Improved localized therapeutic delivery system based on two-stage microparticles.

Abstract

A system for delivering a therapeutic agent to a site within a mucosal tissue or to the skin of a patient is disclosed. The system includes a porous mucoadhesive lyophilized matrix formed by a composition comprising chitosan in an aqueous salt solution of a chloride salt of a monovalent cation. The system further includes a plurality of chitosan microparticles having an average diameter of 500 nm to 2000 nm and comprising a therapeutic agent.

Description

[Technical field]

[0001] Related Patent Cross-References This application claims priority to U.S. Provisional Patent Application No. 63 / 195,469, filed June 1, 2021, which is incorporated by reference in its entirety and for all purposes. [Background technology]

[0002] Cancers that affect the mucous membranes of the body are of growing public health concern. Oral cancer alone affects more than 640,000 people annually worldwide and more than 40,000 in the United States. Its incidence is rising due to the rise in cancer-causing oral HPV disease. Treatment methods include surgery and intravenously administered systemic chemotherapy, often in combination. Surgery is often ineffective due to the difficulty in identifying the margins surrounding oral tumors. This inability to completely remove the tumor through surgery contributes to the high recurrence rate of oral cancer. Although systemic chemotherapy is frequently used, it is not targeted and exposes the patient's entire body to harmful chemotherapy. This method can be dose-limited due to exposure in the bloodstream and other organs, and precautions must be taken to consider the safety of this systemic exposure. Systemic delivery often results in harmful side effects from toxic drugs reacting with the body. These side effects include neurotoxicity, nephrotoxicity, renal failure, hair loss, nausea, and mucositis.

[0003] Furthermore, oral cancer is one of the most debilitating diseases. After surgical removal of oral tumors, permanent disfigurement can occur. A patient's ability to eat, drink, and speak properly after surgery may also be impaired or impossible. For some of these reasons, oral cancer is considered the most costly cancer to treat.

[0004] Emotional side effects also speak to the particularly tragic and debilitating impact of oral cancer compared to other cancers and diseases. The emotional toll on oral cancer patients can be far greater than that of other diseases, primarily due to the physical deformities (including physical disfigurement and lack of clear speech) that result from treatment. These consequences of traditional treatments for oral cancer demonstrate this unmet need and why alternative treatments are desperately needed to address patient suffering.

[0005] Anal cancer accounts for 2.5% of all digestive malignancies in the United States, with approximately 8,000 new cases diagnosed annually. The incidence of anal cancer in the general population has increased over the past 30 years. Furthermore, colorectal cancer (CRC) is a common and deadly disease. It is estimated that approximately 134,490 new cases of CRC are diagnosed annually in the United States, including approximately 95,270 cases of colon cancer and 39,220 cases of rectal cancer. This cancer remains the third leading cause of cancer death in the United States. Approximately 49,190 Americans are expected to die from CRC each year.

[0006] One of the differences between colorectal and anal cancer is the risk factors that contribute to each. The main risk factors for colorectal cancer include age, genetics, race, diabetes, obesity, lack of physical activity, and smoking. On the other hand, the main cause of anal cancer is the increasing prevalence of human papillomavirus (HPV).

[0007] All of these cancers, namely oral, colon, and anal cancers, can be treated with cisplatin, a platinum-containing drug with broad-spectrum antitumor activity. This drug is an alkylating agent and is used to treat solid tumors such as testicular, ovarian, bladder, and epithelial malignancies, as well as esophageal, lung, and head and neck cancers. After entering the target cell by diffusion, water is replaced by one or more chlorine atoms, giving it a positive charge, and the resulting positively charged complex reacts with DNA to inhibit DNA replication. However, the nature of cisplatin makes it susceptible to hydrolysis. The addition of sodium chloride can improve the chemical stability of cisplatin and reduce this risk. Improved methods of delivering cisplatin to treat oral, anal, and colon cancers are needed. The present invention satisfies this need, as well as others. Summary of the Invention

[0008] In one embodiment, the present invention provides a system for delivering cisplatin to a site of mucosal tissue, the system comprising: a porous, mucoadhesive, lyophilized polymer matrix having opposing first and second surfaces; and a plurality of microparticles, the matrix being formed by a composition comprising chitosan in an aqueous solution of a chloride salt of a monovalent cation, the chloride salt having a concentration of about 10% to 18% by weight, the microparticles comprising chitosan and having an average diameter of 500 nm to 2000 nm, the microparticles being embedded within the matrix such that they are immediately surrounded by and in contact with the matrix, the microparticles containing cisplatin. In this embodiment, (i) the first surface of the matrix is ​​configured to adhere to the site of mucosal tissue; (ii) the matrix is ​​configured to release the microparticles through the first surface when the first surface of the matrix is ​​adhered to the site of mucosal tissue; and (iii) the microparticles are configured to release cisplatin.

[0009] In another embodiment, the present invention provides a system comprising a polymer matrix comprising chitosan and a plurality of microparticles, each of which comprises chitosan, about 10-18% (w / w) chloride salt of a monovalent cation, and a therapeutic agent, wherein the average diameter of the microparticles is between 500 nm and 2000 nm.

[0010] In another embodiment, the chloride salt of the monovalent cation is selected from the group consisting of NaCl, KCl, LiCl, RbCl, CsCl, NHCl, and combinations thereof. Optionally, the chloride salt of the monovalent cation is NaCl. Also optionally, the aqueous solution of the chloride salt of the monovalent cation includes propylene glycol at a concentration of about 5% to about 25% by weight. Further optionally, the aqueous solution of the chloride salt of the monovalent cation includes hydroxypropylmethylcellulose (HPMC) at a concentration of about 0.1% to about 10% by weight. In yet another related embodiment, the aqueous solution of the chloride salt of the monovalent cation includes sucralose at a concentration of about 0.1% to about 30% by weight. In yet a further related embodiment, the microparticles are present in the matrix at a concentration of about 10 to about 40% by weight. Optionally, the system further includes a water-permeable backing layer affixed to the matrix.

[0011] In another embodiment, the present invention provides a method of administering a therapeutic agent to a subject in need thereof, the method comprising applying a system of the present invention to the subject such that at least 50% of the therapeutic agent in the system is released from the system in less than 30 minutes.

[0012] In another embodiment, the present invention provides a method for preparing a system of the present invention, the method comprising: preparing a base mixture by forming a first mixture including water, chitosan, a chloride salt, a hydration enhancer, a particle adhesion inhibitor, and a particulate aggregation inhibitor; forming a second mixture comprising the matrix mixture, a first platinum antineoplastic agent, and chitosan microparticles comprising a second platinum antineoplastic agent; removing water from the second mixture to prepare a dry mixture; and Applying the dry mixture to a backing layer, thereby preparing a system.

[0013] In another embodiment, the present invention provides a method for preparing a system of the present invention, the method comprising: forming a first mixture comprising water, chitosan, and acetic acid; forming a second mixture comprising a chloride salt, a therapeutic agent, and sodium tripolyphosphate; forming a third mixture comprising said first mixture and said second mixture, thereby forming microparticles; forming a fourth mixture comprising water, chitosan, acetic acid, a hydration enhancer, and a particle adhesion inhibitor; forming a fifth mixture comprising the fourth mixture, a particle agglomeration inhibitor, and the particulates to form a polymer matrix; removing water from the polymer matrix to form a dry mixture; and applying said dry mixture to a backing layer, thereby preparing the system of the present invention.

[0014] In another embodiment, the present invention provides a method of treating a skin disorder in a subject in need thereof, comprising applying a system of the present invention to the skin of the subject such that a therapeutically effective amount of a therapeutic agent of the system is released from the system and administered to the skin of the subject, thereby treating the skin disorder.

[0015] In another embodiment, the present invention provides a method of treating mucosal cancer, the method comprising the step of applying a system of the present invention to a mucosal cancer in a subject in need thereof, thereby treating said mucosal cancer. [Brief description of the drawings]

[0016] The foregoing features of the embodiments will be more readily understood by reference to the following detailed description taken in conjunction with the accompanying drawings, in which:

[0017] [Figure 1]Figure 1 shows how it is known in the art that the presence of sodium chloride in a solution containing cisplatin improves the stability of cisplatin as an anti-cancer therapeutic by avoiding premature hydrolysis outside the cell. Stable cisplatin enters the cell membrane and then hydrolysis within the cell allows for DNA damage and cell necrosis as described above.

[0018] [Diagram 2] FIG. 2 is a photograph of cisplatin-containing patches made with sodium chloride concentrations of 0%, 5%, 10%, 12%, 15%, 18%, 20%, 22%, 25%, 28%, and 30% (as printed), and shows cracks that occurred at the higher concentrations.

[0019] [Diagram 3] Figure 3 shows the changes in the properties of cisplatin-containing patches due to the presence of sodium chloride, which complicate the optimization of the resulting patches. In one embodiment of the present invention, the addition of NaCl to the formulation improved the chemical stability of the active agent, cisplatin. However, this change caused some challenges and unexpected problems, such as the occurrence of physical damage to the patch after drying, increased stiffness of the patch that is unsuitable for topical application, reduced cationic surface charge of the particles, and reduced mucoadhesion and cellular uptake.

[0020] [Figure 4] FIG. 4 is a set of graphs showing the in vitro dissolution profiles of patches made with varying sodium concentrations from 0% to 35%.

[0021] [Diagram 5] Figure 5 is a set of bar graphs showing the percent release of drug from patches when applied to tissue based on 0% and 18% sodium chloride concentrations in the patch. Release was greater and more reproducible with the addition of NaCl than without (18% NaCl: 92% release, standard deviation 3.2% vs. 0% NaCl: 65% release, standard deviation 12%).

[0022] [Figure 6] 6 is a set of bar graphs showing particulate charge data obtained for various concentrations of NaCl in the patch ranging from 0% to 35%. There is a linear trend between the amount of NaCl present and the drop in charge.

[0023] [Figure 7] FIG. 7 shows two bar graphs depicting biodistribution data comparing tumors and lymph nodes treated with patches containing 18% sodium chloride by weight and patches without sodium chloride.

[0024] [Figure 8] Figures 8A and 8B show application of the patch to the buccal mucosa: Figure 8A is a photograph showing application of the patch to the buccal mucosa, and Figure 8B is a photograph showing application of the patch to a mucosal lesion in the anterior two-thirds of the tongue.

[0025] [Figure 9] Figure 9 shows two plots of the percentage of tumor volume reduction as a function of time for the use of patches containing 18% NaCl and patches without NaCl, with the patches containing NaCl showing a more rapid response and a greater reduction than the patches without NaCl.

[0026] [Figure 10] FIG. 10 shows that the patch 10 includes a layer 12 having opposing first and second surfaces, and a backing layer 14 adjacent one of the surfaces.

[0027] [Figure 11] Figure 11 shows the treatment of a patient for only one week. This patient had a T4 tumor. Per protocol, two patches were used to attempt to cover the tumor with each patch. This treatment reduced the tumor volume by over 50%, as shown in the before and after photos.

[0028] [Figure 12]Figures 12A-C show human data using nanotechnology to treat moderate psoriasis with appropriate patches during outpatient treatments three times per week. Figure 12A shows an untreated patient. Figure 12B shows a patient after three treatments. Figure 12C shows a patient after six treatments.

[0029] [Figure 13] FIG. 13 shows the release rate of carboplatin particles from a system of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] I. Overview The present disclosure describes a patch for the treatment of skin diseases and mucosal cancers with a therapeutic agent delivered from the patch comprising about 18% sodium chloride by weight.

[0031] II. Definition As used in this description and the accompanying claims, unless the context otherwise requires, the following terms shall have the meanings indicated below.

[0032] A "set" includes at least one component.

[0033] "Microparticles" are the set of particles having an average diameter of at least 200 nm and up to 2000 nm.

[0034] "Nanoparticles" are the set of particles having an average diameter of at least 1 nm and less than 200 nm.

[0035] "Matrix" refers to a polymer matrix that is composed primarily of polysaccharide polymers. The matrix may be a porous matrix, a portion of its volume being interstitial space. In some cases, the interstitial space may be passable from the outer surface of the matrix, such that material present in the interstitial space, such as particulates, may migrate to and from the outer surface.

[0036] "Mucooadhesive" refers to a material characterized as having the ability to adhere to mucous membranes within the human body.

[0037] "Chitosan" refers to a polysaccharide of β-1,4-d-glucosamine and N-acetyl-d-glucosamine with an average molecular weight of approximately 3.8 to 20 kDa. "Pure chitosan" is chitosan that is not a chitosan salt.

[0038] "Chloride salt" refers to an organic or inorganic salt having a chloride anion. Representative chloride salts include sodium chloride and potassium chloride.

[0039] "Monovalent cation" refers to a positively charged ion with a valence capable of forming one covalent bond. Examples include alkali metals (sodium, potassium, etc.), ammonium, quaternary ammonium, etc.

[0040] "Hydration enhancer" refers to an additive that increases water absorption and acts as a cryoprotectant during the manufacturing process.

[0041] "Particle adhesion inhibitor" refers to an additive that reduces the attractive forces between a polymer matrix and particles embedded therein. As a result, the particles can pass through the matrix at a higher velocity than they would be able to in the absence of the adhesion inhibitor.

[0042] As used herein, "polydispersity index" (PDI) or simply "dispersion" refers to a measure of the heterogeneity of size of particles in a mixture. PDI measures the size distribution of nanoparticles.

[0043] "Zeta potential" (ZP) as used herein refers to the overall charge that a particle acquires in a particular medium and can be measured with a Zetasizer nano instrument.

[0044] "Particle size" is the length of the longest axis between two points on the surface of a particle.

[0045] "Biocompatibility" refers to the ability of a biomaterial to perform its desired function in relation to a medical therapy that does not induce significant undesirable local or systemic effects in the recipient or beneficiary of that therapy, but rather generates the most appropriate beneficial cellular and tissue response in that particular situation, and optimizes the clinically relevant performance of that therapy.

[0046] "Hydroxypropyl methylcellulose" (HPMC) refers to a nonionic polymer represented by the following structure: [ka]

[0047] "Biodegradable" refers to the property of a material that can be broken down by the action of living organisms, especially into harmless products.

[0048] "Tissue" in the context of embodiments of the present invention refers to organs, epithelia, mucosa, or other tissues present within areas such as the abdomen, pelvis, intraperitoneal cavity, and / or other intraperitoneal surfaces.

[0049] "Surgical cavity" refers to a cavity, opening, site, or tissue surface resulting from surgical removal of tissue.

[0050] "Fast", "fast release", or "fast delivery" in reference to release from a patch refers to release of 20% to 100% of the effective loading of the patch within about 20 minutes.

[0051] "Kilocounts / second" or "Kcps" means count rate (in thousands of counts per second). For example, a threshold can be set to stop the measurement if the count rate of the sample is below 100, i.e., the concentration of the sample is too low for measurement. A sample with an appropriate Kcps can be considered a stable sample with an acceptable concentration for measurement.

[0052] "Mesh" refers to an article, sponge, wafer, etc. that has elements embedded therein that are released through the mesh when applied to a mucous membrane.

[0053] A "polymer matrix and microparticle based therapeutic agent delivery system" may also be referred to as a "drug delivery element" or "delivery patch."

[0054] Unless otherwise specified, the term "wt %" or "% (wt / wt)" refers to the amount of a component of a system for delivery of a therapeutic agent as expressed as a percentage by weight.

[0055] Unless otherwise specified, the "molar mass" of a polymer is intended to mean the number-average molar mass of the polymer molecules.

[0056] "Particle agglomeration inhibitor" refers to an additive that reduces the tendency of particles embedded in a matrix to agglomerate when the matrix is ​​frozen. As a result, the particles are less likely to be damaged or destroyed when freezing occurs.

[0057] "Monosaccharide" refers to the simplest sugars that form the building blocks of more complex forms of sugar. Representative compounds include glucose, fructose, and galactose.

[0058] "Disaccharide" refers to a sugar compound that contains two monosaccharides joined by a glycosidic bond. Representative compounds include sucrose, lactose, and maltose.

[0059] "Sugar alcohol" refers to a compound produced by the reduction of a sugar compound to an alcohol.

[0060] "Chlorinated monosaccharide" refers to a monosaccharide compound that is substituted with at least one chlorine atom.

[0061] "Chlorinated disaccharide" refers to a disaccharide compound substituted with at least one chlorine atom.

[0062] "Sucralose" refers to a chlorinated disaccharide represented by the following structure: [ka]

[0063] "Embedded in a matrix" refers to the state or structure of one or more particles that are directly surrounded by and in contact with the matrix.

[0064] "Directly surrounded by and in contact with" refers to the state or structure of one or more particles that are encapsulated or encased in another substance or material (e.g., a matrix) such that the entire outermost layer of the particle or particles is in direct contact with the surrounding material.

[0065] "Sodium tripolyphosphate" refers to a compound represented by the following structure: [ka]

[0066] "Water-permeable backing layer" refers to a material that is permeable, or at least substantially permeable, to the passage of water.

[0067] "Surface" refers to a particular region or site on a particle that is considered the outermost portion of the particle. Surface may also refer to a region or site that contains reactive sites or species that allow the particle to interact with its surroundings. The surface of a particle may also act as a barrier to one or more layers that are underneath or surrounded by the outermost layer.

[0068] "Polyacrylate adhesive" refers to an adhesive material made from polyacrylates (acrylic polymers), for example, adhesive materials made from monomer esters such as acrylic acid and methacrylic acid. Examples of polyacrylic acid based adhesives are identified as product numbers 87-4098, 87-2287, 87-4287, 87-2516, 87-2051, 87-2052, 87-2054, 87-2196, 87-9259, 87-9261, 87-2979, 87-2510, 87-2353, 87-2100, 87-2852, 87-2074, 87-2258, 87-9085, 87-9301, and 87-5298 manufactured by National Starch (Product Bulletin, 2000, DURO-TAK.RTM. is a trademark of National Starch adhesives).

[0069] "Nonwoven polyester fabric" refers to a fabric made from an assemblage of polyester fibers. The fibers may or may not usually be bonded to one another and may be staple or continuous.

[0070] "Treat", "treating", and "treatment" refer to any indication of success in curing or ameliorating an injury, pathology, condition, or symptom (e.g., pain), including objective or subjective parameters such as relief of symptoms; remission; reduction or making the symptom, injury, pathology, or condition tolerable to the patient; reduction in the frequency or duration of the symptom or condition; or, in some circumstances, prevention of the onset of the symptom.

[0071] "Mucosal tissue" refers to tissue that has an associated mucosa. In particular, mucosal tissue includes mucosa and tissue underlying the mucosa. For example, a "mucosal tissue site" where a cancerous tumor is present may involve not only the mucosa but also the tissue underlying the mucosa. Representative mucosal tissue includes the oral cavity.

[0072] "Mucosal cancer" refers to cancer of the mucosal cells and includes oral cavity, nasopharyngeal, tongue, gastrointestinal, colon, anal, and laryngeal cancer.

[0073] "Tumor" refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. As used herein, "neoplasia" refers to any form of dysregulated or misregulated cell growth, whether malignant or benign, resulting in abnormal tissue growth. Thus, "neoplastic cells" include malignant and benign cells with dysregulated or misregulated cell growth.

[0074] A "therapeutically effective amount or dose" or a "therapeutically sufficient amount or dose" or an "effective or sufficient amount or dose" refers to a dose that produces the therapeutic effect for which it is administered. The exact dose depends on the purpose of the treatment and is recognizable to those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). The therapeutically effective dose in sensitized cells is often lower than the traditional therapeutically effective dose in non-sensitized cells.

[0075] A "subject" or "patient" refers to an animal, such as a mammal, including, but not limited to, a primate (e.g., a human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, etc. In certain embodiments, the subject is a human.

[0076] "Therapeutic agent" refers to a compound, peptide, antibody, or cell that is useful and effective in treating a disease or disorder, such as a skin disease.

[0077] "Release," "released," or "releasing" refers to the transfer of a therapeutic agent from the patch of the present invention to a subject or patient.

[0078] "Skin disease" refers to a disease or disorder that primarily manifests on the skin of a subject.

[0079] "Mucosal cancer" refers to cancer that appears primarily in the mucosa, including but not limited to the oral cavity, vagina, and rectum.

[0080] III. System The device or system of the invention includes drug-loaded particles that are comprised of a polymer having a therapeutic, prophylactic, diagnostic, or nutraceutical agent dispersed or encapsulated therein. Optionally, the particles may include a chemical linker that can attach a targeting ligand and / or additional drug to the particle. The device includes these particles and preferably a permeation enhancer.

[0081] The device or system can be administered orally via tablets, capsules, liquids, syrups, gelatins, or other oral consumables, or via a nasogastric or feeding tube to individuals unable to swallow, and exhibits properties that allow the drug encapsulated in the particle to remain stable in the variable acidic environment of the stomach. The device can deliver drug-loaded particles (also called "loading particles," "LPS") to epithelial cells in the gastrointestinal (GI) tract. These particles can adhere to the intestinal mucosa and degrade to release the encapsulated drug directly into the intestinal epithelium.

[0082] The particles (preferably with an average diameter of 500-2000 nm) penetrate the mucosal tissue of the intestine, and this size is suitable for transporting sufficient therapeutic, diagnostic, or nutraceutical agents to obtain high loading and encapsulation efficiency (greater than 80%), which is desirable for scale-up and commercialization.

[0083] Encapsulation of therapeutic, diagnostic, and / or nutritional agents allows for controlled penetration into mucosa through the means of targeting ligand addition and sustained release properties. In addition, in the case of systemic penetration, encapsulation also reduces uptake by the body's reticuloendothelial system. Smaller particles have a greater surface area to volume ratio, resulting in faster particle dissolution rates than larger particles.

[0084] For many drugs, solubility factors limit delivery. The high surface area to volume ratio of the particles enhances bioadhesion. Combining these factors allows the drug to penetrate deeper into intestinal stem cells (ISCs) for greater benefit.

[0085] There are three main aspects of targeting that operate to achieve localized delivery. 1. Electrostatic charge: Positively charged polymers may be used in the synthesis of the particles contained in this delivery system. The resulting devices exhibit a positive charge that attracts the drug-loaded particles to the negatively charged mucosa of the intestine. 2. Activity: Activity is gained using molecular targeted agents to further focus on intestinal stem cells (ISCs). 3. PH: The particles in the compositions of the present invention can be modified to remain stable or release in a varying pH environment. This decision is made during the synthesis process. Release is targeted by synthesizing particles that encapsulate the drug in the highly acidic environment of the stomach and promote release in the more basic environment of the intestine. These parameters may be modified to include release in a more acidic environment or a combination. These parameters may also be modified to allow release in both the stomach and the intestine. Additionally, different doses and different drug combinations are also possible. Figure 22C shows an example of a particle that is released as the pH approaches a neutral level.

[0086] The present disclosure describes a patch for the treatment of oral cancer that uses a platinum antineoplastic agent stabilized with about 18% sodium chloride by weight in the patch.

[0087] In some embodiments, the present invention provides a system comprising a polymer matrix comprising chitosan and a plurality of microparticles, each of which comprises chitosan, a chloride salt of a monovalent cation having a concentration of about 10-18% (w / w) of the polymer matrix, and a therapeutic agent, wherein the microparticles have an average diameter of 500 nm to 2000 nm.

[0088] As shown in FIG. 10, patch 10 includes layer 12 having opposing first and second surfaces, and backing layer 14 adjacent one of the surfaces. Layer 12 includes a porous, mucoadhesive polymer matrix formed by lyophilization of a composition including at least one therapeutic agent and chitosan. Particles 16 are embedded within the matrix. The particles are directly surrounded by and in contact with the matrix. The particles include a therapeutic agent and have a coating around the therapeutic agent, the coating including chitosan for sustained release of the therapeutic agent from the particles. A portion of the therapeutic agent may be embedded directly into the matrix as a free form of the agent, or may not be coated with chitosan. Typically, the amount of the therapeutic agent in free form comprises 20-80% of the total amount of therapeutic agent in the element. Backing layer 14 is impermeable, or at least substantially impermeable, to the passage of one or more loaded components, such as particles, therapeutic agents, or additives, present in the patch. Examples of backing layer materials include non-woven polyester fabric with or without a polyacrylate adhesive and / or a clear acrylic film.

[0089] In some embodiments, the patch is formed with one side exposed for contact with suitable tissue. Upon contact with suitable tissue, it releases particles containing one or more drugs from this side. As shown in FIG. 8, the particles (spheres) are held within the body of the patch. The body of the patch is a mesh material mainly composed of chitosan. In some embodiments, the other side facing the outside space may be adjacent to a backing layer 14, such as a film, covering, or impermeable membrane, to prevent significant loss of one or more loaded components from the target tissue from the patch on the opposite side into the tissue / cavity. This backing layer 14 may also prevent contamination of the patch by liquids or other substances that may be present.

[0090] Base material Several bioadhesive and mucoadhesive polymers are known. In some embodiments, the polymer is mucoadhesive so that it can bind to mucosal intestinal tissue. In some embodiments, the polymer is multicationic, biocompatible, and biodegradable. In some embodiments, the polymer is chitosan. Chitosan is a multicationic, non-toxic, biocompatible, and biodegradable polymer. Chitosan is commonly used as a drug delivery mechanism to mucosa due to its bioadhesive and permeability properties. The gastrointestinal (GI) epithelial barrier is easily disrupted by chitosan particles, increasing the permeability of the mucosa.

[0091] Various factors affect the production of chitosan particles, including the pH of preparation, polyanion content, charge ratio, degree of deacetylation, and molecular weight of chitosan.

[0092] Chitosan particles have been shown to date to be usable in chemotherapy agents for cancer treatment due to chitosan's sensitivity to low pH. Because cancer tissue is acidic, chitosan particles release drugs faster in acidic environments. However, in contrast to the traditional use of chitosan particles, a novel chitosan particle synthesis process is provided herein that allows for stability in acidic environments and drug release when exposed to basic conditions. The sustained release of drug from chitosan particles ensures that a stable amount of drug penetrates the appropriate gastrointestinal mucosal tissue, minimizing loss and exposure to liquids and other tissues.

[0093] The system may include any suitable polymer matrix. In some embodiments, the polymer matrix is ​​a porous, mucoadhesive, lyophilized polymer matrix. Exemplary polymer matrices useful as the polymer matrix include, but are not limited to, chitosan. The chitosan may be pure chitosan or a salt of chitosan. In some embodiments, the chitosan is pure chitosan. The chitosan may be of any suitable molecular weight, such as about 25 kDa to about 1000 kDa, or about 25 kDa to about 500 kDa, or about 50 kDa to about 500 kDa, or about 50 kDa to about 250 kDa, or about 80 kDa to about 200 KDa. In some embodiments, the molecular weight of the chitosan is about 25 kDa to about 1000 kDa. In some embodiments, the molecular weight of the chitosan is about 25 kDa to about 500 kDa. In some embodiments, the molecular weight of chitosan is between about 80 kDa and 200 kDa.

[0094] Representative examples of matrix materials and particles that can form layer 12 are given in U.S. Patent Application Publication No. 2017 / 0239189, which discloses chitosan particles embedded in a chitosan-based matrix. Chitosan is a deacetylated derivative of chitin, the second most abundant polysaccharide, and has a high density of reactive groups and a wide range of molecular weights. Chitosan is believed to be useful as a bioadhesive material due to its ability to form non-covalent bonds with living tissues, primarily epithelia and mucosa. Bioadhesives formed with natural polymers have unique properties as carriers because they can extend the residence time, thereby improving the absorption of the loaded drug. Chitosan is a biosorbable, biocompatible, biodegradable, antibacterial, and non-toxic polymer.

[0095] Furthermore, chitosan has a variety of functional groups that can be modified. Due to its unique physicochemical properties, chitosan has great potential for various biomedical applications. Chitosan can be used as a delivery mechanism due to its bioadhesive properties and structuring ability to function as an absorption enhancer and penetration enhancer. Mucosal or intraepithelial barriers are easily disrupted by chitosan particles, improving permeability through the mucosa. Chitosan has proven to be an ideal material for achieving patch efficacy and functionality. In experiments, chitosan-based patches were applied within surgical cavities after surgical removal of tumors. Treatment with chitosan-based patches alone caused essentially no recurrence or metastasis of cancer cells. Other patches, such as patches made of simple HPMC, pectin, or alginate, did not have these same effects for unknown reasons. Chitosan is a blood clotting agent, possibly because the positive charge of chitosan attracts and holds negatively charged red blood cells when exposed to blood, thus causing clotting. This clotting, in combination with other unknown factors, may prevent the spread of free cancer cells in the bloodstream and throughout the body. Chitosan also relaxes tight cell junctions in tissues, increasing drug permeation and passage through the tissue. This effect may prevent the spread of cancer cells in local and systemic tissues, in part, by attracting the cancer cells to the patch due to the more acidic properties of the cells or other unknown factors. Permeation studies performed with multiple patch materials showed similar particle permeation in chitosan-based patches as well as non-chitosan-based patches, so additional permeation by itself does not cause high efficacy.

[0096] The most widely deployed particle preparation methods are ionotropic gelation and self-assembly polyelectrolytes. These methods offer many advantages, such as a simple and gentle preparation method that does not require the use of organic solvents and high shear forces. These methods are compatible with a wide range of drugs, including polymers, which are notoriously unstable drugs. In general, factors found to affect particle formation, such as particle size and surface charge, are the molecular weight of chitosan and the degree of deacetylation. The particles can be tailored to be stable in a variety of environments.

[0097] The method of ionotropic gelation is commonly used to prepare chitosan particles. This method is based on electrostatic interactions, and at biological pH, the primary amine groups of chitosan are protonated, making chitosan positively charged. The positive charge can be used to form particles in solution through crosslinking with polyanions (stabilizers), such as sodium tripolyphosphate (STPP), to efficiently encapsulate drugs through electrostatic interactions and promote the internalization of drug-loaded chitosan particles into cells. The polyanionic stabilizer can function as a crosslinker to form particles by acting as a negative counterion to the positively charged amine groups on the chitosan surface. This electrostatic interaction forms ionic bonds that support the structure of the particles. The presence of sodium as a positive counterion may also make STPP a more effective crosslinker than other tripolyphosphate (TPP) salts.

[0098] Some advantages of this simple and gentle method include the use of aqueous solutions, preparation of small particles, manipulation of particle size by varying pH value, and the possibility of encapsulating drugs during particle formation. The presence of KCl at low and moderate concentrations can introduce structural changes by varying the ionic strength, which accentuates the swelling and weakening of ionic interactions between chitosan and STPP.

[0099] The particles can penetrate tissues to deliver the encapsulated drug. The particle size depends on the pH of the aqueous solution in which the particles are prepared and the weight ratio of chitosan to STPP, which affects the release rate of the drug. Other parameters such as the ratio of chitosan to stabilizer (such as STPP) in the aqueous solution during the synthesis process affect the particles, as an increase in the amount of stabilizer leads to a higher degree of cross-linking of chitosan and a decrease in particle size. This allows the particle size to be tuned, allowing the use of a specific particle size range tailored to the tissue for which these particles are selected.

[0100] salt The chloride salt of the monovalent cation may be any suitable chloride salt. In some embodiments, the chloride salt of the monovalent cation is NaCl, KCl, LiCl, RbCl, CsCl, NH4Cl, or combinations thereof. In some embodiments, the chloride salt of the monovalent cation is NaCl.

[0101] The chloride salt may be present in any suitable amount in the polymer matrix. Representative amounts of chloride salt in the polymer matrix include about 10 to about 25% (wt / wt), or about 15 to about 25% (wt / wt), or about 16 to about 24% (wt / wt), or about 17 to about 23% (wt / wt), or about 17 to about 22% (wt / wt), or about 17 to about 21% (wt / wt), or about 17 to about 20% (wt / wt), or about 17 to about 19% (wt / wt). Representative amounts of chloride salt in the polymer matrix include about 15% (wt / wt), or about 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25% (wt / wt). In some embodiments, the chloride salt of the monovalent cation is NaCl and is present in the polymer matrix in an amount of about 18% (w / w) of the polymer matrix.

[0102] Hydration promoter The polymer matrix may include various other components, such as hydration enhancers. Without wishing to be bound by any particular theory, it is believed that the hydration enhancers increase water absorption by the delivery system. This increased hydration allows for rapid release and penetration of the particulates from the matrix. It is also believed that the hydration enhancers improve uniformity and durability by acting as antifreeze agents during the manufacturing process of the delivery system. Again, without being bound by any particular theory, it is believed that the hydration enhancers act as "spacers" between the ice crystals and the matrix polymer molecules to ensure a uniform freezing pattern. The resulting structure is more flexible, uniform, and durable than structures that do not include the hydration enhancer. Exemplary hydration enhancers include, but are not limited to, ethylene glycol, propylene glycol, beta-propylene glycol, glycerol, and combinations thereof.

[0103] In some embodiments, the polymer matrix further comprises a hydration enhancer. In some embodiments, the hydration enhancer is ethylene glycol, propylene glycol, beta-propylene glycol, glycerol, or a combination thereof. In some embodiments, the hydration enhancer is propylene glycol.

[0104] The hydration enhancer may be present in the polymer matrix in any suitable amount. Representative amounts of the hydration enhancer in the polymer matrix include about 1 to about 50% (w / w), or about 5 to about 25% (w / w), or about 5 to about 15% (w / w), or about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or about 15% (w / w). In some embodiments, the hydration enhancer may be present in an amount of about 7.0% (w / w), or 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or about 8.0% (w / w). In some embodiments, the propylene glycol is present in the polymer matrix in an amount of about 5 to about 25% (w / w). In some embodiments, the propylene glycol is present in an amount of about 7.75% (w / w).

[0105] Particle adhesion inhibitors The polymer matrix may contain various other components, such as particle adhesion inhibitors, for example, hydroxypropylmethylcellulose. Without wishing to be bound by any particular theory, it is believed that when the matrix and particles are made of a material such as chitosan that has polar or ionically charged moieties, the mobility of the particles is reduced. In the case of chitosan, it is believed that the interaction between the acetyl and amine moieties of the polymer causes the particles to adhere to the matrix and inhibits their release.

[0106] It has been found that the inclusion of an adhesion inhibitor can reduce adhesion between the particles and the matrix. Without being bound to any particular theory, it is believed that the adhesion inhibitor acts as a "spacer" between the chitosan of the particles and the chitosan in the matrix body, allowing the particles to be released and improving the drug release profile. In some embodiments, the polymer matrix further comprises a particle adhesion inhibitor. In some embodiments, the particle adhesion inhibitor comprises hydroxypropyl methylcellulose (HPMC). The molar mass of HPMC can be from about 1 kDa to about 200,000 kDa and its viscosity can vary between about 10 cps to 100,000 cps.

[0107] The particle adhesion inhibitor may be present in any suitable amount. Representative amounts of particle adhesion inhibitor include about 0.1 to about 10% (w / w), or about 1 to about 10% (w / w), or about 2 to about 8% (w / w), or about 3 to about 6% (w / w), or about 3 to about 5% (w / w), or about 3 to about 4% (w / w). Other representative amounts of particle adhesion inhibitor include, but are not limited to, about 1% (w / w), or about 2, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 5, 6, 7, 8, 9, or about 19% (w / w). In some embodiments, hydroxypropyl methylcellulose (HPMC) is present in the polymer matrix in an amount of about 0.1 to about 10% (w / w). In some embodiments, hydroxypropyl methylcellulose (HPMC) is present in the polymer matrix in an amount of about 3.7% (w / w).

[0108] Particle Aggregation Inhibitors The polymer matrix may include various other components, such as a particle aggregation inhibitor. The process of manufacturing the delivery element includes a freezing step in which ice crystals form within the matrix. Such crystals can bind particulates together to form particle aggregates that can damage or destroy the particles. Again, without wishing to be bound by any particular theory, it is believed that the aggregation inhibitor exerts its cryoprotective effect by forming a crystalline microstructure that prevents the particles from agglomerating. In some embodiments, the polymer matrix further includes a particle aggregation inhibitor.

[0109] The particle aggregation inhibitor may be present in any suitable amount. Representative amounts of the particle aggregation inhibitor include, but are not limited to, about 0.1 to about 50% (wt / wt), or about 1 to about 30% (wt / wt), or about 10 to about 30% (wt / wt), or about 20 to about 30% (wt / wt), or about 20 to about 25% (wt / wt), or about 21 to about 23% (wt / wt). The particle aggregation inhibitor may also be present in an amount of about 1, 5, 10, 15, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or about 30% (wt / wt). In some embodiments, the particle aggregation inhibitor is present in an amount of about 0.1 to about 30% (wt / wt). In some embodiments, the particle aggregation inhibitor is present in an amount of about 20 to about 25% (wt / wt). In some embodiments, the particle aggregation inhibitor is present in an amount of about 22% (w / w).In some embodiments, the particle aggregation inhibitor is present in an amount of about 22.25% (w / w).

[0110] The particle aggregation inhibitor may include carbohydrates, such as, but not limited to, monosaccharides, disaccharides, sugar alcohols, chlorinated monosaccharides, chlorinated disaccharides, and combinations thereof. In some embodiments, the particle aggregation inhibitor is a monosaccharide, a disaccharide, a sugar alcohol, a chlorinated monosaccharide, a chlorinated disaccharide, or a combination thereof. Representative monosaccharides include, among others, glucose, fructose, and galactose. Representative disaccharides include sucrose and lactose. Chlorinated monosaccharides include monosaccharides substituted with at least one chlorine atom. Chlorinated disaccharides include, but are not limited to, disaccharides substituted with at least one chlorine atom, such as sucralose.

[0111] In some embodiments, the particle aggregation inhibitor is sucralose. In some embodiments, the sucralose is present in the polymer matrix in an amount of about 0.1 to about 30% (w / w). In some embodiments, the sucralose is present in the polymer matrix in an amount of about 22.25% (w / w).

[0112] Free Therapeutic Agent It has been found that when the matrix contains a free amount of therapeutic agent embedded directly in the matrix and not coated with chitosan in particles, the device is more effective for treatment than a comparable matrix containing either only free therapeutic agent or only chitosan coated therapeutic agent, In an exemplary embodiment, the free amount of therapeutic agent comprises 20-80% of the total amount of therapeutic agent in the delivery system.

[0113] In some embodiments, the polymer matrix further comprises a free amount of a therapeutic agent in an amount of about 20% to about 80% of the total amount of therapeutic agent in the system.

[0114] fine particles In some embodiments, improved pure chitosan microparticles are provided. Conventional chitosan particles are produced using salts of chitosan, such as chitosan chloride and chitosan glutamate, which are characterized by a high degree of deacetylation and have charged moieties. It has been found that better results are obtained if the particles are produced from pure chitosan, a material characterized as not being a salt, i.e., whose amine groups are not protonated, and which has a degree of deacetylation of at least 70%. In particular, these particles are characterized by a larger diameter than conventional particles. In some embodiments, the average diameter of the pure chitosan particles may range from about 200 to about 2000 nm. In some embodiments, the average diameter ranges from about 500 to about 2000 nm, and in further embodiments, the average diameter ranges from 500 to 1000 nm.

[0115] In some embodiments, the microparticles are embedded within the matrix, directly surrounded by, or in contact with the polymer matrix. The microparticles may be present in the system in any suitable amount, such as 1-75% (w / w), or 10-75% (w / w), or 25-75% (w / w), or 35-65% (w / w), or 45-65% (w / w), or 50-60% (w / w). The microparticles may be present in the system in any suitable amount, such as about 1% (w / w) of the system, or about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or about 75% (w / w). In some embodiments, the microparticles are present in the polymer matrix in an amount of about 10 to about 40% (w / w). In some embodiments, the microparticles are present in the polymer matrix in an amount of about 45 to about 65% (w / w). In some embodiments, the microparticles are present in the polymer matrix at about 55% (w / w).

[0116] Therapeutic Agents Any therapeutic, prophylactic, diagnostic, or nutritional supplement that can be encapsulated and released may be used. Representative agents include biologics, peptides, nucleotides, anti-infectives, antibiotics, antibacterials, antivirals, anti-inflammatory agents, immunomodulators, vaccines, and combinations thereof. Other agents include calcium mobilizers such as nicotinic acid adenine dinucleotide phosphate, and peptides such as glucagon-like peptide-2. Nicotinic acid adenine dinucleotide phosphate and other calcium mobilizers have been found to promote ISC proliferation and intestinal epithelial regeneration. Glucagon-like peptide-2 and its analogs have also been found to promote ISC proliferation and intestinal epithelial regeneration. The efficacy of nicotinic acid adenine dinucleotide phosphate and glucagon-like peptide-2 has been found to be hindered by the lack of proper targeting and delivery within the gastrointestinal tract. The particle-based system provided herein improves upon such shortcomings.

[0117] Platinum antitumor agent The particles may further include any suitable anti-tumor agent. In some embodiments, the therapeutic agent comprises an anti-tumor agent. Exemplary anti-tumor agents include platinum anti-tumor agents, 5-fluorouracil (5-FU), and the like. In some embodiments, the platinum anti-tumor agents include cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin, or combinations thereof. In some embodiments, the therapeutic agent includes carboplatin, cisplatin, oxaliplatin, platinum malonate, ormaplatin, 5-fluorouracil, NAADP, allantoin, insulin, FITC, or rapamycin. In some embodiments, the therapeutic agent includes cisplatin. In some embodiments, the therapeutic agent includes carboplatin. In some embodiments, the therapeutic agent includes allantoin.

[0118] The anti-tumor agent may be present in any suitable amount. Representative amounts of the anti-tumor agent include, but are not limited to, about 0.1 to about 30% (wt / wt), or about 1 to about 30% (wt / wt), or about 10 to about 30% (wt / wt), or about 20 to about 30% (wt / wt), or about 20 to about 25% (wt / wt), or about 21 to about 23% (wt / wt). The anti-tumor agent may also be present in an amount of about 1, 5, 10, 15, 20, 21, 22, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23, 24, 25, 26, 27, 28, 29, or about 30% (wt / wt). In some embodiments, the platinum antineoplastic agent is present in an amount of about 0.1 to about 30% (w / w). In some embodiments, the platinum antineoplastic agent is present in an amount of about 20 to about 25% (w / w). In some embodiments, the platinum antineoplastic agent is present in an amount of about 22% (w / w). In some embodiments, the platinum antineoplastic agent is present in an amount of about 22.5% (w / w).

[0119] In some embodiments, the system comprises about 1 to about 50% (w / w) cisplatin. In some embodiments, the system comprises about 22.5% (w / w) cisplatin.

[0120] The patch, in some embodiments, utilizes well-known chemotherapeutic agents and commercially available excipients while minimizing costs associated with its manufacture. The simplified manufacturing process, relatively low overall cost, and easy administration methods serve as an improvement over all existing surgical treatments and facilitate widespread uptake and utilization of the invention.

[0121] In some embodiments, the patch contains a combination of two or more chemotherapeutic agents that are delivered to the surgical cavity in the abdominal, pelvic and / or abdominal cavity regions, and each chemotherapeutic agent has a certain ratio of free chemotherapeutic agent to chemotherapeutic agent encapsulated in particles.In some embodiments that contain two or more chemotherapeutic agents, one chemotherapeutic agent can be encapsulated in particles, and the other chemotherapeutic agent can remain in free form.For example, when cisplatin and oxaliplatin are the chemotherapeutic agents that are desired to be contained in the patch, one chemotherapeutic agent, cisplatin, can be contained in particle form, and oxaliplatin can be contained in free form.

[0122] In some embodiments that include more than one chemotherapeutic agent, one chemotherapeutic agent is encapsulated in particles, and another chemotherapeutic agent is present in both free form and in particles.For example, when cisplatin and oxaliplatin are the chemotherapeutic agents that are desired to be included in the patch, one chemotherapeutic agent, cisplatin, can be present in particle form, and oxaliplatin can be present in both free form and encapsulated in particles.In further embodiments that include more than one chemotherapeutic agent, two or more chemotherapeutic agents can be present both in particles and both in free form.For example, when cisplatin and oxaliplatin are the chemotherapeutic agents that are desired to be included in the patch, both cisplatin and oxaliplatin can be present in the final patch product in a desired ratio, and both in free form.

[0123] In some embodiments, the at least one agent contained within the patch is an anti-infective agent, which may be in free form, encapsulated within particles, or a combination thereof. In some embodiments, the at least one agent contained within the patch is an antibacterial or antiviral agent, which may be in free form, encapsulated within particles, or a combination thereof. In some embodiments, the majority of the particles have a diameter in the range of 60 nm to 2 μm. In some embodiments, the particles have an average diameter of 100 nm to 1000 nm. In some embodiments, the particles have an average diameter of 200 to 500 nm or 100 to 400 nm.

[0124] Sodium Tripolyphosphate Without wishing to be bound by any particular theory, it is believed that sodium tripolyphosphate (STPP) acts as a cross-linking agent to form the particles by acting as a negative counterion to the positively charged amine groups on the chitosan surface. This electrostatic interaction forms ionic bonds that support the structure of the particles. Without wishing to be further bound by any particular theory, it is believed that the presence of sodium as a positive counterion makes STPP a more effective cross-linking agent than other TPP salts.

[0125] In some embodiments, the microparticles further comprise sodium tripolyphosphate. Representative amounts of sodium tripolyphosphate include, but are not limited to, about 0.1 to about 10% (w / w), or about 2 to about 8% (w / w), or about 2 to about 5% (w / w), or about 2 to about 4% (w / w), or about 1, 2, 3, 4, 5, 6, 7, 8, 9, or about 10% (w / w). In some embodiments, the system comprises about 0.1 to about 10% (w / w) sodium tripolyphosphate. In some embodiments, the system comprises about 3.0% (w / w) sodium tripolyphosphate.

[0126] system In some embodiments, the polymer matrix comprises chitosan in an amount of about 20 to about 30% (wt / wt); cisplatin in an amount of about 20 to about 30% (wt / wt); NaCl in an amount of about 10 to about 18% (wt / wt); propylene glycol in an amount of about 5 to about 25% (wt / wt); hydroxypropyl methylcellulose (HPMC) in an amount of about 0.1 to about 10% (wt / wt); sucralose in an amount of about 0.1 to about 30% (wt / wt); and microparticles in an amount of about 10 to about 40% (wt / wt).

[0127] In some embodiments, the polymer matrix comprises chitosan in an amount of about 22.5% (wt / wt); cisplatin in an amount of about 22.5% (wt / wt); NaCl in an amount of about 18% (wt / wt) of the polymer matrix; propylene glycol in an amount of about 7.75% (wt / wt); hydroxypropyl methylcellulose (HPMC) in an amount of about 3.7% (wt / wt); sucralose in an amount of about 22.25% (wt / wt); and microparticles in an amount of about 55% (wt / wt).

[0128] Backing layer The system may also include a backing layer. A representative backing layer is a water-permeable backing layer. The backing layer prevents significant loss of the loaded components in the device due to diffusion through the second surface, and optionally protects the device from the environment. The backing layer may include a material selected from the group consisting of a polyacrylate adhesive, a polyester nonwoven backing, or a combination thereof.

[0129] In some embodiments, the polymer matrix has opposing first and second surfaces, and the system further includes a water-permeable backing layer affixed to the first surface of the polymer matrix.

[0130] adhesive layer In some embodiments, the second surface comprises a polyacrylate adhesive, a nonwoven polyester fabric, or a combination thereof.

[0131] Manufacturing method The present invention also provides a method of manufacturing a delivery element for delivering a therapeutic agent to tissue, the method comprising the steps of: forming a first mixture comprising a plurality of particles comprising the therapeutic agent and having a coating comprising chitosan around the therapeutic agent; adding chitosan, a hydration promoter, a particle adhesion inhibitor, a particle aggregation inhibitor, or a combination thereof to the first mixture to form a second mixture; freezing the second mixture in a bath containing an alcohol-water solution at a temperature up to -40°C, which is higher than the freezing temperature of the alcohol-water solution, to form a frozen layer precursor; drying the frozen layer precursor to form a porous patch having particles embedded within the polymer matrix of the patch; and sterilizing the patch.

[0132] In some embodiments, a method for producing a multi-layer device and formulations formed according to the method is provided, which includes freezing and lyophilizing a polymer solution containing a therapeutic agent.

[0133] The precursor mixture is first formed and then subjected to freezing or lyophilization. The element may feature multiple layers, and the precursor mixture may be formed separately for each layer. All layers may each contain an independently selected drug to be delivered, with at least one layer containing microparticles further encapsulating at least one of the drugs. The microparticles may be synthesized, for example, according to an ionotropic gelation method in which no alteration of the drug occurs. The microparticles are designed to have an average diameter in the range of 200-2000 nm, 500-2000 nm, or 500-1000 nm. Drugs such as penetration enhancers, taste masking elements, and body structure forming drugs may be added. These drugs may include, among others, propylene glycol, hydroxypropyl methylcellulose, chitosan, sweeteners, peppermint, or other flavorings. Solutions containing drugs but not microparticles may also contain these other drugs.

[0134] Once prepared, the precursor mixture is subjected to freezing. The layer of the element is preferably first frozen in a freezing bath of aqueous alcohol at a temperature of up to -40°C, for example in a bath of aqueous ethanol and dry ice. It has been found that this method results in an element that is able to release almost all of its drug content and penetrate deep into the desired mucosal depth. Without wishing to be bound by any particular theory, this product element is more efficient compared to other freezing methods. If the precursor mixture is placed in a freezer at -80°C, or frozen with dry ice alone, some of the microparticles will rupture and the polymer in the matrix of the element will become harder, resulting in a lower drug release rate and reduced therapeutic efficacy. The bath may include dry ice completely covered with at least 90% by weight of an aqueous solution of ethanol. The precursor mixture (in liquid state) of the first layer of the element is poured into a mold, for example a silicone mold, and immersed about 2 / 3 to 3 / 4 into a bath of ethanol and dry ice to form a frozen layer. It is preferably left for 30 minutes to completely freeze.

[0135] After the first layer is frozen, the second layer may be added by one of two methods. In the first method, while the first layer remains in the ethanol / dry ice bath, the precursor mixture for the second layer is poured onto the top of the frozen first layer in a liquid state. The resulting frozen bottom layer and liquid top layer are then immersed deeper until the overall immersion ratio is 2 / 3 to 3 / 4. The second layer is left for an additional 30 minutes to allow for complete freezing. If more than two layers are required, subsequent layers can be added by the same process.

[0136] In the second method, each layer is frozen separately and simultaneously in its individual mold in a freezing bath. After leaving each layer for 30 minutes to ensure complete freezing, a coating of one or more salts, for example a 0.12% saline solution, is brushed onto the surface of the first initial layer. Within about one minute of coating application, a second layer is applied to the first layer, applying a pressure of about 0.25 kg. This results in a bonded solid layer. Subsequent layers, if more than one layer, can be applied in the same manner.

[0137] After all desired layers have been added, the elements are transferred into the lyophilization chamber for approximately 1-3 days, depending on the number of elements loaded into the chamber. After all the liquid has been removed by lyophilization, the multi-layer element is ready for use.

[0138] In some embodiments, multi-layer elements may be used to deliver multiple drugs simultaneously, for example, one layer may contain a pain relieving drug and one layer may contain a drug for treating mucositis if desired for use in treating mucositis and pain relief.

[0139] In some embodiments, multi-layer elements may be used for delivery of multiple drugs over an extended period of time. Using mucositis as an example again, a multi-layer agent may include a pain relieving agent in free form, a pain relieving agent encapsulated in microparticles, and a mucositis treatment agent encapsulated in microparticles. The initial free form layer may provide immediate pain relief, while the subsequent particle encapsulated layer may deliver the microparticles to lower tissue where the drug may be released over the next few days to provide long-term pain relief and treatment.

[0140] Once the patch has been prepared, it may be subjected to a sterilization process that ensures that the final product meets the sterile requirements for surgical use without significantly degrading the composition or performance of the patch. In particular, care must be taken to ensure that the sterilization process does not significantly affect the structure or efficacy of the therapeutic agent contained in the patch. Gamma irradiation, which uses radiation emitted by radioisotopes such as cobalt-60 to kill microorganisms, has been shown to efficiently sterilize patches while leaving chemotherapeutic agents essentially unaffected.

[0141] In some embodiments, the present invention provides a method of preparing the system of the present invention, the method comprising the steps of forming a first mixture comprising water, chitosan, a chloride salt, a hydration promoter, a particle adhesion inhibitor, and a particle aggregation inhibitor to prepare a base mixture; forming a second mixture comprising the base mixture, a first platinum antitumor agent, and chitosan microparticles comprising a second platinum antitumor agent; removing water from the second mixture to prepare a dry mixture; and applying the dry mixture to a backing layer, thereby preparing the system.

[0142] In some embodiments, a method of preparing the system of the present invention includes forming a first mixture comprising water, chitosan, a chloride salt, propylene glycol, hydroxypropyl methylcellulose, and sucralose to prepare a matrix mixture; forming a second mixture comprising the matrix mixture, cisplatin, and chitosan microparticles comprising chitosan, cisplatin, and sodium tripolyphosphate; removing water from the second mixture to prepare a dry mixture; and applying the dry mixture to a backing layer, thereby preparing the system of the present invention.

[0143] In some embodiments, the present invention provides a method for preparing a system of the present invention, the method comprising: forming a first mixture comprising water, chitosan, and acetic acid; forming a second mixture comprising a chloride salt, a therapeutic agent, and sodium tripolyphosphate; forming a third mixture comprising the first mixture and the second mixture, thereby forming microparticles; forming a fourth mixture comprising water, chitosan, acetic acid, a hydration enhancer, and a particle adhesion inhibitor; forming a fifth mixture comprising the fourth mixture, a particle agglomeration inhibitor, and a particulate to form a polymer matrix; removing water from the polymer matrix to form a dry mixture; and The step includes applying the dry mixture to a backing layer, thereby preparing the system of the present invention.

[0144] In some embodiments, the method further comprises: forming a first mixture comprising water, chitosan, and acetic acid; forming a second mixture comprising sodium chloride, cisplatin, and sodium tripolyphosphate; forming a third mixture comprising the first mixture and the second mixture, thereby forming microparticles; forming a fourth mixture comprising water, chitosan, acetic acid, propylene glycol, and hydroxypropyl methylcellulose; forming a fifth mixture comprising the fourth mixture, sucralose, and microparticles to form a polymer matrix; removing water from the polymer matrix to form a dry mixture; and The step includes applying the dry mixture to a backing layer, thereby preparing the system.

[0145] IV. Localized Delivery of Drugs In some embodiments, one or more of the above improvements can be applied to a multi-layer drug delivery element. The multi-layer element can deliver the same or multiple drugs stepwise over a period of time, or multiple drugs can be delivered simultaneously by adjusting the structure of each layer. The element and the method of making the element have been developed to address the unmet need for multiple forms of drug delivery locally to mucosal tissue. The multiple layers in this platform can be used for a variety of purposes.

[0146] Traditional drug delivery to mucosa consists of an initial bolus of drug followed by a steady decrease in exposure over time. The platform can mitigate this tendency by having multiple layers and containing microparticles within at least one layer. The materials forming the structure of each layer can be optionally selected to degrade over time and can be selected to contain the same drug (such as cisplatin for the localized treatment of cancerous tumors) in each of the multiple layers.

[0147] In some embodiments, the device can thus be designed to release cisplatin locally in multiple stages, providing treatment over a very long period of time without the side effects, multiple dose requirements, or dose-limiting inhibitions associated with parenterally administered cisplatin. The inclusion of microparticles within the device further aids the device's ability to provide a sustained local dose. The microparticles contained within the device are released immediately upon application, penetrate the mucosal tissue, and remain locally within the tissue beneath the device. These microparticles then degrade over time to provide a more sustained, longer-term dose of the drug. Additional objectives can be achieved when different drugs are included within each layer. For example, when the device is applied to treat a fresh open wound, a painkiller and an anti-infective agent may each be included within one layer.

[0148] When applied in the oral cavity, the device is placed directly on the affected oral tissue surface in the mouth to release drugs for the controlled and targeted treatment of oral diseases. Drugs contained in free form (such as painkillers in the first layer) may be designed to have an immediate effect on the underlying tissue, while drugs (such as chemotherapeutic agents) encapsulated in microparticles may be contained in the second or subsequent layers. The microparticles can then act independently of the first drug to penetrate the underlying tissue and provide sustained and long-lasting delivery of drugs to the tissue. The device provides the ability to adjust duration and treatment sequence parameters to provide multiple stages and periods of treatment, overcoming other shortcomings of the prior art.

[0149] In some embodiments, the present invention provides a method of administering a therapeutic agent to a subject in need thereof, comprising applying a system of the present invention to the subject such that at least 50% of the therapeutic agent in the system is released from the system in less than 30 minutes.

[0150] The system may be applied to any suitable tissue of the subject. Exemplary tissues include, but are not limited to, the skin, mucosa, oral cavity, vagina, and rectum. In some embodiments, the system is applied to the mucosa of the subject. In some embodiments, the system is applied to the oral cavity of the subject. In some embodiments, the system is applied to the skin of the subject.

[0151] The therapeutic agent can be administered to the subject at any suitable rate, for example, at least 50% of the therapeutic agent in the system is released from the system in less than 60 minutes, or at least 75% of the therapeutic agent in the system is released from the system in less than 60 minutes, or at least 90% of the therapeutic agent in the system is released from the system in less than 60 minutes, or at least 50% of the therapeutic agent in the system is released from the system in less than 45 minutes, or at least 50% of the therapeutic agent in the system is released from the system in less than 30 minutes, or at least 50% of the therapeutic agent in the system is released from the system in less than 15 minutes.

[0152] In some embodiments, at least 75% of the therapeutic agent in the system is released from the system in less than 45 minutes, or at least 75% of the therapeutic agent in the system is released from the system in less than 30 minutes, or at least 75% of the therapeutic agent in the system is released from the system in less than 15 minutes. In some embodiments, at least 75% of the therapeutic agent in the system is released from the system in less than 30 minutes.

[0153] In some embodiments, at least 90% of the therapeutic agent in the system is released from the system in less than 45 minutes, or at least 90% of the therapeutic agent in the system is released from the system in less than 30 minutes, or at least 90% of the therapeutic agent in the system is released from the system in less than 15 minutes. In some embodiments, at least 90% of the therapeutic agent in the system is released from the system in less than 30 minutes. In some embodiments, at least 90% of the therapeutic agent in the system is released from the system in less than 15 minutes.

[0154] V.Kit The kit further comprises an element and a penetration enhancer. Exemplary penetration enhancers are selected from the group consisting of 2(N,N-dimethylamino)dodecylpropionate, bile salts, surfactants, fatty acids, glycerides, polyacrylic acid derivatives, chelating agents, nitric oxide donors, salicylates, chitosan, zona occludens toxin, sodium cholate, sodium deoxycholate, sodium glycodeoxycholate, sodium taurocholate, sodium glycocholate, N-lauryl-b-maltopyranoside, and combinations thereof. Exemplary surfactants include oleic acid, sodium dodecyl sulfate, sodium lauryl sulfate, polysorbate 80, lauryl esters, and combinations thereof.

[0155] In some embodiments, at least one patch is included as a component of a kit for treating diseases of the abdomen, pelvis, and / or intraperitoneal cavity that have been made accessible by surgery. The kit may include materials necessary for proper application of the patch as well as proper and safe disposal of the patch after application and cleaning of the treatment area. For example, FOLFOX (5-FU, leucovorin, and oxaliplatin) or CapeOx (capecitabine and oxaliplatin) therapy are known as common agents for the traditional treatment of colon cancer. These chemotherapy agents can be used in a safe manner to locally treat colon tumors that may have metastasized within the abdomen / pelvis. However, extensive precautions must be taken to ensure that (1) proper handling procedures are followed during treatment, (2) the time for preparation and application of the patch is reduced to minimize the time the patient's abdomen / pelvis remains exposed, and (3) contact between these agents and both the patient and the personnel applying the patch is minimized. Additional items that may be included in the kit for safety purposes include forceps or other instruments for placing the patch, disposable packaging for remaining portions of the patch after application, and other safety items.

[0156] The release of the drug from the element is partially activated by exposure to moisture. Thus, a moistening solution such as saline may be provided with the element used during the application process. In addition, a penetration enhancer in powder or solution form may be included that is administered externally to the mucosa prior to application of the element. The penetration enhancer may be included in a powder form that requires reconstitution, if necessary. A powder form may be included to maintain the stability of the penetration enhancer. If included in this form, the kit may include additional materials, such as at least one glass vial (capacity 5 mL to 20 mL) containing sterile water for reconstitution, if necessary. The kit may further include a syringe (e.g., a 3 mL Luer lock syringe) and an aspiration needle (e.g., an 18G needle) for reconstitution of the penetration enhancer.

[0157] Furthermore, when the device is used for certain indications (such as oral indications), care must be taken to ensure safe application and removal of the product to prevent choking or swallowing. The kits disclosed herein address these concerns by including all the materials necessary to ensure a safe application of the device. An example kit includes at least a pair of forceps (either multi-use metal forceps or disposable plastic forceps) or other similar instrument that is used to position or place the device so as to prevent exposure of the agent to the person or exposure of the device to the throat.

[0158] Disposable packaging may also be included in the kit to segregate materials used during treatment to ensure safe handling and contamination prevention during the treatment process, such as hazardous waste or biohazard packaging used during administration of toxic drugs such as those used in the treatment of oral cancer or melanoma, and empty flash emission vials may also be included for post-treatment collection of used elements for purposes such as residual drug analysis.

[0159] VI. Treatment of Skin Diseases In some embodiments, the present invention provides a method of treating a skin condition in a subject in need thereof, comprising applying a system of the present invention to the skin of the subject such that a therapeutically effective amount of a therapeutic agent in the system is released from the system and administered to the skin of the subject, thereby treating the skin condition.

[0160] As noted above, the therapeutic agent may be released from the systems of the present invention at any suitable rate, hi some embodiments, at least 50% of the therapeutic agent is released from the system in less than 30 minutes.

[0161] The methods of the present invention can be used to treat a variety of skin diseases or disorders. Representative skin conditions include, but are not limited to, aging of the skin, skin eruptions including bedsores, decubitus ulcers, inflamed sensitive and unaesthetic skin, erythema, rashes, skin edema, bacterial, viral, fungal, and parasitic skin infections such as psoriasis, eczema, lichen, hardhead, abscesses, cellulitis, erysipelas, folliculitis, and impetigo, lice, scabies, and herpes simplex, acne, rashes, atopic dermatitis, allergic contact dermatitis (see Scholzen, TE; Luger, TA Exp Dermatol. 2004; 13 Suppl 4:22-6), and dermatitis including neurodermatitis, radiation injury, sunburn, pruritus, itching, urticaria (EP0622361; Frigas, E.; Park, M. Immunol. Allergy Clin. North Am. 2006, 26, 739-51; Luquin, E.; Kaplan, AP; Ferrer, M. Clin. Exp. Allergy 2005, 35, 456-60; Kaplan, AP; Greaves, MWJ Am. Acad. Dermatol. 2005, 53, 373-88; quiz 389-92), wounds including psoriasis, mycoses, tissue ulceration, epidermolysis bullosa, abnormal wound healing, and burns (Nwariaku, FE; Sikes, PJ; Lightfoot, E.; Mileski, WJ; Baxter, C. Burns 1996, 22, 324-7; Neely, AN; Imwalle, AR; Holder, IA Burns 1996, twenty two, 520-3), frostbite, venom-induced skin inflammation and swelling, alopecia, hair scales, corns, warts, and whitlow.

[0162] Other skin disorders include keratinizing skin disorders. Representative keratotic skin diseases include, but are not limited to, Darier's disease, Hailey-Hailey disease, erythrodermic autosomal recessive lamellar ichthyosis, non-erythrodermic autosomal recessive lamellar ichthyosis, autosomal dominant lamellar ichthyosis, bullous congenital ichthyosiform erythroderma, palmoplantar keratoderma, fluctuating erythrokeratoderma, verrucous epidermal nevus, pityriasis erythematosus pilaris, Netherton syndrome, idiopathic ichthyosis vulgaris, ichthyosis vulgaris, monilethrix, keratosis pilaris, bullous ichthyosiform erythroderma, non-bullous congenital ichthyosis, Sjogren-Larsson syndrome, erythrokeratoderma variabilis, lenticular keratosis, variant Eythrokeratosis, Vauwinkel's cutting keratosis, Harlequin ichthyosis, and Tay syndrome (see International Patent Application PCT / US2009 / 031101).

[0163] A new term has recently been introduced for keratinizing skin diseases (see Akiyama M. et al., J Dermatol Sci. 2018 May;90(2):105-111, "Autoinflammatory keratinization diseases: An emerging concept encompassing various inflammatory keratinization disorders of the skin").

[0164] In some embodiments, the skin disease is skin cancer, inflammatory skin disease, autoimmune skin disease, acne, atopic dermatitis, contact dermatitis, eczema, impetigo, rash, psoriasis, plaque psoriasis, or Behcet's disease. Inflammatory skin diseases may include, but are not limited to, acne, psoriasis, rosacea, eczema, actinic keratosis, ichthyosis, Bowen's disease, keratoderma, lichen sclerosus, hidradenitis suppurativa, pityriasis lichenoides, dermatitis, atopic dermatitis, contact dermatitis, eczematous dermatitis, or seborrheic dermatitis. In some embodiments, the skin disease is basal cell carcinoma, squamous cell carcinoma, or melanoma.

[0165] In some embodiments, the skin disease is an inflammatory skin disease. In some embodiments, the inflammatory skin disease or disorder is selected from the group consisting of psoriasis, atopic dermatitis (AD), eczema, actinic keratosis, ichthyosis, pemphigus vulgaris, acne, Grover's disease (transient acantholytic dermatosis), keratoderma, hidradenitis suppurativa, seborrheic keratosis, pityriasis lichenoides, alopecia areata, basal cell carcinoma, Bowen's disease, congenital erythropoietic porphyria, contact dermatitis, Darier's disease, dystrophy, and the like. The inflammatory skin disease is selected from epidermolysis bullosa erythematosus, epidermolysis bullosa simplex, erythropoietic protoporphyria, fungal infection of the nail, herpes simplex, hidradenitis suppurativa, ichthyosis, impetigo, keloid, keratosis pilaris, lichen planus, lichen sclerosus, pemphigus vulgaris, plantar warts (verrucae), pityriasis lichenoides, polymorphous mild exanthema, pyoderma gangrenosum, rosacea, herpes zoster, squamous cell carcinoma, Sweet's syndrome, and vitiligo. In some embodiments, the inflammatory skin disease is caused by microbial infection-induced dermatitis, photodermatitis, atopic dermatitis, or allergic contact dermatitis. In some embodiments, the inflammatory skin disease or disorder is psoriasis. In some embodiments, the inflammatory skin disease or disorder is atopic dermatitis (AD).

[0166] In some embodiments, the skin disease is an autoimmune skin disease. In some embodiments, the autoimmune skin disease is lupus, psoriasis, atopic dermatitis, alopecia areata, or Behcet's disease.

[0167] VII. Cancer Treatment Oral mucositis, not just oral cancer, is also a significant disease, due in part to the fact that if systemic chemotherapy is administered for any reason, the disease may occur in the mouth. In some embodiments, the therapeutic element in the kit of the present disclosure may include a drug that treats or reduces pain, or a drug that addresses oral mucositis. Unlike existing treatments for mucositis, the kit of the present invention includes an element that contains microparticles with an encapsulated drug therein. Similar to its effectiveness in treating oral cancer, the microparticles released from the element are mucoadhesive, so they remain localized at the site of mucositis. Due to the nano-dimensions of the particles, they can penetrate tissue and release the encapsulated drug deeper into the affected area than other current treatments, without extensive exposure to the drug. Administration via this kit allows for a much more efficient delivery of the drug to the area affected by mucositis.

[0168] In some embodiments, the kits described further are used to deliver drugs for the treatment of precancerous / premalignant oral lesions. Precancerous / premalignant lesions are often left untreated when discovered because ideal treatment options do not exist. Diagnosis is often combined with surveillance of malignancies rather than early treatment, as chemotherapy or surgery may be considered too drastic for early lesions. It is also difficult to distinguish precancerous / premalignant lesions from other non-malignant lesions. For this reason, it is often unwilling to administer harmful systemic chemotherapy to less likely life-threatening problems. To address these conditions, the kits of the present invention can be used to administer lower doses of chemotherapeutic or other drugs to these lesions. Due to the high efficacy and significantly higher safety achieved with such small doses, there is the prospect of performing treatments on a much larger scale. Based on these reasons, the kits of the present invention are considered a significant improvement and viable alternative to current treatments. Moreover, the inclusion of a therapeutic element in the kit is considered a significant improvement over U.S. Patent Application No. 2014 / 0234212, in which only a therapeutic element is disclosed, for the safety and efficacy reasons discussed above.

[0169] In some embodiments, the kit includes a mucoadhesive drug delivery element comprising microparticles encapsulating an active agent, components useful for successful application and treatment of the element such as an oral permeation enhancer incorporated within the delivery element or provided with the delivery element in the kit, and a mouthwash used to rinse the mouth before and after treatment.

[0170] In some embodiments, the present invention provides a method of treating mucosal cancer, the method comprising applying a system of the present invention to a mucosal cancer in a subject in need thereof, thereby treating the mucosal cancer. In some embodiments, the mucosal cancer is an oral cancer. In some embodiments, the system of the present invention is applied to a tumor in the oral cavity of a subject in need thereof.

[0171] VIII. Gastrointestinal Drug Delivery Methods In some embodiments, the particle-based drug delivery systems of the present disclosure are developed for the treatment of gastrointestinal diseases and conditions. The delivery elements disclosed herein are effective in part due to their ability to adhere to the intestinal mucosa.

[0172] To properly develop a delivery system, it is first necessary to understand the properties of the mucus itself. Mucus is a viscoelastic gel layer that protects tissues exposed to the external environment. Mucus is primarily composed of cross-linked and intertwined mucin fibers secreted by goblet cells and submucosal glands. Mucins are large molecules, typically 0.5-40 MDa in size, and are coated with complex and highly diverse proteoglycan strings. The pH of mucus can vary greatly depending on the mucosal surface, with highly acidic environments allowing aggregation of mucin fibers and a large increase in the viscoelasticity of the mucus. In the human gastrointestinal tract, the mucus layer is thickest in the stomach and colon. Gastric mucus is exposed to a wide range of pH, and large pH gradients exist within the same mucus cross section, increasing from pH: 1-2 in the lumen to pH: 7 at the epithelial surface.

[0173] Thus, provided herein is a gastrointestinal drug delivery system that can modulate the release of drug in response to the pH of the environment, thereby allowing specific targeting of the drug within the gastrointestinal tract. Described herein is an approach to targeting drug delivery to the gastrointestinal tract through the design of a mucoadhesive delivery system that releases its payload only within the pH environment of the gastrointestinal (GI) tract, and more specifically, only to specific regions within the GI tract. As the lining of the gastrointestinal tract is mucosa, mucosal attraction and mucoadhesion are key factors for this device.

[0174] For orally administered drugs to be delivered to the stomach, they must survive the extreme pH range of the digestive tract. In the human stomach, the volume of gastric juice ranges from 20 to 100 mL and the pH ranges from 1.5 to 3.5. Gastric juice is composed of hydrochloric acid, potassium chloride, and sodium chloride. Secretion of fluid occurs in several stages. Hydrogen and chloride ions are secreted and mixed in the tubules. The lumen of the acid-secreting gland secretes gastric acid that reaches the stomach lumen. Secretion of chloride and sodium ions creates a negative potential of approximately -35 to -65 mV, which allows the diffusion of potassium and sodium ions from the cytoplasm.

[0175] Carbonic anhydrase catalyzes the reaction between water and carbon dioxide to produce carbonic acid, which allows dissociation into hydrogen ions and bicarbonate ions. The hydrogen ions then leave the cell. The sodium ions are reabsorbed. In the tubules, the hydrogen and chloride ions mix and are secreted into the lumen of the acid-secreting gland.

[0176] Gastric acid production is divided into three phases. The first of these phases is the cephalic phase, in which approximately 30% of gastric acid production is stimulated by the smell, taste, or expectation of food following signals from the brain. Approximately 50% of gastric acid is produced during the gastric phase, in which the presence of food in the stomach stimulates production by releasing amino acids from digested material. The enteric phase is the final phase of acid production, in which the remaining 20% ​​of acid is produced when the chyme (semi-liquid of partially digested food) enters the small intestine. For oral delivery of drugs targeted to the gastrointestinal mucosa, the delivery system must remain intact and stable through the gastric acid in the stomach. Development of a system that can remain stable in this environment as well as in multiple pH conditions allows oral administration for delivery of drugs into the gastrointestinal mucosa. In contrast to conventional products with enteric coatings, the system can contain a combination of particles that can not only withstand various pH levels but also be released at the desired pH conditions.

[0177] For an alternative to orally administered enteric capsules to be effective in treating gastrointestinal disorders, such an alternative must have the ability to maintain stability throughout the described acidic and dynamic gastric digestive process. Similarly, since many gastrointestinal disorders may involve multiple regions of the gastrointestinal tract across multiple pH ranges, it would be advantageous to develop a delivery system that can withstand and release at various pH changes. An effective alternative should further be characterized by the ability to be attracted by mucoadhesion to the intestinal mucosal lining and to be released upon contact or at a specified time thereafter. Thus, provided herein are therapeutic, diagnostic, and / or prophylactic delivery devices for local and systemic administration and delivery into and / or beyond the gastrointestinal mucosa, which can be attracted / attached to and penetrate the intestinal mucosa, and remain stable in the acidic conditions of the stomach. The devices described herein can provide extended or delayed release, programmable release, and site-specific release within the gastrointestinal region.

[0178] In many cases, oral administration is not possible if the patient cannot swallow capsules or tablets. This can happen with young children who are less compliant, or with the elderly who are in pain or unable to take oral medications. People who wear feeding tubes or nasogastric tubes are also examples of these cases. In some embodiments, the present invention provides a method for oral delivery of medication to patients who cannot otherwise receive oral medication. This is accomplished in part by the optional use of liquid and gelatin forms in oral administration for patients who cannot swallow solid tablets or capsules, as well as nasal administration or ingestion via a nasogastric or feeding tube. In contrast to conventional administration techniques, this delivery system allows for successful delivery by these means. The particles may be provided in a variety of forms and may be tailored to specific needs.

[0179] The gastrointestinal delivery system also provides an effective therapeutic, diagnostic, and / or prophylactic delivery element in the presence or potential presence of gastrointestinal fluids, in contrast to the traditional irrigation problems associated with gastrointestinal fluids discussed above, and further provides a route for administering therapeutic, diagnostic, and / or prophylactic agents to one or more specific regions of the intestinal epithelium, through the design of the system with one or more particle sets that can be tolerated and released over multiple pH ranges.

[0180] For these and other purposes, the gastrointestinal delivery system disclosed herein may function as an element for specific targeted delivery to the gastrointestinal mucosa within the gastrointestinal tract. In some embodiments, the delivery element comprises pH-targeted mucoadhesive particles that adhere to gastrointestinal mucosal tissue, can withstand the low pH acidic environment of the stomach, and have one or more encapsulated drugs. The element may also include a penetration enhancer sufficient to facilitate penetration of the drug through the mucosal layer of the gastrointestinal tract.

[0181] One of the unique properties of this platform is that the release and targeting attributes can be controlled based on desired parameters. Particles may be controlled to remain stable within a desired pH level and release at another desired pH level. This ability can be utilized to create targeted particle combinations that can remain stable regardless of pH exposure through any component of the gastrointestinal tract, including the stomach, esophagus, and intestinal components.

[0182] In addition to stability, the timing of release of the drug encapsulated in the particle may be controlled. The purpose of this characteristic is to further target delivery to a site in the gastrointestinal tract. For example, if the interference time between oral ingestion and delivery to desired delivery under normal digestive conditions is known, the particle in the delivery system may be further designed to release the drug-carrying component at that amount of time after oral contact with the delivery system. An equation has been developed that may determine the release time. The parameters and equation are shown below. Degree of deacetylation (DA) Molecular weight (MW) combinations, Time (T) Exposure to humidity, moisture content (WC) Solution pH during synthesis (SpH) Viscosity (DV) Synthesis methods such as particle freezing (K is a constant) formula: **Release degree (DR)= a(DA)+ b(MW)+ c (SpH)+ d(T)+ e(WC)+ f(DV)+ k **It has been found that the use of sodium nitrite allows for further control of the degree of deacetylation and molecular weight of chitosan.

[0183] The pH adjustment and configurable release timing enhance the efficacy of the delivery system and demonstrate how innovative it is compared to conventional systems. Without being bound to any particular theory, it is believed that its superior properties are a product of previously unknown effects of the degree of deacetylation and molecular weight of chitosan. The various pH levels of the gastrointestinal tract and the relationship between pH and site can be exploited to target delivery. For example, the particles can be programmed to release only at pH levels between 5.8 and 6.2, thereby allowing specific targeting to the duodenum.

[0184] Targeted release to multiple sites can be achieved by including individualized particle mixtures within the delivery system, allowing for targeting of a series of desired sites when the disease or condition is located in multiple areas or when the drug is best delivered to an entire region of the site. EXAMPLES

[0185] Example 1: Preparation of a system according to Goldberg et al., U.S. Pat. No. 10,398,655 ("Goldberg") Preparation of microparticles All reagents and chemicals used are of excipient or pharmaceutical grade. Solution A: 0.1% cisplatin in 0.1% tripolyphosphate (STPP) Solution B: 0.1% chitosan (CL 113) in 0.175% acetic acid

[0186] 10 mL of solution B was placed in a glass beaker and stirred with a magnetic stirrer at 600 rpm. A total of 10 mL of solution A was transferred dropwise onto the stirred solution B with the aid of a peristaltic pump or any other pump capable of providing a constant flow rate of 1.5 mL / min herein, which is varied to obtain different size, charge, polydispersity, NP yield, and drug encapsulation efficiency properties.

[0187] Various ratios of solution A to solution B (A:B) were used, ranging from 1:1 (same as above) to 1.1:0.85. When half of solution A was transferred, the stirring speed of solution B was gradually increased to 650 rpm. After the transfer of solution A was completed, the stirring speed was gradually increased to 700 rpm, and then the disaccharide trehalose was gradually added to the solution to a final trehalose concentration of 2%. Stirring was continued until all the added trehalose was dissolved (or for at least 10 minutes) to allow the solution to equilibrate. The Z-average, polydispersity index (PDI), average diameter of each peak, and microparticle yield (count rate) of the resulting microparticles were measured.

[0188] For storage, the final microparticle solution is placed in a suitable container and frozen using liquid nitrogen, in dry ice, or in a deep freezer until completely frozen, and then lyophilized until all the solvent is removed.

[0189] Preparation of the base material Devices were fabricated following the teachings of Goldberg using processes A through F described herein.

[0190] A. Aqueous polymer mixtures were prepared from chitosan along with propylene glycol (at concentrations between 5 and 25 wt%) as a hydration enhancer, HPMC (at concentrations between 0.1 and 10 wt%) as a particle adhesion inhibitor, and sucralose (at concentrations between 0.1 and 30 wt%) as a particle aggregation inhibitor.

[0191] B. To this mixture was added the active pharmaceutical ingredient, chitosan-coated cisplatin microparticles having an average diameter of 500 nm to 2000 nm, at a concentration of 10 to 40% by weight.

[0192] C. The resulting mixture was stirred at room temperature for up to 3 hours.

[0193] D. The mixture was frozen and lyophilized under conditions of 0 to 5000 mTorr.

[0194] E. The resulting lyophilized product is a matrix containing chitosan-coated cisplatin microparticles embedded in a polymer matrix.

[0195] F. This matrix was then applied to a water-permeable backing and cut to size to provide an element (herein referred to as a "patch") according to the teachings of Goldberg.

[0196] Example 2: Preparation of improved devices The devices were prepared according to the procedure of steps A-F of Example 1, except that the aqueous mixture of step A further contained various concentrations of sodium chloride as listed herein. The results are summarized in Table 1. Most of the concentrations caused significant problems with the physical properties, clinical administration, and efficacy of the patches. Figure 2 shows photographs of cisplatin-containing patches prepared with sodium chloride concentrations of 0%, 5%, 10%, 12%, 15%, 18%, 20%, 22%, 25%, 28%, and 30% (as marked), with cracking occurring at higher concentrations. Even at concentrations where cracking was not an issue at all, the sodium chloride concentrations were still too high, as the patches were hard and difficult to apply locally to irregularly shaped tumors due to the hardness and rigidity of the patches. Furthermore, sodium chloride caused a general lack of structural integrity in the particles embedded in the matrix, resulting in an immediate burst release profile rather than a sustained release profile.

[0197] The table below shows the effect of various sodium chloride concentrations. [Table 1]

[0198] In this embodiment, equivalent post-lyophilization concentrations of 35% (wt / wt) and 18% (wt / wt) correspond to liquid concentrations of 0.9% (wt / vol) and 0.12% (wt / vol), respectively.

[0199] Following testing as described herein, too much salt made the patch too brittle to be used, while too little salt demonstrated suboptimal in vivo efficacy. Figure 3 illustrates the change in properties of the cisplatin-containing patch due to the presence of sodium chloride, complicating optimization of the resulting patch. The favorable result was a physically flexible patch with improved cell killing and superior in vivo tumor shrinkage.

[0200] Sodium chloride in the freeze-dried patch, i.e., in the range of 10.0% (w / w) to 18.0% w / w, maintained the chemical stability of cisplatin and prevented premature hydrolysis of the drug before it entered the cells, preserving patch performance characteristics such as release characteristics, surface cationic charge, and physical integrity. The sodium chloride concentration range of 10.0% to 18.0% w / w in the freeze-dried patch was able to protect the active drug and improve the efficacy of cisplatin, all while utilizing a significantly lower amount of sodium chloride than the prior art teaches. However, to one of skill in the art, the use of a concentration of 0.12% (w / v) rather than 0.9% (w / v) would not make sense, as this is much lower than the minimum required to prevent hydrolysis. [Table 2]

[0201] Improved release profile: The inventors have found in human studies that an optimal range of sodium concentrations further enhances the release of particles from the patch matrix during patch application. Figure 4 is a set of graphs showing the in vitro dissolution profiles of patches made with varying sodium concentrations from 0% to 35%, showing that the release profile at 18% is slower and more linear and smoother than at 0%. This improved release has had clinical benefits during trials, with increased and consistent release of particles from the patch matrix reducing dose variability between patches.

[0202] Figure 5 is a set of bar graphs showing the drug release rate from patches when applied to tissue for concentrations of 0% and 18% by weight of sodium chloride in the patch. Patches containing the newly developed concentration of sodium chloride (18.0% by weight) elicited superior dose precision and release rate (92% vs. 65% for no sodium chloride) with a standard deviation of only 3.2% (for 182 patches) compared to a standard deviation of 12% for patches without sodium chloride.

[0203] Improved Performance: Literature shows that increasing the concentration of "charge shielding agents" such as sodium chloride reduces the surface charge (also known as the zeta potential) of particles. (International Standard ISO 13099-1, 2012, "Colloidal systems - Methods for Zeta potential determination- Part 1: Electroacoustic and Electrokinetic phenomena") (Dukhin, AS; Goetz, PJ (2017). Characterization of liquids, nano- and micro- particulates and porous bodies using Ultrasound. Elsevier) (Russel, WB; Saville, DA; Schowalter, WR (1989). Colloidal Dispersions. Cambridge University Press). This reduction in surface charge would theoretically lead to reduced efficacy of the patch due to reduced cellular uptake and reduced particle stability. Figure 6 is a set of bar graphs showing microparticle charge data obtained for various concentrations of NaCl in the patch ranging from 0% to 35%. Figure 6 shows that there is a linear trend between the amount of NaCl present and the reduction in charge.

[0204] 7 shows two bar graphs depicting biodistribution data comparing tumors and lymph nodes treated with patches containing 18% sodium chloride by weight and patches without sodium chloride. The figure shows that despite the reduced surface charge resulting from increased sodium chloride concentration, the addition of sodium chloride in the ranges described in this application surprisingly improved drug tissue retention in tumors and lymph nodes by over 400% and 1000%, respectively, compared to the formulation of Example 1. This improvement was shown in clinical trials of the formulations of this application versus the formulation referenced in Example 1.

[0205] FIG. 8A is a photograph showing application of a patch to the buccal mucosa according to one embodiment of the present invention, and FIG. 8B is a photograph showing application of the patch to a mucosal lesion in the anterior two-thirds of the tongue.

[0206] 9 shows two plots of percent tumor volume reduction as a function of time using a patch according to an embodiment of the invention containing 18% NaCl and a patch without NaCl, demonstrating the significant improvement in percent tumor volume reduction for this embodiment compared to the formulation of Example 1.

[0207] Example 3: Preparation of the system 0.676 g of chitosan was mixed in 3372 g of purified water with constant stirring at 500 RPM. 6.29 g of acetic acid was added to the mixture and further stirred at 500 RPM until the chitosan was dissolved. 1.01 g of sodium chloride was dissolved in 844 g of purified water and heated to 37°C. To this, 1.26 g of cisplatin was added and allowed to dissolve for 30 minutes. 0.169 g of sodium tripolyphosphate was added and mixed at 500 RPM for 5 minutes until dissolved. The cisplatin-sodium tripolyphosphate solution was added at a constant flow rate to the chitosan solution to form microparticles.

[0208] The sucralose solution was prepared by adding 1.26 g of sucralose to 12.6 g of purified water and vortexing for 1 minute. 0.633 g of chitosan was mixed in purified water with constant stirring at 500 RPM for 3 minutes. 3.36 g of acetic acid was added to the mixture and further stirred until the chitosan was dissolved. 0.211 g of hypromellose and 422 mL of propylene glycol were added to this solution and stirred until completely dissolved. This solution was then combined with the microparticles along with the sucralose solution and thoroughly mixed to create the pharmaceutical solution.

[0209] The drug solution was dispensed into the molds and flash frozen. The molds were transferred to a freeze dryer and the drug was freeze-dried until all the water was removed. [Table 3] [Table 4]

[0210] Example 4: Treatment of Lip Cancer The patient was diagnosed with advanced stage 4 SCC of the lip and had a poorly differentiated tumor that was characterized as a very rapidly growing tumor. The patient was treated with patches over a one week period including four outpatient treatments. The treatment included 12 mg of cisplatin at each visit (two patches placed adjacent to each other for 10 minutes, repeated three times). The patient received a total of 48 mg of cisplatin over the course of one week. The patient demonstrated a remarkable response to treatment, including safety and reduction in tumor size (Figure 11).

[0211] Example 5: Treatment of Psoriasis Patches were prepared in the same manner as above, substituting allantoin for cisplatin. A patient with moderate psoriasis was treated with the allantoin patches three times a week. See Figure 12.

[0212] The above-described embodiments of the present invention are intended to be merely exemplary, however, many changes and modifications will be apparent to those skilled in the art. All such changes and modifications are intended to be within the scope of the present invention as defined in the appended claims. Although the above-described invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art will recognize that certain changes and modifications may be made within the scope of the appended claims. Furthermore, each of the references provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. In the event of any inconsistency between this application and the references provided herein, this application shall control.

Claims

1. 1. A system including a polymer matrix, comprising: The polymer matrix comprising: Chitosan; a chloride salt of a monovalent cation having a concentration of about 10 to about 18% (w / w) of the polymer matrix; and a plurality of microparticles each comprising chitosan and a therapeutic agent, said plurality of microparticles having an average diameter of 500 nm to 2000 nm; The system comprising:

2. The system of claim 1, wherein the molecular weight of the chitosan is about 80 kDa to 200 kDa.

3. The chloride salts of the monovalent cations are NaCl, KCl, LiCl, RbCl, CsCl, NH 4 Cl, or a combination thereof.

4. 2. The system of claim 1, wherein the chloride salt of the monovalent cation is NaCl.

5. The system of claim 1 , wherein the therapeutic agent comprises an anti-tumor agent.

6. The system of claim 1 , wherein the polymer matrix further comprises a hydration enhancer, the hydration enhancer being ethylene glycol, propylene glycol, beta-propylene glycol, glycerol, or a combination thereof.

7. The system of claim 1 , wherein the polymer matrix further comprises a particle adhesion inhibitor, the particle adhesion inhibitor comprising hydroxypropyl methylcellulose (HPMC).

8. The system of claim 1 , wherein the polymer matrix further comprises a particle agglomeration inhibitor, the particle agglomeration inhibitor being a monosaccharide, a disaccharide, a sugar alcohol, a chlorinated monosaccharide, a chlorinated disaccharide, or a combination thereof.

9. The system of claim 1 , wherein the polymer matrix further comprises a free amount of the therapeutic agent in an amount of about 20 to about 80% of the total amount of the therapeutic agent in the system.

10. The system of claim 1, comprising about 1 to about 50% (weight / weight) cisplatin.

11. The system of claim 1 , wherein the microparticles further comprise sodium tripolyphosphate.

12. 12. The system of claim 11 comprising about 0.1 to about 10% (w / w) sodium tripolyphosphate.

13. 12. The system of claim 11 comprising about 3.0% by weight sodium tripolyphosphate.

14. The polymer matrix is Chitosan in an amount of about 20 to about 30% (w / w); Cisplatin in an amount of about 20 to about 30% (w / w); NaCl in an amount of about 10 to about 18% (w / w); propylene glycol in an amount of about 5 to about 25% (w / w); Hydroxypropyl methylcellulose (HPMC) in an amount of about 0.1 to about 10% (w / w); Sucralose in an amount of about 0.1 to about 30% (w / w); and The system of claim 1 comprising microparticles in an amount of about 10 to about 40% (w / w).

15. The polymer matrix is Chitosan in an amount of about 22.5% (w / w); Cisplatin in an amount of about 22.5% (w / w); NaCl in an amount of about 18% (w / w) of said polymer matrix; propylene glycol in an amount of about 7.75% (w / w); Hydroxypropyl methylcellulose (HPMC) in an amount of about 3.7% (w / w); and 10. The system of claim 1 comprising sucralose in an amount of about 22.25% (w / w).

16. A method for preparing a system according to any one of claims 1 to 15, comprising the steps of: preparing a matrix mixture by forming a first mixture including water, chitosan, a chloride salt, a hydration enhancer, a particle adhesion inhibitor, and a particle aggregation inhibitor; forming a second mixture comprising the matrix mixture, a first platinum antineoplastic agent, and chitosan microparticles comprising a second platinum antineoplastic agent; removing water from the second mixture to prepare a dry mixture; and applying the dry mixture to a backing layer, thereby preparing a system.

17. A method for preparing a system according to any one of claims 1 to 15, comprising the steps of: forming a first mixture comprising water, chitosan, and acetic acid; forming a second mixture comprising a chloride salt, a therapeutic agent, and sodium tripolyphosphate; forming a third mixture comprising said first mixture and said second mixture, thereby forming microparticles; forming a fourth mixture comprising water, chitosan, acetic acid, a hydration enhancer, and a particle adhesion inhibitor; forming a fifth mixture comprising the fourth mixture, a particle agglomeration inhibitor, and the particulates to form the polymer matrix; removing water from the polymer matrix to form a dry mix; and A method comprising the step of applying said dry mixture to a backing layer, thereby preparing a system according to any one of claims 1 to 15.

18. A system described in any one of claims 1 to 15 for use in treating a skin disease in a subject in need of treatment.

19. A system described in any one of claims 1 to 15 for use in treating mucosal cancer in a subject in need of treatment.

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