Mucosal adhesive polymeric drug delivery compositions and methods

Abstract

The present invention provides compositions for controlled local deposition of one or more drugs within an individual. More specifically, described herein are compositions comprising a) a polyethylene glycol (PEG) composition having a first low molecular weight PEG (Mw of 200-500 Da) and a second low molecular weight PEG (Mw of 500-2000 Da) and b) a mucoadhesive polymer. Alternatively, the compositions can comprise a) a polyethylene glycol (PEG) composition having a first low molecular weight PEG (Mw of 200-500 Da) and a second low molecular weight PEG (Mw of 500-2000 Da), b) a water insoluble polymer and c) a mucoadhesive polymer. In addition, the compositions can further comprise one or more drugs. Also provided are methods of making and administering the compositions described herein, which are used as biodegradable, injectable, mucoadhesive, low viscosity pastes.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Patent Application Serial No. 62 / 971882, filed on February 7, 2020, entitled “Mucosal Adhesive Polymer Drug Delivery Composition and Method”. Technical Field

[0003] This invention relates to biodegradable polymeric low-viscosity pastes suitable for drug delivery. More specifically, this invention relates to injectable mucosal adhesive polymeric low-viscosity pastes comprising a polyethylene glycol (PEG) composition, a water-insoluble polymer, and a mucosal adhesive polymer. Furthermore, the composition may also contain one or more drugs released in a controlled manner. Background of the Invention

[0005] Treatment with local medication injected into the renal pelvis

[0006] Kidney disease and renal dysfunction are often difficult to treat. Most kidney medications require high systemic drug concentrations, which can be associated with side effects such as abnormal glomerular filtration, tubular secretion, or proteinuria. Furthermore, high systemic drug concentrations may not translate into high concentrations in target cells, and drug distribution to the kidneys may be insufficient to meet treatment goals. Therefore, renal-targeted drug delivery is often necessary in the treatment of kidney disease. Untreated or poorly treated kidney disease often requires dialysis, long-term medication, or even kidney transplantation to prolong life.

[0007] Intravesical administration of anticancer drugs reduces the recurrence and progression of bladder cancer. However, delivering drugs to treat malignancies of the renal pelvis and ureter is challenging. Locally applied drugs are washed away by the constant flow of urine through the upper and lower urinary tracts, and surgery is the only radical treatment for urothelial carcinoma of the renal pelvis or ureter.

[0008] Upper urothelial carcinoma

[0009] Urothelial carcinoma (UC) can occur in the lower urinary tract (bladder or urethra) or the upper urinary tract (UUT: renal pelvis and ureter) (Lughezzani et al. 2012). More than 90% of UCs are located in the bladder, and less than 10% occur in the upper urinary tract. Patients with bladder cancer are often diagnosed at an early stage, and the cancer is confined to the superficial urothelial tract. This is partly due to the easy accessibility of diagnostic equipment through the urethra. However, many patients with UTC are not diagnosed early and may have already developed invasive disease. Staging of UTC can also be difficult because the tissue is fragile, with only limited muscle tissue, so biopsies do not always accurately describe the level of disease.

[0010] Once diagnosed, radical nephroureterectomy (RNU) with bladder cuff resection 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 spillage can be a problem with this type of procedure. Furthermore, many patients are not suitable for this treatment. Some patients with low-risk disease may be offered more conservative treatments, such as endoscopic ablation or segmental resection (Lughezzani et al. 2012). Clearly, the prognosis for these UTC patients is poor with subsequent diagnosis. Chemotherapy options are limited for these patients, especially since cisplatin-based regimens are associated with nephrotoxicity, which may be exacerbated when a kidney is removed. Other drugs used to treat bladder cancer, such as mitomycin C and gemcitabine, have better toxicity profiles. When used to treat bladder cancer, these drugs can be delivered intravesical at high concentrations (directly into the bladder), allowing for a 2-hour retention time that enables proper uptake of the drug into the tissue after tumor resection. Recently, docetaxel has been investigated as a chemotherapy option for local treatment of bladder cancer and for systemic delivery of UTC. The combination of gemcitabine and docetaxel is also being investigated as an improvement over using either drug alone (Gitlitz et al. 2003).

[0011] Because UUT tissue cannot be treated locally with drug solutions (the renal pelvis is accessible, but the drug solution will quickly flush into the bladder), a company called UroGen Pharma, Inc. TM The company has developed a device called JELMYTO TM (Mitogel TM This is a gel formulation of mitomycin C. The gel undergoes a heat-reversible gel transformation in vivo, thus allowing it to be injected as a liquid to form a semi-solid gel in the renal pelvis of the kidney. The gel, based on Pranicol, dissolves slowly but allows some of the drug to remain in the tissue at the target site.

[0012] Injectable polymer paste

[0013] Drugs are typically delivered orally or by injection to allow for systemic uptake and circulation to most parts of the body. This route of administration is ideally suited for many drugs, such as insulin for diabetes or statins for heart disease. However, many diseases are localized, and a preferred approach is to deliver the drug directly to the site of action. Examples include analgesics for chronic localized pain, anticancer drugs for localized tumors, and antiarthritis drugs for relieving symptoms of arthritis and joint pain. Therefore, numerous attempts have been made to design locally injectable systems to deliver drugs to specific body sites. This targeted approach also minimizes systemic toxicity typically associated with conventional drug delivery methods. Intravenous delivery of anticancer drugs often causes serious side effects, and systemic toxicity usually limits drug dosage. Local polymeric drug delivery systems can reduce systemic side effects and allow for the delivery of high local doses.

[0014] Poly(DL-lactide-co-glycolic acid) (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 has been used as a drug delivery carrier and scaffold for tissue engineering (Bouissou et al. 2006; Jain 2000). PLGA degradation depends on many factors, including but not limited to the LA / GA ratio, crystallinity, polymer weight-average molecular weight, matrix shape, and the type and amount of drug incorporated (Siegel et al. 2006; Makadia and Siegel 2011). The LA / GA ratio affects degradation, and polymers with higher amounts of the more hydrophilic GA generally degrade faster. The degradation products of PLGA are hydrolysis products LA and GA. Both can enter the citric acid cycle and can be excreted as water and carbon dioxide, or, in the case of GA, primarily excreted unchanged by the kidneys (Makadia and Siegel 2011). Mild toxicities, such as transient inflammation, have been reported in some PLGA-based implants (Athanasiou, Niederauer, and Agrawal 1996), but these may reflect increased exposure time and reduced clearance of degradation products.

[0015] Injectable drug-loaded polymer pastes are attractive for local drug delivery because ultrasound- or MRI-guided systems allow for precise targeting when guiding needle or catheter systems to the target area. Others have described injectable liquids (e.g., Atrigel) consisting of organic solvents such as acetone or polyvinylpyrrolidone and drugs. TM(Dunn 2002) When injected into the body, the liquid solidifies as it dissolves in the solvent. Such systems are flawed because introducing organic solvents into potentially sensitive tissue areas can cause undesirable local toxicity. Local drug delivery systems ranging from drug-loaded polymer coatings on stents, injectable microspheres (Jackson et al. 2007), perivascular membranes (Jackson et al. 2004) to injectable polymer pastes (Jackson et al. 2000) have been described. In these examples, the antiproliferative drug paclitaxel is used to inhibit proliferative events associated with restenosis, cancer, and arthritis. Various polymer formulations for various applications are known in the art (Yu and Ferguson, 2016; Konorty and Hakim, 2014; Pauletti, 2004; and Lughezazzniet et al. 2012).

[0016] Early polymeric paste systems described in the literature were based on blends of polycaprolactone and methoxy polyethylene glycol, which were injectable (molten) at temperatures above body temperature but solidified into implants at 37°C to release the drug (Winternitz et al. 1996). The implants were rigid and brittle, and high-temperature delivery was unsuitable for injection into sensitive sites. Injectable paclitaxel-loaded polymeric pastes made from mixtures of triblock copolymers and methoxy polyethylene glycol were also described, which were injectable at room temperature and formed solid implants in vivo (Jackson et al. 2000). These pastes performed poorly because the release rates of paclitaxel and other hydrophobic drugs were too slow to reach sufficient tissue levels of active drug, and the polymer degradation profile was too long to potentially interfere with follow-up injections. Diblock copolymers containing various compositions in solid (non-paste) microspheres have previously been described (Jackson et al. 2007). In this context, the dissolution of the diblock from the microspheres allows for increased hydrophobic drug release, as well as the openness of the matrix to water and enhanced degradation. Microsphere formulations are entirely different from pastes. They do not flow upon injection and therefore must be injected in a liquid suspension. Consequently, they can be easily dispersed from the target tissue region. Invention Overview

[0018] This invention relates to improved polymeric pastes for controlled drug delivery to mucosa. The compositions described herein allow for the formulation and injection of low-viscosity compositions into an individual, whereby the composition can coat a mucosal surface at a local site and remain at that site for an extended period after initial injection. In one aspect, the invention provides delayed drug release from a polymer-coated delivery system by using selected polyethylene glycol (PEG) compositions, selected water-insoluble polymers, and selected mucosal adhesive polymers to modulate the properties of the polymeric formulation and to regulate the release rate and in-situ residence time of the drug payload. The polymeric compositions can be prepared from simple polymers that form injectable polymeric mucosal adhesive compositions that can release drugs and / or drug combinations in a controlled manner. The invention is based on the surprising discovery that only defined proportions and compositions of polyethylene glycol (PEG), water-insoluble polymers, and mucosal adhesive polymers can be used to efficiently form injectable drug delivery systems with mucosal adhesion for in vivo delivery. The compositions described herein are low-viscosity and only gel after application to an aqueous environment (e.g., which allows injection into hard-to-access areas). The compositions described herein can be injected via long catheter lines without additional equipment, and some of the compositions described herein can be delivered for embolization purposes.

[0019] In a first aspect, a composition is provided comprising: a polyethylene glycol (PEG) composition, said PEG composition being from about 85% to about 96% by weight, and comprising (i) a first low molecular weight PEG (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 an adhesive polymer.

[0020] In another aspect, a composition is provided comprising: a polyethylene glycol (PEG) composition, said PEG composition being from about 85% to about 96% by weight, and comprising (i) a first low molecular weight PEG (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 an adhesive polymer having a molecular weight of ≥50 kDa.

[0021] In a first aspect, a composition is provided comprising: a polyethylene glycol (PEG) composition, said PEG composition being from about 85% to about 99% by weight, and comprising (i) a first low molecular weight PEG (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 an adhesive polymer.

[0022] In another aspect, a composition is provided comprising: a polyethylene glycol (PEG) composition, said PEG composition being from about 85% to about 99% by weight, and comprising (i) a first low molecular weight PEG (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 an adhesive polymer having a molecular weight of ≥50 kDa.

[0023] In another aspect, a composition is provided comprising: a polyethylene glycol (PEG) composition, said PEG composition being from about 85% to about 96% by weight, and comprising (i) a first low molecular weight PEG (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 about 4% to about 15% by weight of an undissolved mucosal adhesive polymer. The composition may further comprise a water-insoluble polymer. Alternatively, the water-insoluble polymer may be from about 2% to about 10% by weight; and the undissolved mucosal adhesive polymer may be from about 2% to about 5% by weight. The mucosal adhesive polymer may have a molecular weight of ≥50 kDa.

[0024] In another aspect, a composition is provided comprising: a polyethylene glycol (PEG) composition, said PEG composition being from about 85% to about 99% by weight, and comprising (i) a first low molecular weight PEG (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 about 4% to about 15% by weight of an undissolved mucosal adhesive polymer. The composition may further comprise a water-insoluble polymer. Alternatively, the water-insoluble polymer may be from about 2% to about 10% by weight; and the undissolved mucosal adhesive polymer may be from about 2% to about 5% by weight. The mucosal adhesive polymer may have a molecular weight of ≥50 kDa.

[0025] In another aspect, a composition is provided comprising: a polyethylene glycol (PEG) composition, said PEG composition being from about 85% to about 99% by weight, and comprising (i) a first low molecular weight PEG (PEG) having an average molecular weight of about 200 Da to about 500 Da, and (ii) a second low molecular weight PEG (PEG) having an average molecular weight of about 500 Da to about 2,000 Da; and about 1% to about 15% by weight of an adhesive polymer having a molecular weight of ≥50 kDa. The composition may further comprise a water-insoluble polymer. Alternatively, the composition may have about 85% to about 96% by weight of the polyethylene glycol (PEG) composition. Alternatively, the composition may have about 4% to about 15% by weight of an adhesive polymer having a molecular weight of ≥50 kDa.

[0026] In another aspect, a composition is provided comprising: a polyethylene glycol (PEG) composition, said PEG composition being from about 85% to about 96% by weight, and comprising (i) a first low molecular weight PEG (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% by weight of an undissolved mucosal adhesive polymer having a molecular weight of ≥50 kDa. The composition may further comprise a water-insoluble polymer.

[0027] In another aspect, a composition is provided comprising: a polyethylene glycol (PEG) composition, said PEG composition being from about 85% to about 96% by weight, and comprising (i) a first low molecular weight PEG (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 undissolved mucosal adhesive polymer. The composition may further comprise a water-insoluble polymer.

[0028] In another aspect, a non-aqueous polymer composition is provided, the composition comprising: (i) low molecular weight (below 500 Da) polyethylene glycol (PEG) or propylene glycol and (ii) higher molecular weight (500-2,000) PEG, and (iii) suspended hyaluronic acid. The composition may also comprise a water-insoluble polymer.

[0029] In another aspect, a non-aqueous polymer composition is provided comprising: (i) a low molecular weight (below 500 Da) polyethylene glycol (PEG) or propylene glycol and (ii) a higher molecular weight (500-2,000) PEG, (iii) a suspended hyaluronic acid and (iiii) a small molecule drug, wherein the composition is injectable by hand pressure through an 18-gauge needle.

[0030] On the other hand, the use of the compositions described herein in the preparation of a medicine is provided.

[0031] On the other hand, the use of the compositions described herein for treating medical conditions treated with medication is provided.

[0032] In another aspect, the use of the compositions described herein for treating mucosal surface areas that benefit from local drug delivery is provided.

[0033] On the other hand, a method for applying a drug to a mucosal surface region is provided, the method comprising: (a) combining the composition described herein with the drug to form a drug-loaded composition, and (b) delivering the drug-loaded composition to the mucosal surface region.

[0034] On the other hand, the compositions described herein are provided for the treatment of medical conditions.

[0035] On the other hand, commercial packaging is provided, which includes: (a) the composition described herein; and (b) instructions for use.

[0036] The pharmaceutical compositions described herein may be combined with pharmaceutically acceptable diluents or carriers.

[0037] The second low molecular weight PEG may comprise up to 20% by weight of the composition. The second low molecular weight PEG may comprise about 5% by weight to about 20% by weight of the composition. The second low molecular weight PEG may comprise about 2% by weight to about 25% by weight of the composition. The second low molecular weight PEG may comprise about 1% by weight to about 30% by weight of the composition.

[0038] The water-insoluble polymer may be selected from one or more of the following: polylactic acid-glycolic acid copolymer (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 acrylate and methacrylate. The molar ratio of lactic acid monomer to glycolic acid monomer may be from 90:10 to 50:50.

[0039] Mucosal adhesive 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 carboxymethyl cellulose (CMC); hydroxypropyl cellulose; polycarbofil; chitosan; alginate; gellan gum; xanthan gum; thiolized poly(acrylic acid); poloxamer; cellulose phthalate acetate; ethyl cellulose; methyl cellulose; hydroxyethyl cellulose; poly(amidoamine) dendrimer; poly(dimethylsiloxane); and poly(vinylpyrrolidone). Mucosal adhesive polymers may be selected from one or more of the following: hyaluronic acid; poly(acrylic acid); carbomer; sodium carboxymethyl cellulose; alginate. Mucosal adhesive polymers may 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 carboxymethyl cellulose (CMC); hydroxypropyl cellulose; polycarbofibril; thiolated poly(acrylic acid); poloxamer; cellulose acetate phthalate; ethyl cellulose; methyl cellulose; hydroxyethyl cellulose; poly(amide amine) dendrimer; poly(dimethylsiloxane); and poly(vinylpyrrolidone).

[0040] 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 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; 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; and PEG 1800. The second low molecular weight PEG is selected from one of the following: PEG500; PEG600; PEG700; PEG800; PEG900; PEG1000; PEG1100; PEG1200; PEG1300; PEG1400; PEG1500; PEG1600; and PEG1700. The second low molecular weight PEG is selected from one of the following: PEG500; PEG600; PEG700; PEG800; PEG900; PEG1000; PEG1100; PEG1200; PEG1300; PEG1400; PEG1500; and PEG1600. 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 of about 200 Da to about 2,000 Da.

[0041] The composition may further comprise 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.

[0042] The composition may comprise one or more pharmaceutical compounds or pharmaceutically acceptable salts, solvates, or solvates of said salts. The one or more pharmaceutical compounds or pharmaceutically acceptable salts, solvates, or solvates of said salts 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; antirestenosis drugs (sirolimus-based drugs and taxane-based drugs); anesthetic drugs; neuromodulatory drugs; and analgesics.

[0043] The one or more pharmaceutical compounds or their pharmaceutically acceptable salts, solvates, or solvates of said salts may be anticancer drugs 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; deoxyfluorouridine; doxorubicin; epirubicin; epothilone; etoposide; fluorouracil; gemcitabine; hydroxyurea; idarubicin; imatinib; irinotecan; nitrogen mustard; mercaptopurine; methotrexate; mitoxantrone; oxaliplatin; paclitaxel; pemetrexed; teniposide; thioguanine; topotecan; penoxuridine; vemurafenib; vincristine; vinblastine; vindesine; and vinorelbine. The drug may be selected from one or more of gemcitabine HCl, gemcitabine, mitomycin, docetaxel, and paclitaxel. The one or more drug compounds or their pharmaceutically acceptable salts, solvates, or solvates of said salts may be anesthetic drugs, and the anesthetic may be a local anesthetic selected from one or more of the following: procaine; benzocaine; chloroprocaine; cocaine; cyclomethicaine; dimethicaine / larocaine; piperacaine; propyloxycaine; procaine / novocaine; promecaine; tetracaine / dicaine; articaine; bupivacaine; cincocaine / debucaine; eticaine; levobupivacaine; lidocaine / linocaine / cerocaine; carbocaine; prilocaine; ropivacaine; and trimethaine.

[0044] The one or more pharmaceutical compounds or their pharmaceutically acceptable salts, solvates, or solvates of said salts can be antibiotic drugs, which may include penicillins, cephalosporins, polymyxins, rifamycins, leptomycins, quinolones, sulfonamides, macrolides, lincosamides, tetracyclines, aminoglycosides, lipopeptides, glycylcyclines, oxazolidinones and leptomycins, cephalexin, cefazolin, gentamicin, ciprofloxacin, clindamycin, nitrofurantoin, tobramycin, rifampin, dapoxetine, linezolid, vancomycin, fusidic acid, silver compounds, cannabinoids, etc. Antibiotic drugs may also include silver and cannabinoids.

[0045] The one or more pharmaceutical compounds or their pharmaceutically acceptable salts, solvates, or solvates of said salts may be antifungal drugs, such as polyenes, azoles, triazoles, antimetabolites, allylamines, and echinocandins. Antifungal drugs may include, for example, but not limited to, amphotericin B, nystatin, clotrimazole, econazole, miconazole, fluconazole, terbinafine, fluconazole, ketoconazole, caspofungin, tolnaftate, ivermectin, flucytosine, and griseofulvin.

[0046] The mucosal surface area may be selected from one or more of the following: the urogenital tract; the gastrointestinal tract; and the respiratory tract. The mucosal surface area may be selected from one or more of the following: the kidney; ureter; bladder; urethra; uterus; vagina; penis; oral cavity; esophagus; stomach; small intestine; large intestine; rectum; anus; sinuses; pharynx; larynx; trachea; bronchi; bronchioles; and lungs. The medical condition may be selected from one or more of the following: cancer; trauma; and inflammation. The drug-loaded composition may be used to treat one or more of the following: cancer; trauma; and inflammation.

[0047] The composition may further comprise a water-insoluble polymer, which may be selected from one or more of the following: polylactic acid-glycolic acid copolymer (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 acrylate and methacrylate. The molar ratio of lactic acid monomer to glycolic acid monomer may be from 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 constitute up to 20% by weight of the composition. The water-insoluble polymer may constitute 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.

[0048] Methods for forming implants in vitro and in vivo using the above-described compositions are provided. In vivo methods include injecting the composition into a site within an individual where a drug-eluting implant can be formed. An injection device containing the compositions described herein is also provided.

[0049] Brief description of the attached figures

[0050] Figure 1 A schematic diagram of gemcitabine paste in the renal pelvis is shown.

[0051] Figure 2 The semi-logarithmic plot of concentration versus time data after gemcitabine paste was applied to the renal pelvis (1000 mg / pig).

[0052] Figure 3 The semi-logarithmic plot (mean plot) shows the amount of gemcitabine excreted (mg) at each collection time interval after the gemcitabine paste was administered to the renal pelvis (1000 mg / pig).

[0053] Figure 4 This indicates the tissue concentration of gemcitabine after application of the gemcitabine paste to the renal pelvis. Kidney tissue was collected 1 hour after in vivo drug exposure (one sample per tissue).

[0054] Figure 5 This indicates the tissue concentration of gemcitabine after application of the gemcitabine paste to the renal pelvis. Kidney tissue was collected 3 hours after in vivo drug exposure (n=4).

[0055] Figure 6 Serum data following administration of gemcitabine HCl (~30 mg / kg) after intravenous administration and after local administration to the renal pelvis: Renal pelvis injection: porcine serum data (exponential fit of measured serum levels, n=3); Intravenous administration: approximations of IV curves using literature pharmacokinetic (PK) parameters derived from 30-minute gemcitabine HCl infusions and a 1-compartment model in 12 patients.

[0056] Figure 7 The viscosity of formulations A, F1, F2, F3, and F4 at ambient temperature is shown in Table 7 before they are mixed with water.

[0057] Figure 8 The viscosity of formulations A, F1, F2, F3, and F4 mixed with water at a 1:1 ratio at ambient temperature is shown in Table 7.

[0058] Figure 9 The viscosity of formulations A, B1, B2, B2, B4, and B5 at ambient temperature is shown in Table 6 before they are mixed with water.

[0059] Figure 10The viscosity of formulations A, B1, B2, B2, B4, and B5 mixed with water at a 1:1 ratio at ambient temperature is shown in Table 6.

[0060] Figure 11 The viscosity of formulations A, E1, E2, and E3 at ambient temperature is shown in Table 10.

[0061] Figure 12 The release of docetaxel, gemcitabine HCl, and albumin from formulation A is shown in Table 8.

[0062] Detailed description of the invention

[0063] This article describes novel formulations that adhere to the renal pelvis and ureter or other mucosa for local delivery of chemotherapeutic agents (e.g., gemcitabine), and we evaluate the feasibility, safety, and pharmacokinetic properties of injectable mucosal adhesive polymer compositions.

[0064] Previous pastes were 50 / 50 PEG 300 / PLGA paste containing 10% gemcitabine and 69 / 31 PEG 300 / PLGA paste containing 5% gemcitabine with 2% sodium hyaluronate. The pastes were safe (in some cases of mild hydronephrosis in pigs) and resulted in low systemic concentrations of gemcitabine. Several improvements were made to the pastes to produce gemcitabine compositions that were easily injectable and exhibited some renal pelvis adhesion without interacting with the ureter.

[0065] The gemcitabine paste composition described herein features a reduced PLGA content, more hyaluronic acid, a combination of PEGs with different molecular weights, and uses gemcitabine HCl instead of gemcitabine.

[0066] The working principle of the compositions disclosed herein is not based on retention through setting, but rather on gelation and mucosal adhesion. A large injection volume of 10 mL can be used to coat the entire renal pelvis. Figure 1 (See the schematic diagram shown). The paste is injected into the renal pelvis through a 5F catheter. After at least 5 minutes, the ureteral catheter is removed, and the paste slowly moves down into the bladder without obstructing the ureter. Due to the mucosal adhesive properties of the paste, the renal pelvis remains coated with the paste, and gemcitabine is continuously released into the tissue.

[0067] In embodiments of the present invention, water-insoluble polymers can be used to control the consistency of biocompatible polymer pastes and subsequently release various drugs therefrom.

[0068] For polymers whose viscosity cannot be directly measured (e.g., PLGA-wax blocks), the polymer is dissolved in a suitable solvent, and the relative viscosity is calculated by 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, usually reported in deciliters per gram (dL / g). IV is simple, inexpensive, and reproducible. Gel permeation chromatography (GPC) can be used as a chromatographic method for measuring molecular size. Molecular size can be expressed as the molecular weight (MW) in Daltons, calibrated using a standard polymer (e.g., polystyrene standards in chloroform). The molecular weight of styrene is 104 Daltons, and polystyrene standards are known to be readily available. The MW obtained by GPC is highly method-dependent and may not be very reproducible between laboratories. Alternatively, molecular weight can be measured by size exclusion chromatography (SEC), high-temperature gel permeation chromatography (HT-GPC), or mass spectrometry (MALDI TOF-MS).

[0069] The water-insoluble polymer can be a polyester. The water-insoluble polymer can be polylactic-co-glycolic acid copolymer (PLGA), wherein the LA:GA ratio is equal to or less than 75:25. The LA:GA ratio can be approximately 50:50. Durect Corporation TM The PLGA used in these experiments are provided, with plots of the specific logarithmic viscosity (IV) (dL / g) in hexafluoroisopropanol (HFIP) versus molecular weight (Daltons) for their 50:50 LA:GA polymers and 65:35 LA:GA polymers. Similarly, when Durect TM When calculating the IV values ​​(dL / g) of 75:25 PLGA and 85:15 PLGA, chloroform was used as the solvent. The relationship between IV and molecular weight (Daltons) varies depending on the LA:GA ratio. As described herein, a specific logarithmic viscosity of 0.15 dL / g to 0.25 dL / g is an optional range, but an IV of 0.25 dL / g to 0.5 dL / g is also suitable. Alternatively, the range could be from about 0.15 dL / g to about 0.5 dL / g.

[0070] Using 0.15 dL / g to 0.25 dL / g, 50:50 PLGA 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 0.15 dL / g to 0.25 dL / g, 65:35 PLGA is approximately equivalent to a range of about 6,500 Da to about 14,200 Da, and a range of 0.25 to 0.5 dL / g is approximately equivalent to a range of about 14,200 Da to about 39,000 Da. The wider range of 0.15 dL / g to 0.5 dL / g corresponds to 50:50 PLGA of about 4,300 Da to about 26,600 Da and 65:35 PLGA of about 6,500 Da to about 39,000 Da. Therefore, the range of PLGA can be any value between 4,300 Da and approximately 39,000 Da. Alternatively, if 75:25 is used, the range of PLGA can be any value between 4,300 and approximately 40,000 or higher (i.e., molecular weights up to 56,500 Da). For 50:50, 65:35, and 75:25 LA:GA polymers, an IV of 0.5 dL / g approximately corresponds to molecular weights of 26,600, 39,000, and 56,500, respectively. As tested, Durect with an IV of 0.25 dL / g... TM 50:50 is approximately 6,700 Da, with an IV concentration of 0.47 dL / g. TM 75:25 is approximately 55,000 Da and has a Durecton concentration of 0.55 dL / g to 0.75 dL / g. TM 85:15 is approximately 76,000 Da to approximately 117,000 Da.

[0071] PLGA pastes having a 50:50 LA:GA ratio and an IV (i.e., a molecular weight of 4,300 Da to 6,700 Da) of 0.15 dL / g to 0.25 dL / g are of particular interest. However, PLGA pastes having a 50:50 LA:GA ratio and an IV (i.e., a molecular weight of about 6,700 Da to about 26,600 Da) of 0.25 dL / g to 0.5 dL / g are also useful.

[0072] The molecular weight of PLGA polymers can be reported as a specific logarithmic viscosity (IV). IV can be 0.15–0.5 dL / g. PLGA polymer IV can be <0.3 dL / g. IV can be 0.15–0.25 dL / g. Mild heating can completely miscible low molecular weight forms of PLGA with a 50:50 LA:GA ratio and a specific logarithmic viscosity below 0.3 dL / g with low molecular weight biocompatible diols to form viscous or flowable pastes at room temperature.

[0073] The drug delivery compositions described herein can be 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.

[0074] The drug delivery compositions described herein can release one or more drugs over time periods of hours or months as needed. The compositions described herein can be used to locally deliver one or more drugs to an individual. Examples of drugs that can be delivered using these compositions are not limited and may include anticancer drugs; anti-inflammatory agents; antibacterial drugs; antiviral drugs; antifungal drugs; antiproliferative drugs; antifibrotic drugs; anti-restenosis drugs (sirolimus-based and taxane-based drugs); anesthetic drugs; neuromodulatory drugs; and analgesics, depending on one or more conditions being treated or improved. Other examples are drugs for treating neurological conditions, and drugs for treating gastrointestinal conditions such as diverticulosis and peptic ulcers. The compositions described herein are suitable for any drug that benefits from adhesion to mucosal tissue surfaces and / or prolonged release from a paste implant.

[0075] Examples of anticancer drugs that can 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 agents); bicalutamide, enzalutamide, ivermectin, tamoxifen, sunitinib, and erlotinib. Anticancer biological agents can also be used in formulations, such as antibody-based therapies like Herceptin, Avastin, Erbitux, or radiolabeled antibodies or targeted radiotherapy, such as PSMA-radioligands.

[0076] Anti-inflammatory agents may include acetaminophen and nonsteroidal drugs such as ibuprofen, acetylsalicylic acid, naproxen, diclofenac, meloxicam, as well as steroids such as prednisone.

[0077] Local analgesics or local anesthetics may include one or more of the following, for example: procaine; benzocaine; chloroprocaine; cocaine; cyclomethicaine; dimethicaine / larocaine; piperocaine; propyloxycaine; procaine / novocaine; propylmecaine; tetracaine / dicaine; articaine; bupivacaine; cincocaine / debucaine; eticaine; levobupivacaine; lidocaine / linocaine / cerocaine; carbocaine; prilocaine; ropivacaine; and trimethaine.

[0078] Antibiotics may include penicillins, cephalosporins, polymyxins, rifamycins, leptomycins, quinolones, sulfonamides, macrolides, lincosamides, tetracyclines, aminoglycosides, lipopeptides, glycylcyclines, oxazolidinones and leptomycins, cephalexin, cefazolin, gentamicin, ciprofloxacin, clindamycin, nitrofurantoin, tobramycin, rifampin, dapoxetine, linezolid, vancomycin, fusidic acid, silver compounds, cannabinoids, etc.

[0079] Examples of antifungal drugs include polyenes, azoles, triazoles, antimetabolites, allylamines, and echinocandins. Antifungal drugs may include, for example but not limited to, amphotericin B, nystatin, clotrimazole, econazole, miconazole, fluconazole, terbinafine, fluconazole, ketoconazole, caspofungin, tolnaftate, ivermectin, flucytosine, and griseofulvin.

[0080] The drug can be hydrophobic or hydrophilic. Specific drugs can be selected from one or more of the following: docetaxel; ivermectin; bicalutamide; cephalexin; sunitinib; tamsulosin; deoxymethasone; gemcitabine; rapamycin; and ibuprofen.

[0081] Drug delivery compositions can be prepared and used to treat or prevent a variety of diseases or conditions, particularly those at or near the mucosal tissue site. Examples of treatable diseases or conditions 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 aforementioned renal pelvis. The paste can be applied to any mucosal surface or moist tissue area for local drug delivery. Particularly important is its ability to treat the interior of the GI tract, such as cancer, trauma (e.g., ulcers), or inflammation (e.g., inflammatory bowel disease: ulcerative colitis, Crohn's disease). The paste can also be applied with medication to treat or fill inflamed diverticula. Diseases of the oral cavity, vagina, and rectal region can be treated. Topical application of hyaluronic acid is used to prevent surgical adhesions; therefore, an improvement could be made by using this paste and including an anti-adhesion medication. Trauma and postoperative pain may be suitable indications.

[0082] As used herein, “mucosal tissue” or “mucosa” refers to the membrane that lines the various cavities within the body (i.e., the urogenital tract; the gastrointestinal tract; and the respiratory tract) and covers the surface of internal organs. Mucosa consists of one or more layers of epithelial cells lining connective tissue. The urogenital tract includes the kidneys, ureters, 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.

[0083] As used herein, “mucosal adhesive polymer” means any polymer that has the property of causing the polymer to adhere to a mucosal surface. Such polymer is preferably biocompatible. Mucosal adhesive polymers may be selected from one or more of the following: hyaluronic acid (HA); poly(acrylic acid) and poly(methacrylic acid) derivatives; cyanoacrylates; poly(acrylic acid) (carbomer); sodium carboxymethyl cellulose (CMC); hydroxypropyl cellulose; polycarbofil; chitosan; alginate; gellan gum; thiolized poly(acrylic acid); poloxamer; cellulose phthalate acetate; ethyl cellulose; methyl cellulose; hydroxyethyl cellulose; poly(amidoamine) dendrimer; poly(dimethylsiloxane); and poly(vinylpyrrolidone) (Roy et al. 2009). As described herein, HA is generally not used as a dispersion in non-aqueous coagulation. Furthermore, the compositions described herein contain a proportion of PEG such that the HA does not settle at certain temperatures. 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 carboxymethyl cellulose; hydroxypropyl cellulose; polycarbofer; chitosan; alginate; gellan gum; thiolized poly(acrylic acid); poloxamer; cellulose phthalate acetate; ethyl cellulose; methyl cellulose; hydroxyethyl cellulose; poly(amide amine) dendrimer; poly(dimethylsiloxane); and poly(vinylpyrrolidone).

[0084] Furthermore, as described in this article, PEGs are combined to tailor formulations for specific applications (e.g., long catheter lines) and for stability (e.g., storage, no sedimentation) and disintegration properties, because PEGs with higher MW have lower water solubility.

[0085] As used herein, “water-insoluble polymer” means any polymer that is insoluble in water. Such polymer is preferably biocompatible. The water-insoluble polymer may be selected from one or more of the following: polylactic acid glycolic acid copolymer (PLGA); poly(ε-caprolactone) (PCL); and polylactic acid (PLA). Alternatively, the water-insoluble polymer may be a copolymer of acrylates and methacrylates.

[0086] As used herein, "polylactic acid glycolic acid copolymer" (PLGA) is a copolymer having the following structure PLGA is a copolymer of lactic acid and glycolic acid, where "x" represents the number of lactic acid (lactide) subunits and "y" represents the number of glycolic acid (glycolic acid) subunits. Different forms of PLGA can be obtained depending on the ratio of lactide to glycolide used in polymerization: these are typically determined by the molar ratio of the monomers used (e.g., PLGA 75:25 is defined as a copolymer of 75% lactic acid and 25% glycolic acid). A suitable molar ratio can be any value between 90:10 and 50:50. This ratio can typically affect 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) to fully degrade.

[0087] When used, PLGA can be from 2% to approximately 20% by weight. The IV for PLGA 50 / 50 is approximately 0.15 dL / g, but an IV of 0.25 dL / g for 65 / 35 PLGA is also useful. 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 be from approximately 90:10 to approximately 50:50.

[0088] As used herein, depending on its molecular weight, "polyethylene glycol" (PEG) or polyethylene oxide or polyethylene oxide is a substance having the following structure The polyether compounds. The first low molecular weight PEG used herein may be selected from one of the following: PEG 100; PEG 200; PEG 300; PEG 400; and PEG 500. A second low molecular weight PEG also exists, which is 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. The PEG compositions described herein may further comprise 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 1400; PEG 1500; PEG 1600; PEG 1700; PEG 1800; PEG 1900; and PEG 2000. 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.

[0089] The polyethylene glycol (PEG) used in this article 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. PEG may have an average molecular weight of about 100 Da to about 1,450 Da. PEG may have an average molecular weight of about 100 Da to about 2,000 Da. PEG may have a molecular weight of about 300 Da to about 1,450 Da. Polyethylene glycol (PEG) can have molecular weights of about 300 Da to about 500 Da and about 500 Da to about 2000 Da.

[0090] Alternatively, instead of PEG, suitable compositions containing propylene glycol or glycerin can be used, or they can be used in combination with PEG.

[0091] Local anesthetics are generally classified into two categories: aminoamides and amino esters. Most local anesthetics have the suffix "-caine". Local anesthetics in the amino ester group can be selected from one or more of the following: procaine; benzocaine; chloroprocaine; cocaine; cyclomethicaine; dimethicaine / larocaine; piperocaine; propyloxycaine; procaine / novocaine; prilocaine; and tetracaine / dicaine. Local anesthetics in the aminoamide group can be selected from one or more of the following: articaine; bupivacaine; cincocaine / debucaine; eticaine; levobupivacaine; lidocaine / linocaine / cerocaine; carbocaine; prilocaine; ropivacaine; and trimethaine. Combinations of local anesthetics (e.g., lidocaine / prilocaine or lidocaine / dicaine) can also be used.

[0092] In addition, injectable local anesthetics can be mixed with vasoconstrictors to increase residence time, and the maximum dose of local anesthetics can be higher when used in combination with vasoconstrictors (e.g., prilocaine hydrochloride and epinephrine; lidocaine, bupivacaine and epinephrine; lidocaine and epinephrine; or articaine and epinephrine).

[0093] Anticancer drugs that can be used in the compositions described herein can be classified as alkylating agents (bifunctional and monofunctional), anthracyclines, cytoskeleton disruptors, epothilone, topoisomerase inhibitors (I and II), kinase inhibitors, nucleotide analogs and prodrug analogs, peptide antibiotics, platinum-based agents, vinca alkaloids, and retinoids. Alkylating agents can be bifunctional alkylating agents (e.g., cyclophosphamide, nitrogen mustard, chlorambucil, and melphalan) or monofunctional alkylating agents (e.g., dacarbazine (DTIC), nitrosourea, and temozolomide). Examples of anthracyclines are daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, and pentorubicin. Cytoskeleton disruptors or taxanes are paclitaxel, docetaxel, abraxane, and taxotere. Epothilone can be epothilone or a related analogue. Histone deacetylase inhibitors can be vorinostatin or romidesin. Inhibitors of topoisomerase I may include irinotecan and topotecan. Inhibitors of topoisomerase II may include etoposide, teniposide, or tafluposide. Kinase inhibitors may be selected from bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, or vemodigine. Nucleotide analogs and pro-analytes may be selected from azacitidine, azathioprine, capecitabine, cytarabine, deoxyfluorouridine, 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 retinoic acid, irinotecan, or bexarotin. Vinca alkaloids and derivatives may be selected from vinblastine, vincristine, vinorelbine, and vinorelbine.

[0094] Anticancer drugs that can be used 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; deoxyfluorouridine; doxorubicin; epirubicin; epothilone; etoposide; fluorouracil; gemcitabine; hydroxyurea; idarubicin; imatinib; irinotecan; nitrogen mustard; mercaptopurine; methotrexate; mitoxantrone; oxaliplatin; paclitaxel; pemetrexed; teniposide; thioguanine; topotecan; penoxuridine; vemurafenib; vincristine; vinblastine; vindesine; and vinorelbine. Alternatively, anticancer drugs can be biological agents and can be selected from Herceptin (trastuzumab), Ado-trastuzumab, lapatinib, neratinib, pertuzumab, Avastin, Erbitux, or radiolabeled antibodies or targeted radiotherapy, such as PSMA radioligand. Anticancer drugs can be androgen receptor, estrogen receptor, epidermal growth factor receptor (EGFR) antagonists, or tyrosine kinase inhibitors (TKIs). Anti-angiogenic agents can be selected from Avastin, epidermal growth factor receptor (EGFR) antagonists, or tyrosine kinase inhibitors (TKIs). Immunomodulators such as BCG (Bacillus Calmette-Guérin) can also be used.

[0095] As used herein, "medicine" refers to any therapeutic component, including small molecules and biological agents (e.g., proteins, peptides, nucleic acids). Furthermore, biological agents include antibodies and antigens. As used herein, the term "medicine" in some embodiments may include any therapeutic component or a subset of therapeutic components. For example, but not limited to one or more potentially overlapping subsets and one or more medicines, such as: hydrophobic medicines, hydrophilic medicines; cancer treatment medicines; local anesthetics; antibacterial medicines; antiviral medicines; anti-inflammatory medicines; pain medicines; antiproliferative medicines; antifibrotic medicines; or any medicine that may benefit from local and / or sustained release.

[0096] The term "antibody" as used in this article refers to polypeptides belonging to the immunoglobulin superfamily. Specifically, "antibody" includes immunoglobulin molecules or immunologically active fragments of immunoglobulin molecules (i.e., molecules containing antigen-binding sites), immunoglobulin heavy chains (alpha (α), mu (μ), delta (δ), or epsilon (ε)) or their variable domains (VH domains), immunoglobulin light chains (kappa (κ) or lambda (λ)) or their variable domains (VL domains), or polynucleotides encoding immunoglobulin molecules or immunologically active fragments of immunoglobulin molecules. Antibodies include single-chain antibodies (e.g., immunoglobulin light chains or immunoglobulin heavy chains), 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 in this article, "antigen" refers to any epitope-binding fragment and any polynucleotide (DNA or RNA) encoding any of the above.

[0097] As used herein, "paste" means any composition described herein that has both solid and liquid properties depending on the applied load and temperature. Specifically, the viscosity of the paste can be any injectable viscosity at room temperature and can be measured by any number of methods known to those skilled in the art. Many types of viscometers and rheometers are known in the art. For example, Anton Paar... TM , MCR 502 or MCR72 rheometer.

[0098] method

[0099] Paste preparation

[0100] For example, Table 1 provides the formulation of a basic paste for the renal pelvis.

[0101] The paste is prepared by weighing the polymer into a glass vial and stirring at 60°C. When the polymer forms a homogeneous melt, a mucosal adhesive polymer is added. If a drug is to be added, it is added after the preparation of the polymer paste. The value of the paste polymer (i.e., about 85% to about 96% by weight of a polyethylene glycol (PEG) composition comprising (i) a first low molecular weight polyethylene glycol (PEG) and (ii) optionally a second low molecular weight polyethylene glycol (PEG), wherein the average molecular weight of the first low molecular weight PEG and the second low molecular weight PEG is about 100 Da to about 1,500 Da; about 2% to about 10% by weight of a water-insoluble polymer; and about 2% to 5% by weight of a mucosal adhesive polymer) is prepared as a total % of 100%. When a drug is added, the associated % is the percentage of the total composition containing the drug, and the "pre-drug paste" component % is based on their proportions before the drug is added. For example, 4% means 4 grams of drug in 100 grams of paste. Use a water mill or mortar and pestle to mix in the medicine.

[0102] The injectability of a paste will depend on many parameters (i.e., needle gauge, needle length, volume, tissue back pressure, and the strength of the person applying the paste). Generally, it is preferred that the paste be easily aspirated into a syringe using an 18- to 14-gauge needle, and easily injected into the tissue area with a small amount of additional pressure using an 18-gauge needle or even smaller. However, for specific applications and depending on the needle gauge, a more viscous paste (i.e., more difficult to inject) may be desirable. The polymer compositions described herein can be injected by hand through an 18-gauge needle.

[0103] Table 1: Exemplary base pastes for injection into the renal pelvis.

[0104] polymer percentage(%) PEG 300 78 PEG 1000 14 Polylactic-co-glycolic acid copolymer (PLGA) 5 Hyaluronic acid (HA) (>1800kDa) 3

[0105] Animal program

[0106] Paste injection

[0107] Using a retrograde approach, the new formulation of gemcitabine was injected into a renal pelvis of the pig via cystoscopy and a ureteral catheter. Urine was collected from the catheter bag at 3-hour intervals over 24 hours, and blood was collected via an intravenous catheter. Ultrasound was performed to monitor for urinary tract obstruction.

[0108] sampling

[0109] Blood samples were collected from the intravenous catheter at 15 minutes, 1 hour, 4 hours, 8 hours, 12 hours, 18 hours, and 24 hours and collected in serum tubes. The blood was stored in a refrigerator and stabilized with tetrahydrouridine. Urine was continuously collected in a catheter bag at 3-hour intervals up to 24 hours via a transurethral catheter (0-3h, 3-6h, 6-9h, 9-12h, 12-15h, 15-18h, 18-21h, 21-24h). The urine was stabilized with gemcitabine with tetrahydrouridine and stored in a refrigerator until further processing.

[0110] Ultrasound and nephrectomy

[0111] Baseline and daily ultrasound scans were performed to monitor hydronephrosis. The kidney was removed on day 4 following the injection of gemcitabine paste.

[0112] Analytical methods

[0113] LCMS / MS for serum and urine sample analysis

[0114] Liquid chromatography-mass spectrometry (LC-MS) methods for serum and urine analysis are known in the art.

[0115] HPLC / UV for tissue extraction experiments

[0116] Instruments and methods:

[0117] The gemcitabine assay for tissue extracts uses the instruments and parameters outlined in Table 2. For samples of unknown concentration, routine calibration curves are run from 0.75 μg / mL to 100 μg / mL. The calibrator is serially diluted from a 1 mg / mL stock solution of gemcitabine in methanol (containing 1% water) using PBS or a 50% water / methanol mixture.

[0118] Table 2: HPLC / UV instrument and parameters used for gemcitabine HCl analysis.

[0119] pump Waters 1525 Binary HPLC Pump Automatic sampler Waters 717 Plus Autosampler column <![CDATA[Waters C-18 TM ,Nova-Pak,4μm,3.9x150mm]]> detector <![CDATA[Waters 2489 TM UV / Visible Light Detector Flow rate 1mL / min Column temperature Ambient temperature, no temperature control Injection volume 20μL Washout isotropic mobile phase <![CDATA[92.5% ammonium acetate buffer 1 > 6% methanol 1.5% acetonitrile Retention time 2.5min wavelength 254nm (dual 220nm) diluent for standard products PBS 7.4

[0120] 1 The ammonium acetate buffer solution consisted of ammonium acetate (M = 77 g / mol), 1.542 g / L water, and pH adjusted to 6.3 with approximately 3.6 mL of 85% phosphoric acid.

[0121] Sample preparation for tissue extraction

[0122] Gemcitabine was extracted from tissue samples using a 50 / 50 mixture of water and methanol, centrifuged, and the supernatant was measured directly.

[0123] Viscosity measurement

[0124] Using Anton Parr TMThe viscosity of the paste was determined using an MCR72 viscometer. A parallel plate with a 25mm geometry and a 0.5mm gap (PP25 measurement system) and a RheoCompass 1.20 were used. TM Rheological profiles were determined using rotational shear rates of 1–100 1 / s at ambient temperatures (20–25 °C). Example

[0125] Example 1: Serum Data-PK Analysis

[0126] To calculate the PK parameters for the pig experiments, Phoenix 64 was used. TM (Build 6.3.0.395)WinNonlin 6.3 TM Perform non-compartmental analysis. Concentration versus time data are shown below. Figure 2 In the middle. Pharmacokinetic parameters: area under the curve (AUC), area under the curve of first moment (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 The mean residence time (MRT) and volume of distribution (V / F, for extravascular administration) are shown in Table 3. The results show that the paste remained in the renal pelvis, especially when compared with serum IV data (see further analysis example 4).

[0127] Table 3: Non-atrioventricular PK parameters of serum data after gemcitabine paste injection into the renal pelvis.

[0128]

[0129]

[0130] Example 2: Urine Data - PK Analysis

[0131] To calculate the PK parameters of urine, Phoenix 64 was used. TM (Build 6.3.0.395)WinNonlin 6.3 TM Perform non-compartmental analysis. Concentration versus time data are shown below. Figure 3 In the pharmacokinetic parameters, the area under the midpoint of the excretion rate versus time interval curve (ΔURC), and the terminal half-life (t) are considered. 1 / 2 ), terminal rate constant (k el or λ z The maximum excretion rate (rate max), the percentage of drug recovered (recovered), and the total urine volume collected are shown in Table 4.

[0132] Table 4: Non-atrioventricular PK parameters of urine data after gemcitabine paste is injected into the renal pelvis.

[0133] parameter unit numerical values <![CDATA[AURC 0-inf ]]> mL·μg / mL 873583.2±132794.4 <![CDATA[t 1 / 2(终末) ]]> h 2.1±0.6 <![CDATA[k el ]]> 1 / h 0.35±0.1 rate max μg / h 279857.1±105042.8 Recycled ％ 107.3±29.2 Total urine volume mL 1230.3±145.9

[0134] Example 3: Extraction of Gemcitabine from Tissue Data

[0135] Following nephrectomy, the kidney is incised, and tissue is collected from the upper, middle, and lower parts of the renal pelvis and calyces, from the proximal, middle, and distal ureters, and from the bladder. For sectioning, the tissue samples are fixed in a Cryomatrix. TM Droplets were placed on the sample and sliced ​​into 30 μm thick sections. Two sections were collected from each of eight tubes to produce depth distributions of 0–60, 60–120, 120–180, 180–240, 240–300, 300–360, 360–420, and 420–480 μm. For tissue extraction, 500 μL of a 50 / 50 methanol / water solution was added, the tube tip was sonicated and rotated, and the supernatant was directly measured using HPLC / UV. The tissue concentration for 1-h-exposed tissue was very high, ranging from 2000–8000 μg / g tissue. Figure 4 For tissues exposed for 3 hours, the tissue concentration of gemcitabine is approximately 5-10 μg / g tissue. Figure 5 ).

[0136] Example 4: Renal pelvis injection vs. intravenous gemcitabine

[0137] When comparing serum data after gemcitabine injection into the renal pelvis with serum data after intravenous administration of gemcitabine, in c max AUC and terminal half-life t 1 / 2 Significant differences existed between them. To illustrate these differences, a representative dataset for intravenous administration was modeled using data from Liston et al. (Liston and Davis 2017) and compared with an extravascular dataset. Reference values ​​from (Liston and Davis 2017; Dy et al. 2005) are listed in Table 5. After infusion (0.5 h), the dose, c(0.5 h) = c max V and k el To plot data using a 1-compartment approximation ( Figure 6 ).

[0138] Table 5: Literature PK parameters for gemcitabine (IV) infusion over 30 minutes and current experimental PK parameters for gemcitabine paste injection into the renal pelvis.

[0139] parameter unit numerical values dose <![CDATA[1250mg / m 2 (32.1mg / kg)]]> 1000mg / pig (26.4mg / kg) <![CDATA[c max ]]> 23500ng / mL 5532ng / mL <![CDATA[AUC 0-inf ]]> 12500 ng·h / mL 37839 ng·h / mL <![CDATA[t 1 / 2(终末) ]]> 0.23h 4.12h Clear <![CDATA[25.9L(V ss )]]> <![CDATA[4.5L / kg(V d )]]> <![CDATA[k el ]]> 3.18 1 / h 0.18 1 / h

[0140] In summary, the renal injection profiles indicate that gemcitabine is continuously absorbed from the renal pelvis into the bloodstream. It can be assumed that the injected paste delivers gemcitabine to tissues over several hours, as the half-life is prolonged from 0.2 hours to approximately 4 hours compared to intravenous administration (Liston and Davis 2017; Fogli et al. 2002). In terms of safety assessment, the peak concentration of 23,000 ng / mL observed with intravenous administration was not present, but the total exposure to gemcitabine (AUC) was significantly higher.

[0141] The formulation and procedure were well tolerated and caused only mild, transient hydronephrosis without a clinically relevant increase in serum creatinine. Urinary gemcitabine concentrations were highest during the first collection interval, with 100% of gemcitabine recovered in urine within 24 hours. Peak serum concentrations of gemcitabine (c...) max The concentration was low, at 5500 ng / mL, but prolonged, with a terminal half-life (t). 1 / 2 The mean residence time (MRT) was 4.1 hours, the total area under the curve (AUC) was 6.7 hours, and the total area under the curve (AUC) was 37,800 h·ng / mL. One hour after infusion, the formulation remained detectable in the upper urinary tract, and tissue concentrations of gemcitabine in the renal calyces, renal pelvis, and ureter at 1 and 3 hours supported this prolonged drug exposure.

[0142] Preclinical evaluation of a mucosal adhesive formulation of gemcitabine administered intravenously into the upper urinary tract showed promising results regarding tolerability and safety. Administration of this formulation to the renal pelvis resulted in high, prolonged local gemcitabine concentrations and low overall systemic uptake. Such pharmacokinetic profiles are favorable for the treatment of upper urinary tract malignancies and support further clinical evaluation.

[0143] Example 5: Preparation of pastes with polymers possessing various hydrophobic and mucosal adhesion properties.

[0144] Prepare the polymer paste according to Table 6-10. In the absence of a mucosal adhesive, heat the composition to 60°C and stir. Once a homogeneous formulation is obtained, suspend the mucosal adhesive polymer in the formulation. Then, use lead formulation A as a control to observe the homogeneity, viscosity, gelling properties, mucosal adhesion, and injectability of the composition.

[0145] Polymers PLGA, PLA, and PCL were uniformly dispersed or dissolved in PEG-based pastes with varying degrees of opacity. The addition of CMC, HA, or alginate had little effect on viscosity, and all pastes became cloudy due to the presence of suspended solids. Increasing the amount of PLGA resulted in a slight decrease in viscosity. In summary, except for the addition of carbomer (which caused a significant increase in viscosity), all pastes had viscosities very similar to formulation A. These compositions and results are summarized in Table 11.

[0146] Table 6. Compositions of formulations with different mucosal adhesives

[0147]

[0148] 1 50:50 Poly(DL-lactic acid-co-glycolic acid) (IV 0.15-0.25 dL / g)

[0149] 2 MW molecular weight

[0150] Table 7. Compositions of formulations containing increased amounts of hyaluronic acid

[0151]

[0152] 1 50:50 Poly(DL-lactic acid-co-glycolic acid) (IV 0.15-0.25 dL / g)

[0153] 2 MW molecular weight

[0154] Table 8. Compositions of formulations with different drugs

[0155]

[0156] 1 50:50 Poly(DL-lactic acid-co-glycolic acid) (IV 0.15-0.25 dL / g)

[0157] 2 MW molecular weight

[0158] Table 9. Compositions of formulations with different hydrophobic polymers

[0159]

[0160]

[0161] 1 50:50 Poly(DL-lactic acid-co-glycolic acid) (IV 0.15-0.25 dL / g)

[0162] 2 MW molecular weight

[0163] 3 PCL (poly(ε-caprolactone))

[0164] 4 PLA (polylactic acid)

[0165] Table 10. Compositions of formulations containing increased amounts of hydrophobic polymers

[0166]

[0167] 1 50:50 Poly(DL-lactic acid-co-glycolic acid) (IV 0.15-0.25 dL / g)

[0168] 2 MW molecular weight

[0169] Table 11. Observations on homogeneity, viscosity, gelation, mucosal adhesion, and injectability of the composition compared to composition A.

[0170]

[0171]

[0172] 1 1 = similar uniformity, - = less uniformity

[0173] 2 1 = similar viscosity, + = more viscous, - = less viscous

[0174] 3 1 = Similar gelling properties, + = More gel, - = Less gel

[0175] 4 1 = similar adhesion, + = more adhesive, - = less adhesive 5 1 = similar injectability, + = easier injectability, - = more difficult injectability

[0176] Example 6: Mucosal adhesion, the mucosal adhesion effect of pastes containing different mucosal adhesion polymers.

[0177] Pastes containing 3% by weight of the mucosal adhesion polymers HA, CMC, carbomer, alginate, or no mucosal adhesion polymers, and containing 5% PLGA and 92% PEG, were prepared. Additionally, pastes with increased amounts of HA (1%, 2%, 3%, 4%, 5%) were prepared. Several fragments of renal pelvis were excised from frozen porcine kidneys and kept moist with PBS (pH 7.4). 250 mg of the preparation was placed on top of each tissue sample. The sample was covered and held at 37°C for 5 minutes. The tissue samples were then rinsed with excess water and stained in a dilute methylene blue solution for 1 minute, followed by rinsing again. At this point, any remaining paste was scraped off the tissue to reveal the level of unstained tissue. Using this method, any tissue not covered by the mucosal adhesion paste coating was stained blue.

[0178] All the pastes showed clear color demarcations on the tissue, with the outer edges of the unpainted areas stained blue and the paste-covered areas stained pink. Control tissues (pastes without paste or without mucosal adhesive polymers) were completely stained blue (image not shown); however, these results are summarized in Table 11 using mucosal adhesion scores compared to formulation A.

[0179] Example 7: Drug Release Study: Application of Lead Formulations for Controlled Release of Hydrophilic, Hydrophobic, and Biologic Drugs

[0180] Formulation A, comprising PLGA 5%, HA 3%, and PEG 92%, was prepared as described in Table 8. Gemcitabine HCl, docetaxel, or bovine serum albumin (BSA – used as a protein model for biotherapy) were added to the paste using a spatula at loadings of 1% w / w, 0.3% w / w, and 1% w / w, respectively, until a completely homogeneous mixture was formed. 100 mg of each formulation was placed in a dialysis cutoff chamber (Millipore) with a cutoff of 7000 Da. TM For protein studies, do not seal the chamber; instead, use a small retention sponge. Place the chamber in 5 mL of PBS (pH 7.4 or PBS containing albumin to increase docetaxel solubility) and incubate at 37°C. At specified time points, remove all PBS and quantify the amounts of gemcitabine and docetaxel in the release medium using HPLC (isocratic elution at 1 mL / min, wavelengths: 254 nm and 228 nm, retention times: 2.1 min and 7.1 min), or for proteins, use the Bradford assay. Figure 12 As shown, all drugs were released from the paste in a controlled manner over 30 hours. Gemcitabine was released faster than the other two agents, but all drugs were still being released over 30 hours.

[0181] Viscosity

[0182] The paste was prepared as described in Table 6-10. Anton Parr MCR72 was used. TM Viscometer, Software: RheoCompass 1.20 TM Rheological curves (rotational shear rates of 1–100 1 / s) were determined using parallel plates with a 25 mm geometry (PP25 measurement system) and a 0.5 mm gap dimension at ambient temperature (20–25 °C) and analyzed using power-law fitting. In separate experiments, the gel was hydrated with an equal weight of water and kept equilibrated for 5–10 minutes. The viscosity of the gel was determined using the same measurement system as described above, with oscillation at 1 Hz and strain ranging from 0.01% to 100%.

[0183] Determinations were performed using shear rates from 1 to 100 1 / s and strains from 0.01 to 100%. For most samples, viscosity was high at very low stress rates but decreased at higher shear rates or higher stresses. This type of shear thinning can be reflected in easier injection using higher pressure / shear in a syringe. Viscosity plots are shown in... Figure 7-11 As shown, viscosity scores are given for the samples and summarized in Table 11.

[0184] Viscosity of non-hydrated samples

[0185] Adding 5% PLGA had no effect on viscosity at low or high shear rates. However, at 10% and 15% PLGA loadings, the paste was less viscous. Figure 11 These data indicate that all pastes containing PLGA function well as injectable pastes. The addition of CMC, carbomer, alginate, or HA (each at 3% loading and HA also individually at 1, 2, 3, 4, and 5%) allows for slightly higher paste viscosity compared to pastes without mucosal adhesive components, but all values ​​are very similar. Figure 7 and Figure 10 These data indicate that adding a mucosal adhesion component to the paste does not affect injectability. Although the addition of carbomer resulted in a net increase in viscosity, the paste remained sufficiently fluid to be handled with a spatula, suggesting it can be loaded into a syringe for injection or extrusion. With HA, adding an increased concentration of this polysaccharide resulted in almost no difference in paste viscosity, indicating that HA has no effect on injectability.

[0186] Viscosity of hydrated samples

[0187] Compared to the undiluted paste, all hydrated pastes exhibited increased viscosity. These data do not reflect injectability, as the paste only becomes hydrated after injection. These values ​​(approximately 80,000 to 100,000 mPa·s) are similar for all pastes at both low and high strains; pastes containing HA, CMC, and carbomer exhibit higher viscosity than the control or alginate pastes. Figure 8 and Figure 10 Adding an increased amount of HA resulted in a concentration-dependent increase in the viscosity of all pastes under both high and low shear strain conditions.

[0188] Although various embodiments of the invention have been disclosed herein, many modifications and alterations can be made within the scope of the invention based on common knowledge to those skilled in the art. Such modifications include replacing any known equivalents of any aspect of the invention to achieve the same results in substantially the same manner. Numerical ranges include the numbers that define the range. The word “comprising” is used herein as an open-ended term, substantially equivalent to the phrase “including but not limited to,” and the word “comprises” has the corresponding meaning. As used herein, the singular forms “a,” “an,” and “the” include plural indicators unless the context clearly specifies otherwise. Thus, for example, a reference to “thing” includes more than one such thing. References cited herein are not an admission that these references are prior art to embodiments of the invention. The invention includes all embodiments and variations substantially as described above and with reference to the embodiments and drawings.

[0189] References

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Claims

1. A composition comprising: (a) 85% to 96% by weight of a polyethylene glycol (PEG) composition comprising: (i) a first low molecular weight polyethylene glycol (PEG) having an average molecular weight of 200 Da to 500 Da, and (ii) a second low molecular weight polyethylene glycol (PEG) having an average molecular weight higher than that of the first low molecular weight PEG and being 500 Da to 2,000 Da. (b) 2% to 10% by weight of a water-insoluble polymer, wherein the water-insoluble polymer is selected from one or more of the following: polylactic acid glycolic acid copolymer (PLGA), poly(ε-caprolactone) (PCL), and polylactic acid (PLA); and (c) 2% to 5% by weight of a mucosal adhesive polymer.

2. The composition of claim 1, wherein the water-insoluble polymer is PLGA.

3. The composition of claim 1, wherein the water-insoluble polymer is PLGA, and wherein the molar ratio of lactic acid monomer to glycolic acid monomer is 90:10 to 50:

50.

4. The composition of claim 1, wherein the mucosal adhesive polymer is selected from one or more of the following: hyaluronic acid; poly(methacrylic acid); cyanoacrylate; poly(acrylic acid); sodium carboxymethyl cellulose; hydroxypropyl cellulose; polycarbofibril; chitosan; alginate; gellan gum; xanthan gum; thiolized poly(acrylic acid); poloxamer; cellulose phthalate acetate; ethyl cellulose; methyl cellulose; hydroxyethyl cellulose; poly(amide amine) dendrimer; poly(dimethylsiloxane); and poly(vinylpyrrolidone).

5. The composition of claim 1, wherein the mucosal adhesive polymer is hyaluronic acid.

6. The composition of claim 1, wherein the first low molecular weight PEG is selected from one of the following: PEG200; PEG300; PEG400; and PEG500.

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

8. The composition of claim 1, wherein the PEG composition further comprises one or more low molecular weight PEGs 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.

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

10. The composition of claim 1, further comprising one or more pharmaceutical compounds or pharmaceutically acceptable salts, solvates, or solvates of said salts.

11. The composition of claim 10, wherein the one or more pharmaceutical compounds thereof or a pharmaceutically acceptable salt, solvate, or solvate of the 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 drugs; neuromodulatory drugs; and analgesics.

12. The composition of claim 10, wherein the one or more pharmaceutical compounds or their pharmaceutically acceptable salts, solvates, or solvates of said salts are anticancer drugs 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; deoxyfluorouridine; doxorubicin; epirubicin; epothilone; etoposide; fluorouracil; gemcitabine; hydroxyurea; idarubicin; imatinib; irinotecan; nitrogen mustard; mercaptopurine; methotrexate; mitoxantrone; oxaliplatin; paclitaxel; pemetrexed; teniposide; thioguanine; topotecan; penoxuridine; vemurafenib; vincristine; vinblastine; and vinorelbine. The drug mentioned is gemcitabine HCl. The one or more pharmaceutical compounds thereof, or pharmaceutically acceptable salts, solvates, or solvates of said salts, are anesthetic drugs, said anesthetic drugs being local anesthetics selected from one or more of the following: procaine; benzocaine; chloroprocaine; cocaine; cyclomethicaine; dimethicaine; piperocaine; propyloxycaine; novocacaine; promecaine; tetracaine; articaine; bupivacaine; cincocaine; eticaine; levobupivacaine; lidocaine; carbocaine; prilocaine; ropivacaine; and trimethaine, and The one or more pharmaceutical compounds thereof, or pharmaceutically acceptable salts, solvates, or solvates of said salts, are selected from one or more of the following antimicrobial agents: penicillins, cephalosporins, polymyxins, rifamycins, leptomycins, quinolones, sulfonamides, macrolides, lincosamides, tetracyclines, aminoglycosides, lipopeptides, glycylcyclines, oxazolidinones and leptomycins, cephalexin, cefazolin, gentamicin, ciprofloxacin, clindamycin, nitrofurantoin, tobramycin, rifampin, dapoxetine, linezolid, vancomycin, fusidic acid, and silver compounds.

13. The composition of claim 1, wherein the mucosal adhesive polymer has a molecular weight of ≥ 50 kDa.

14. A pharmaceutical composition comprising the composition of claim 10 and a pharmaceutically acceptable diluent or carrier.

15. Use of the composition of claim 1 in the preparation of a medicament for delivering a pharmaceutical compound to a mucosal surface region, wherein the composition of claim 1 is combined with a pharmaceutical compound to form a drug-loaded composition, and the drug-loaded composition is delivered to the mucosal surface region.

16. The use as claimed in claim 15, wherein the mucosal surface region is selected from one or more of the following: the urogenital tract; the gastrointestinal tract; and the respiratory tract.

17. The use as described in claim 15, wherein the mucosal surface region is selected from one or more of the following: kidney; ureter; bladder; urethra; uterus; vagina; penis; oral cavity; esophagus; stomach; small intestine; large intestine; rectum; anus; sinus; pharynx; larynx; trachea; bronchus; bronchioles; lung.

18. The use as described in claim 15, wherein the drug-loaded composition is used to treat one or more of the following: cancer; pain; trauma; and inflammation.

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