Mucoadhesive polymeric drug dispensing compositions and methods

Abstract

MUCOADHESIVE POLYMERIC COMPOSITIONS FOR DRUG DISPENSING AND METHODS. This invention provides compositions for controlled localized deposition of one or more drugs within an individual. More particularly, compositions comprising a) a polyethylene glycol (PEG) composition with a first low molecular weight PEG (Mw between 200 and 500 Da) and a second low molecular weight PEG (Mw between 500 and 2000 Da) and b) a mucoadhesive polymer are described in this document. Alternatively, the composition may comprise a) a polyethylene glycol (PEG) composition with a first low molecular weight PEG (Mw between 200 and 500 Da) and a second low molecular weight PEG (Mw between 500 and 2000 Da), b) a water-insoluble polymer and c) a mucoadhesive polymer. Furthermore, the composition may additionally include one or more drugs.Methods for manufacturing and administering the compositions described in this document, which are used as biodegradable, injectable, mucoadhesive, low-viscosity pastes, are also provided.

Description

1 / 66 Descriptive Report of the Invention Patent for: “MUCOADHESIVE POLYMERIC COMPOSITIONS FOR DRUG DISPENSING AND METHODS” CROSS-REFERENCE ON RELATED REQUEST

[001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 62 / 971,882 filed February 7, 2020, entitled “MUCOADHERSIVE POLYMERIC DRUG DELIVERY COMPOSITIONS AND METHODS”. FIELD OF THE INVENTION

[002] This invention relates to low-viscosity biodegradable polymer pastes suitable for drug delivery. More particularly, the invention relates to injectable low-viscosity mucoadhesive polymer pastes comprising a composition of polyethylene glycol (PEG), a water-insoluble polymer, and a mucoadhesive polymer. In addition, the composition may further comprise one or more drugs that are released in a controlled manner. FUNDAMENTALS OF THE INVENTION Local drug treatment by injection into the renal pelvis.

[003] Kidney disease and kidney abnormalities are generally difficult to treat. Most renal drug treatments require the systemic administration of high concentrations of drugs, which may be associated with Petition 870220089251, dated 09 / 29 / 2022, page 6 / 79 2 / 66 adverse effects, such as abnormal glomerular filtration, tubular secretion, or proteinuria. Furthermore, high systemic drug concentrations may not translate to high concentrations in the target cell, and drug delivery to the kidney may be insufficient to achieve therapeutic goals. Consequently, targeted drug delivery to the kidney is often necessary in the treatment of kidney disease. Untreated or inadequately treated kidney disease usually requires dialysis, long-term medication, or even kidney transplantation to prolong life.

[004] Intravesical administration of anticancer drugs has reduced the recurrence and progression of bladder cancer. However, dispensing drugs to treat malignancies of the renal pelvis and ureter is a challenge. The constant flow of urine through the upper and lower urinary tract washes away the locally administered drug, and the only curative treatment for urothelial carcinoma of the renal pelvis or ureter is surgery. Upper Tract Urothelial Carcinoma

[005] Urothelial carcinomas (UCs) can occur in the lower urinary tract (bladder or urethra) or in the upper urinary tract (UUT: pyelocaliceal cavities and ureter) (Lughezzani et al. 2012). More than 90% of UCs are located in the bladder, with less than 10% occurring in the upper urinary tract. Petition 870220089251, dated 09 / 29 / 2022, page 7 / 79 3 / 66 superior (UTC). Patients with bladder cancer are usually diagnosed with early-stage disease and the cancer confined to the superficial urothelium. This is partly due to the easy access of diagnostic equipment through the urethra. However, many patients with UTCs are not diagnosed early and may have already progressed to invasive disease. Staging UTCs can also be difficult because the tissue is fragile with only limited muscle, so biopsies do not always accurately describe the level of disease.

[006] Once diagnosed, radical nephroureterectomy (RNU) with bladder cuff removal is considered the standard treatment for UTC (Audenet et al. 2013; Roupret et al. 2013). This procedure involves the complete removal of the kidney, ureter, and bladder cuff. Tumor cell shedding can be a problem with such procedures. Furthermore, many patients are not candidates for this treatment. Some patients with low-risk disease may receive more conservative treatment, such as endoscopic ablation or segmental removal (Lughezzani et al. 2012). Clearly, with late diagnosis, the prognosis for these patients with UTC is poor. Chemotherapy options are limited for these patients, especially since cisplatin-based regimens are associated with nephrotoxicity, which can be exacerbated when a kidney is removed. Other drugs used to treat bladder cancer, such as Mitomycin C and Petition 870220089251, dated 09 / 29 / 2022, page 8 / 79 4 / 66 Gemcitabine may have a preferred toxicity profile. When used to treat bladder cancer, these drugs can be administered in high concentrations intravesically (directly into the bladder), so that a 2-hour retention allows for reasonable absorption of the drug into the tissues after tumor resection. More recently, the drug docetaxel is under investigation as a chemotherapeutic option to treat bladder cancer locally and UTC by systemic dispensing. The combination of gemcitabine and docetaxel is also being studied as an improvement over the use of either drug alone (Gitlitz et al. 2003).

[007] Because UUT tissues cannot be treated locally with a drug solution (the pelvis is accessible, but drug solutions would quickly reach the bladder), one company, UroGen Pharma, Inc.™, developed a mitomycin gel formulation called JELMYTO™ (Mitogel™). This gel undergoes a thermoreversible gel transition in the body so that it can be injected as a liquid to form a semi-solid gel in the renal pelvis. The pluronic acid-based gel dissolves slowly but allows some retention of the drug in the tissues at the target site. Injectable Polymer Paste

[008] Drugs are normally dispensed orally or by injection to allow systemic absorption and Petition 870220089251, dated 09 / 29 / 2022, p. 9 / 79 5 / 66 circulation to most parts of the body. For many drugs, this route of administration is ideally suited, for example, insulin for diabetes or statins for heart disease. However, many diseases are localized, and the preferred method is to dispense the drug directly to the site of action. For example, analgesics for localized chronic pain, anticancer drugs for local tumors, and antiarthritic drugs to relieve arthritis symptoms and joint pain. Consequently, there have been numerous attempts to design locally injectable systems to dispense drugs to specific body sites. This targeted approach can also minimize the systemic toxicity often associated with conventional drug administration methods. Intravenous administration of anticancer drugs often causes severe side effects, and systemic toxicities often limit the drug dose.Local polymeric drug delivery systems can mitigate systemic side effects and allow for the dispensing of high local doses.

[009] Poly(DL-lactide-co-glycolide) (PLGA) is a common constituent of polymeric drug delivery systems. It is an FDA-approved biopolymer of lactic acid (D,L-LA) and glycolic acid (GA) and has been used both as a drug delivery carrier and as a support. Petition 870220089251, dated 09 / 29 / 2022, page 10 / 79 6 / 66 for tissue engineering (Bouissou et al. 2006; Jain 2000). PLGA degradation depends on many factors, including but not limited to the LA to GA ratio, crystallinity, average molecular weight of the polymer, matrix shape, and type and amount of incorporated drug (Siegel et al. 2006; Makadia and Siegel 2011). The LA to GA ratio influences degradation, and polymers with a higher amount of the more hydrophilic GA generally degrade more rapidly. The degradation products of PLGA are the LA and GA hydrolysis products. Both can enter the citric acid cycle and can be excreted as water and carbon dioxide, or in the case of GA, mainly excreted unchanged by the kidney (Makadia and Siegel 2011). Minor toxicities, such as transient inflammation, have been reported for some PLGA-based implants (Athanasiou, Niederauer, and Agrawal 1996), but likely reflect increased exposure times and reduced clearance of degradation products.

[0010] Drug-loaded injectable polymer pastes are attractive for local drug administration because ultrasound or magnetic resonance-guided systems allow for precise targeting of a needle or catheter system to a target area. Others have described injectable liquids (e.g., Atrigel™) (Dunn 2002) composed of an organic solvent such as acetone or polyvinylpyrrolidone and a drug that, when injected into the body, Petition 870220089251, dated 09 / 29 / 2022, page 11 / 79 7 / 66 solidified as the solvent dissolved. Such a system is flawed because the introduction of an organic solvent into potentially sensitive tissue areas can induce unwanted local toxicity. Local drug delivery systems have been described ranging from polymeric coatings for drug-loaded stents, injectable microspheres (Jackson et al. 2007), perivascular films (Jackson et al. 2004), and injectable polymeric pastes (Jackson et al. 2000). In these examples, the antiproliferative drug paclitaxel was used to inhibit proliferative events associated with restenosis, cancer, and arthritis. Several polymer formulations for a variety of applications are known in the art (Yu and Ferguson, 2016; Konorty and Hakim, 2014; Pauletti, 2004; and Lughezzani et al. 2012).

[0011] An early polymer paste system described in the literature was based on a mixture of polycaprolactone and methoxypolyethylene glycol that was injectable (melted) at temperatures above body temperature, but fitted to an implant at 37°C to release the drug (Winternitz et al. 1996). The implant was brittle, hard, and the high-temperature dispensing was unsuitable for injection into sensitive sites. An injectable polymer paste loaded with paclitaxel, made from a mixture of a triblock copolymer and methoxypolyethylene glycol, was also described as injectable at Petition 870220089251, dated 09 / 29 / 2022, p. 12 / 79 8 / 66 room temperature and formed a solid implant in vivo (Jackson et al. 2000). This paste performed poorly, as the release rate of the drug paclitaxel and other hydrophobic drugs was too slow to achieve adequate tissue levels of the active drug, and the polymer degradation profile was too long, potentially interfering with retreatment injections. The inclusion of diblock copolymers of various compositions in solid microspheres (not in paste) has been previously described (Jackson et al. 2007). In this case, the dissolution of the diblock from the microspheres allowed for increased hydrophobic drug release, as well as matrix opening to water and intensified degradation. Microsphere formulations are quite different from pastes. They do not flow under injection, therefore they must be injected in a liquid suspension. As such, they can easily disperse from a target tissue area. SUMMARY OF THE INVENTION

[0012] This invention relates to improved polymeric pastes for controlled delivery of drugs to a mucous membrane. The compositions described herein allow the formulation and injection of a low-viscosity composition into the body of an individual wherein the composition is able to coat the mucosal surface at a localized site and remain at that site for an extended period of time after the initial injection to the site. In one aspect, the present Petition 870220089251, dated 09 / 29 / 2022, page 13 / 79 The invention provides delayed drug release from a polymer-coated dispensing system using selected compositions of polyethylene glycol (PEG), selected water-insoluble polymers, and selected mucoadhesive polymers to adjust the properties of the polymer formulation and regulate the release rates of the drug payload(s) and in situ residence time. The polymer composition can be manufactured from simple polymers that form an injectable polymeric mucoadhesive composition, which can release the drug and / or drug combinations in a controlled manner. This invention is based on the surprising finding that only defined ratios and compositions of polyethylene glycol (PEG), a water-insoluble polymer, and a mucoadhesive polymer can be used to effectively form a mucoadhesive and injectable drug dispensing system for in vivo dispensing.The compositions described herein are of low viscosity and become a gel only after application in an aqueous environment (for example, allowing them to be injected into hard-to-reach areas). The compositions described herein can be injected through long catheter lines without additional devices, and certain compositions described herein can be administered for embolic purposes.

[0013] In a first aspect, a composition is provided, the composition including: a polyethylene glycol composition Petition 870220089251, dated 09 / 29 / 2022, page 14 / 79 10 / 66 (PEG) comprising between about 85% and about 96% by weight, comprising (i) a first low molecular weight polyethylene glycol (PEG), wherein the first low molecular weight PEG has an average molecular weight between about 200 Da and about 500 Da, and (ii) a second low molecular weight polyethylene glycol (PEG) wherein the second low molecular weight PEG has an average molecular weight between about 500 Da and about 2,000 Da; a water-insoluble polymer comprising between about 2% and about 10% by weight; and a mucoadhesive polymer comprising between about 2% and about 5% by weight.

[0014] In a further aspect, a composition is provided, the composition including: a polyethylene glycol (PEG) composition comprising between about 85% and about 96% by weight, comprising (i) a first low molecular weight polyethylene glycol (PEG), wherein the first low molecular weight PEG has an average molecular weight between about 200 Da and about 500 Da, and (ii) a second low molecular weight polyethylene glycol (PEG) wherein the second low molecular weight PEG has an average molecular weight between about 500 Da and about 2,000 Da; a water-insoluble polymer comprising between about 2% and about 10% by weight; and a mucoadhesive polymer comprising between about 2% and about 5% by weight and having a molecular weight > 50 kDa. Petition 870220089251, dated 09 / 29 / 2022, page 15 / 79 11 / 66

[0015] In a first aspect, a composition is provided, the composition including: a polyethylene glycol (PEG) composition comprising between about 85% and about 99% by weight, comprising (i) a first low molecular weight polyethylene glycol (PEG), wherein the first low molecular weight PEG has an average molecular weight between about 200 Da and about 500 Da, and (ii) a second low molecular weight polyethylene glycol (PEG) wherein the second low molecular weight PEG has an average molecular weight between about 500 Da and about 2,000 Da; a water-insoluble polymer comprising between about 2% and about 10% by weight; and a mucoadhesive polymer comprising between about 2% and about 5% by weight.

[0016] In a further aspect, a composition is provided, the composition including: a polyethylene glycol (PEG) composition comprising between about 85% and about 99% by weight, comprising (i) a first low molecular weight polyethylene glycol (PEG), wherein the first low molecular weight PEG has an average molecular weight between about 200 Da and about 500 Da, and (ii) a second low molecular weight polyethylene glycol (PEG), wherein the second low molecular weight PEG has an average molecular weight between about 500 Da and about 2,000 Da; a water-insoluble polymer comprising between about 2% and about 10% by weight; and a mucoadhesive polymer which is Petition 870220089251, dated 09 / 29 / 2022, page 16 / 79 12 / 66 comprises between approximately 2% and approximately 5% by weight and has a molecular weight > 50 kDa.

[0017] In a further aspect, a composition is provided, the composition including: a polyethylene glycol (PEG) composition that is between about 85% and about 96% by weight, comprising (i) a first low molecular weight polyethylene glycol (PEG), wherein the first low molecular weight PEG has an average molecular weight between about 200 Da and about 500 Da, and (ii) a second low molecular weight polyethylene glycol (PEG) wherein the second low molecular weight PEG has an average molecular weight between about 500 kDa and about 2,000 Da; and an undissolved mucoadhesive polymer comprising between about 4% and about 15% by weight. The composition may additionally include a water-insoluble polymer. Alternatively, the water-insoluble polymer may comprise between about 2% and about 10% by weight; and an undissolved mucoadhesive polymer comprising between about 2% and about 5% by weight. The mucoadhesive polymer may have a molecular weight > 50 kDa.

[0018] In a further aspect, a composition is provided, the composition including: a polyethylene glycol (PEG) composition that is between about 85% and about 99% by weight, comprising (i) a first low molecular weight polyethylene glycol (PEG), wherein the Petition 870220089251, dated 09 / 29 / 2022, page 17 / 79 13 / 66 The first low molecular weight PEG has an average molecular weight between about 200 Da and about 500 Da, and (ii) a second low molecular weight polyethylene glycol (PEG) wherein the second low molecular weight PEG has an average molecular weight between about 500 kDa and about 2,000 Da; and an undissolved mucoadhesive polymer that is between about 4% and about 15% by weight. The composition may additionally include a water-insoluble polymer. Alternatively, the water-insoluble polymer may be between about 2% and about 10% by weight; and an undissolved mucoadhesive polymer that is between about 2% and about 5% by weight. The mucoadhesive polymer may have a molecular weight > 50 kDa.

[0019] In a further aspect, a composition is provided, the composition including: a polyethylene glycol (PEG) composition comprising between about 85% and about 99% by weight, comprising (i) a first low molecular weight polyethylene glycol (PEG), wherein the first low molecular weight PEG has an average molecular weight between about 200 Da and about 500 Da, and (ii) a second low molecular weight polyethylene glycol (PEG) wherein the second low molecular weight PEG has an average molecular weight between about 500 Da and about 2,000 Da; and a mucoadhesive polymer comprising between about 1% and about 15% by weight and having a molecular weight > 50 kDa. The composition Petition 870220089251, dated 09 / 29 / 2022, page 18 / 79 14 / 66 may additionally include a water-insoluble polymer. Alternatively, the composition may have a polyethylene glycol (PEG) composition that is between about 85% and about 96% by weight. Alternatively, the composition may have a mucoadhesive polymer that is between about 4% and about 15% by weight and has a molecular weight > 50 kDa.

[0020] In a further aspect, a composition is provided, the composition including: a polyethylene glycol (PEG) composition comprising between about 85% and about 96% by weight, comprising (i) a first low molecular weight polyethylene glycol (PEG), wherein the first low molecular weight PEG has an average molecular weight between about 200 Da and about 500 Da, and (ii) a second low molecular weight polyethylene glycol (PEG) wherein the second low molecular weight PEG has an average molecular weight between about 500 Da and about 2 kDa; and an undissolved mucoadhesive polymer comprising between about 4% and about 15% by weight and having a molecular weight > 50 kDa. The composition may further include a water-insoluble polymer.

[0021] In a further aspect, a composition is provided, the composition including: a polyethylene glycol (PEG) composition that is between about 85% and about 96% by weight, comprising (i) a first low molecular weight polyethylene glycol (PEG), wherein the Petition 870220089251, dated 09 / 29 / 2022, page 19 / 79 15 / 66 The first low molecular weight PEG has an average molecular weight between about 200 Da and about 500 Da, and (ii) a second low molecular weight polyethylene glycol (PEG) wherein the second low molecular weight PEG has an average molecular weight between about 500 Da and about 2 kDa; and an undissolved mucoadhesive polymer that is between about 4% and about 15%. The composition may additionally include a water-insoluble polymer.

[0022] In a further aspect, a non-aqueous polymeric composition is provided, the composition including: (i) low molecular weight (below 500 Da) polyethylene glycol (PEG) or propylene glycol with (ii) a higher molecular weight (500 to 2,000) PEG and (iii) suspended hyaluronic acid. The composition may additionally include a water-insoluble polymer.

[0023] In a further aspect, a non-aqueous polymeric composition is provided, the composition including: (i) low molecular weight (below 500 Da) polyethylene glycol (PEG) or propylene glycol with (ii) a higher molecular weight PEG (500 to 2000), (iii) suspended hyaluronic acid and (iii) a small molecule drug wherein the composition is injectable via an 18 gauge needle under manual pressure. Petition 870220089251, dated 09 / 29 / 2022, page 20 / 79 16 / 66

[0024] In a further aspect, a use is provided for a composition described in this document, for the manufacture of a medicament.

[0025] In a further aspect, a use is provided for a composition described in this document, for the treatment of a medical condition for which the drug is used.

[0026] In a further aspect, a use is provided for of a composition described herein, for the treatment of a mucosal surface area that would benefit from localized drug delivery.

[0027] In a further aspect, a method of administering a drug to a mucosal surface area is provided, the method including: (a) combining the composition described herein with a drug to form a drug-loaded composition and (b) delivering the drug-loaded composition to the mucosal surface area.

[0028] In a further aspect, a composition described in this document is provided for use in the treatment of a medical condition.

[0029] In a further aspect, a commercial package is provided including: (a) the composition described herein; and (b) instructions for use.

[0030] A pharmaceutical composition described herein may be combined with a pharmaceutically acceptable diluent or carrier. Petition 870220089251, dated 09 / 29 / 2022, page 21 / 79 17 / 66

[0031] The second low molecular weight PEG may comprise up to 20% by weight of the composition. The second low molecular weight PEG may comprise between about 5% and about 20% by weight of the composition. The second low molecular weight PEG may comprise between about 2% and about 25% by weight of the composition. The second low molecular weight PEG may comprise between about 1% and about 30% by weight of the composition.

[0032] The water-insoluble polymer may be selected from one or more of the following: polylactic-coglycolic acid (PLGA), poly(ε-caprolactone) (PCL), polylactic acid (PLA). The water-insoluble polymer may be PLGA. Alternatively, the water-insoluble polymer may be a copolymer of acrylic and methacrylic acid esters. The molar ratio of lactic acid to glycolic acid monomers may be between 90:10 and 50:50.

[0033] The mucoadhesive polymer may be selected from one or more of the following: hyaluronic acid; poly(acrylic acid) and poly(methacrylic acid) derivatives; cyanoacrylates; poly(acrylic acid); carbomer; sodium carboxymethylcellulose (CMC); hydroxypropylcellulose; polycarbophil; chitosan; alginate; gellan; xanthan; thiolated poly(acrylic acid); poloxamer; cellulose acetate phthalate; ethylcellulose; methylcellulose; hydroxyethylcellulose; poly(amidoamine) dendrimers; poly(dimethylsiloxane); and Petition 870220089251, dated 09 / 29 / 2022, page 22 / 79 18 / 66 poly(vinylpyrrolidone). The mucoadhesive polymer may be selected from one or more of the following: hyaluronic acid; poly(acrylic acid); carbomer; sodium carboxymethylcellulose; alginic acid. The mucoadhesive polymer may be hyaluronic acid. Alternatively, the mucoadhesive polymer may be selected from one or more of the following: hyaluronic acid; poly(acrylic acid) and poly(methacrylic acid) derivatives; cyanoacrylates; poly(acrylic acid); carbomer; sodium carboxymethylcellulose (CMC); hydroxypropylcellulose; polycarbophil; thiolated poly(acrylic acid); poloxamer; cellulose acetate phthalate; ethylcellulose; methylcellulose; hydroxyethylcellulose; poly(amidoamine) dendrimers; poly(dimethylsiloxane); and poly(vinylpyrrolidone).

[0034] The first low molecular weight PEG can be selected from one of the following approximate molecular weights: PEG 200; PEG 300; PEG 400; and PEG 500. The first low molecular weight PEG can be selected from one of the following: PEG 100; PEG 200; PEG 300; PEG 400; and PEG 500. The second low molecular weight PEG is selected from one of the following approximate molecular weights: PEG 500; PEG 600; PEG 700; PEG 800; PEG 900; PEG 1000; PEG 1100; PEG 1200; PEG 1300; PEG 1400; PEG 1450; PEG 1500; PEG 1600; PEG 1700; PEG 1800; PEG 1900; and PEG 2000. The second low molecular weight PEG is selected from one of the Petition 870220089251, dated 09 / 29 / 2022, page 23 / 79 The following 19 / 66: PEG 500; PEG 600; PEG 700; PEG 800; PEG 900; PEG 1000; PEG 1100; PEG 1200; PEG 1300; PEG 1400; PEG 1500; PEG 1600; PEG 1700; PEG 1800; and PEG 1900. The second low molecular weight PEG is selected from one of the following: PEG 500; PEG 600; PEG 700; PEG 800; PEG 900; PEG 1000; PEG 1100; PEG 1200; PEG 1300; PEG 1400; PEG 1500; PEG 1600; PEG 1700; The second low molecular weight PEG is selected from one of the following: PEG 500; PEG 600; PEG 700; PEG 800; PEG 900; PEG 1000; PEG 1100; PEG 1200; PEG 1300; PEG 1400; PEG 1500; PEG 1600; and PEG 1700. and PEG 1600. The second low molecular weight PEG is selected from one of the following: PEG 500; PEG 600; PEG 700; PEG 800; PEG 900; PEG 1000; PEG 1100; PEG 1200; PEG 1300; PEG 1400; and PEG 1500.PEG can have an average molecular weight between approximately 200 Da and approximately 2,000 Da.

[0035] The composition may additionally include one or more low molecular weight PEG polymers selected from one or more of the following: PEG 200; PEG 300; PEG 400; PEG 500; PEG 600; PEG 700; PEG 800; PEG 900; PEG 1000; PEG 1100; PEG 1200; PEG 1300; PEG 1400; PEG 1500; PEG 1600; PEG 1700; PEG 1800; PEG 1900; and PEG 2000. Petition 870220089251, dated 09 / 29 / 2022, page 24 / 79 20 / 66

[0036] The composition may additionally include one or more pharmaceutically acceptable drug compounds or salts, solvates or solvates of salts thereof. The one or more pharmaceutically acceptable drug compounds or salts, solvates or solvates of salts thereof may be selected from one or more of the following categories: anticancer drugs; anti-inflammatory agents; antibacterial drugs; antiviral drugs; antifungal drugs; antiproliferative drugs; antifibrotic drugs; antistenotic drugs (sirolimus-based drugs and taxane-based drugs); anesthetic drugs; neuromodulatory drugs; and analgesics.

[0037] One or more drug compounds or salt, solvate or pharmaceutically acceptable solvate of the salt thereof may be an anticancer drug selected from one or more of the following: Actinomycin; Todotrans retinoic acid; Azacitidine; Azathioprine; Bleomycin; Bortezomib; Carboplatin; Capecitabine; Cisplatin; Chlorambucil; Cyclophosphamide; Cytarabine; Daunorubicin; Docetaxel; Doxyfluridine; Doxorubicin; Epirubicin; Epothilone; Etoposide; Fluorouracil; Gemcitabine; Hydroxyurea; Idarubicin; Imatinib; Irinotecan; Mechlorethamine; Mercaptopurine; Methotrexate; Mitoxantrone; Oxaliplatin; Paclitaxel; Pemetrexed; Teniposide; Thioguanine; Topotecan; Valrubicin; Vemurafenib; Vinblastine; Petition 870220089251, dated 09 / 29 / 2022, page 25 / 79 21 / 66 Vincristine; Vindesine; and Vinorelbine. The drug may be selected from one or more of: Gemcitabine HCl, gemcitabine, mitomycin, docetaxel, and paclitaxel. One or more drug compounds or a pharmaceutically acceptable salt, solvate, or solvate of the salt thereof may be an anesthetic drug, and the anesthetic may be a local anesthetic selected from one or more of the following: Procaine; Benzocaine; Chloroprocaine; Cocaine; Cyclomethicone; Dimethocaine / Larocaine; Piperocaine; Propoxycaine; Procaine / Novocaine; Proparacaine; Tetracaine / Amethocaine; Articaine; Bupivacaine; Cinchocaine / Dibucaine; Etidocaine; Levobupivacaine; Lidocaine / Lignocaine / Xylocaine; Mepivacaine; Prilocaine; Ropivacaine; and Trimecaine.

[0038] One or more drug compounds or salt, solvate or pharmaceutically acceptable solvate of the salt thereof may be an antibiotic drug, which may include penicillins, cephalosporins, polymyxins, rifamycins, lipiarmycins, quinolones, sulfonamides, macrolides, lincosamides, tetracyclines, aminoglycosides, lipopeptides, glycylcyclines, oxazolidinones and lipiarmycins, cephalexin, cefazolin, gentamicin, ciprofloxacin, clindamycin, macrodantin, tobramycin, rifampicin, daptomycin, linezolid, vancomycin, fusidic acid, silver compounds, cannabinoids and others. An antibiotic may also include silver and a cannabinoid. Petition 870220089251, dated 09 / 29 / 2022, page 26 / 79 22 / 66

[0039] One or more drug compounds or salt, solvate or pharmaceutically acceptable solvate of the salt thereof may be an antifungal drug, such as polyenes, azoles, triazoles, antimetabolites, allylamines, echinocandins. Antifungal drugs may include, for example, but are not limited to, amphotericin B, nystatin, clotrimazole, econazole, miconazole, fluconazole, terbinafine, fluconazole, ketoconazole, caspofungin, tolnaftate, ivermectin, flucytosine, griseofulvin.

[0040] The mucosal surface area may be selected from one or more of the following: urogenital tract; gastrointestinal tract; and respiratory tract. The mucosal surface area may be selected from one or more of the following: kidney; ureter; bladder; urethra; uterus; vagina; penis; mouth; esophagus; stomach; small intestine; large intestine; rectum; anus; sinuses; pharynx; larynx; trachea; bronchi; bronchioles; lungs. The medical condition may be selected from one or more of the following: cancer; injury; and inflammation. The drug-loaded composition may be for the treatment of one or more of the following: cancer; injury; and inflammation.

[0041] The composition may additionally include a water-insoluble polymer which may be selected from one or more of: polylactic-co-glycolic acid (PLGA); poly(scaprolactone) (PCL); and polylactic acid (PLA). The polymer Petition 870220089251, dated 09 / 29 / 2022, page 27 / 79 23 / 66 water-insoluble polymer may be PLGA. Alternatively, the water-insoluble polymer may be PCL or PLA. Alternatively, the water-insoluble polymer may be a copolymer of acrylic and methacrylic acid esters. The molar ratio of lactic acid to glycolic acid monomers may be between 90:10 and 50:50. The water-insoluble polymer may comprise between 2% and 20% by weight of the composition. The water-insoluble polymer may comprise between 2% and 15% by weight of the composition. The water-insoluble polymer may comprise up to 20% by weight of the composition. The water-insoluble polymer may comprise up to 15% by weight of the composition. PLGA may comprise between 2% and 20% by weight of the composition. PLGA may comprise between 2% and 15% by weight of the composition. PLGA can comprise up to 20% by weight of the composition. PLGA can comprise up to 15% by weight of the composition.

[0042] Methods are provided for using the compositions mentioned above to form implants in vitro and in vivo. In vivo methodologies include injecting the composition into a site on an individual's body where the drug-containing implant can be formed. Injection devices containing the composition described herein are also provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] FIGURE 1 shows a schematic of gemcitabine paste in the renal pelvis. Petition 870220089251, dated 09 / 29 / 2022, page 28 / 79 24 / 66

[0044] FIGURE 2 shows a semi-log graph of concentration versus time data after administration of a gemcitabine paste into the renal pelvis (1000 mg / pig).

[0045] FIGURE 3 shows a semi-log graph of the amount of gemcitabine (mg) excreted per collection interval (plotted mean) after administration of a gemcitabine paste into the renal pelvis (1000 mg / pig).

[0046] FIGURE 4 shows the tissue concentrations of gemcitabine after administration of gemcitabine paste to the renal pelvis. Renal tissue was collected after 1 h of in vivo drug exposure (one sample per tissue).

[0047] FIGURE 5 shows the tissue concentrations of gemcitabine after administration of gemcitabine paste to the renal pelvis. Renal tissue was collected after 3 h of in vivo drug exposure (n = 4).

[0048] FIGURE 6 shows serum data after administration of gemcitabine HCl (~30 mg / kg) after IV administration and after local administration in the renal pelvis: Renal pelvis injection: pig serum data (exponential adjustment of measured serum levels, n = 3), intravenous administration: approximation of an IV profile using pharmacokinetic parameters from the literature (PK) derived from 30 min infusions of gemcitabine HCl in 12 patients and a 1-compartment model. Petition 870220089251, dated 09 / 29 / 2022, page 29 / 79 25 / 66

[0049] FIGURE 7 shows the viscosities of formulations A, F1, F2, F3, F4 (TABLE 7) at room temperature BEFORE mixing them with water.

[0050] FIGURE 8 shows the viscosities of formulations A, F1, F2, F3, F4 (TABLE 7) at room temperature AFTER mixing them 1:1 with water.

[0051] FIGURE 9 shows the viscosities of formulations A, B1, B2, B2, B4, B5 (TABLE 6) at room temperature BEFORE mixing them with water.

[0052] FIGURE 10 shows the viscosities of formulations A, B1, B2, B2, B4, B5 (TABLE 6) at room temperature AFTER mixing them 1:1 with water.

[0053] FIGURE 11 shows the viscosities of formulations A, E1, E2, E3 (TABLE 10) at room temperature.

[0054] FIGURE 12 shows the release of docetaxel, gemcitabine HCl and albumin from formulation A (TABLE 8). DETAILED DESCRIPTION OF THE INVENTION

[0055] A novel formulation that adheres to the renal pelvis and ureter or other mucous membrane to deliver the chemotherapeutic agent (e.g., gemcitabine) locally is described here, and the feasibility, safety, and pharmacokinetic properties of an injectable mucoadhesive polymer composition are evaluated here.

[0056] The previous pastes were 50 / 50 PEG 300 / PLGA with 10% gemcitabine and 2% sodium hyaluronate in paste form. Petition 870220089251, dated 09 / 29 / 2022, page 30 / 79 26 / 66 69 / 31 PEG300 / PLGA with 5% gemcitabine. The pastes were safe (mild hydronephrosis in some pigs) and the systemic concentration of gemcitabine was low. Several improvements were made to the paste to create a gemcitabine composition that is easily injectable and shows some pelvic adhesion and no interaction with the urinary catheter.

[0057] A gemcitabine paste composition as described herein has a reduced PLGA content, more hyaluronic acid, a combination of PEGs of different molecular weights, and uses gemcitabine HCl instead of gemcitabine.

[0058] The operating principle of the compositions described herein is not based on retention by fixation, but on gelation and mucoadhesion. A large injection volume of 10 mL can be used to coat the entire renal pelvis (scheme shown in FIGURE 1). The paste is injected through a 5F catheter into the renal pelvis. After at least 5 min, the ureteral catheter is removed and the paste slowly descends into the bladder without blocking the ureter. Due to the mucoadhesive properties of the paste, the renal pelvis remains coated with paste and gemcitabine release into the tissue is maintained.

[0059] In embodiments of the invention, water-insoluble polymers can be used to control the consistency of biocompatible polymer pastes and the Petition 870220089251, dated 09 / 29 / 2022, p. 31 / 79 27 / 66 subsequent release of a variety of drugs from them.

[0060] For polymers where viscosity cannot be measured directly (e.g., PLGA - waxy lumps), the polymer is dissolved in an appropriate solvent and the relative viscosity is calculated by dividing the viscosity of the polymer solution by the viscosity of the pure solvent. Most polymers exhibit a distinct relationship between molar mass and viscosity, and as a rule, the viscosity of polymer solutions increases with increasing molar mass. Inherent viscosity (IV) is the ratio of the natural logarithm of relative viscosity to the polymer mass concentration and is provided as a measure of molecular size and is typically reported in deciliters per gram (dL / g). IV is simple, inexpensive to obtain, and reproducible. Gel Permeation Chromatography (GPC) can be used as a chromatographic method to measure molecular size.Molecular size can be expressed as molecular weight (MW) in Daltons obtained by calibration with a standard polymer (e.g., polystyrene standards in chloroform). The molecular weight of styrene is 10⁴ Daltons, and known polystyrene standards are readily available. MWs obtained by GPC are highly method-dependent and may be less reproducible between laboratories. Alternatively, molecular weight can be measured by exclusion chromatography. Petition 870220089251, dated 09 / 29 / 2022, page 32 / 79 28 / 66 by size (SEC), high-temperature gel permeation chromatography (HT-GPC), or mass spectrometry (MALDI TOFMS).

[0061] A water-insoluble polymer can be a polyester. The water-insoluble polymer can be a polylactic-co-glycolic acid (PLGA), where the LA:GA ratio is equal to or less than 75:25. The LA:GA ratio can be approximately 50:50. Durect Corporation™, which supplied the PLGA used in these experiments, represents the inherent viscosity (IV) in dL / g in hexafluoroisopropanol (HFIP) relative to the molecular weight in Daltons for its LA:GA 50:50 and 65:35 polymers. Similarly, when Durect™ calculated the IV values ​​in dL / g for PLGA 75:25 and PLGA 85:15, chloroform was used as the solvent. The relationship between IV and molecular weight in Daltons is different depending on the LA:GA ratio. As described in this document, an inherent viscosity between 0.15 and 0.25 dL / g is an optional range, but an IR in the range of 0.25 to 0.5 dL / g would also be suitable. Alternatively, the range could be between approximately 0.15 dL / g and approximately 0.5 dL / g.

[0062] Using a 50:50 PLGA, a range of 0.15 to 0.25 dL / g is approximately equivalent to a range of about 4,300 Da to about 6,700 Da, and a range of 0.25 to 0.5 dL / g is approximately equivalent to a range of about 6,700 Da to about 26,600 Da. Using a 65:35 PLGA, a range of 0.15 to 0.25 dL / g is approximately equivalent to a range Petition 870220089251, dated 09 / 29 / 2022, page 33 / 79 29 / 66 of approximately 6,500 Da to approximately 14,200 Da and a range of 0.25 to 0.5 dL / g is approximately equivalent to a range of approximately 14,200 Da to approximately 39,000 Da. The wider range of 0.15 to 0.5 dL / g is equivalent to approximately 4,300 Da to approximately 26,600 Da for PLGA 50:50 and approximately 6,500 Da to approximately 39,000 Da for PLGA 65:35. Consequently, the range for PLGA can be anywhere between 4,300 Da and about 39,000 Da. Alternatively, the range for PLGA can be anywhere between 4,300 and about 40,000 or higher if you are using 75:25 (i.e., up to a molecular weight of 56,500 Da). For LA:GA 50:50, 65:35 and 75:25 polymers, an IV of 0.5 g / dL corresponds approximately to molecular weights of 26,600, 39,000 and 56,500. As tested, Durect™ 50:50 with an IV of 0.25 dL / g is approximately 6,700 Da, Durect™ 75:25 with an IV of 0.47 dL / g is approximately 55,000 Da, and Durect™ 85:15 with an IV of 0.55 dL / g is in the range of approximately 76,000 Da to approximately 117,000 Da.

[0063] Of particular interest are PLGA pastes with an LA:GA ratio of 50:50 with an IV between 0.15 dL / g and 0.25 dL / g (i.e., molecular weights between 4,300 Da and 6,700 Da). However, PLGA pastes with an LA:GA ratio of 50:50 with an IV of 0.25 dL / g and 0.5 dL / g (i.e., a molecular weight of about 6,700 Da to about 26,600 Da) are also useful. Petition 870220089251, dated 09 / 29 / 2022, p. 34 / 79 30 / 66

[0064] The molecular weight of the PLGA polymer can be reported as inherent viscosity (IV). The IV can be from 0.15 to 0.5 dL / g. The PLGA polymer IV can be < 0.3 dL / g. The IV can be between 0.15 and 0.25 dL / g. Low molecular weight versions of PLGA with a 50:50 LA:GA ratio and an inherent viscosity below 0.3 dL / g can be fully miscible with a biocompatible low molecular weight glycol using gentle heating to form a viscous or fluid paste at room temperature.

[0065] The drug dispensing compositions described herein may exist in a variety of paste forms. Examples of paste forms may include paste or liquid paste, depending on the polymers used, the amount of polymers used, and the temperature.

[0066] The drug dispensing compositions described herein may release one or more drugs over a period of several hours or several months, depending on the need. The compositions described herein may be used for localized dispensing of one or more drugs to an individual. Examples of drugs that may be administered using these compositions are not limited and may include anticancer drugs; anti-inflammatory agents; antibacterial drugs; antiviral drugs; antifungal drugs; antiproliferative drugs; antifibrotic drugs; antistenotic drugs (drugs based on...) Petition 870220089251, dated 09 / 29 / 2022, page 35 / 79 31 / 66 of sirolimus and taxane-based drugs); anesthetic drugs; neuromodulatory drugs; and analgesics, depending on the condition or conditions to be treated or improved. Other examples are drugs for the treatment of neurological conditions, drugs for treating gastrointestinal diseases such as diverticulosis and food ulcers. The compositions described herein are suitable for any drug that benefits from adherence to a mucosal tissue surface and / or prolonged release from a paste implant.

[0067] Examples of anticancer drugs that can be used with the compositions of the present invention include docetaxel, paclitaxel, mitomycin, cisplatin, etoposide, vinca alkaloid drugs, doxorubicin drugs, rapamycin, camptothecins, gemcitabine, finasteride (or other cytotoxic agents); bicalutamide, enzalutamide, ivermectin, tamoxifen, sunitinib, erlotinib. Anticancer biological agents can also be used in the formulation, such as antibody-based therapies, for example, herceptin, avastin, erbitux or radiolabeled antibodies or targeted radiotherapies, such as PSMA radioligands.

[0068] Anti-inflammatory agents may include acetaminophen and nonsteroidal drugs such as ibuprofen, Petition 870220089251, dated 09 / 29 / 2022, page 36 / 79 32 / 66 acetylsalicylic acid, naproxen, diclofenac, meloxicam, as well as steroids such as prednisone and others.

[0069] Local analgesia or local anesthetic medications may include, for example, one or more of the following: Procaine; Benzocaine; Chloroprocaine; Cocaine; Cyclomethicone; Dimethocaine / Irocaine; Piperocaine; Propoxycaine; Procaine / Novocaine; Proparacaine; Tetracaine / Amethocaine; Articaine; Bupivacaine; Cinchocaine / Dibucaine; Etidocaine; Levobupivacaine; Lidocaine / Lignocaine / Xylocaine; Mepivacaine; Prilocaine; Ropivacaine; and Trimecaine.

[0070] Antibiotic medications may include penicillins, cephalosporins, polymyxins, rifamycins, lipiarmycins, quinolones, sulfonamides, macrolides, lincosamides, tetracyclines, aminoglycosides, lipopeptides, glycylcyclines, oxazolidinones and lipiarmycins, cephalexin, cefazolin, gentamicin, ciprofloxacin, clindamycin, macrodantin, tobramycin, rifampicin, daptomycin, linezolid, vancomycin, fusidic acid, silver compounds, cannabinoids, and others.

[0071] Examples of antifungal drugs are polyenes, azoles, triazoles, antimetabolites, allylamines, echinocandins. Antifungal drugs may include, for example, but are not limited to, amphotericin B, nystatin, clotrimazole, econazole, miconazole, fluconazole, terbinafine, Petition 870220089251, dated 09 / 29 / 2022, page 37 / 79 33 / 66 fluconazole, ketoconazole, caspofungin, tolnaftate, ivermectin, flucytosine, and griseofulvin.

[0072] Drugs can be hydrophobic or hydrophilic. Specific drugs can be selected from one or more of the following: docetaxel; ivermectin; bicalutamide; cephalexin; sunitinib; tamsulosin; desoximetasone; gemcitabine; rapamycin; and ibuprofen.

[0073] Drug dispensing compositions can be prepared and used to treat or prevent a variety of diseases or conditions, particularly where the treatment site is in or near mucosal tissue. Examples of diseases or conditions that can be treated may include, for example, cancer, pain, inflammatory conditions, fibrotic conditions, benign tumors (including benign prostatic hyperplasia), and infections. For example, the compositions described herein can be used to treat the renal pelvis as described above. The paste can be applied to any mucosal surface or moist tissue area for localized drug dispensing. Of particular importance may be the treatment of the interior of the GI tract, such as to treat cancer, wounds (e.g., ulcers), or inflammation (e.g., inflammatory bowel diseases: ulcerative colitis, Crohn's disease). Additionally, the paste can be applied with drugs to treat or fill inflamed diverticula.Diseases of the mouth, vagina, and surrounding areas. Petition 870220089251, dated 09 / 29 / 2022, page 38 / 79 34 / 66 rectal lesions can be treated. Localized application of hyaluronic acid is used to prevent surgical adhesions; therefore, an improvement may be achieved by using this paste and including an anti-adhesive drug. Postoperative wounds and pain may be appropriate indications.

[0074] As used in this document, “mucosal tissue” or “mucous membrane” or “mucosa,” as used in this document, refers to a membrane that lines various body cavities (i.e., urogenital tract; gastrointestinal tract; and respiratory tract) and covers the surface of internal organs. The mucous membrane consists of one or more layers of epithelial cells that cover connective tissue. The urogenital tract includes the kidney, ureter, bladder, urethra, uterus, vagina, and penis. The gastrointestinal tract (GI tract) includes the mouth, esophagus, stomach, small intestine, large intestine, rectum, and anus. The respiratory tract includes the mouth, sinuses, pharynx, larynx, trachea, bronchi, bronchioles, and lungs.

[0075] As used in this document, a “mucoadhesive polymer” refers to any polymer that has properties that cause the polymer to adhere to a mucosal surface. Such polymers are preferably biocompatible. Mucoadhesive polymers may be selected from one or more of the following: hyaluronic acid (HA); poly(acrylic acid) derivatives and poly(acid) derivatives. Petition 870220089251, dated 09 / 29 / 2022, page 39 / 79 35 / 66 methacrylic); cyanoacrylates; poly(acrylic acid) (carbomer); sodium carboxymethylcellulose (CMC); hydroxypropylcellulose; polycarbophil; chitosan; alginate; gellan; thiolated poly(acrylic acid); poloxamer; cellulose acetate phthalate; ethylcellulose; methylcellulose; hydroxyethylcellulose; poly(amidoamine) dendrimers; poly(dimethylsiloxane); and poly(vinylpyrrolidone) (Roy et al. 2009). Generally, HA is not used in a non-aqueous environment as a dispersion, as described in this document. Furthermore, the compositions described in this document contain PEGs for a reason why HA will not settle at a certain temperature.Alternatively, mucoadhesive polymers may be selected from one or more of the following: hyaluronic acid; poly(acrylic acid) and poly(methacrylic acid) derivatives; cyanoacrylates; poly(acrylic acid) (carbomer); sodium carboxymethylcellulose; hydroxypropylcellulose; polycarbophil; chitosan; alginate; gellan; thiolated poly(acrylic acid); poloxamer; cellulose acetate phthalate; ethylcellulose; methylcellulose; hydroxyethylcellulose; poly(amidoamine) dendrimers; poly(dimethylsiloxane); and poly(vinylpyrrolidone).

[0076] In addition, as described in this document, PEGs are combined to tailor the formulation for specific administration (e.g., long catheter lines) and stability (e.g., storage, without Petition 870220089251, dated 09 / 29 / 2022, page 40 / 79 36 / 66 sedimentation) and disintegration properties, as PEGs of Higher MW values ​​are less soluble in water.

[0077] As used in this document, a “water-insoluble polymer” refers to any polymer that is insoluble in water. Such polymers are preferably biocompatible. Water-insoluble polymers may be selected from one or more of: polylactic-co-glycolic acid (PLGA); poly(ε-caprolactone) (PCL); and polylactic acid (PLA). Alternatively, the water-insoluble polymer may be a copolymer of acrylic and methacrylic acid esters.

[0078] As used in this document, “polylactic-co-glycolic acid (PLGA) is a copolymer of lactic acid and glycolic acid with the structure where “x” represents the number of lactic acid (lactide) subunits and “oy” represents the number of glycolic acid (glycolide) subunits. Depending on the ratio of lactide to glycolide used for polymerization, different forms of PLGA can be obtained: these are usually identified in relation to the molar ratio of the monomers used (for example, PLGA 75:25 identifies a copolymer whose composition is 75% lactic acid and 25% glycolic acid). Suitable molar ratios can be anywhere between 90:10 and 50:50. Petition 870220089251, dated 09 / 29 / 2022, page 41 / 79 37 / 66 Generally, the ratio can dictate the degradation of PLGA. For example, PLGA 50:50 shows a rapid degradation rate (e.g., 2 months), while PLGA 75:25 takes longer (e.g., 5 months) and PLGA 85:15 can take even longer (e.g., 6 months) for complete degradation.

[0079] When used, PLGA can be between 2% and about 20% by weight. An IR for 50 / 50 PLGA is about 0.15 dL / g, but an IR of 0.25 dL / g for 65 / 35 PLGA would also be useful. A useful IR range of 0.1 dL / g to 0.3 dL / g for PLGA would be suitable. The molar ratio of lactic acid to glycolic acid monomers can be between about 90:10 and about 50:50.

[0080] As used in this document, polyethylene glycol (PEG) or polyethylene oxide or polyoxyethylene, depending on its molecular weight, is a A polyether compound with the structure. As used in this document, there is a first low molecular weight PEG that can be selected from one of the following: PEG 100; PEG 200; PEG 300; PEG 400; and PEG 500. There is also a second low molecular weight PEG selected from one of the following: PEG 100; PEG 200; PEG 300; PEG 400; PEG 500; PEG 600; PEG 700; PEG 800; PEG 900; PEG 1000; PEG 1100; PEG 1200; PEG 1300; PEG 1400; PEG 1500; PEG 1600; PEG 1700; PEG 1800; PEG 1900; and PEG 2000. A Petition 870220089251, dated 09 / 29 / 2022, page 42 / 79 The PEG composition, as described herein, may also additionally include one or more low molecular weight PEGs selected from one or more of the following: PEG 100; PEG 200; PEG 300; PEG 400; PEG 500; PEG 600; PEG 700; PEG 800; PEG 900; PEG 1000; PEG 1100; PEG 1200; PEG 1300; PEG PEG 1400; PEG 1500; PEG 1600; PEG 1700; PEG 1800; PEG 1900; and PEG 2000. The PEG polymers as used herein may have an average molecular weight between about 100 Da and about 2,000 Da. The PEG polymers as used herein may have an average molecular weight between about 200 Da and about 2,000 Da.

[0081] The polyethylene glycol (PEG) as used in this document may be selected from: PEG 100; PEG 200; PEG 300; PEG 400; PEG 500; PEG 600; PEG 700; PEG 800; PEG 900; PEG 1000; PEG 1100; PEG 1200; PEG 1300; PEG 1400; PEG 1500; PEG 1600; PEG 1700; PEG 1800; PEG 1900; and PEG 2000. Polyethylene glycol (PEG) can have an average molecular weight between approximately 100 Da and approximately 1,450 Da. Polyethylene glycol (PEG) can have an average molecular weight between approximately 100 Da and approximately 2,000 Da. Polyethylene glycol (PEG) can have a molecular weight between approximately 300 Da and approximately 1,450 Da. Polyethylene glycol (PEG) can have a molecular weight between about 300 Da and about 500 Da and a molecular weight between about 500 Da and about 2000 Da. Petition 870220089251, dated 09 / 29 / 2022, page 43 / 79 39 / 66

[0082] Alternatively, instead of PEG, suitable compositions may comprise propylene glycol or glycerol may be used or may be used in combination with PEG.

[0083] Local anesthetics generally fall into one of two classes: aminoamide and aminoester. Most local anesthetics have the suffix -caine. Local anesthetics in the aminoester group can be selected from one or more of the following: Procaine; Benzocaine; Chloroprocaine; Cocaine; Cyclomethicaine; Dimethocaine / Irocaine; Piperocaine; Propoxycaine; Procaine / Novocaine; Proparacaine and Tetracaine / Amethocaine. Local anesthetics in the aminoamide group can be selected from one or more of the following: Articaine; Bupivacaine; Cinchocaine / Dibucaine; Etidocaine; Levobupivacaine; Lidocaine / Lignocaine / Xylocaine; Mepivacaine; Prilocaine; Ropivacaine; and Trimecaine. Local anesthetics can also be combined (for example, lidocaine / prilocaine or lidocaine / tetracaine).

[0084] In addition, local anesthetics used for injection can be mixed with vasoconstrictors to increase residence time, and maximum doses of local anesthetics can be higher when used in combination with a vasoconstrictor (e.g., prilocaine hydrochloride and epinephrine; lidocaine, bupivacaine and Petition 870220089251, dated 09 / 29 / 2022, page 44 / 79 40 / 66 epinephrine; lidocaine and epinephrine; or articaine and epinephrine).

[0085] The anticancer drugs that can be used in the composition described herein can be categorized as alkylating agents (bi- and monofunctional), anthracyclines, cytoskeletal disruptors, epothilone, topoisomerase inhibitors (I and II), kinase inhibitors, nucleotide analogs and precursor analogs, peptide antibiotics, platinum-based agents, vinca alkaloids, and retinoids. Alkylating agents can be bifunctional alkylators (e.g., Cyclophosphamide, Mechlorethamine, Chlorambucil, and Melphalan) or monofunctional alkylators (e.g., Dacarbazine (DTIC), Nitrosoureas, and Temozolomide). Examples of anthracyclines are Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone, and Valrubicin. Cytoskeletal disruptors or taxanes include Paclitaxel, Docetaxel, Abraxane, and Taxotere. Epothilones may be epothilones or related analogues. Histone deacetylase inhibitors may include Vorinostat or Romidepsin.Topoisomerase I inhibitors may include irinotecan and topotecan. Topoisomerase II inhibitors may include etoposide, teniposide, or tafluposide. Kinase inhibitors may be selected from bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, or vismodegib. Nucleotide analogs and precursor analogs may also be used. Petition 870220089251, dated 09 / 29 / 2022, page 45 / 79 41 / 66 selected from Azacitidine, Azathioprine, Capecitabine, Cytarabine, Doxyfluridine, Fluorouracil, Gemcitabine, Hydroxyurea, Mercaptopurine, Methotrexate, or Thioguanine / Thioguanine. Peptide antibiotics such as Bleomycin or Actinomycin. Platinum-based agents may be selected from Carboplatin, Cisplatin, or Oxaliplatin. Retinoids may be Tretinoin, Alitretinoin, or Bexarotene. Vinca alkaloids and derivatives may be selected from Vinblastine, Vincristine, Vindesine, and Vinorelbine.

[0086] An anticancer drug that can be used with the compositions described in this document may be selected from one or more of: Actinomycin; All-trans retinoic acid; Azacitidine; Azathioprine; Bleomycin; Bortezomib; Carboplatin; Capecitabine; Cisplatin; Chlorambucil; Cyclophosphamide; Cytarabine; Daunorubicin; Docetaxel; Doxyfluridine; Doxorubicin; Epirubicin; Epothilone; Etoposide; Fluorouracil; Gemcitabine; Hydroxyurea; Idarubicin; Imatinib; Irinotecan; Mechlorethamine; Mercaptopurine; Methotrexate; Mitoxantrone; Oxaliplatin; Paclitaxel; Pemetrexed; Teniposide; Thioguanine; Topotecan; Valrubicin; Vemurafenib; Vinblastine; Vincristine; Vindesine and Vinorelbine. Alternatively, the anticancer drug may be a biological agent and may be selected from Herceptin. Petition 870220089251, dated 09 / 29 / 2022, page 46 / 79 42 / 66 (Trastuzumab), Ado-trastuzumab, Lapatinib, Neratinib, Pertuzumab, Avastin, Erbitux, or radiolabeled antibodies or targeted radiotherapies, such as PSMA radioligands. The anticancer drug may be an androgen receptor antagonist, an estrogen receptor antagonist, an epidermal growth factor receptor (EGFR) antagonist, or a tyrosine kinase inhibitor (TKI). An antiangiogenesis agent may be selected from Avastin, an epidermal growth factor receptor (EGFR) antagonist, or a tyrosine kinase inhibitor (TKI). An immune modulator, such as Bacillus Calmette-Guerin (BCG).

[0087] As used in this document, a drug refers to any therapeutic fraction, which includes small molecules and biological agents (e.g., proteins, peptides, nucleic acids). In addition, a biological agent must include antibodies and antigens. As used in this document, the term drug may, in certain embodiments, include any therapeutic fraction or a subset of therapeutic fractions. For example, but not limited to, one or more of the potentially overlapping subsets and one or more drugs, as follows: hydrophobic drugs, hydrophilic drugs; a cancer therapeutic drug; a local anesthetic drug; an antibiotic drug; an antiviral drug; an anti-inflammatory drug; an analgesic; an antiproliferative drug; Petition 870220089251, dated 09 / 29 / 2022, page 47 / 79 43 / 66 an antifibrotic drug; or any drug that may benefit from localized and / or prolonged release.

[0088] As used in this document, “an antibody” is a polypeptide belonging to the immunoglobulin superfamily. In particular, “an antibody” includes an immunoglobulin molecule or an immunologically active fragment of an immunoglobulin molecule (i.e., a molecule(s) containing an antigen-binding site), an immunoglobulin heavy chain (alpha (α), mu (μ), delta (δ), or epsilon (ε)) or a variable domain thereof (VH domain), an immunoglobulin light chain (kappa (κ) or lambda (λ)) or a variable domain thereof (VL domain), or a polynucleotide encoding an immunoglobulin molecule or an immunologically active fragment of the immunoglobulin molecule.Antibodies include a single-chain antibody (e.g., an immunoglobulin light chain or an immunoglobulin heavy chain), a single-domain antibody, a variable antibody fragment (Fv), a single-chain variable fragment (scFv), a scFv zipper, an scFvFc, a disulfide-linked Fv (sdFv), a Fab fragment (e.g., CLVL or CHVH), an F(ab') fragment, monoclonal antibodies, and polyclonal antibodies. As used in this document, “antigen” refers to any epitope-binding fragment and a polynucleotide (DNA or RNA) that encodes any of the above. Petition 870220089251, dated 09 / 29 / 2022, pp. 48 / 79 44 / 66

[0089] As used in this document, a paste is any composition described in this document that has the characteristics of both a solid and a liquid depending on the applied load and temperature. Specifically, the viscosity of a paste can be anywhere it is injectable at room temperature and can be measured by any number of methods known to those skilled in the art. Numerous types of viscometers and rheometers are known in the art. For example, Anton Paar™ rheometers, MCR 502 or MCR72. METHODS Paste preparation

[0090] For example, the recipe for the base paste for renal pelvis is shown in TABLE 1.

[0091] The paste was prepared by weighing the polymers in a glass vial and stirring at 60°C. When the polymers formed a homogeneous melt, the mucoadhesive polymer was added. If the drug is to be added, it is added after the preparation of the polymer paste. The values ​​for the polymer paste (i.e., a polyethylene glycol (PEG) composition that is between about 85% and about 96% by weight, comprising (i) a first low molecular weight polyethylene glycol (PEG) and (ii) a second low molecular weight polyethylene glycol (PEG) wherein the first low molecular weight PEG and the second PEG Petition 870220089251, dated 09 / 29 / 2022, page 49 / 79 45 / 66 low molecular weight (average molecular weight between about 100 Da and about 1,500 Da); a water-insoluble polymer that is between about 2% and about 10% by weight; and a mucoadhesive polymer that is between about 2% and about 5% by weight) are prepared as a total 100% before mixing with the drug. When the drug is added, the % associated with it is a percentage of the total composition with the drug, and the %s of the predrug paste component are based on their proportions before the addition of the drug. For example, 4% means 4g of drug in 100g of paste. The drug(s) was / were incorporated using levigation or a mortar and pestle.

[0092] The injectability of a paste will depend on many parameters (i.e., needle size, needle length, volume, tissue backpressure, force of the person administering the paste). It is usually preferable that a paste be easily placed in a syringe using an 18-14 gauge needle and easily injected into a tissue zone using an 18 gauge needle or even smaller with a small amount of extra pressure. However, for particular uses and depending on the needle gauge, it may be desirable to have a more viscous paste (i.e., more difficult to inject). The polymer compositions described herein can be injected through 18 gauge lines under manual pressure. Petition 870220089251, dated 09 / 29 / 2022, pp. 50 / 79 46 / 66 TABLE 1: Sample base paste for injection into the renal pelvis. Polymer Percentage (%) PEG 300 78 PEG 1000 14 Polylactic-co-glycolic acid (PLGA) 5 Hyaluronic acid (HA) (> 1800 kDa) 3 Animal Procedures Paste injection

[0093] Using a retrograde approach, pigs received an injection of the novel gemcitabine formulation into a renal pelvis via cystoscopy and a ureteral catheter. Over 24 hours, urine was collected at three-hour intervals from urinary catheter bags, and blood was collected via venous catheters. Ultrasound was performed to monitor urinary tract obstruction. Sampling

[0094] Blood was collected from venous catheters and collected in serum tubes at 15 min, 1 h, 4 h, 8 h, 12 h, 18 h, and 24 h. Blood was stored in the refrigerator and stabilized with tetrahydrouridine. Urine was collected continuously at 3-h intervals in catheter bags via transurethral catheter for up to 24 h (0-3 h, 3-6 h, 6-9 h, 9-12 h, 12-15 h, 15-18 h, 18-18 h, 21 h, 21-24 h). Urinary gemcitabine was stabilized with tetrahydrouridine and stored in the refrigerator until further processing. Petition 870220089251, dated 09 / 29 / 2022, pp. 51 / 79 47 / 66 Ultrasound and Nephrectomy

[0095] Baseline and daily ultrasounds were performed to monitor hydronephrosis. The kidneys were removed on day 4 after gemcitabine paste injection. Analytical methods LCMS / MS for serum and urine sample analysis

[0096] Liquid Chromatography-Mass Spectrometry (LC-MS) methods are known in the art for serum and urine analysis. HPLC / UV for tissue extraction experiment Instrumentation and method:

[0097] The gemcitabine assay used for tissue extracts uses the instrumentation and parameters described in TABLE 2. A calibration curve ranging from 0.75 to 100 pg / mL was routinely run with samples of unknown concentration. Calibrators are serially diluted from a 1 mg / mL gemcitabine stock solution in methanol (containing 1% water) using PBS or a 50% water / methanol mixture. TABLE 2: HPLC / UV instrumentation and parameters for gemcitabine HCl analysis. Waters 1525 binary HPLC pump; Waters 717 Plus autosampler; Waters C-18™ Nova-Pak column, 4 µm, 3.9 x 150 mm; Waters 2489™ UV / Visible detector; Flow rate 1 mL / min; Column temperature Ambient, no temperature control. Petition 870220089251, dated 09 / 29 / 2022, page 52 / 79 48 / 66 Injection volume 2.0 pL. Isocratic elution. Mobile phase 92.5%. Ammonium acetate buffer 1.6%, Methanol 1.5%, Acetonitrile. Retention time 2.5 min. Wavelength 254 nm (double with 220 nm). Standard diluent PBS 7.4 1. Ammonium acetate buffer is ammonium acetate (M = 77 g / mol), 1.542 g / L of water, pH 6.3 adjusted with approximately 3.6 mL of phosphoric acid (85%). Sample preparation for tissue extraction

[0098] Gemcitabine was extracted from tissue samples using a 50 / 50 mixture of water and methanol, centrifuged, and the supernatant measured directly. Viscosity measurement

[0099] An Anton Parr™ MCR72 viscometer was used to determine the paste viscosities. A 25 mm parallel plate geometry (PP25 measuring system), a 0.5 mm gap size, and RheoCompass 1.20™ software were used to determine the flow curves using rotational shear rates between 1 and 100 l / s at room temperature (20 to 25°C). EXAMPLES EXAMPLE 1: Serum data - PK analysis

[00100] To calculate the PK parameters for the pig experiment, a non-compartmental analysis was performed using Phoenix 64™ (Build 6.3.0.395) WinNonlin 6.3™. Concentration versus time data are presented. Petition 870220089251, dated 09 / 29 / 2022, page 53 / 79 49 / 66 in FIGURE 2. The pharmacokinetic parameters area under the curve (AUC), area under the curve at first moment (AUMC), clearance (Cl / F, for extravascular dosage), maximum observed concentration (cmax), terminal half-life (ti / 2), terminal rate constant (kei or λζ), mean residence time (MRT) and volume of distribution (V / F, for extravascular dosage) are presented in TABLE 3. The results show that there is paste retention in the renal pelvis, especially when compared with IV serum data (see additional analysis EXAMPLE 4). TABLE 3: Non-compartmental pharmacokinetic parameters for serum data after injection of a gemcitabine paste into the renal pelvis. Parameter Unit Value AUCo-inf h • ng / mL 37838.8 ± 9415.1 AUCo-inf h · h • ng / mL 249543.5 ± 40423.1 Cl / F mL / h / kg 727.1 ± 187 Cmax ng / mL 5532.2 ± 771.7 t1 / 2 h 4.1 ± 1.4 kel 1 / h 0.18 ± 0.05 MRT h 6.7 ± 0.8 V / F mL / kg 4521.6 ± 2549 EXAMPLE 2: Urine data - PK analysis

[00101] To calculate the PK parameters for urine, a non-compartmental analysis was performed using Phoenix 64™ (Build 6.3.0.395) WinNonlin 6.3™. Concentration versus time data are presented in FIGURE 3. The area under the excretion rate versus the midpoint of the time interval curve (AURC) of the pharmacokinetic parameters, Petition 870220089251, dated 09 / 29 / 2022, pp. 54 / 79 50 / 66 terminal half-life (ti / 2), terminal rate constant (kei or λζ), maximum excretion rate (Taxa max) and % of drug recovered (Recuperado) and the total volume of urine collected are shown in TABLE 4. TABLE 4: Non-compartmental pharmacokinetic parameters for urine data after injection of a gemcitabine paste into the renal pelvis. Parameter Unit Value AURCo-inf mL ^g / mL 873583.2 ± 132794.4 t1 / 2 (terminal) h 2.1 ± 0.6 kel 1 / h 0.35 ± 0.1 Max rate μg / h 279857.1 ± 105042.8 Recovered % 107.3 ± 29.2 Total urine mL 1230.3 ± 145.9 EXAMPLE 3: Tissue data - Gemcitabine extraction

[00102] After nephrectomy, the kidneys were opened and tissue was collected from the upper, middle, and lower renal pelvis and calyces, the proximal, middle, and distal ureter, and the bladder. For sectioning, tissue samples were mounted in a drop of Cryomatrix™ and cut into 30 μm thick slices. Two slices were collected from each of the 8 tubes to create a depth profile of 0-60, 60-120, 120-180, 180-240, 240-300, 300-360, 360-420, 420-480 μm. For tissue extraction, 500 μL of methanol / water 50 / 50 was added, the tubes were vortexed with a sonicated tip and rotated, then the supernatant was measured directly using HPLC / UV. Tissue concentrations for tissues exposed for 1 hour were quite high at 2,000. Petition 870220089251, dated 09 / 29 / 2022, pp. 55 / 79 51 / 66 8,000 μg / g of tissue (FIGURE 4). For tissues exposed for 3h, tissue concentrations of gemcitabine were around 5 to 10 μg / g of tissue (FIGURE 5). EXAMPLE 4: Renal pelvis injection vs. intravenous gemcitabine

[00103] When comparing serum data after gemcitabine injection into the renal pelvis with serum data after intravenous administration of gemcitabine, there are pronounced differences in cmax, AUC, and terminal half-life ti / 2. To visualize the differences, data from Liston et al. (Liston and Davis 2017) were used to model a representative dataset for intravenous administration and compare it with the extravascular dataset. Literature values ​​(Liston and Davis 2017; Dy et al. 2005) are listed in TABLE 5. The dose, c(0.5h) = cmax, V, and kei were used to plot the data using a 1-compartment approximation (FIGURE 6) after the end of the infusion (0.5 h). TABLE 5: Pharmacokinetic parameters from the literature for a 30-minute infusion of gemcitabine (IV) and the pharmacokinetic parameters of the current experiment after injection of gemcitabine paste into the renal pelvis. Parameter Unit Value Dose 1250 mg / m2 (32.1 mg / kg) 1000 mg / pig (26.4 mg / kg) cmax 23500 ng / mL 5532 ng / mL AUCo-inf 12500 ng-h / mL 37 839 ng-h / mL t1 / 2 (terminal) 0.23 h 4.12 h Clearance 25.9 L (Vss) 4.5 L / kg (Vd) kel 3.18 l / h 0.18 l / h Petition 870220089251, dated 09 / 29 / 2022, pp. 56 / 79 52 / 66

[00104] Overall, the renal injection profile indicates sustained absorption of gemcitabine from the renal pelvis into the bloodstream. It can be assumed that the injected paste releases gemcitabine into the tissue for several hours, since the half-life is extended to approximately 4 h from 0.2 h when compared to an intravenous injection (Liston and Davis 2017; Fogli et al. 2002). From a safety assessment, the observed peak of 23,000 ng / mL for intravenous administration is absent, but the overall gemcitabine exposure is higher (AUC).

[00105] The formulation and procedure were well tolerated and caused only mild and transient hydronephrosis without a clinically relevant increase in serum creatinine. Gemcitabine concentrations in urine were highest in the first collection interval, and 100% of the gemcitabine was recovered in the urine within 24 hours. Peak serum concentrations (cmax) of gemcitabine were low at 5500 ng / mL, but extended, with a terminal half-life (ti / 2) of 4.1 hours, a mean residence time (MRT) of 6.7 hours, and an overall area under the curve (AUC) of 37,800 h² • ng / mL. One hour after instillation, the formulation was still detectable in the upper urinary tract, and tissue concentrations of gemcitabine from the calyces, pelvis, and ureter at one and three hours were favorable to this prolonged drug exposure. Petition 870220089251, dated 09 / 29 / 2022, pp. 57 / 79 53 / 66

[00106] Preclinical evaluation of a mucoadhesive gemcitabine formulation for instillation into the upper urinary tract showed promising results regarding tolerability and safety. Administration of this formulation into the renal pelvis leads to locally high and extended gemcitabine concentrations with low overall systemic absorption. This pharmacokinetic profile may be advantageous for the treatment of upper urothelial tract malignancies and support further clinical evaluation. EXAMPLE 5: Manufacturing pastes with various hydrophobic and mucoadhesive polymers.

[00107] The polymer pastes were prepared according to TABLES 6 to 10. The compositions were heated to 60°C without the mucoadhesive agent and stirred. Once a homogeneous formulation was achieved, the mucoadhesive polymer was suspended in the formulation. The compositions were then observed for homogeneity, viscosity, gelling characteristics, mucoadhesion, and injectability using the lead A formulation as a comparison.

[00108] PLGA, PLA, and PCL polymers were homogeneously dispersed or dissolved in PEG-based paste with varying degrees of opacity. The addition of CMC, HA, or alginic acid had little effect on viscosity, and all pastes appeared cloudy due to the presence of suspended solids. Increasing the amount of PLGA resulted in a Petition 870220089251, dated 09 / 29 / 2022, pp. 58 / 79 54 / 66 slight decrease in viscosity. Overall, all pastes showed viscosities very similar to formulation A, except for the addition of carbomer, which caused a significant increase in viscosity. These compositions and results are summarized in TABLE 11. TABLE 6. Compositions of formulations with different mucoadhesive agents Excipient % (weight) Formulation A B1 B2 B3 B4 B5 PEG 300 78 78 78 78 78 79 PEG 1000 14 14 14 14 14 15 PLGA1 5 5 5 5 5 6 Hyaluronic acid (high MW2) 3 — — — — — Sodium carboxymethylcellulose — 3 — — — — Carbomer 940 — — 3 — — — Alginic acid — — — 3 — — Hyaluronic acid (low MW) — — — — 3 — 250:50 Poly(DL-lactic-co-glycolic) acid (IV 0.15-0.25 dL / g) 2MW molecular weight TABLE 7. Compositions of formulations with increasing amounts of hyaluronic acid. Excipient % (weight) Formulation F1 F2 A F3 F4 PEG 300 79 78.5 78 77.5 77 PEG 1000 15 14.5 14 13.5 13 PLGA1 5 5 5 5 5 Hyaluronic acid (high MW2) 1 2 3 4 5 250:50 Poly(DL-lactic-co-glycolic) acid (IV 0.15-0.25 dL / g) 2MW molecular weight TABLE 8. Compositions of formulations with different drugs Excipient % (weight) Formulation A A1 A2 A3 PEG 300 78 99 99.7 99 Petition 870220089251, dated 09 / 29 / 2022, pp. 59 / 79 55 / 66 PEG 1000 14 PLGA1 5 Hyaluronic acid (high MW2) 3 HCl gemcitabine — 1 — — Docetaxel — — 0.3 — Albumin — — 1 150:50 Poly(DL-lactic-co-glycolic) acid (IV 0.15-0.25 dL / g) 2MW molecular weight TABLE 9. Compositions of formulations with different hydrophobic polymers Excipient % (weight) Formulation ACD D1 PEG 300 78 78 78 78 PEG 1000 14 14 14 14 PLGA1 5 — — — PCL3 — 5 — — PLA4 (high MW2) — — 5 — PLA (low MW) — — — 5 Hyaluronic acid (high MW) 3 3 3 3 150:50 Poly(DL-lactic-co-glycolic) acid (IV 0.15-0.25 dL / g) 2MW molecular weight 3PCL Poly(ε-caprolactone) 4PLA polylactic acid TABLE 10. Compositions of formulations with increasing amounts of hydrophobic polymer Excipient % (weight) Formulation A E1 E2 E3 PEG 300 78 75.5 73 80.5 PEG 1000 14 11.5 9 16.5 PLGA1 5 10 15 — Hyaluronic acid (high MW2) 3 3 3 3 150:50 Poly(DL-lactic-co-glycolic) acid (IV 0.15-0.25 dL / g) 2MW molecular weight Petition 870220089251, dated 09 / 29 / 2022, pp. 60 / 79 56 / 66 TABLE 11. Observations on compositions regarding homogeneity, viscosity, gelation, mucoadhesion, and injectability compared to composition A. Composition Homogeneity score 1 Viscosity score 2 Gelation score 3 Mucoadhesion score 4 Injectability score 5 B1 (CMC) 1 1 1 1 1 B2 (Carbomer) - + 1 1 - B3 (Alginic acid) 1 1 - - 1 B4 (Hyaluronic acid, low MW) 1 1 1 1 1 B5 (none) 1 1 - - 1 C (PCL) - n / dn / dn / d - D (PLA, high MW) - n / dn / dn / d - D1 (PLA, low MW) - n / dn / dn / d - E1 (PLGA medium high) 1 - n / dn / d 1 E2 (PLGA high) 1 - n / dn / d 1 E3 (no PLGA) 1 1 n / dn / d 1 F1 (1% HA) 1 1 - 1 1 F2 (2% HA) 1 1 - 1 1 F3 (4% HA) 1 1 1 1 1 F4 (5% HA) 1 1 + 1 1 = similar homogeneity, - = less homogeneous21 = similar viscosity, + = more viscous, - = less viscous31 = similar gelling characteristics, + = more gels, - = fewer gels = similar adhesion, + = adheres more, - = adheres less51 = similar injectability, + = easier injectability, - = more difficult injectability EXAMPLE 6: Mucoadhesion, the mucoadhesive effect of pastes containing different mucoadhesive polymers.

[00109] The pastes were made containing 3% by weight of the mucoadhesive polymers HA, CMC, Carbomer, Alginic acid or no mucoadhesive polymer with 5% PLGA and 92% PEG. In addition, pastes were prepared with increasing amounts of HA (1, 2, 3, 4, 5%). Pieces of renal pelvis were cut from frozen pig kidneys and kept moist. Petition 870220089251, dated 09 / 29 / 2022, pp. 61 / 79 57 / 66 with PBS (pH 7.4). 250 mg of formulation were placed on top of each tissue sample. The samples were covered and kept at 37°C for 5 minutes. The tissue samples were then washed with excess water and stained in a diluted methylene blue solution for 1 minute, then rinsed again. At this point, any remaining paste was scraped from the tissue to reveal the level of unstained tissue. Using this method, any tissue not covered by a layer of mucoadhesive paste was stained blue.

[00110] All pastes showed a clear color demarcation in the tissue, where the peripheral edges not coated with paste were stained blue and the area covered with paste was tissue-colored pink. The control tissues (without paste or paste without mucoadhesive polymer) were entirely stained blue (images not shown), however, these results are summarized in TABLE 11 using the mucoadhesion score compared to formulation A. EXAMPLE 7: Drug release studies: The use of lead formulations for the controlled release of hydrophilic, hydrophobic, and biological drugs.

[00111] Formulation A of PLGA 5%, HA 3%, PEG 92% was prepared as described in TABLE 8. Gemcitabine HCl, docetaxel, or bovine serum albumin (BSA - used as a model protein for a biological therapeutic agent) was levigated into the paste at a loading (%w / w) of 1, 0.3, and 1 Petition 870220089251, dated 09 / 29 / 2022, pp. 62 / 79 58 / 66 (respectively) using a spatula until a completely homogeneous mixture was formed. 100 mg of each formulation was placed in a cut-off mini-dialysis chamber (Millipore™) with a 7000 Da cut-off. For the protein study, the mini-chamber was not sealed, but a small retention sponge was applied. The chamber was placed in 5 mL of PBS (pH 7.4 or PBS containing albumin to increase docetaxel solubility) and placed in an incubator at 37°C. At defined time points, all PBS was removed and the amount of gemcitabine and docetaxel in the delivery medium was quantified using HPLC methods (isocratic elution at 1 mL / min, wavelengths: 254 nm and 228 nm, retention time: 2.1 min and 7.1 min) or a Bradford assay for protein. All released drugs form pastes in a controlled manner over 30 hours, as shown in FIGURE 12.Gemcitabine was released faster than the other two agents, but all drugs were still being released within 30 hours. Viscosity

[00112] The pastes were manufactured as described in TABLES 6 to 10. Using an Anton Parr MCR72™ viscometer, the software: RheoCompass 1.20™, a 25 mm parallel plate geometry (PP25 measuring system) and a 0.5 mm gap size, flow curves (rotational shear rates between 1 - 100 l / s) were determined at Petition 870220089251, dated 09 / 29 / 2022, pp. 63 / 79 59 / 66 room temperature (20-25°C) and analyzed using a power law fitting. In separate experiments, the pastes were hydrated with an equal weight of water and left in equilibrium for 5 to 10 minutes. Using the same measurement system as above, the viscosities of the gels were determined using oscillations at 1 Hz and a voltage between 0.01 and 100%.

[00113] Determinations were made using a shear rate of 1 to 100 l / s and a strain of 0.01 to 100%. For most samples, viscosity was higher at very low stress rates but decreased at higher shear rates or higher stress. This type of shear thinning may reflect easier injection using higher pressures / shear in a syringe. Viscosity graphs are shown in FIGURES 7 to 11 and a viscosity score is given to the samples and summarized in TABLE 11. Viscosities of unhydrated samples

[00114] The addition of 5% PLGA had no effect on viscosity at low or high shear rates. However, at 10% and 15% PLGA loadings, the pastes were less viscous (FIGURE 11). These data demonstrate that all pastes containing PLGA would work well as injectable pastes. The addition of CMC, Carbomer, Alginic Acid, or HA (each at a 3% loading, and HA separately also at 1, 2, 3, 4, 5%) allowed for slightly higher paste viscosities. Petition 870220089251, dated 09 / 29 / 2022, pp. 64 / 79 60 / 66 comparison with pastes without a mucoadhesive component, but all values ​​were very similar (FIGURES 7 and 10). These data demonstrate that the addition of mucoadhesive components to the paste did not affect injectability. Although the addition of carbomer caused a net increase in viscosity, the paste remained fluid enough to be manipulated with a spatula, indicating that it could be loaded into a syringe for injection or extrusion. Using HA, the addition of increasing concentrations of this polysaccharide resulted in little difference in the paste's viscosity, demonstrating that HA would have no effect on injectability. Viscosities of hydrated samples

[00115] All hydrated pastes showed increased viscosity compared to non-hydrated pastes. These data do not reflect injectability, as the paste only becomes hydrated after injection. These values ​​(approximately 80,000 to 100,000 mPa-s) were similar for all low and high strain pastes; pastes containing HAs, CMC, and Carbomer showed higher viscosities than the control or alginic acid pastes (FIGURES 8 and 10). The addition of increasing amounts of HA caused a concentration-dependent increase in viscosity for all pastes at both high and low shear stress.

[00116] Although several embodiments of the invention are described in this document, many adaptations and modifications Petition 870220089251, dated 09 / 29 / 2022, pp. 65 / 79 61 / 66 modifications can be made within the scope of the invention according to the common general knowledge of those skilled in this art. Such modifications include substituting known equivalents for any aspect of the invention in order to achieve the same result substantially in the same manner. The numerical ranges include the numbers that define the range. The word comprising is used in this document as an open term, substantially equivalent to the phrase including, but not limited to, and the word comprises has a corresponding meaning. As used in this document, the singular forms a, an, or include plural referents, unless the context clearly indicates otherwise. Thus, for example, reference to a thing includes more than one such thing. Citation of references herein is not an admission that such references are techniques prior to an embodiment of the present invention.The invention includes all embodiments and variations substantially as described above and with reference to the examples and drawings. REFERENCES

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Jackson, John K, Tawny Hung, Kevin Letchford, and Helen M Burt. 2007. “The Characterization of Paclitaxel-Loaded Microspheres Manufactured from Blends of Poly (Lactic-CoGlycolic Acid)(PLGA) and Low Molecular Weight Diblock Petição 870220089251, de 29 / 09 / 2022, pág. 68 / 79 64 / 66 Copolymers.” International Journal of Pharmaceutics 342 (1): 6-17. Jackson, John K, Janet Smith, Kevin Letchford, Kelly Anne Babiuk, Lindsay Machan, Pierre Signore, William L Hunter, Kaiyue Wang, and Helen M Burt. 2004. “Characterization of Perivascular Poly(Lactic-Co-Glycolic Acid) Films Containing Paclitaxel.” International Journal of Pharmaceutics 283 (12): 97-109. https: / / doi.org / http: / / dx.doi.org / 10.1016 / j.ijpharm.2004.06 .025. 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Lughezzani, G, M Burger, V Margulis, S F Matin, G Novara, M Roupret, S F Shariat, C G Wood, and R Zigeuner. 2012. “Prognostic Factors in Upper Urinary Tract Urothelial Petição 870220089251, de 29 / 09 / 2022, pág. 69 / 79 65 / 66 Carcinomas: A Comprehensive Review of the Current Literature.” European Urology 62 (1): 100-114. https: / / doi.org / 10.1016 / j.eururo.2012.02.030. Maffezzini, Massimo, Fabio Campodonico, Matteo Puntoni, Antonietta Martelli, and Francesca Mattioli. 2009. “Systemic Absorption and Pharmacokinetics of Single-Dose Intravesical Gemcitabine After Transurethral Resection of the Bladder in Non-Muscle-Invasive Bladder Cancer.” Urology 74 (5): 107883. https: / / doi.org / 10.1016 / j.urology.2009.05.094. Makadia, Hirenkumar K, and Steven J Siegel. 2011. “Poly Lactic-Co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier.” Polymers 3 (3): 1377-97. https: / / doi.org / 10.3390 / polym3031377. 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Claims

1 / 6 CLAIMS 1. Composition, characterized in that it comprises: (a) a polyethylene glycol (PEG) composition comprising between 85% and 96% by weight, comprising (i) a first low molecular weight polyethylene glycol (PEG), wherein the first low molecular weight PEG has an average molecular weight between 200 Da and 500 Da, and (ii) a second higher low molecular weight polyethylene glycol (PEG) wherein the second low molecular weight PEG has an average molecular weight between 500 Da and 2,000 Da; (b) a water-insoluble polymer comprising between 2% and 10% by weight, wherein the water-insoluble polymer is selected from one or more of: polylactic-co-glycolic acid (PLGA), poly(ε-caprolactone) (PCL); and polylactic acid (PLA); and (c) a mucoadhesive polymer that is between 2% and 5% by weight.

2. Composition according to claim 1, characterized in that the water-insoluble polymer is PLGA.

3. Composition according to claim 2, characterized in that the molar ratio of lactic acid to glycolic acid monomers is between 90:10 and 50:

50. Petition 870260060781, dated 06 / 22 / 2026, page 17 / 22 2 / 6 4. Composition, according to any one of claims 1 to 3, characterized in that the mucoadhesive polymer is selected from one or more of the following: hyaluronic acid; poly(acrylic acid) and poly(methacrylic acid) derivatives; cyanoacrylates; poly(acrylic acid); carbomer; sodium carboxymethylcellulose; hydroxypropylcellulose; polycarbophil; chitosan; alginate; gellan; xanthan; thiolated poly(acrylic acid); poloxamer; cellulose acetate phthalate; ethylcellulose; methylcellulose; hydroxyethylcellulose; poly(amidoamine) dendrimers; poly(dimethylsiloxane); and poly(vinylpyrrolidone).

5. Composition, according to any one of claims 1 to 4, characterized in that the mucoadhesive polymer is hyaluronic acid.

6. Composition, according to any one of claims 1 to 5, characterized in that the first low molecular weight PEG is selected from one of the following: PEG 200; PEG 300; PEG 400; and PEG 500.

7. Composition, according to any one of claims 1 to 6, characterized in that the second low molecular weight PEG is selected from one of the following: PEG 500; PEG 600; PEG 700; PEG 800; PEG 900; PEG 1000; PEG 1100; PEG 1200; PEG 1300; PEG 1400; PEG 1500; PEG 1600; PEG 1700; PEG 1800; PEG 1900; and PEG 2000, Petition 870260060781, dated 06 / 22 / 2026, p. 18 / 22 3 / 6 provided that when the first low molecular weight PEG is PEG 500, the second highest low molecular weight PEG is selected from one of the following: PEG 600; PEG 700; PEG 800; PEG 900; PEG 1000; PEG 1100; PEG 1200; PEG 1300; PEG 1400; PEG 1500; PEG 1600; PEG 1700; PEG 1800; PEG 1900; and PEG 200.

8. Composition, according to any one of claims 1 to 7, characterized in that it further comprises one or more pharmaceutically acceptable drug compounds or salt, solvate or solvate of its salt.

9. Composition according to claim 8, characterized in that one or more drug compounds or salt, solvate or solvate of its pharmaceutically acceptable salt is selected from one or more of the following categories: anticancer drugs; anti-inflammatory agents; antibacterial drugs; antiviral drugs; antiproliferative drugs; antifibrotic drugs; anesthetic drug; neuromodulatory drugs; and analgesics.

10. Composition, according to claim 8 or 9, characterized in that one or more drug compounds or salt, solvate or solvate of its pharmaceutically acceptable salt is an anticancer drug selected from one or more of the following: Actinomycin; Petition 870260060781, dated 06 / 22 / 2026, page 19 / 22 4 / 6 All-trans retinoic acid; Azacitidine; Azathioprine; Bleomycin; Bortezomib; Carboplatin; Capecitabine; Cisplatin; Chlorambucil; Cyclophosphamide; Cytarabine; Daunorubicin; Docetaxel; Doxyfluridine; Doxorubicin; Epirubicin; Epotilone; Etoposide; Fluorouracil; Gemcitabine; Hydroxyurea; Idarubicin; Imatinib; Irinotecan; Mechlorethamine; Mercaptopurine; Methotrexate; Mitoxantrone; Oxaliplatin; Paclitaxel; Pemetrexed; Teniposide; Thioguanine; Topotecan; Valrubicin; Vemurafenib; Vinblastine; Vincristine; Vindesine; and Vinorelbine.

11. Composition according to claim 10, characterized in that the drug is gemcitabine or its salt, solvate or pharmaceutically acceptable solvate of its salt.

12. Composition, according to claim 8 or 9, characterized in that one or more drug compounds or salt, solvate or solvate of its pharmaceutically acceptable salt is an anesthetic drug that is a local anesthetic selected from one or more of the following: Procaine; Benzocaine; Chloroprocaine; Cocaine; Cyclomethicone; Dimethocaine; Piperocaine; Propoxycaine; Novocaine; Proparacaine; Tetracaine; Articaine; Bupivacaine; Cincocaine; Etidocaine; Levobupivacaine; Lidocaine; Mepivacaine; Prilocaine; Ropivacaine; and Trimecaine. Petition 870260060781, dated 06 / 22 / 2026, page 20 / 22 5 / 6 13. Composition according to claim 8 or 9, characterized in that one or more drug compounds or salt, solvate or solvate of its pharmaceutically acceptable salt is an antibacterial drug selected from one or more of the following: penicillins, cephalosporins, polymyxins, rifamycins, lipiarmycins, quinolones, sulfonamides, macrolides, lincosamides, tetracyclines, aminoglycosides, lipopeptides, glycylcyclines, oxazolidinones and lipiarmycins, cephalexin, cefazolin, gentamicin, ciprofloxacin, clindamycin, macrodantin, tobramycin, rifampicin, daptomycin, linezolid, vancomycin, fusidic acid, and silver compounds.

14. Composition, according to any one of claims 1 to 13, characterized in that the mucoadhesive polymer has a molecular weight > 50 kDa.

15. Composition according to claim 8, characterized in that the drug compound is a neuromodulator drug or a pharmaceutically acceptable salt, solvate or solvate of its salt.

16. Composition according to claim 15, characterized in that it further comprises lidocaine or salt, solvate or solvate of its pharmaceutically acceptable salt. Petition 870260060781, dated 22 / 06 / 2026, pp. 21 / 22 6 / 6 17. Composition according to any one of claims 8 to 11, characterized in that: a) the polyethylene glycol composition consists of (i) PEG300 and (ii) PEG 1000; b) the water-insoluble polymer is polylactic-coglycolic acid (PLGA), wherein the molar ratio of lactic acid to glycolic acid monomers is 50:50; c) the mucoadhesive polymer is hyaluronic acid; d) one or more additional drug compounds is gemcitabine or its salt, solvate or solvate of its pharmaceutically acceptable salt.

18. Use of a composition as defined in any one of claims 1 to 17, characterized in that it is for the manufacture of a medicament.

19. Use of a composition as defined in any one of claims 11 or 17, characterized in that it is for the manufacture of a medicament for the treatment of urothelial carcinoma.

20. Commercial packaging characterized in that it comprises: (a) a composition as defined in any one of claims 1 to 17; and (b) instructions for use. Petition 870260060781, dated 06 / 22 / 2026, page 22 / 22

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