplasms, and include “chemotherapeutic agents”, which are drugs used to treat cancer. In a preferred embodiment, the antineoplastic agent is a taxane.

The terms “antineoplastic agent particles”, “antineoplastic particles” or “particles of an antineoplastic agent”, as used herein are particles of an antineoplastic agent and have a mean particle size (number) of from about 0.1 microns to about 5 microns (about 100 nm to about 5000 nm) in diameter. In a preferred embodiment, the antineoplastic particles are taxane particles.

As used herein, the terms “cystic neoplasm” and “cyst” can be used interchangeably and mean an abnormal sac in the body that may be filled with a liquid or semisolid substance. An “epithelial” cystic neoplasm or “epithelial” cyst, has an epithelial inner lining. In some embodiments, the epithelial cyst is benign. In some embodiments, the cyst is precancerous.

As used herein, the terms “treat”, “treatment”, “treated”, or “treating” with respect to cystic neoplasms (cysts) means accomplishing one or more of the following: (a) reducing cyst volume/size; (h) reducing cyst growth rate; (c) eliminating a cyst; (d) ablation of a cyst; or (e) reducing pain associated with the cyst.

As used herein, the term “suspension” means a suspension dosage form composition where antineoplastic particles are dispersed (suspended) within a continuous earner or a continuous carrier/diluent mixture. The antineoplastic particles can be completely dispersed, partially dispersed and partially dissolved, but not completely dissolved in the carrier or carrier, diluent mixture.

The terms “subject” or “patient” as used herein mean a vertebrate animal. In some embodiments, the vertebrate animal can be a mammal. In some embodiments, the mammal can be a primate, including a human.

The term “room temperature” (RT) as used herein, means 20-25° C.

The term “surfactant” or “surface active agent” as used herein, means a compound or a material or a substance that exhibits the ability to lower the surface tension of water or to reduce the interfacial tension between two immiscible substances.

As used herein, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. “And” as used herein is interchangeably used with “or” unless expressly stated otherwise.

The terms “about” or “approximately” as used herein mean +/− five percent (5%) of the recited unit of measure.

For this application, a number value with one or more decimal places can be rounded to the nearest whole number using standard rounding guidelines, i.e. round up if the number being rounded is 5,6,7,8, or 9; and round down if the number being rounded is 0, 1, 2, 3, or 4. For example, 3.7 can be rounded to 4.

Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise”, “comprising”, and the like are to be construed in an inclusive or open-ended sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”. Words using the singular or plural number also include the plural and singular number, respectively. Additionally, the words “herein,” “above,” and “below” and words of similar import, when used in this application, shall refer to this application as a whole and not to any particular portions of the application. The compositions and methods for their use can “comprise,” “consist essentially of,” or “consist of” any of the ingredients or steps disclosed throughout the specification. With respect to the phrase “consisting essentially of,” a basic and novel property of the methods of the present invention are their ability to treat epithelial cystic neoplasms by intracystic injection of compositions of antineoplastic particles.

It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method or composition of the invention, and vice versa. furthermore, compositions of the invention cat be used to achieve methods of the invention.

The description of embodiments of the disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. While the specific embodiments of, and examples for, the disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the disclosure, as those skilled in the relevant art will recognize.

