Mucosal-adhering polymer drug delivery composition and method

Abstract

The present invention provides compositions for the controlled local deposition of one or more drugs within a subject. More specifically, described herein are compositions comprising: a) a polyethylene glycol (PEG) composition having a first low molecular weight PEG (Mw: 200-500 Da) and a second low molecular weight PEG (Mw: 500-2000 Da); and b) a mucoadhesive polymer. Alternatively, the composition comprises: a) a polyethylene glycol (PEG) composition having a first low molecular weight PEG (Mw: 200-500 Da) and a second low molecular weight PEG (Mw: 500-2000 Da); b) a water-insoluble polymer; and c) a mucoadhesive polymer. Furthermore, the composition may further comprise one or more drugs. Also provided are methods for producing and administering the compositions described herein, wherein the compositions are used as a biodegradable, injectable, mucoadhesive, low-viscosity paste.

Description

Cross-reference of related applications

[0001] This application claims the benefits of U.S. Provisional Patent Application No. 62 / 971,882, filed on February 7, 2020, entitled "MUCOADHERSIVE POLYMERIC DRUG DELIVERY COMPOSITIONS AND METHODS". [Technical Field]

[0002] The present invention relates to a biodegradable polymer low viscosity paste suitable for drug delivery. More specifically, the present invention relates to an injectable mucosal-adhesion polymer low viscosity paste comprising a polyethylene glycol (PEG) composition, a water-insoluble polymer, and a mucosal-adhesion polymer. Furthermore, the composition may further comprise one or more drugs to be released in a controlled manner. [Background technology]

[0003] Local drug therapy by infusion into the renal pelvis Renal diseases and abnormalities are generally difficult to treat. Most renal drug therapies require systemic administration of high concentrations of drugs, which can be associated with adverse effects such as abnormal glomerular filtration, tubular secretion, or proteinuria. Furthermore, high systemic drug concentrations may not be converted to high concentrations in target cells, and drug distribution to the kidneys may be insufficient to meet treatment goals. Therefore, targeted drug delivery to the kidneys is often necessary when treating renal diseases. Untreated or inadequately treated renal diseases often require dialysis, long-term medication, or even kidney transplantation to extend survival.

[0004] Intravesical administration of anticancer drugs reduces the recurrence and progression of bladder cancer. However, the delivery of drugs to treat malignancies of the renal pelvis and ureters is difficult. The constant flow of urine through the upper and lower urinary tract washes away locally administered drugs, and surgery is the only curative treatment for urothelial carcinoma of the renal pelvis or ureter.

[0005] Upper tract urothelial carcinoma Urothelial carcinoma (UC) can occur in the lower urinary tract (bladder or urethra) or the upper urinary tract (UUT: renal pelvis and ureters) (Lughezzani et al. 2012). Over 90% of UC cases are located in the bladder, and less than 10% occur in the upper canal (UTC). Patients with bladder cancer are usually diagnosed with the disease in its early stages, and the cancer is confined to superficial urothelium. This is partly due to the easy access of diagnostic equipment through the urethra. However, many patients with UTC may not be diagnosed early and may have already progressed to an invasive disease. Furthermore, staging UTC can be difficult because the tissue is fragile, consisting only of limited muscle tissue, and biopsies do not always accurately describe the disease level.

[0006] 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 complete removal of the kidney, ureter, and bladder cuff. Leakage of tumor cells can be a challenge with such a procedure. Furthermore, many patients are not candidates for this treatment. Some patients with low-risk disease may be offered more conservative treatments such as endoscopic ablation or segment debridement (Lughezzani et al. 2012). Clearly, at later diagnoses, the prognosis for these UTC patients is poor. In particular, cisplatin-based regimens are associated with nephrotoxicity, and nephrotoxicity may worsen if one kidney is removed, limiting chemotherapy options for these patients. Other drugs used to treat bladder cancer, such as mitomycin C and gemcitabine, may have favorable toxicity profiles. When used to treat bladder cancer, these drugs can be delivered in high concentrations into the bladder (directly into the bladder), and as a result, a 2-hour retention period allows for reasonable drug uptake into the tissue after tumor resection. More recently, docetaxel has been studied as a chemotherapy option for treating bladder cancer locally and UTC by systemic delivery. The combination of gemcitabine and docetaxel has also been studied as an improvement over the use of either drug alone (Gitlitz et al. 2003).

[0007] Because UUT tissue cannot be treated locally with drug solutions (although the renal pelvis is accessible, drug solutions are rapidly flushed into the bladder), a company, UroGen Pharma, Inc.®, developed a mitomycin gel formulation called JELMYTO® (Mitogel®). This gel undergoes thermoreversible gel transformation in the body, so it can be injected as a liquid and form a semi-solid gel in the renal pelvis of the kidney. Pluronic-based gels dissolve slowly but allow for some retention of the drug in the target tissue.

[0008] Injectable polymer paste Drugs are typically delivered orally or by infusion to allow for circulation and systemic uptake 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 local, and the preferred method is to deliver the drug directly to the site of action. Examples include analgesics for chronic local pain, anticancer drugs for local tumors, and antiarthritis drugs to alleviate symptoms of arthritis and joint pain. Therefore, many attempts have been made to design locally injectable systems to deliver drugs to specific body parts. This targeted approach can minimize systemic toxicity, which is often associated with conventional drug delivery methods. Intravenous delivery of anticancer drugs often causes serious side effects, and systemic toxicity usually limits the drug dose. Local polymer drug delivery systems can reduce systemic side effects and allow for high-dose local delivery.

[0009] Poly(DL-lactide-co-glycolide) (PLGA) is a common component of polymeric drug delivery systems. It is an FDA-approved biopolymer of lactic acid (D,L-LA) and glycolic acid (GA) and is used both as a drug delivery carrier and as a scaffold for tissue engineering (Bouissou et al. 2006; Jain 2000). The degradation of PLGA depends on many factors, including but not limited to the ratio of LA to GA, crystallinity, weight-average molecular weight of the polymer, matrix shape, and the type and amount of drug taken up (Siegel et al. 2006; Makadia and Siegel 2011). The ratio of LA to GA affects degradation, and polymers with a higher proportion of more hydrophilic GA generally degrade more quickly. The degradation products of PLGA are hydrolysis products LA and GA. Both can enter the citric acid cycle and be excreted as water and carbon dioxide, or, in the case of GA, can be excreted unchanged, mainly by the kidneys (Makadia and Siegel 2011). While minor toxicity, such as transient inflammation, has been reported for some PLGA-based implants (Athanasiou, Niederauer, and Agrawal 1996), these are likely to reflect increased exposure time and reduced clearance of degradation products.

[0010] Because ultrasound or MRI-guided systems allow for pinpoint precision when directing needle or catheter systems to target areas, injectable, drug-loaded polymeric pastes are attractive for local drug delivery. Some have described injectable liquids (e.g., Atrigel®) (Dunn 2002) consisting of an organic solvent such as acetone or polyvinylpyrrolidone and a drug that solidifies when injected into the body, with the solvent dissolving in the solvent. Such systems are flawed because introducing organic solvents into potentially sensitive tissue areas can induce undesirable local toxicity. Local drug delivery systems have been described ranging from drug-loaded polymer coatings for stents, injectable microspheres (Jackson et al. 2007), perivascular membranes (Jackson et al. 2004), and injectable polymer pastes (Jackson et al. 2000). In these examples, the antiproliferative drug paclitaxel was used to inhibit proliferative events associated with restenosis, cancer, and arthritis. Various polymer formulations for diverse applications are known in this technology (Yu and Ferguson, 2016; Konorty and Hakim, 2014; Pauletti, 2004; and Lughezzani et al. 2012).

[0011] The early polymer paste systems described in these literatures were based on a mixture of polycaprolactone and methoxypolyethylene glycol. This mixture was injectable (melted) at temperatures above body temperature, but was set into implants at 37°C to release the drug (Winternitz et al. 1996). The implants were brittle and rigid, and high-temperature delivery was unsuitable for injection into sensitive sites. An injectable paclitaxel-containing polymer paste made from a mixture of triblock copolymer and methoxypolyethylene glycol has also been described, which was injectable at room temperature and formed a solid implant in vivo (Jackson et al. 2000). This paste was inadequate in that the release rate of the drug paclitaxel and other hydrophobic agents was too slow to achieve adequate tissue levels of the active drug, and the polymer degradation profile was too long, potentially interfering with retreatment injection. The inclusion of various compositions of diblock copolymer in solid (not paste) microspheres has been described previously (Jackson et al. 2007). In this case, the dissolution of the diblock from the microspheres increased the release of the hydrophobic agent, opening the matrix to water and accelerating its degradation. Microsphere formulations are quite different from pastes. They do not flow during injection and therefore must be injected in a liquid suspension. Consequently, they disperse easily from the target tissue area. [Overview of the project]

[0012] The present invention relates to an improved polymer paste for controlled drug delivery to mucous membranes. The compositions described herein enable the injection and formulation of low-viscosity compositions into the body of a subject. Thereafter, the composition can coat the mucosal surface at a local site and remain at the site for an extended period after the initial injection. In one embodiment, the present invention provides delayed drug release from a polymer-coated delivery system by using a selected polyethylene glycol (PEG) composition, a selected water-insoluble polymer, and a selected mucosal-adhering polymer to modify the properties of the polymer formulation and adjust the release rate and residence time of the drug(s) payload at that site. The polymer composition can be manufactured from simple polymers to form an injectable polymer mucosal-adhering composition that can release drugs and / or drug combinations in a controlled manner. The present invention is based on the remarkable discovery that only defined ratios and compositions of polyethylene glycol (PEG), water-insoluble polymers, and mucosal-adhering polymers can be used to effectively form a drug delivery system having mucosal adhesion and injectability for in vivo delivery. The compositions described herein are low viscosity and become gel only after application to an aqueous environment (for example, enabling injection into hard-to-reach areas). The compositions described herein are injected via long catheter lines without additional equipment, and certain compositions described herein may be supplied for embolization purposes.

[0013] In a first embodiment, a composition is provided comprising: a polyethylene glycol (PEG) composition in an amount of about 85% to about 96% by weight, comprising (i) a first low molecular weight polyethylene glycol (PEG) having an average molecular weight of about 200 Da to about 500 Da; and (ii) a second low molecular weight polyethylene glycol (PEG) having an average molecular weight of about 500 Da to about 2,000 Da; a water-insoluble polymer in an amount of about 2% to about 10% by weight; and a mucosal-adhering polymer in an amount of about 2% to about 5% by weight.

[0014] In a further embodiment, a composition is provided comprising: a polyethylene glycol (PEG) composition in an amount of about 85% to about 96% by weight, comprising (i) a first low molecular weight polyethylene glycol (PEG) having an average molecular weight of about 200 Da to about 500 Da; and (ii) a second low molecular weight polyethylene glycol (PEG) having an average molecular weight of about 500 Da to about 2,000 Da; about 2% to about 10% by weight of a water-insoluble polymer; and about 2% to about 5% by weight of a mucosal-adhering polymer having a molecular weight of 50 kDa or more.

[0015] In a first embodiment, a composition is provided comprising: a polyethylene glycol (PEG) composition in an amount of about 85% to about 99% by weight, comprising (i) a first low molecular weight polyethylene glycol (PEG) having an average molecular weight of about 200 Da to about 500 Da; and (ii) a second low molecular weight polyethylene glycol (PEG) having an average molecular weight of about 500 Da to about 2,000 Da; a water-insoluble polymer in an amount of about 2% to about 10% by weight; and a mucosal-adhering polymer in an amount of about 2% to about 5% by weight.

[0016] In a further embodiment, a composition is provided comprising: a polyethylene glycol (PEG) composition in an amount of about 85% to about 99% by weight, comprising (i) a first low molecular weight polyethylene glycol (PEG) having an average molecular weight of about 200 Da to about 500 Da; and (ii) a second low molecular weight polyethylene glycol (PEG) having an average molecular weight of about 500 Da to about 2,000 Da; about 2% to about 10% by weight of a water-insoluble polymer; and about 2% to about 5% by weight of a mucosal-adhering polymer having a molecular weight of 50 kDa or more.

[0017] In a further embodiment, a composition is provided comprising a polyethylene glycol (PEG) composition in an amount of about 85% to about 96% by weight, comprising (i) a first low molecular weight polyethylene glycol (PEG) having an average molecular weight of about 200 kDa to about 500 kDa, and (ii) a second low molecular weight polyethylene glycol (PEG) having an average molecular weight of about 500 kDa to about 2,000 kDa, and an undissolved mucoadhesive polymer in an amount of about 4% to about 15% by weight. The composition may further contain a water-insoluble polymer. Alternatively, the water-insoluble polymer may be about 2% to about 10% by weight, and the undissolved mucoadhesive polymer may be about 2% to about 5% by weight. The mucoadhesive polymer may have a molecular weight of 50 kDa or more.

[0018] In a further embodiment, a composition is provided comprising a polyethylene glycol (PEG) composition in an amount of about 85% to about 99% by weight, comprising (i) a first low molecular weight polyethylene glycol (PEG) having an average molecular weight of about 200 kDa to about 500 kDa, and (ii) a second low molecular weight polyethylene glycol (PEG) having an average molecular weight of about 500 kDa to about 2,000 kDa, and an insoluble mucosal adhesive polymer in an amount of about 4% to about 15% by weight. The composition may further contain a water-insoluble polymer. Alternatively, the water-insoluble polymer may be about 2% to about 10% by weight, and the insoluble mucosal adhesive polymer may be about 2% to about 5% by weight. The mucosal adhesive polymer may have a molecular weight of 50 kDa or more.

[0019] In a further embodiment, a composition is provided comprising a polyethylene glycol (PEG) composition in an amount of about 85% to about 99% by weight, comprising (i) a first low molecular weight polyethylene glycol (PEG) having an average molecular weight of about 200 Da to about 500 Da, and (ii) a second low molecular weight polyethylene glycol (PEG) having an average molecular weight of about 500 Da to about 2,000 Da, and a mucosal adhesive polymer in an amount of about 1% to about 15% by weight, having a molecular weight of 50 kDa or more. The composition may further comprise a water-insoluble polymer. Alternatively, the composition may have an amount of about 85% to about 96% by weight of the polyethylene glycol (PEG) composition. Alternatively, the composition may have an amount of about 4% to about 15% by weight of a mucosal adhesive polymer having a molecular weight of 50 kDa or more.

[0020] In a further embodiment, a composition is provided comprising a polyethylene glycol (PEG) composition in an amount of about 85% to about 96% by weight, comprising (i) a first low molecular weight polyethylene glycol (PEG) having an average molecular weight of about 200 Da to about 500 Da, and (ii) a second low molecular weight polyethylene glycol (PEG) having an average molecular weight of about 500 Da to about 2 kDa, and an insoluble mucosal adhesive polymer in an amount of about 4% to about 15% by weight having a molecular weight of 50 kDa or more. The composition may further contain a water-insoluble polymer.

[0021] In a further embodiment, a composition is provided comprising a polyethylene glycol (PEG) composition in an amount of about 85% to about 96% by weight, comprising (i) a first low molecular weight polyethylene glycol (PEG) having an average molecular weight of about 200 Da to about 500 Da, and (ii) a second low molecular weight polyethylene glycol (PEG) having an average molecular weight of about 500 Da to about 2 kDa, and about 4% to about 15% of an insoluble mucosal adhesive polymer. The composition may further comprise a water-insoluble polymer.

[0022] In a further aspect, a non-aqueous polymer composition is provided that comprises (i) a low molecular weight (less than 500 Da) polyethylene glycol (PEG) or propylene glycol, and (ii) a high molecular weight (500 - 2,000) PEG, and (iii) a suspended hyaluronic acid. The composition may further comprise a water-insoluble polymer.

[0023] In a further aspect, a composition is provided that comprises (i) a low molecular weight (less than 500 Da) polyethylene glycol (PEG) or propylene glycol, and (ii) a high molecular weight (500 - 2,000) PEG, and (iii) a suspended hyaluronic acid, and (iiii) a small molecule drug, and is injectable through an 18-gauge needle under manual pressure.

[0024] In a further aspect, there is provided the use of a composition described herein for the manufacture of a pharmaceutical.

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

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

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

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

[0029] In a further aspect, there is provided a commercial package comprising (a) a composition described herein and (b) instructions for use.

[0030] The pharmaceutical compositions described herein may be combined with pharmaceutically acceptable diluents or carriers.

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

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

[0033] The mucosal adhesive polymer may be selected from one or more of the following: hyaluronic acid, poly(acrylic acid) and poly(methacrylic acid) derivatives, cyanoacrylate, poly(acrylic acid), carbomer, sodium carboxymethylcellulose (CMC), hydroxypropylcellulose, polycarbophil, chitosan, alginate, gellan, xanthan gum, thiolated poly(acrylic acid), poloxamer, cellulose acetophthalate, ethylcellulose, methylcellulose, hydroxyethylcellulose, poly(amidoamine) dendrimer, poly(dimethylsiloxane), and poly(vinylpyrrolidone). The mucosal adhesive polymer may be selected from one or more of the following: hyaluronic acid, poly(acrylic acid), carbomer, sodium carboxymethylcellulose, and alginic acid. The mucosal adhesive polymer may also be hyaluronic acid. Alternatively, the mucosal adhesive polymer may be selected from one or more of the following: hyaluronic acid, poly(acrylic acid) and poly(methacrylic acid) derivatives, cyanoacrylate, poly(acrylic acid), carbomer, sodium carboxymethylcellulose (CMC), hydroxypropylcellulose, polycarbophil, thiolated poly(acrylic acid), poloxamer, cellulose acetophthalate, ethylcellulose, methylcellulose, hydroxyethylcellulose, poly(amideamine) dendrimer, poly(dimethylsiloxane), and poly(vinylpyrrolidone).

[0034] The first low molecular weight PEG may be selected from one of the following approximate molecular weights: PEG200, PEG300, PEG400, and PEG500. The first low molecular weight PEG may be selected from PEG100, PEG200, PEG300, PEG400, and PEG500. The second low molecular weight PEG may be selected from one of the following approximate molecular weights: PEG500, PEG600, PEG700, PEG800, PEG900, PEG1000, PEG1100, PEG1200, PEG1300, PEG1400, PEG1450, PEG1500, PEG1600, PEG1700, PEG1800, PEG1900, and PEG2000. The second low molecular weight PEG is selected from one of PEG500, PEG600, PEG700, PEG800, PEG900, PEG1000, PEG1100, PEG1200, PEG1300, PEG1400, PEG1500, PEG1600, PEG1700, PEG1800, and PEG1900. The second low molecular weight PEG is selected from one of PEG500, PEG600, PEG700, PEG800, PEG900, PEG1000, PEG1100, PEG1200, PEG1300, PEG1400, PEG1500, PEG1600, PEG1700, and PEG1800. The second low molecular weight PEG is selected from PEG500, PEG600, PEG700, PEG800, PEG900, PEG1000, PEG1100, PEG1200, PEG1300, PEG1400, PEG1500, PEG1600, and PEG1700. The second low molecular weight PEG is selected from PEG500, PEG600, PEG700, PEG800, PEG900, PEG1000, PEG1100, PEG1200, PEG1300, PEG1400, PEG1500, and PEG1600. The second low molecular weight PEG is selected from PEG500, PEG600, PEG700, PEG800, PEG900, PEG1000, PEG1100, PEG1200, PEG1300, PEG1400, and PEG1500. PEG can have an average molecular weight of approximately 200 Da to approximately 2,000 Da.

[0035] The composition may further contain one or more low molecular weight PEG polymers selected from one or more of PEG200, PEG300, PEG400, PEG500, PEG600, PEG700, PEG800, PEG900, PEG1000, PEG1100, PEG1200, PEG1300, PEG1400, PEG1500, PEG1600, PEG1700, PEG1800, PEG1900, and PEG2000.

[0036] The composition may further comprise one or more drug compounds or their pharmaceutically acceptable salts, solvates, or solvates of such salts. The one or more drug compounds or their pharmaceutically acceptable salts, solvates, or solvates of such salts may be selected from one or more of the following categories: anticancer agents, anti-inflammatory agents, antibacterial agents, antiviral agents, antifungal agents, antiproliferative agents, antifibrotic agents, antirestenotic agents (sirolimus and taxanes), anesthetic agents, neuromodulators, and analgesics.

[0037] One or more drug compounds or their pharmaceutically acceptable salts, solvates, or solvates of such salts are: actinomycin; all-trans retinoic acid; azacitidine; azathioprine; bleomycin; bortezomib; carboplatin; capecitabine; cisplatin; chlorambucil; cyclophosphamide; cytarabine; daunorubicin; docetaxel; doxifluridine; doxorubicin; epirubicin; epotilon; etoposhi The anticancer agent is selected from one or more of the following: docetaxel; fluorouracil; gemcitabine; hydroxyurea; idarubicin; imatinib; irinotecan; mechloretamine; mercaptopurine; methotrexate; mitoxantrone; oxaliplatin; paclitaxel; pemetrexed; teniposide; thioguanine; topotecan; barurubicin; vemurafenib; vinblastine; vincristine; vindesine; and vinorelbine. The agent may be selected from one or more of gemcitabine hydrochloride, gemcitabine, mitomycin, docetaxel, and paclitaxel. One or more drug compounds or their pharmaceutically acceptable salts, solvates, or solvates of such salts may be anesthetics. The anesthetic may be a local anesthetic selected from one or more of the following: procaine, benzocaine, chloroprocaine, cocaine, cyclomethicaine, dimethocaine / larocaine, pipelocaine, propoxycaine, procaine / novocaine, propalacaine, tetracaine / amesocaine, alticaine, bupivacaine, cincocaine / dibucaine, etidocaine, levobupivacaine, lidocaine / lignocaine / xylocaine, mepivacaine, prilocaine, ropivacaine, and trimecaine.

[0038] One or more drug compounds or their pharmaceutically acceptable salts, solvates, or solvates of such salts may be antibiotics containing penicillin, cephalosporins, polymyxins, rifamycin, lipiarmycins, quinolones, sulfonamides, macrolides, lincosamides, tetracyclines, aminoglycosides, lipopeptides, glycylcyclines, oxazolidinones, lipiarmycin, cephalexin, cefazolin, gentamicin, ciprofloxacin, clindamycin, macrodantine, tobramycin, rifampicin, daptomycin, linezolid, vancomycin, fusidic acid, silver compounds, cannabinoids, etc. Furthermore, antibiotics may contain silver and cannabinoids.

[0039] One or more drug compounds or their pharmaceutically acceptable salts, solvates, or solvates of such salts may be antifungal agents such as polyenes, azoles, triazoles, antimetabolites, allylamines, and echinocandins. Examples of antifungal agents include, but are not limited to, amphotericin B, nystatin, clotrimazole, econazole, miconazole, fluconazole, terbinafine, ketoconazole, caspofungin, tolnaftate, ivermectin, flucytosine, and griseofulvin.

[0040] The mucosal surface area may be selected from one or more of the urogenital tract, gastrointestinal tract, and respiratory tract. The mucosal surface area may be selected from one or more of the kidneys, ureters, bladder, urethra, uterus, vagina, penis, oral cavity, esophagus, stomach, small intestine, large intestine, rectum, anus, nasal cavity, pharynx, larynx, trachea, bronchi, bronchioles, and lungs. The medical condition may be selected from one or more of cancer, wounds, and inflammation. The drug-containing composition may be for the treatment of one or more of cancer, wounds, and inflammation.

[0041] The composition may further contain a water-insoluble polymer, which may be selected from one or more of polylactic acid-co-glycolic acid (PLGA), poly(ε-caprolactone) (PCL), and polylactic acid (PLA). The 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 acid ester and methacrylic acid ester. The molar ratio of lactic acid to glycolic acid monomers may be 90:10 to 50:50. The water-insoluble polymer may be 2% to 20% by weight of the composition. The water-insoluble polymer may be 2% to 15% by weight of the composition. The water-insoluble polymer may be up to 20% by weight of the composition. The water-insoluble polymer may be up to 15% by weight of the composition. PLGA may be 2% to 20% by weight of the composition. PLGA may be 2% to 15% by weight of the composition. PLGA may be up to 20% by weight of the composition. PLGA may be up to 15% by weight of the composition.

[0042] Methods are provided for using the aforementioned compositions to form implants in vitro and in vivo. The in vivo methodology involves injecting the composition into a site in the body of a target where a drug-containing implant may be formed. An injection device containing the compositions described herein is also provided. [Brief explanation of the drawing]

[0043] [Figure 1] Figure 1 shows a schematic diagram of gemcitabine paste in the renal pelvis. [Figure 2] Figure 2 shows a semi-logarithmic plot of concentration-versus-time data after administration of gemcitabine paste to the renal pelvis (1000 mg / pig). [Figure 3] Figure 3 shows a semi-logarithmic plot of gemcitabine (mg) excreted per collection interval (mean plotted) after administration of gemcitabine paste to the renal pelvis (1000 mg / pig). [Figure 4]Figure 4 shows gemcitabine tissue concentrations after administration of gemcitabine paste to the renal pelvis. Renal tissue was collected after 1 hour of in vivo drug exposure (1 sample per tissue). [Figure 5] Figure 5 shows gemcitabine tissue concentrations after administration of gemcitabine paste to the renal pelvis. Renal tissue was collected after 3 hours of in vivo drug exposure (n=4). [Figure 6] Figure 6 shows serum data after administration of gemcitabine hydrochloride (~30 mg / kg) after IV administration and local administration to the renal pelvis: Renal pelvis infusion: Porcine serum data (exponential fit of measured serum levels, n=3), Intravenous administration: Approximation of IV profile using literature pharmacokinetic (PK) parameters derived from a one-compartment model and 30-minute gemcitabine hydrochloride infusion in 12 patients. [Figure 7] Figure 7 shows the viscosity of formulations A, F1, F2, F3, and F4 (Table 7) at ambient temperature before mixing with water. [Figure 8] Figure 8 shows the viscosity at ambient temperature after mixing formulations A, F1, F2, F3, and F4 (Table 7) with water in a 1:1 ratio. [Figure 9] Figure 9 shows the viscosity of formulations A, B1, B2, B3, B4, and B5 (Table 6) at ambient temperature before mixing with water. [Figure 10] Figure 10 shows the viscosity at ambient temperature after mixing formulations A, B1, B2, B3, B4, and B5 (Table 6) with water in a 1:1 ratio. [Figure 11] Figure 11 shows the viscosity of formulations A, E1, E2, and E3 (Table 10) at ambient temperature. [Figure 12] Figure 12 shows the release of docetaxel, gemcitabine hydrochloride, and albumin from formulation A (Table 8). [Modes for carrying out the invention]

[0044] This specification describes novel formulations for topical delivery of chemotherapeutic agents (e.g., gemcitabine) by adhering to the renal pelvis and ureter or other mucous membranes, and evaluates the feasibility, safety, and pharmacokinetic properties of injectable mucosal-adhering polymer compositions.

[0045] The previous paste was a 50 / 50 PEG300 / PLGA paste containing 10% gemcitabine and 2% sodium hyaluronate in a 69 / 31 PEG300 / PLGA paste containing 5% gemcitabine. The paste was safe (mild hydronephrosis in some pigs) and systemic gemcitabine concentrations were low. Several improvements were made to the paste to create a gemcitabine composition that was easily injectable, showed some renal pelvis adhesion, and did not interact with urethral catheters.

[0046] The gemcitabine paste compositions described herein have a low content of PLGA, a higher amount of hyaluronic acid, and a combination of PEGs of different molecular weights, and utilize gemcitabine hydrochloride instead of gemcitabine.

[0047] The principle of action of the compositions disclosed herein is based on gelation and mucosal adhesion, rather than retention by hardening (setting). A large injection of 10 mL can coat the entire renal pelvis (schematically shown in Figure 1). The paste is injected into the renal pelvis via a 5F catheter. After at least 5 minutes, the ureteral catheter is removed, and the paste slowly moves into the bladder without obstructing the ureter. Due to the mucosal adhesion properties of the paste, the renal pelvis remains coated with the paste, and the release of gemcitabine into the tissue is sustained.

[0048] In embodiments of the present invention, a water-insoluble polymer is used to control the consistency of a biocompatible polymer paste, from which various drugs can then be released.

[0049] For polymers whose viscosity cannot be directly measured (e.g., PLGA - waxy lumps), the relative viscosity is calculated by dissolving the polymer in a suitable solvent and dividing the viscosity of the polymer solution by the viscosity of the pure solvent. Most polymers show a clear relationship between molar mass and viscosity, and generally, the viscosity of the polymer solution increases with increasing molar mass. Inherent viscosity (IV) is the ratio of the natural logarithm of the relative viscosity to the mass concentration of the polymer, and is provided as a measure of molecular size, typically reported in deciliters per gram (dL / g). IV is readily available, inexpensive, and reproducible. Gel permeation chromatography (GPC) can be used as a chromatographic method for measuring molecular size. Molecular size can be expressed as molecular weight (MW) in Dalton units obtained from calibration using a standard polymer (e.g., a polystyrene standard in chloroform). The molecular weight of styrene is 10⁴ Daltons, and known polystyrene standards are readily available. MW obtained by GPC is highly method-dependent and may have low interlaboratory reproducibility. Alternatively, molecular weight can be measured by size exclusion chromatography (SEC), high-temperature gel permeation chromatography (HT-GPC), or mass spectrometry (MALDI TOF-MS).

[0050] The water-insoluble polymer may be a polyester. The water-insoluble polymer may also be polylactic acid-co-glycolic acid (PLGA) with an LA:GA ratio of 75:25 or less. The LA:GA ratio may be approximately 50:50. Durect Corporation®, which supplied the PLGA used in these experiments, graphs the intrinsic viscosity (IV) in hexafluoroisopropanol (HFIP) in dL / g for the molecular weight (Daltons) of their 50:50 and 65:35 LA:GA polymers. Similarly, when Durect® calculated the IV values ​​(dL / g) for 75:25 PLGA and 85:15 PLGA, chloroform was used as the solvent. The relationship between IV and molecular weight in Dalton units varies depending on the LA:GA ratio. As described herein, an intrinsic viscosity of 0.15–0.25 dL / g is any range, but an IV in the range of 0.25–0.5 dL / g is also preferred. Alternatively, the intrinsic viscosity may be in the range of approximately 0.15 dL / g to approximately 0.5 dL / g.

[0051] Using a 50:50 PLGA, the range of 0.15 to 0.25 dL / g roughly corresponds to the range of approximately 4,300 Da to 6,700 Da, and the range of 0.25 to 0.5 dL / g roughly corresponds to the range of approximately 6,700 Da to 26,600 Da. Using a 65:35 PLGA, the range of 0.15 to 0.25 dL / g roughly corresponds to the range of approximately 6,500 Da to 14,200 Da, and the range of 0.25 to 0.5 dL / g roughly corresponds to the range of approximately 14,200 Da to 39,000 Da. The broader range of 0.15–0.5 dL / g corresponds to approximately 4,300 Da–26,600 Da for 50:50 PLGA and approximately 6,500 Da–39,000 Da for 65:35 PLGA. Therefore, the PLGA range can be any of the ranges between 4,300 Da and approximately 39,000 Da. Alternatively, the PLGA range may be 4,300–40,000 or higher when using 75:25 (i.e., up to a molecular weight of 56,500 Da). For 50:50, 65:35, and 75:25 LA:GA polymers, 0.5 g / dL of IV corresponds to molecular weights of approximately 26,600, 39,000, and 56,500, respectively. Analysis revealed that Durect® 50:50 with an IV of 0.25 dL / g had a total energy of approximately 6,700 Da, Durect® 75:25 with an IV of 0.47 dL / g had a total energy of approximately 55,000 Da, and Durect® 85:15 with an IV of 0.55 dL / g to 0.75 dL / g had a total energy of approximately 76,000 Da to 117,000 Da.

[0052] Of particular interest is the PLGA paste with an LA:GA ratio of 50:50 and an IV of 0.15 dL / g to 0.25 dL / g (i.e., a molecular weight of 4,300 Da to 6,700 Da). However, PLGA pastes with an LA:GA ratio of 50:50 and an IV of 0.25 dL / g to 0.5 dL / g (i.e., a molecular weight of approximately 6,700 Da to approximately 26,600 Da) are also useful.

[0053] The molecular weight of PLGA polymers can be reported as intrinsic viscosity (IV). IV can be between 0.15 and 0.5 dL / g. PLGA polymer IV can be less than 0.3 dL / g. IV can be between 0.15 and 0.25 dL / g. A low molecular weight version of PLGA with an LA:GA ratio of 50:50 and an intrinsic viscosity of less than 0.3 dL / g can be fully miscible with low molecular weight biocompatible glycols using gentle heating to form a viscous or fluid paste at room temperature.

[0054] The drug supply compositions described herein may exist in various “paste” forms. Examples of paste forms may include liquid pastes or pastes, depending on the polymer used, the amount of polymer used, and the temperature.

[0055] The drug delivery compositions described herein may release one or more drugs over several hours or months, as needed. The compositions described herein may be used for topical delivery of one or more drugs to a subject. Examples of drugs that may be delivered using these compositions include, but are not limited to, anticancer agents, anti-inflammatory agents, antibacterial agents, antiviral agents, antifungal agents, antiproliferative agents, antifibrotic agents, anti-restenotic agents (sirolimus and taxanes), anesthetic agents, neuromodulators, and analgesics, depending on the condition being treated or improved. Further examples include drugs for the treatment of neurological conditions, and drugs for the treatment of gastrointestinal conditions such as diverticulosis and peptic ulcers. The compositions described herein are suitable for any drug that benefits from adhesion to a mucosal tissue surface and / or long-term release from a paste implant.

[0056] Examples of anticancer agents that may be used with the compositions of the present invention include docetaxel, paclitaxel, mitomycin, cisplatin, etoposide, vinca alkaloids, doxorubicin, rapamycin, camptothecin, gemcitabine, finasteride (or other cytotoxic substances), bicalutamide, enzalutamide, ivermectin, tamoxifen, sunitinib, and erlotinib. Furthermore, anticancer biological agents may be used in formulations such as antibody-based therapies, e.g., Herceptin, Avastin, Erbitux, or radiolabeled antibodies, or targeted radiotherapies such as PSMA-radioligands.

[0057] Anti-inflammatory agents may include non-steroidal anti-inflammatory drugs such as acetaminophen, ibuprofen, acetylsalicylic acid, naproxen, diclofenac, and meloxicam, as well as steroids such as prednisone.

[0058] Examples of local analgesics or local anesthetics include one or more of the following: procaine, benzocaine, chloroprocaine, cocaine, cyclomethicaine, dimethocaine / larocaine, pipelocaine, propoxycaine, procaine / novocaine, propalacaine, tetracaine / amesocaine, alticaine, bupivacaine, cincocaine / dibucaine, etidocaine, levobupivacaine, lidocaine / lignocaine / xylocaine, mepivacaine, prilocaine, ropivacaine, and trimecaine.

[0059] Antibiotics may include penicillin, cephalosporins, polymyxins, rifamycin, ripialmycin, quinolones, sulfonamides, macrolides, lincosamides, tetracyclines, aminoglycosides, lipopeptides, glycylcyclines, oxazolidinones, and ripialmycin, cephalexin, cefazolin, gentamicin, ciprofloxacin, clindamycin, macrodantine, tobramycin, rifampicin, daptomycin, linezolid, vancomycin, silver fusidate compounds, cannabinoids, etc.

[0060] Examples of antifungal agents include polyenes, azoles, triazoles, antimetabolites, allylamines, and echinocandins. Other antifungal agents include, but are not limited to, amphotericin B, nystatin, clotrimazole, econazole, miconazole, fluconazole, terbinafine, ketoconazole, caspofungin, tolnaftate, ivermectin, flucytosine, and griseofulvin.

[0061] The drugs may be hydrophobic or hydrophilic. Specific drugs may be selected from one or more of the following: docetaxel, ivermectin, bicalutamide, cephalexin, sunitinib, tamsulosin, desoximetazon, gemcitabine, rapamycin, and ibuprofen.

[0062] Drug delivery compositions can be prepared and used to treat or prevent a variety of diseases or conditions, particularly when the treatment site is located in or near mucosal tissue. Examples of treatable diseases or conditions include, for example, cancer, pain, inflammatory conditions, fibrous conditions, benign tumors (including benign prostatic hyperplasia), and infections. For example, the compositions described herein may be used to treat the renal pelvis as described above. The paste can be applied to any mucosal surface or moist tissue area for topical drug delivery. Particularly important may be the treatment of the inside of the GI duct, such as for treating cancer, wounds (e.g., ulcers) or inflammation (e.g., inflammatory bowel disease: ulcerative colitis, Crohn's disease). The paste may also be applied in conjunction with drugs to treat or fill inflammatory diverticula. Diseases of the oral, vaginal, and rectal regions may be treated. Topical application of hyaluronic acid is used to prevent surgical adhesions, and therefore this can be improved by using this paste and including an antiadhesive drug. Wound and postoperative pain may be appropriate indications.

[0063] As used herein, “mucosal tissue” or “mucous membrane or mucosa” refers to the membranes that cover various cavities in the body (i.e., the urogenital tract; the digestive tract; and the respiratory tract) and the surfaces of internal organs. Mucosa consists of one or more layers of epithelial cells covering connective tissue. The urogenital tract includes the kidneys, ureters, bladder, urethra, uterus, vagina, and penis. The digestive tract (GI tract) includes the oral cavity, esophagus, stomach, small intestine, large intestine, rectum, and anus. The respiratory tract includes the oral cavity, nasal cavity, pharynx, larynx, trachea, bronchi, bronchioles, and lungs.

[0064] As used herein, “mucosal-adhering polymer” refers to any polymer having the property of adhering to mucosal surfaces. Such polymers are preferably biocompatible. Mucosal-adhering polymers can be selected from one or more of the following: hyaluronic acid (HA), poly(acrylic acid) and poly(methacrylic acid) derivatives, cyanoacrylate, poly(acrylic acid) (carbomer), sodium carboxymethylcellulose (CMC), hydroxypropylcellulose, polycarbophil, chitosan, alginate, gellan, thiolated poly(acrylic acid), poloxamer, cellulose acetophthalate, ethylcellulose, methylcellulose, hydroxyethylcellulose, poly(amidoamine) dendrimers, poly(dimethylsiloxane), and poly(vinylpyrrolidone) (Roy et al. 2009). Generally, HA is not used as a dispersion in a non-aqueous setting as described herein. The compositions described herein also contain PEG in a ratio such that the HA does not settle at a particular temperature. Alternatively, the mucosal adhesive polymer may be selected from one or more of the following: hyaluronic acid, poly(acrylic acid) and poly(methacrylic acid) derivatives, cyanoacrylate, poly(acrylic acid) (carbomer), sodium carboxymethylcellulose, hydroxypropylcellulose, polycarbophil, chitosan, alginate, guerlain, thiolated poly(acrylic acid), poloxamer, cellulose acetophthalate, ethylcellulose, methylcellulose, hydroxyethylcellulose, poly(amidoamine) dendrimer, poly(dimethylsiloxane), and poly(vinylpyrrolidone).

[0065] Furthermore, as described herein, higher MW PEGs have lower water solubility, so multiple PEGs are combined to adjust formulations for specific administration (e.g., long catheter lines), stability (e.g., storage, no precipitation), and disintegration characteristics.

[0066] As used herein, “water-insoluble polymer” refers to any polymer that is insoluble in water. Such polymers are preferably biocompatible. The water-insoluble polymer may be selected from one or more of polylactic acid-co-glycolic acid (PLGA), poly(ε-caprolactone) (PCL), and polylactic acid (PLA). Alternatively, the water-insoluble polymer may be a copolymer of acrylic acid esters and methacrylic acid esters.

[0067] As used herein, "polylactic acid-co-glycolic acid" (PLGA) is a copolymer of lactic acid and glycolic acid having the following structure: x represents the number of lactic acid (lactide) subunits, and y represents the number of glycolic acid (glycolide) subunits. Different forms of PLGA can be obtained depending on the lactide-to-glycolide ratio used in polymerization. These are usually identified with respect to the molar ratio of the monomers used (e.g., PLGA75:25 identifies a copolymer whose composition is 75% lactic acid and 25% glycolic acid). A suitable molar ratio can be any of the ranges from 90:10 to 50:50. Generally, this ratio can determine the degradation of PLGA. For example, for complete degradation, PLGA50:50 exhibits a fast degradation rate (e.g., 2 months), while PLGA75:25 takes longer (e.g., 5 months), and PLGA85:15 takes even longer (e.g., 6 months). JPEG0007829490000001.jpg22166

[0068] PLGA can be present in amounts ranging from 2% to approximately 20% by weight when used. The IV of PLGA 50 / 50 is approximately 0.15 dL / g, while IV of 65 / 35 PLGA is also useful at 0.25 dL / g. For PLGA, a useful IV range of 0.1 dL / g to 0.3 dL / g would be appropriate. The molar ratio of lactic acid to glycolic acid monomers can range from approximately 90:10 to approximately 50:50.

[0069] As used herein, "polyethylene glycol" (PEG), polyethylene oxide, or polyoxyethylene is a polyether compound having the following structure, depending on its molecular weight. As used herein, there is a first low molecular weight PEG, which may be selected from one of PEG100, PEG200, PEG300, PEG400, and PEG500. There is also a second low molecular weight PEG, which may be selected from one of PEG100, PEG200, PEG300, PEG400, PEG500, PEG600, PEG700, PEG800, PEG900, PEG1000, PEG1100, PEG1200, PEG1300, PEG1400, PEG1500, PEG1600, PEG1700, PEG1800, PEG1900, and PEG2000. Furthermore, the PEG compositions described herein may contain one or more low molecular weight PEGs selected from one or more of PEG100, PEG200, PEG300, PEG400, PEG500, PEG600, PEG700, PEG800, PEG900, PEG1000, PEG1100, PEG1200, PEG1300, PEG1400, PEG1500, PEG1600, PEG1700, PEG1800, PEG1900, and PEG2000. The PEG polymers used herein may have an average molecular weight of about 100 Da to about 2,000 Da. The PEG polymers used herein may have an average molecular weight of about 200 Da to about 2,000 Da. JPEG0007829490000002.jpg17166

[0070] Polyethylene glycol (PEG) used herein may be selected from PEG100, PEG200, PEG300, PEG400, PEG500, PEG600, PEG700, PEG800, PEG900, PEG1000, PEG1100, PEG1200, PEG1300, PEG1400, PEG1500, PEG1600, PEG1700, PEG1800, PEG1900, and PEG2000. Polyethylene glycol (PEG) may have an average molecular weight of about 100 Da to about 1,450 Da. Polyethylene glycol (PEG) may have an average molecular weight of about 100 Da to about 2,000 Da. Polyethylene glycol (PEG) may have a molecular weight of about 300 Da to about 1,450 Da. Polyethylene glycol (PEG) can have molecular weights of approximately 300 Da to 500 Da and approximately 500 Da to 2000 Da.

[0071] Alternatively, instead of PEG, a suitable composition may contain propylene glycol, or glycerol may be used, or may be used in combination with PEG.

[0072] Local anesthetics are typically classified into one of two classes: aminoamides and aminoesters. Most local anesthetics have the suffix "-caine". Local anesthetics in the aminoester group may be selected from one or more of the following: procaine, benzocaine, chloroprocaine, cocaine, cyclomethicaine, dimethocaine / larocaine, pipelocaine, propoxycaine, procaine / novocaine, propalacaine, and tetracaine / amesocaine. Local anesthetics in the aminoamide group may be selected from one or more of the following: articaine, bupivacaine, cincocaine / dibucaine, etidocaine, levobupivacaine, lidocaine / lignocaine / xylocaine, mepivacaine, prilocaine, ropivacaine, and trimecaine. Local anesthetics may be combined (e.g., lidocaine / prilocaine or lidocaine / tetracaine).

[0073] Furthermore, the local anesthetic used for injection may be mixed with a vasoconstrictor to increase the residence time, and the maximum dose of the local anesthetic may be higher when used in combination with a vasoconstrictor (e.g., prilocaine hydrochloride and epinephrine; lidocaine, bupivacaine and epinephrine; lidocaine and epinephrine; or alticaine and epinephrine).

[0074] The anticancer agents that may be used in the compositions described herein may be classified as alkylating agents (bifunctional and monofunctional), anthracyclines, cytoskeletal disruptors, epotilones, topoisomerase inhibitors (I and II), kinase inhibitors, nucleotide analogs and precursor analogs, peptide antibiotics, platinum-based drugs, vinca alkaloids, and retinoids. Alkylating agents may be bifunctional alkylating agents (e.g., cyclophosphamide, mechloretamine, chlorambucil, and melphalan) or monofunctional alkylating agents (e.g., dacarbazine (DTIC), nitrosourea, and temozolomide). Examples of anthracyclines are daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, and barrubicin. Cytoskeletal disruptors or taxanes are paclitaxel, docetaxel, abraxane, and taxotere. Epotilones may be epotilone or related analogs. Histone deacetylase inhibitors may be 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 bismodegib. Nucleotide analogs and precursor analogs may be selected from azacitidine, azathioprine, capecitabine, cytarabine, doxifluridine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, or thioguanine. Peptide antibiotics include bleomycin or actinomycin. The platinum-based drug may be selected from carboplatin, cisplatin, or oxaliplatin. The retinoid may be tretinoin, alitretinoin, or bexarotene. The vinca alkaloid and derivative may be selected from vinblastine, vincristine, vindesine, and vinorelbine.

[0075] Anticancer agents that can be used in combination with the compositions described herein may be selected from one or more of the following: actinomycin; all-trans retinoic acid; azacitidine; azathioprine; bleomycin; bortezomib; carboplatin; capecitabine; cisplatin; chlorambucil; cyclophosphamide; cytarabine; daunorubicin; docetaxel; doxifluridine; doxorubicin; epirubicin; epotilon; etoposide; fluorouracil; gemcitabine; hydroxyurea; idarubicin; imatinib; irinotecan; mechloretamine; mercaptopurine; methotrexate; mitoxantrone; oxaliplatin; paclitaxel; pemetrexed; teniposide; thioguanine; topotecan; barrubicin; vemurafenib; vinblastine; vincristine; vindesine; and vinorelbine. Alternatively, the anticancer agent may be a biological agent and may be selected from Herceptin (trastuzumab), Ado-trastuzumab, lapatinib, neratinib, pertuzumab, Avastin, Erbitux, or radiolabeled antibodies, or targeted radiotherapy such as PSMA-radioligand. The anticancer agent may be an androgen receptor, estrogen receptor, epidermal growth factor receptor (EGFR) antagonist, or tyrosine kinase inhibitor (TKI). The anti-angiogenic agent may be selected from Avastin, an epidermal growth factor receptor (EGFR) antagonist, or a tyrosine kinase inhibitor (TKI). Immunomodulatory agents include BCG (Bacillus Calmette-Guerin).

[0076] As used herein, “drug” refers to any therapeutic moiety, including small molecules and biological agents (e.g., proteins, peptides, nucleic acids). Furthermore, biological agents mean including antibodies and antigens. As used herein, the term drug may, in certain embodiments, include any therapeutic moiety or subset of therapeutic moieties. Examples include, but are not limited to, one or more potentially overlapping subsets and one or more drugs, such as hydrophobic agents, hydrophilic agents, cancer agents, local anesthetics, antibiotics, antivirals, anti-inflammatory agents, analgesics, antiproliferative agents, antifibrotic agents, or any drugs that may benefit from topical and / or sustained release.

[0077] As used herein, “antibody” is a polypeptide belonging to the immunoglobulin superfamily. In particular, “antibody” includes an immunoglobulin molecule or an immunologically active fragment of an immunoglobulin molecule (i.e., a molecule containing an antigen-binding site), an immunoglobulin heavy chain (alpha (α), mu (μ), delta (δ), or epsilon (ε)) or its variable domain (VH domain), an immunoglobulin light chain (kappa (κ) or lambda (λ)) or its variable domain (VL domain), or a polynucleotide encoding an immunoglobulin molecule or an immunologically active fragment of an immunoglobulin molecule. Antibodies include single-chain antibodies (e.g., immunoglobulin light chain or immunoglobulin heavy chain), single-domain antibodies, antibody variable fragments (Fv), single-chain variable fragments (scFv), scFv zippers, scFv-Fc, disulfide-linked Fv (sdFv), Fab fragments (e.g., CLVL or CHVH), F(ab') fragments, monoclonal antibodies, and polyclonal antibodies. As used herein, “antigen” refers to any epitope-binding fragment and a polynucleotide (DNA or RNA) encoding any of the above.

[0078] As used herein, “paste” is any composition described herein having solid and liquid properties depending on the applied load and temperature. Specifically, the viscosity of the paste may be any, as long as it is pourable 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, there are rheometers by Anton Paar®, such as the MCR502 or MCR72.

[0079] method Paste preparation Table 1 shows an example of a base paste formula for the renal pelvis. The paste was prepared by weighing the polymer into a glass vial and stirring at 60°C. When the polymer formed a homogeneous melt, the mucosal adhesive polymer was added. If a drug is to be added, it is added after the polymer paste is prepared. The values ​​for the paste polymer (i.e., a polyethylene glycol (PEG) composition between about 85% and about 96% by weight, comprising (i) a first low molecular weight polyethylene glycol (PEG) and (ii) any second low molecular weight polyethylene glycol (PEG), wherein the first and second low molecular weight PEGs are polyethylene glycol (PEG) compositions having an average molecular weight between about 100 Da and about 1,500 Da; a water-insoluble polymer between about 2% and about 10% by weight; and a mucosal adhesive polymer between about 2% and about 5% by weight) are prepared as a total percentage out of 100% before mixing with the drug. When a drug is added, the percentage associated with it is the percentage of the total composition containing the drug, and the percentage of each component in the "pre-drug paste" is based on their proportion before the drug was added. For example, 4% means 4g of drug in 100g of paste. The drug was incorporated using a levigation or mortar and pestle.

[0080] The injectability of a paste depends on many parameters (i.e., needle size, needle length, volume, tissue backpressure, and the strength of the person administering the paste). Typically, it is preferable that the paste is easily drawn into an injector using an 18-14 gauge needle and easily injected into the tissue zone with a small amount of extra pressure using an 18 gauge or smaller needle. However, for specific applications and depending on the needle gauge, a more viscous (i.e., more difficult to inject) paste may be desirable. The polymer compositions described herein can be injected via an 18 gauge line under manual pressure.

[0081] JPEG0007829490000003.jpg42153

[0082] Animal treatment paste injection Using a retrograde approach, the pigs received infusions of a novel gemcitabine formulation into one renal pelvis via cystoscopy and ureteral catheterization. For 24 hours, urine was collected every 3 hours from a urethral catheter bag, and blood was collected via intravenous catheterization. Ultrasonography was performed to monitor for urinary tract obstruction.

[0083] sampling Blood was collected via intravenous catheter and placed in serum tubes at 15 minutes, 1 hour, 4 hours, 8 hours, 12 hours, 18 hours, and 24 hours. The blood was stored in a refrigerator and stabilized with tetrahydrouridine. Urine was continuously collected via a transurethral catheter into a catheter bag at 3-hour intervals up to 24 hours (0-3 hours, 3-6 hours, 6-9 hours, 9-12 hours, 12-15 hours, 15-18 hours, 18-21 hours, 21-24 hours). The urinary gemcitabine was stabilized with tetrahydrouridine and stored in a refrigerator until further processing.

[0084] Ultrasound and nephrectomy Baseline and daily ultrasound examinations were performed to monitor for hydronephrosis. The kidney was removed four days after the administration of gemcitabine paste.

[0085] Analysis method LC-MS / MS for serum and urine sample analysis Liquid chromatography-mass spectrometry (LC-MS) is a well-known method in the field of serum and urine analysis.

[0086] HPLC / UV for tissue extraction experiments Equipment and methods: For the gemcitabine assay used for tissue extraction, the instruments and parameters outlined in Table 2 were used. Calibration curves in the range of 0.75–100 μg / mL were periodically run with samples of unknown concentrations. Calibrators were sequentially diluted from a 1 mg / mL stock solution of gemcitabine in methanol (containing 1% water) using PBS or a 50% water / methanol mixture.

[0087] JPEG0007829490000004.jpg109166

[0088] Sample preparation for tissue extraction Gemcitabine was extracted from tissue samples using a 50 / 50 mixture of water and methanol, rotated, and the supernatant was measured directly.

[0089] Viscosity measurement Paste viscosity was measured using an Anton Parr® MCR72 viscometer. Flow curves were determined using a 25mm parallel plate configuration (measurement system PP25), a 0.5mm gap size, and RheoCompass 1.20® software, with rotational shear rates of 1 to 100 1 / s at ambient temperatures (20 to 25°C). [Examples]

[0090] Example 1: Serum data - PK analysis Non-compartmental analysis was performed using Phoenix64® (Build 6.3.0.395) and WinNonlin 6.3® to calculate the PK parameters of the pig experiment. Concentration and time data are shown in Figure 2. Pharmacokinetic parameters include area under the curve (AUC), area under the first moment curve (AUMC), clearance (Cl / F, for extravascular administration), and maximum observed concentration (c max ), terminal half-life (t 1 / 2 ), terminal rate constant (k el or λ z Table 3 shows the mean residence time (MRT) and volume of distribution (V / F, for extravascular administration). The results indicate that the paste is retained in the renal pelvis, particularly when compared with serum IV data (see Example 4 for further analysis).

[0091] JPEG0007829490000005.jpg58153

[0092] Example 2: Urine Data - PK Analysis Non-compartmental analysis was performed using Phoenix64® (Build 6.3.0.395) and WinNonlin 6.3® to calculate the PK parameters of urine. Concentration and time data are shown in Figure 3. The pharmacokinetic parameters area under the rate of excretion versus midpoint of time interval curve (AURC) and terminal half-life (t) are shown. 1 / 2 ), terminal rate constant (k el or λ z Table 4 shows the maximum excretion rate, the percentage of recovered drug, and the total amount of urine collected.

[0093] JPEG0007829490000006.jpg47153

[0094] Example 3: Tissue Data - Gemcitabine Extraction After nephrectomy, the kidney was incised, and tissues were collected from the upper, middle, and lower parts of the renal pelvis and calyces, from the proximal, central, and distal ureters, and from the bladder. For sorting, tissue samples were placed on droplets of Cryomatrix® and cut into slices with a thickness of 30 μm. Two slices were collected in each of eight tubes to create depth profiles of 0 - 60 μm, 60 - 120 μm, 120 - 180 μm, 180 - 240 μm, 240 - 300 μm, 300 - 360 μm, 360 - 420 μm, and 420 - 480 μm. For tissue extraction, 500 μL of 50 / 5 aqueous methanol was added, the tubes were sonicated with a vortexed tip, rotated, and then the supernatant was measured directly using HPLC / UV. The tissue concentration of the 1-hour exposure tissue was extremely high at 2000 - 8000 μg / g tissue (Figure 4). In the 3-hour exposure tissue, the gemcitabine tissue concentration was approximately 5 - 10 μg / g tissue (Figure 5).

[0095] Example 4: Intravenous Gemcitabine vs. Renal Pelvis Injection When comparing the serum data after gemcitabine injection into the renal pelvis with the serum data after intravenous administration of gemcitabine, there are significant differences in c max , AUC, and the terminal half-life t 1 / 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 from (Liston and Davis 2017; Dy et al. 2005) are listed in Table 5. Using the dose, c(0.5h)=c max , V, and k el , the data were plotted using a one-compartment approximation after the end of injection (0.5 hour) (Figure 6).

[0096] [[ID=于18]]JPEG0007829490000007.jpg58166

[0097] Overall, the renal infusion profile implies sustained absorption of gemcitabine from the renal pelvis into the bloodstream. Since the half-life is extended from 0.2 hours to approximately 4 hours compared to intravenous injection (Liston and Davis 2017; Fogli et al. 2002), it can be assumed that the infused paste supplies gemcitabine to tissues for several hours. While safety assessments did not show the spike observed with intravenous administration at 23,000 ng / mL, overall exposure to gemcitabine is greater (AUC).

[0098] The formulation and procedure were well-tolerated and caused only mild transient hydronephrosis without any clinically significant increase in serum creatinine. Urinary gemcitabine concentrations were highest during the first sampling interval, and 100% of gemcitabine was recovered in the urine within 24 hours. The peak blood concentration of gemcitabine (c max ) was low at 5500 ng / mL, but the terminal half-life (t 1 / 2 The infusion time was 4.1 hours, the mean residence time (MRT) was 6.7 hours, and the total area under the curve (AUC) was 37,800 h·ng / mL, indicating extended drug exposure. One hour after infusion, the formulation was still detectable in the upper urinary tract, and gemcitabine tissue concentrations in the renal calyces, renal pelvis, and ureters at 1 and 3 hours supported this extended drug exposure.

[0099] Preclinical evaluation of a mucosal-adherent formulation of gemcitabine for upper urinary tract infusion showed promising results in terms of tolerability and safety. Administration of this formulation to the renal pelvis results in overall low systemic uptake and locally high and dilated gemcitabine concentrations. Such a pharmacokinetic profile is advantageous for the treatment of upper urothelial malignancies and supports further clinical evaluation.

[0100] Example 5: Preparation of pastes containing various hydrophobic and mucosal-adhering polymers Polymer pastes were prepared according to Tables 6 to 10. The compositions were heated to 60°C without a mucosal adhesive and stirred. Once a homogeneous formulation was obtained, the mucosal adhesive polymer was suspended in the formulation. Next, the homogeneity, viscosity, gelation properties, mucosal adhesion, and injectability of the compositions were observed using lead formulation A as a comparison.

[0101] The polymers PLGA, PLA, and PCL were homogeneously dispersed or dissolved in PEG-based pastes at 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 slightly decreased viscosity. Overall, all pastes had 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.

[0102] JPEG0007829490000008.jpg72166

[0103] JPEG0007829490000009.jpg50166

[0104] JPEG0007829490000010.jpg66166

[0105] JPEG0007829490000011.jpg74166

[0106] JPEG0007829490000012.jpg50166

[0107] JPEG0007829490000013.jpg107166

[0108] Example 6: Mucosal adhesion, mucosal adhesion effect of pastes containing different mucosal adhesion polymers The paste was composed of either 3 wt% of the mucosal adhesive polymer HA, CMC, carbomer, and alginic acid, or a paste without the mucosal adhesive polymer, using 5% PLGA and 92% PEG. Furthermore, pastes with increased amounts of HA were prepared (1%, 2%, 3%, 4%, and 5%). A section of the renal pelvis was excised from frozen pig kidneys and kept moist in PBS (pH 7.4). 250 mg of the preparation was placed on each tissue sample. The sample was covered and kept at 37°C for 5 minutes. The tissue sample was then rinsed with excess water, stained in diluted methylene blue solution for 1 minute, and then rinsed again. At this point, any remaining paste was discarded from the tissue to reveal the level of unstained tissue. Using this method, tissue not covered by the mucosal adhesive paste coating was stained blue.

[0109] All pastes exhibited clear color boundaries on the tissue, with the uncoated periphery staining blue and the paste-coated area coloring the tissue pink. Control tissues (both paste-free and no paste) were completely stained blue (image not shown), and these results are summarized in Table 11, using mucoadhesion scores compared to formulation A.

[0110] Example 7: Drug Release Study: Use of Lead Formulations for Controlled Release of Hydrophilic, Hydrophobic, and Biological Drugs Preparation A, consisting of PLGA 5%, HA 3%, and PEG 92%, was prepared as shown in Table 8. Gemcitabine hydrochloride, docetaxel, or bovine serum albumin (BSA - used as a protein model for biological therapeutic agents) were mixed homogeneously into the paste using a spatula at loads of 1, 0.3, and 1 (respectively) (%w / w) until a completely homogeneous mixture was formed. 100 mg of each preparation was placed in a dialysis cutoff minichamber (Millipore®) with a cutoff of 7000 Da. For protein studies, the minichamber was not closed and a small retaining sponge was applied. The chamber was placed in 5 mL of PBS (PBS containing albumin to increase the solubility of docetaxel or pH 7.4) and placed in an incubator at 37°C. At the specified time, all PBS was removed, and the amounts of gemcitabine and docetaxel in the release medium were quantified using HPLC (isocratic elution at 1 mL / min, wavelengths: 254 nm and 228 nm, retention times: 2.1 min and 7.1 min) or the Bradford test for proteins. All drugs were released from the paste in a controlled manner over 30 hours, as shown in Figure 12. Gemcitabine was released faster than the other two drugs, but all drugs were still being released after 30 hours.

[0111] viscosity The paste was prepared as described in Tables 6 to 10. Using an Anton Parr MCR72® viscometer, RheoCompass 1.20® software, a 25 mm parallel plate geometry (measurement system PP25), and a 0.5 mm gap size, the flow curve (rotational shear rate between 1 and 100 1 / s) was determined at ambient temperature (20-25°C) and analyzed using power-law fit. In another experiment, the paste was hydrated with equal weight of water and equilibrated for 5-10 minutes. Using the same measurement system as above, the viscosity of the gel was determined using vibration at 1 Hz and strain from 0.01 to 100%.

[0112] Measurements were performed using shear rates of 1–100 1 / s and strains of 0.01–100%. For most samples, viscosity was higher at very low stress rates but decreased at higher shear rates or higher stresses. This type of shear thinning may reflect easier injection using higher pressure / shear in the syringe. Viscosity graphs are shown in Figures 7–11, viscosity scores are assigned to the samples, and the results are summarized in Table 11.

[0113] Viscosity of unhydrated samples The addition of 5% PLGA did not affect viscosity at low or high shear rates. However, pastes containing 10% and 15% PLGA had lower viscosity (Figure 11). These data demonstrate that all PLGA-containing pastes function well as injectable pastes. The addition of CMC, carbomer, alginate, or HA (1%, 2%, 3%, 4%, and 5% respectively for 3% load and HA) allowed for a slightly higher viscosity of the paste compared to pastes without mucosal adhesion components, although all values ​​were very similar (Figures 7 and 10). These data demonstrate that the addition of mucosal adhesion components to the paste did not affect its injectability. The addition of carbomer caused a net increase in viscosity, but the paste retained sufficient fluidity to be manipulated with a spatula and filled into syringes for injection or extrusion. With HA, increasing the concentration of this polysaccharide and adding it resulted in little difference in paste viscosity, demonstrating that HA does not affect injectability.

[0114] Viscosity of hydrated sample All hydrated pastes exhibited increased viscosity compared to the unhydrated pastes. These data do not reflect injectability, as the pastes only hydrate after injection. These values ​​(approximately 80,000–100,000 mPa·s) were similar for all pastes under low and high strain, and pastes containing HA, CMC, and carbomer had higher viscosity than the control or alginate paste (Figures 8 and 10). Increasing the amount of HA added increased the viscosity of all pastes in a concentration-dependent manner, under both high and low shear strains.

[0115] While various embodiments of the present invention are disclosed herein, many adaptations and modifications can be made within the scope of the invention according to the common general knowledge of those skilled in the art. Such modifications include substituting any aspect of the invention with known equivalents to achieve substantially the same results in substantially the same manner. Numerical ranges include the numerical values ​​that define the range. The term “comprising” is used herein as an open-ended term substantially equivalent to the phrase “including, but not limited to,” and the term “comprises” has a corresponding meaning. Where used herein, the singular forms “a,” “an,” and “the” include multiple referents unless the context clearly indicates otherwise. Thus, for example, a reference to “one thing” includes two or more such things. Citations of references herein do not constitute an admission that such references are prior art to embodiments of the present invention. The present invention includes substantially all embodiments and modifications described above with reference to the examples and drawings.

[0116] References Athanasiou, K A, G G Niederauer, and C M Agrawal. 1996. “Sterilization, Toxicity, Biocompatibility and Clinical Applications of Polylactic Acid / Polyglycolic Acid Copolymers.” Biomaterials 17 (2): 93-102. http: / / www.sciencedirect.com / science / article / pii / 0142961296857541. Audenet, F, D R Yates, O Cussenot, and M Roupret. 2013. “The Role of Chemotherapy in the Treatment of Urothelial Cell Carcinoma of the Upper Urinary Tract (UUT-UCC).” Urol Oncol 31 (4): 407-13. https: / / doi.org / 10.1016 / j.urolonc.2010.07.016. Bouissou, C, J J Rouse, R Price, and van der C F Walle. 2006. “The Influence of Surfactant on PLGA Microsphere Glass Transition and Water Sorption: Remodeling the Surface Morphology to Attenuate the Burst Release.” Pharmaceutical Research 23 (6): 1295-1305. https: / / doi.org / 10.1007 / s11095-006-0180-2. Dunn, Richard L. 2002. “The Atrigel Drug Delivery System.” In Modified-Release Drug Delivery Technology, 647-55. 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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-Co-Glycolic Acid)(PLGA) and Low Molecular Weight Diblock 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 (1-2): 97-109. https: / / doi.org / http: / / dx.doi.org / 10.1016 / j.ijpharm.2004.06.025. Jain, Rajeev A. 2000. “The Manufacturing Techniques of Various Drug Loaded Biodegradable Poly(Lactide-Co-Glycolide) (PLGA) Devices.” Biomaterials, Orthopaedic Polymeric Biomaterials: Basic Aspects of Biodegradables, 21 (23): 2475-90. https: / / doi.org / 10.1016 / S0142-9612(00)00115-0. Konorty, M., and G. Hakim. 2014 Material and method for treating internal cavities. US 10,471,150. Liston, Dane R., and Myrtle Davis. 2017. “Clinically Relevant Concentrations of Anticancer Drugs: A Guide for Nonclinical Studies.” Clinical Cancer Research. American Association for Cancer Research Inc. https: / / doi.org / 10.1158 / 1078-0432.CCR-16-3083. 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 Carcinomas: A Comprehensive Review of the Current Literature.” European Urology 62 (1): 100-114. https: / / doi.org / 10.1016 / j.eururo.2012.02.030. 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Liquid formulation compositions, medication delivery devices, and methods of preparation and use thereof. WO2016019627.

Claims

1. (a) A polyethylene glycol (PEG) composition comprising (i) a first low molecular weight polyethylene glycol (PEG) having an average molecular weight of about 200 Da to about 500 Da, and (ii) a second low molecular weight polyethylene glycol (PEG) having an average molecular weight of about 500 Da to about 2,000 Da, wherein the second low molecular weight PEG has a higher average molecular weight than the first low molecular weight PEG, comprising about 85% to about 96% by weight. (b) A water-insoluble polymer in an amount of about 2% to about 10% by weight, wherein the water-insoluble polymer is polylactic acid-co-glycolic acid (PLGA), (c) Approximately 2% to 5% by weight of a mucosal adhesive polymer, A composition characterized by containing the following:

2. The composition according to claim 1, wherein the molar ratio of lactic acid monomer to glycolic acid monomer in the PLGA is 90:10 to 50:

50.

3. The composition according to claim 1, wherein the mucosal adhesive polymer is selected from one or more of hyaluronic acid, poly(acrylic acid) and poly(methacrylic acid) derivatives, cyanoacrylate, poly(acrylic acid), sodium carboxymethylcellulose, hydroxypropylcellulose, polycarbophil, chitosan, alginate, gellan, xanthan gum, thiolated poly(acrylic acid), poloxamer, cellulose acetophthalate, ethylcellulose, methylcellulose, hydroxyethylcellulose, poly(amidoamine) dendrimer, poly(dimethylsiloxane), and poly(vinylpyrrolidone).

4. The composition according to claim 1, wherein the mucosal adhesive polymer is hyaluronic acid.

5. The composition according to claim 1, wherein the first low molecular weight PEG is selected from one of PEG200, PEG300, PEG400, and PEG500.

6. The composition according to claim 1, wherein the second low molecular weight PEG is selected from one of PEG500, PEG600, PEG700, PEG800, PEG900, PEG1000, PEG1100, PEG1200, PEG1300, PEG1400, PEG1500, PEG1600, PEG1700, PEG1800, PEG1900, and PEG2000.

7. The composition according to claim 1, further comprising one or more low molecular weight PEGs selected from one or more of PEG200, PEG300, PEG400, PEG500, PEG600, PEG700, PEG800, PEG900, PEG1000, PEG1100, PEG1200, PEG1300, PEG1400, PEG1500, PEG1600, PEG1700, PEG1800, PEG1900, and PEG2000.

8. The composition according to claim 1, wherein the PEG has an average molecular weight of about 200 Da to about 2,000 Da.

9. The composition according to claim 1, further comprising one or more pharmaceutical compounds or pharmaceutically acceptable salts, solvates, or solvates of the salt thereof.

10. The composition according to claim 9, wherein the one or more drug compounds or their pharmaceutically acceptable salts, solvates, or solvates of the salts are selected from one or more of the following categories: anticancer agents, anti-inflammatory agents, antibacterial agents, antiviral agents, antiproliferative agents, antifibrotic agents, anesthetic agents, neuromodulators, and analgesics.

11. The one or more drug compounds or their pharmaceutically acceptable salts, solvates, or solvates of the salts include: (a) actinomycin; all-trans retinoic acid; azacitidine; azathioprine; bleomycin; bortezomib; carboplatin; capecitabine; cisplatin; chlorambucil; cyclophosphamide; cytarabine; daunorubicin; docetaxel; doxifluridine; doxorubicin; epirubicin; epotilon; Anticancer agents selected from one or more of the following: etoposide; fluorouracil; gemcitabine; hydroxyurea; idarubicin; imatinib; irinotecan; mechloretamine; mercaptopurine; methotrexate; mitoxantrone; oxaliplatin; paclitaxel; pemetrexed; teniposide; thioguanine; topotecan; barrubicin; vemurafenib; vinblastine; vincristine; vindesine; and vinorelbine. (b) Gemcitabine hydrochloride, (c) Anesthetic or local anesthetic selected from one or more of the following: procaine; benzocaine; chloroprocaine; cocaine; cyclomethicaine; dimethocaine; pipelocaine; propoxycaine; novocaine; proparacaine; tetracaine; articaine; bupivacaine; cincocaine; etidocaine; levobupivacaine; lidocaine; mepivacaine; prilocaine; ropivacaine; and trimecaine, or (d) The composition according to claim 10, wherein the antimicrobial agent is selected from one or more of the following: penicillin, cephalosporin, polymyxin, rifamycin, ripialmycin, quinolone, sulfonamide, macrolide, lincosamide, tetracycline, aminoglycoside, lipopeptide, glycylcycline, oxazolidinone, ripialmycin, cephalexin, cefazolin, gentamicin, ciprofloxacin, clindamycin, macrodantin, tobramycin, rifampicin, daptomycin, linezolid, vancomycin, fusidic acid, and silver compounds.

12. The composition according to claim 1, wherein the mucosal adhesive polymer has a molecular weight of 50 kDa or more.

13. A pharmaceutical composition comprising the composition according to claim 9, together with a pharmaceutically acceptable diluent or carrier.

14. Use of the composition according to claim 1 for the production of a pharmaceutical product by combining the composition according to claim 1 with a pharmaceutical compound or a pharmaceutically acceptable salt, solvate, or solvate of the salt thereof.

15. The use according to claim 14, wherein the pharmaceutical product is suitable for application to a mucosal surface selected from one or more of the urogenital tract, the gastrointestinal tract, and the respiratory tract.

16. The use of the pharmaceutical product according to claim 14, wherein the pharmaceutical product is suitable for application to a mucosal surface selected from one or more of the kidneys, ureters, bladder, urethra, uterus, vagina, penis, oral cavity, esophagus, stomach, small intestine, large intestine, rectum, anus, nasal cavity, pharynx, larynx, trachea, bronchi, bronchioles, and lungs.

17. The use of the pharmaceutical product according to claim 14, wherein the pharmaceutical product is suitable for the treatment of one or more of cancer, pain, wounds, and inflammation.

18. (a) A polyethylene glycol (PEG) composition comprising (i) a first low molecular weight polyethylene glycol (PEG) having an average molecular weight of about 200 Da to about 500 Da, and (ii) a second low molecular weight polyethylene glycol (PEG) having an average molecular weight of about 500 Da to about 2,000 Da, wherein the second low molecular weight PEG has a higher average molecular weight than the first low molecular weight PEG, comprising about 85% to about 96% by weight. (b) A mucosal adhesive polymer in an amount of about 1% to about 5% by weight, wherein the mucosal adhesive polymer is hyaluronic acid, (c) A composition characterized by comprising polylactic acid-co-glycolic acid (PLGA).

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