阅读说明：本技术 囊内注射抗肿瘤颗粒治疗上皮囊肿 (Intracyst injection anti-tumor particle for treating epithelial cyst ) 是由 G·迪泽雷加 M·贝特佐 C·戴瑟度 S·坎贝尔 M·麦卡洛里 M·亚科布奇 H·毛尔哈 于 2018-06-08 设计创作，主要内容包括：本文公开了在受试者中通过囊内注射包含抗肿瘤颗粒的组合物治疗上皮囊肿(包括胰腺囊肿)的方法,所述抗肿瘤颗粒包括紫杉烷颗粒,例如紫杉醇颗粒和多西他赛颗粒。(Disclosed herein are methods of treating epithelial cysts (including pancreatic cysts) in a subject by intravesicular injection of compositions comprising anti-tumor particles, including taxane particles, such as paclitaxel particles and docetaxel particles.)

1. A method of treating an epithelial cyst, the method comprising directly injecting into the cyst a composition comprising an effective amount of an anti-tumor particle, wherein the particle has an average particle size (number) of from 0.1 microns to 5 microns, thereby treating the epithelial cyst.

2. The method of claim 1, wherein the composition further comprises a liquid carrier, and wherein the composition comprises a suspension of the anti-tumor particles dispersed in the carrier.

3. The method of claim 2, wherein the carrier is an aqueous carrier.

4. The method of claim 3, wherein the aqueous carrier comprises a 0.9% salt solution.

5. The method of any one of claims 3 or 4, wherein the aqueous carrier comprises a surfactant.

6. The method of claim 5, wherein the surfactant is a polysorbate.

7. The method of claim 6, wherein the polysorbate is polysorbate 80, and wherein the polysorbate 80 is present in the aqueous carrier at a concentration of about 0.01% v/v to about 1% v/v.

8. The method of any one of claims 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 anti-tumor particles dispersed in the carrier/diluent mixture.

9. The method of claim 8, wherein the diluent is a 0.9% salt solution.

10. The method of any one of claims 1 to 9, wherein the anti-tumor particle is a taxane particle.

11. The method according to claim 10, wherein the taxane particles comprise at least 95% taxane, wherein the taxane particles have an average particle size (number) of 0.1 to 1.5 microns, and wherein the composition and taxane particles do not comprise albumin.

12. The method of any one of claims 10 to 11, wherein the concentration of taxane particles in the composition is about 6mg/mL to about 15 mg/mL.

13. The method of any one of claims 10 to 12, wherein the taxane particles are paclitaxel particles.

14. The method of claim 13, wherein the paclitaxel particles have a Specific Surface Area (SSA) of at least 18m²/g、20m²/g、25m²/g、30m²/g、32m²/g、34m²G or 35m²(ii)/g; or about 18m²G to about 50m²/g。

15. The method of any one of claims 13 to 14,wherein the paclitaxel particles have a density of 0.05g/cm³To 0.15g/cm³Bulk density (not tapped).

16. The method of any one of claims 10 to 12, wherein the taxane particles are docetaxel particles.

17. The method of claim 16, wherein the docetaxel particles have a Specific Surface Area (SSA) of at least 18m²/g、20m²/g、25m²/g、30m²/g、35m²/g、40m²(ii)/g, or 42m²(ii)/g; or about 18m²G to about 60m²/g。

18. The method of any one of claims 16 to 17, wherein the docetaxel particles have a density of 0.05g/cm³To 0.15g/cm³Bulk density (not tapped).

19. A method as claimed in any one of claims 1 to 18, wherein cyst fluid is withdrawn from the cyst prior to injection of the composition.

20. The method of claim 19, wherein a volume of the composition injected into the cyst is equal to a volume of cyst fluid removed from the cyst.

21. The method of any one of claims 1-20, wherein the epithelial cyst is a pancreatic cyst.

22. The method of claim 21, wherein the pancreatic cyst is a mucinous pancreatic cyst.

23. The method of any one of claims 1 to 22, wherein said injecting of said composition is performed by endoscopic ultrasound guided fine needle injection (EUS-FNI).

24. The method of any one of claims 1 to 25, wherein the epithelial cyst is reduced in volume/size, reduced in growth rate, eliminated or ablated after injection of the composition, and/or wherein cyst-related pain is reduced.

25. The method of any one of claims 1 to 24, wherein the epithelial cyst is benign.

26. 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 intravesicular injection by: combining the contents of the first vial and the second vial to form a suspension, and optionally diluting the suspension with a diluent.

27. The kit of claim 26, wherein the aqueous carrier is a 0.9% saline solution, wherein the surfactant is a polysorbate, and wherein the polysorbate is at a concentration of about 0.01% v/v to about 1% v/v.

28. The kit of any one of claims 26 to 27, wherein the diluent is a 0.9% saline solution.

29. The kit of any one of claims 26 to 28, wherein the taxane particles comprise at least 95% taxane, wherein the taxane particles have an average particle size (number) of 0.1 to 1.5 microns, and wherein the taxane particles do not comprise albumin.

30. The kit of any one of claims 26 to 29, wherein the taxane particles are solid, uncoated (pure) individual particles; wherein the taxane particle is not bound to any substance; wherein no substance is absorbed or adsorbed onto the surface of the taxane particle; wherein the taxane particles are not encapsulated, contained, enclosed, or embedded in any material; wherein the taxane particle is uncoated by any substance; wherein the taxane particle is not a microemulsion, nanoemulsion, microsphere, or liposome; wherein the taxane particle is not bound to or encapsulated by a monomer, polymer (or biocompatible polymer), protein, surfactant or albumin or is not coated with a monomer, polymer (or biocompatible polymer), protein, surfactant or albumin; and/or wherein monomers, polymers (or biocompatible polymers), proteins, surfactants or albumin are not absorbed or adsorbed onto the surface of the taxane particle.

31. The kit of any one of claims 26 to 30, wherein the taxane particles are paclitaxel particles.

32. The kit of claim 31, wherein the paclitaxel particles have a Specific Surface Area (SSA) of at least 18m²/g、20m²/g、25m²/g、30m²/g、32m²/g、34m²G or 35m²(ii)/g; or about 18m²G to about 50m²/g。

33. The kit of any one of claims 31 to 32, wherein the paclitaxel particles have 0.05g/cm³To 0.15g/cm³Bulk density (not tapped).

34. The kit of any one of claims 26 to 30, wherein the taxane particles are docetaxel particles.

35. The kit of claim 34, wherein the docetaxel particles have a Specific Surface Area (SSA) of at least 18m²/g、20m²/g、25m²/g、30m²/g、35m²/g、40m²(ii)/g, or 42m²(ii)/g; or about 18m²G to about 60m²/g。

36. The kit of any one of claims 34 to 35, wherein the docetaxel particles have a density of 0.05g/cm³To 0.15g/cm³Bulk density (not tapped).

37. A method of administering a composition comprising anti-tumor 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 anti-tumor particles have an average particle size (number) of 0.1 to 5 microns, and wherein the anti-tumor particles are crystalline particles.

38. The method of claim 37, wherein the anti-tumor particles have an average particle size (number) of 0.3 to 5 microns.

39. The method of any one of claims 37 or 38, wherein the anti-tumor particle is a taxane particle.

Technical Field

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

Background

Cystic tumours (cysts) are abnormal sacs in the body which can be filled with liquid or semi-solid substances. Cysts can form in any part of the body, including bones, organs, and soft tissues. Typically cysts are non-cancerous (benign), but benign cysts may be precancerous and become malignant growths. An epithelial cyst is a cyst having an epithelial lining. Examples of epithelial cysts include gastrointestinal cysts such as liver cysts, pancreatic cysts, spleen cysts, colon cysts; urinary cysts such as renal cyst, epididymal cyst, and prostate cyst; 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; and other cysts such as popliteal cysts (Baker's cysts), pulmonary cysts, lymphocysts, and pericardial cysts.

The frequency of pancreatic cystic tumours was higher and higher due to improvements in cross-sectional imaging and routine examinations (Pitman 2010). Mucinous pancreatic cystic tumors account for approximately 75% of all pancreatic cystic tumors, and are divided into two categories: intraductal papillary mucinous tumors (IPMN) and mucinous cystic tumors (MCN). Both types of mucinous pancreatic tumors may develop symptoms of abdominal pain, pancreatitis, jaundice, weight loss, malabsorption, nausea, vomiting, and palpable abdominal mass (Tanaka 2005; muthusmy 2016). Typically, cysts do not show any symptoms at all, and for other reasons the imaging improves when examining the patient, so cysts are found by chance.

Mucinous pancreatic cystic tumours have a malignant potential and therefore every patient diagnosed is at risk of developing pancreatic cancer (Farrell 2015; Sarr 2000). In a study of 401 pancreatic cyst patients, 11% of resected cysts contained invasive cancer (Ferrone 2009). Patients diagnosed with IPMN have a 40% chance of infiltrating cancer, while 58% have potentially malignant characteristics, while patients with MCN have a 10% to 50% risk of malignancy (Greer 2016; Allen 2007). To avoid pancreatic Cancer that progresses to an aggressive and fatal disease, all patients with mucinous pancreatic cysts should be carefully evaluated and provided with treatment (National Cancer Institute 2016; Fern a ndez-delCastillo 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 lavage (EUS guided) of ethanol as an ablative agent to induce cell death by membrane lysis, protein denaturation and vascular occlusion (Jani 2011; DeWitt 2009). However, examination of cyst volume response to ethanol injection failed to standardize its technology and ethanol concentration/volume, and a decade-long study conducted by G Lo mez (G Lo mez 2016) revealed that only 9% of patients experienced complete cyst regression (G Lo mez 2016; Kirtane 2016). There is controversy regarding current treatment methods and practices for pancreatic cysts (Farrell 2013, Tanaka2016, McGrath 2017).

Current methods for determining malignancy in a mucinous cyst provide unreliable results. Without resection, it is difficult to determine the histology of the cyst. About 25% of non-surgical histological diagnoses are inaccurate. The physician performs surgical resection to compensate for this deficiency by suggesting patients with cysts (with features such as symptoms, cytology positives, murals, or greater than 3 cm) (Pitman 2010). Due to concerns about mucin leakage, pancreatic fistulas and recurrence, the standard surgical treatment for invasive and non-invasive MCNs and IPMNs is pancreatectomy with lymph node dissection, rather than focal non-anatomical resection or resection without lymph node dissection or splenectomy (Tanaka 2012). In a study of 37 high volume centers (2694 patients), pancreatectomy mortality was reported to be 1.3%, increasing to 3.0% in patients over 80 years of age, with overall complication rates ranging from 20.0% to 72.2% (Tamirisa 2016). In patients that can be diagnosed with a malignant tumor rate of less than 3%, the risk of death from pancreatectomy is higher than that of malignancy (Allen 2007). Even after surgery, the recurrence rate of cysts may be as high as 20% (Tanaka 2012). However, cysts that were not observed may develop into malignant disease upon observation (Allen 2007).

Disclosure of Invention

The present invention provides a solution to the above-mentioned limitations and deficiencies in the art, related to the treatment of cystic tumors (cysts), particularly epithelial cysts including pancreatic cysts, by direct injection of anti-tumor particles (e.g., taxane particles) into the cysts (intracapsular injection). When a composition of anti-tumor particles, such as taxane particles (e.g., paclitaxel particles or docetaxel particles), is injected into a cyst, the anti-tumor particles will reside in the cyst for a longer period of time than a solution of the anti-tumor agent injected into the cyst because the solution will be more easily and quickly cleared from the cyst by the body. While not being bound by theory, it is speculated that the use of anti-tumor drug particles results in increased efficacy and decreased toxicity compared to solutions of the anti-tumor drug due, at least in part, to the slow release of the anti-tumor drug from the suspended particles. It is also speculated that due to the physical properties of the anti-tumor particles, they may be embedded within or on the inner intraepithelial layer of the cyst, resulting in longer residence times compared to the use of solution or albumin coated particles. Direct infusion (encapsulation) of a suspension of anti-tumor particles into pancreatic cysts produces a depot effect (depot effect) in which the anti-tumor agent is slowly released from the particles into the cysts, resulting in prolonged local exposure of the anti-tumor agent. Decreased pancreatic clearance, decreased systemic antitumor levels, further limiting systemic toxicity. In a preferred embodiment, the anti-tumor particles are taxane particles, such as paclitaxel particles or docetaxel particles.

In one aspect of the invention, a method of treating an epithelial cyst is disclosed, the method comprising directly injecting into the cyst (intracapsular injection) a composition comprising an effective amount of an anti-tumor particle, wherein the particle has an average particle size (number) of 0.1 microns to 5 microns, thereby treating the epithelial cyst. In a preferred embodiment, the anti-tumor particle is a taxane particle. In some embodiments, the particles of the antineoplastic agent have an average particle size (number) of 0.1 microns to 1.5 microns. In some embodiments, the taxane particle is a paclitaxel particle. In some embodiments, the composition and taxane particle do not include albumin. In other embodiments, the taxane particles are docetaxel particles. In some embodiments, the epithelial cyst is a pancreatic cyst, e.g., a mucinous pancreatic cyst. In some embodiments, the volume/size of the epithelial cyst is reduced, the growth rate is reduced, eliminated, or ablated following treatment by injection of the composition. In some embodiments, pain associated with an epithelial cyst is reduced after injection of the composition.

In another aspect of the invention, a kit is disclosed comprising: (a) a first vial comprising taxane particles; (b) a second vial comprising a pharmaceutically acceptable aqueous carrier and a surfactant; (c) instructions for reconstituting the anti-tumor particles into a suspension useful for intravesicular injection by: the contents of the first vial and the second vial are combined to form a suspension, and the suspension is optionally diluted with a diluent. In some embodiments, the taxane particles have an average particle size (number) of 0.1 to 1.5 microns. In some embodiments, the surfactant is a polysorbate. In some embodiments, the taxane particle is a paclitaxel particle. In other embodiments, the taxane particles are docetaxel particles.

In addition, the following embodiments 1 to 39 are disclosed in the present disclosure:

Drawings

Figure 1 is a graph of paclitaxel flux (flux) (delivered dose of paclitaxel active drug across porcine bladder membrane as a function of time) from various paclitaxel formulations.

Figure 2 is a graph of paclitaxel flux (delivered dose of paclitaxel active drug across porcine intestinal membranes as a function of time) from various paclitaxel formulations.

Figure 3 is a graph of docetaxel flux (delivered dose of docetaxel active drug across porcine bladder membrane as a function of time) from various docetaxel formulations.

embodiment 1 is a method of treating an epithelial cyst, comprising directly injecting into the cyst a composition comprising an effective amount of an anti-tumor particle, wherein the particle has an average particle size (number) of 0.1 microns to 5 microns, thereby treating the epithelial cyst.