Biocompatible system for local and sustained-release drug delivery as well as preparation method and use method thereof

Abstract

The present disclosure provides a biocompatible drug delivery system capable of locally and continuously delivering a drug; in addition, the invention also provides a preparation method of the drug delivery system and a method for applying the drug delivery system to treatment of diseases and conditions.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 590,133, filed October 13, 2023, 35 USC § 119(e) (the entire contents of which are incorporated herein by reference). Technical Field

[0003] This disclosure relates to a biocompatible system for local and sustained-release drug delivery, as well as a method for preparing and using the system. Background Technology

[0004] Drugs can be administered via various routes, including oral, inhalation, subcutaneous, intramuscular, intraperitoneal, transdermal, intrapleural, and intravenous injection. These methods all fall under the category of systemic drug delivery. Once absorbed, a drug circulates throughout the body via the bloodstream, eventually reaching its target organs or tissues. In most cases, a minimum concentration must be reached to exert its therapeutic effect. To reduce the need for frequent dosing, the maximum tolerated dose can be administered clinically, or the drug can be formulated into a sustained-release formulation to prolong its duration of action. Unfortunately, systemic administration often leads to adverse toxic reactions; chemotherapy drugs are a typical example. Most chemotherapy drugs primarily target rapidly dividing cells, including tumor cells and normal cells. Therefore, while killing tumor cells, these drugs also damage other rapidly proliferating cells such as bone marrow (responsible for producing blood cells) and hair follicles, resulting in adverse reactions of varying degrees. To mitigate or eliminate these adverse reactions, local or regional drug delivery is often the preferred clinical approach.

[0005] Cancer is a major public health challenge, with both its incidence and mortality rates on the rise. There are many types of cancer, each requiring specific treatment strategies. Some types respond best to surgical intervention, while others respond better to chemotherapy and other drug therapies. Still others employ a comprehensive treatment approach combining surgery and chemotherapy. Lung cancer is a typical example of such a comprehensive treatment. For some patients with non-small cell lung cancer (NSCLC), treatment options encompass surgical resection, combined with immunotherapy and chemotherapy; details of this have been elaborated by PM Forde et al. in the New England Journal of Medicine (NEJM) 386:1973-85 (2022).

[0006] It is worth noting that current chemotherapy, as a treatment method, acts systemically rather than locally. Another local treatment for lung cancer is brachytherapy, as discussed by TA d'Amato et al. in Chest, 114:1112-5 (1998). Brachytherapy involves placing radioactive particles ("seeds") into a biocompatible Vicryl mesh, which is then fixed to the lung tissue to cover the resection anastomosis (i.e., the anastomosis suture).

[0007] In a related development, Schwartz et al. obtained a patent (US Patent No. 10,888,530) for a novel implantable drug delivery composition in which paclitaxel is encapsulated in a matrix of polylactic-co-glycolic acid (PLGA) and polyethylene glycol (PEG) 8000. The composition sheet is then securely attached to lung tissue using staples. Summary of the Invention

[0008] This disclosure provides a biocompatible system for achieving localized and sustained drug delivery. Specific objects, features, and advantages of this disclosure will be summarized in the detailed description with reference to specific exemplary embodiments. The foregoing objects and advantages of this disclosure will be realized and achieved through the compositions and methods specifically pointed out in the written description and claims.

[0009] In one aspect, this disclosure provides a biocompatible delivery system for local and sustained drug release, comprising: (i) a biocompatible polymer having a plurality of electrophilic groups; (ii) a biocompatible polymer having a plurality of nucleophilic groups; and (iii) one or more drugs.

[0010] In another aspect, this disclosure provides a medical patch for treating diseases or conditions, which includes a plurality of the biocompatible delivery systems disclosed herein.

[0011] In another aspect, this disclosure provides a method for treating a disease or condition, comprising: administering a therapeutically effective amount of a therapeutic agent to a subject in need of treatment via a biocompatible delivery system or medical patch according to any embodiment of this disclosure.

[0012] The advantages and safety benefits of this system and its applications are summarized below. The system adheres firmly to tissues through cross-linking without the need for staples. It enables local and sustained drug release for a month or longer, ensuring that the drug maintains the desired concentration level at the local site for an extended period. This results in minimal systemic drug release and reduces or even eliminates systemic adverse reactions. Furthermore, the system demonstrates excellent adaptability to a wide range of drugs.

[0013] Other advantages and benefits of this disclosure will be more fully understood in conjunction with the following figures, detailed description, embodiments and claims. Attached Figure Description

[0014] Figure 1 The study demonstrates the in vitro sustained release of cisplatin over time (days) in various examples of drug delivery systems.

[0015] Figure 2 The process of pressing 18 tablets onto a matrix was demonstrated. Figure 2 A shows the arrangement of these 18 pills on the patch. Figure 2 B demonstrates that the patch is folded three times to form a four-layer structure, allowing it to pass through sleeves with a diameter of 10 mm or larger. Detailed Implementation

[0016] In one aspect, this disclosure provides a biocompatible delivery system for local and sustained-release drug administration, the system comprising: (i) a biocompatible polymer having a plurality of electrophilic groups; (ii) a biocompatible polymer having a plurality of nucleophilic groups; and (iii) a drug.

[0017] In one embodiment, the biocompatible delivery system also includes polyethylene glycol (PEG).

[0018] In another embodiment, the biocompatible delivery system also comprises polylactic acid-glycolic acid copolymer (PLGA).

[0019] In yet another embodiment, the biocompatible delivery system comprises both polyethylene glycol and polylactic acid-glycolic acid copolymer.

[0020] In some embodiments, the biocompatible delivery system also includes fillers and / or binders.

[0021] In some embodiments, all components of the biocompatible delivery system are in powder form and are compressed into tablets.

[0022] In some embodiments, in this biocompatible delivery system, the biocompatible polymer having multiple electrophilic groups is multi-arm polyethylene glycol-succinimide glutarate, while the biocompatible polymer having multiple nucleophilic groups is multi-arm polyethylene glycol amine.

[0023] In some embodiments, the biocompatible delivery system is in tablet form and can be applied directly to the lesion site by mechanical means. In some embodiments, the lesion site is a tumor site.

[0024] In some embodiments, the biocompatible delivery system is in tablet form and can be converted into a rod shape for injection into body cavities.

[0025] This local sustained-release drug delivery system can be used for the sustained-release delivery of various drugs, including but not limited to: chemotherapy drugs, analgesics, antipsychotic drugs, and anti-infective antibiotics.

[0026] In some embodiments, this biocompatible delivery system can be used to deliver drugs selected from the following classes: cyclophosphamide, cisplatin, carboplatin, melphalan, methotrexate, 5-fluorouracil (5-FU), gemcitabine, cytarabine, vincristine, vincaine, paclitaxel, docetaxel, etoposide, irinotecan, doxorubicin, bleomycin, mitomycin, prednisone, dexamethasone, bevacizumab, trabectedin, pemetrexed; analgesics such as ibuprofen, naproxen, diclofenac, celecoxib, acetaminophen, morphine, oxycodone, hydrocodone, fentanyl, lidocaine, bupivacaine, amitriptyline, duloxetine, gabapentin, pregabalin, capsaicin, prednisone, dexamethasone; and antipsychotics such as haloperidol, chlorpromazine, fluphenazine, thiophanate-methyl. Lidaridine, loxapine, perphenazine, trifluoperazine, thiothoxane, prochlorperazine, cloprothoxane, risperidone, olanzapine, quetiapine, aripiprazole, clozapine, ziprasidone, paliperidone, lurasidone, ipraridone, and asenapine; and antibiotics used for the treatment of infections, such as amoxicillin, penicillin V, flucloxacillin, cephalexin, cefuroxime, ceftriaxone, doxycycline, tetracycline, minocycline, azithromycin, erythromycin, clarithromycin, gentamicin, tobramycin, amikacin, ciprofloxacin, levofloxacin, moxifloxacin, trimethoprim / sulfamethoxazole, sulfamethoxazole, clindamycin, lincomycin, vancomycin, teicoplanin, linezolid, terdizolid, imipenem / cilastatin, meropenem, ertapenem, and aztreonam, or similar substances.

[0027] In another aspect, this disclosure provides a medical patch that includes a plurality of biocompatible delivery systems according to any of the embodiments disclosed herein.

[0028] In some embodiments, the biocompatible delivery system is in tablet form and is arranged and pressed onto the medical patch.

[0029] In some embodiments, the medical patch is folded into a multi-layered structure and can be delivered into a body cavity via a cannula.

[0030] In some embodiments, the medical patch unfolds within a body cavity and adheres to the tissue surface.

[0031] In some embodiments, the tissue surface of the medical patch is located at or near the tumor site.

[0032] In another aspect, this disclosure provides a method for treating a disease or condition, comprising administering a therapeutically effective amount of a therapeutic agent to a subject in need of treatment via a biocompatible delivery system or medical patch according to any embodiment of this disclosure.

[0033] There are no limitations on the diseases or conditions that can be treated using the drug delivery system disclosed herein. In some embodiments (sometimes preferably), the diseases are selected from cancer, pain, mental health-related disorders, and infections.

[0034] In some embodiments, and sometimes preferably, the disease or condition is cancer.

[0035] In some embodiments, and sometimes preferably, the cancer is selected from tumors / cancers of the lungs, kidneys, stomach, esophagus, intestines, bladder, prostate, liver, pancreas, heart, ovaries, uterus, and any organ within a body cavity.

[0036] In some embodiments, this disclosure relates to a biocompatible system for achieving local and sustained drug delivery, comprising: (i) a biocompatible polymer having a plurality of electrophilic groups; (ii) a biocompatible polymer having a plurality of nucleophilic groups; and (iii) a drug.

[0037] In some embodiments, this disclosure relates to a biocompatible system for achieving local and sustained-release drug delivery, comprising: (i) a biocompatible polymer having a plurality of electrophilic groups; (ii) a biocompatible polymer having a plurality of nucleophilic groups; (iii) PEG; and (iv) a drug.

[0038] In some embodiments, this disclosure relates to a biocompatible system for achieving local and sustained-release drug delivery, comprising: (i) a biocompatible polymer having a plurality of electrophilic groups; (ii) a biocompatible polymer having a plurality of nucleophilic groups; (iii) PEG; (iv) PLGA; and (v) a drug.

[0039] In some embodiments, this disclosure relates to a biocompatible system for achieving local and sustained-release drug delivery, comprising: (i) a biocompatible polymer having a plurality of electrophilic groups; (ii) a biocompatible polymer having a plurality of nucleophilic groups; (iii) PLGA; and (iv) a drug. In some embodiments, and sometimes preferably, the biocompatible polymer is bioinert and water-soluble, including polyethylene glycol (PEG), polyethylene oxide (PEO), polyethylene oxide-co-propylene oxide (PPO), polyethylene oxide block or random copolymers, and polyvinyl alcohol (PVA); polyvinylpyrrolidone (PVP); polyamino acids; dextran, etc. In some embodiments, polyethylene glycol (PEG) is preferred. In some embodiments, the molecular weight of the PEG is about 5,000 Daltons to about 40,000 Daltons (i.e., about 5 kDa to about 40 kDa); sometimes preferably about 5 kDa to about 10 kDa; sometimes preferably about 5 kDa to about 20 kDa; sometimes preferably about 10 kDa to about 30 kDa; sometimes preferably about 10 kDa to about 20 kDa; sometimes preferably about 10 kDa to about 30 kDa; sometimes preferably about 5 kDa; sometimes preferably about 10 kDa; sometimes preferably about 15 kDa; sometimes preferably about 20 kDa.

[0040] In some embodiments, the electrophilic group is preferably a succinimide group. In some embodiments, preferred electrophilic polymers include PEG-succinimide glutarate (PEG-SG), PEG-succinimide propionate (PEG-SE), PEG-succinimide succinamide (PEG-SSA), PEG-succinimide carbonate (PEG-SC), and other polymer derivatives containing a succinimide group.

[0041] In some embodiments, and preferably, the electrophilic polymer in this disclosure is polyethylene glycol containing two or more succinimide groups, denoted as “n arm-PEG-SG” or “n-arm-PEG-SG”, where “n” refers to the number of PEG arms in the molecule. An example of such multi-arm PEG-SG is a 4-arm PEG-SG (or “4-arm-PEG-SG”) with a molecular weight ranging from about 5,000 to 40,000 Daltons; sometimes preferably about 5 kDa to 10 kDa, sometimes preferably about 5 kDa to 20 kDa, sometimes preferably about 5 kDa to 30 kDa, sometimes preferably about 10 kDa to 20 kDa, sometimes preferably about 10 kDa to 30 kDa; sometimes preferably about 5 kDa, sometimes preferably about 10 kDa, sometimes preferably about 15 kDa, sometimes preferably about 20 kDa. Another example of such multi-arm PEG-SG is an 8-arm PEG-SG with a molecular weight range of about 5,000 to 40,000 Daltons; sometimes preferably about 5 kDa to 10 kDa, sometimes preferably about 5 kDa to 20 kDa, sometimes preferably about 5 kDa to 30 kDa, sometimes preferably about 10 kDa to 20 kDa, sometimes preferably about 10 kDa to 30 kDa; sometimes preferably about 5 kDa, sometimes preferably about 10 kDa, sometimes preferably about 15 kDa, sometimes preferably about 20 kDa.

[0042] In some embodiments, the nucleophilic group is preferably a primary amino group, a thiol group, or their salt forms (e.g., salts formed with hydrogen chloride). Some polypeptides contain a primary amino group (e.g., polylysine) and a thiol group (e.g., cysteine). Other biological peptides (such as proteins) may also provide a primary amino group for cross-linking with the electrophilic group. Serum albumin is a typical example. In some embodiments, a primary amino group is preferred over a thiol group because the reaction of a thiol group with an electrophilic group tends to be slower than the reaction of a primary amino group with an electrophilic group.

[0043] In some embodiments, the polymer with the nucleophilic group is preferably polyethylene glycol containing two or more amino groups; for example, 4-arm PEG-Amine, with a molecular weight range of about 5 kDa to 40 kDa. Sometimes a preferred range is about 5 kDa to 10 kDa; sometimes about 5 kDa to 20 kDa; sometimes about 50 kDa to 30 kDa; sometimes about 10 kDa to 20 kDa; sometimes about 10 kDa to 30 kDa; sometimes about 5 kDa; sometimes about 10 kDa; sometimes about 15 kDa; sometimes about 20 kDa.

[0044] Polymer powders containing multiple electrophilic groups are mixed with polymer powders containing multiple nucleophilic groups, and drug powder and filler powders such as mannitol are added. The mixture is then placed in a mold for tableting. The pressure applied during compression removes as much air as possible from the mixture. Mannitol acts as a filler and binder to aid in the formation of the tablet (i.e., the drug delivery system). After the tablet is placed on the surface of the tumor site, the surgeon can drip saline solution onto it, and the tablet will absorb some of the liquid. Subsequently, the tablet will cross-link with the amino groups on the tissue proteins, thus adhering firmly to the tissue surface. Furthermore, the polymers containing multiple electrophilic groups and the polymers containing multiple nucleophilic groups also cross-link with each other, forming a PEG gel. Thanks to the hydrophilic properties of these polymers, the drug can be sustained in the short term through diffusion; in the long term, sustained drug release mainly relies on the synergistic effect of diffusion and polymer degradation.

[0045] In some embodiments, the selected PEG preferably has a molecular weight between 5,000 and 20,000 Daltons. In some embodiments, the formulation includes PEG10k (or PEG5k to PEG20k), which effectively reduces the drug diffusion rate by sealing certain micropores within the cross-linked gel. If PLGA polymer is added additionally during sample preparation, some of the drug will be trapped (or embedded) within the polymer matrix, further reducing the overall drug diffusion rate. Therefore, when PLGA polymer is used alone without the addition of PEG10k, the drug release rate is minimized (i.e., the release process is slowest). In summary, the sustained drug release time in this drug delivery system exhibits the following increasing order: First Embodiment < Second Embodiment < Third Embodiment < Fourth Embodiment. (See also...) Figure 1 (and Table 3).

[0046] This drug delivery system can be prepared in various forms to suit different drug delivery applications. The fifth embodiment of this disclosure relates to a method for preparing a biocompatible patch system designed for delivery to organs or tissues via a trocar. Specifically, multiple tablets are pressed and fixed onto a woven fiber matrix to form the patch. Before use, the patch can be folded into a compact shape to facilitate passage through a trocar with a diameter of 10 mm or larger. Once inside the body and unfolded, the patch can be applied to the surface of the target tissue (including the tumor itself or the area surrounding the tumor). After being moistened with saline solution, the patch is gently pressed, allowing the polymer containing multiple electrophilic groups to form crosslinks on the tissue surface. Figure 2 Preferred fiber matrix can be any absorbable fiber patch or mesh, such as Tistat absorbable hemostatic agent (woven sodium carboxymethyl cellulose), Vicryl woven mesh, PROCEED surgical mesh, SURGICEL hemostatic agent, and INTERCEED (Ethicon Inc., New Brunswick, New Jersey).

[0047] In some embodiments, this disclosure relates to a method of treating tumor tissue in a patient. The method includes applying the system to a tracheal tumor region. A tablet (or a smaller tablet) is delivered to the tracheal tumor site, which can be achieved via bronchoscopy or a robot-assisted bronchoscopy procedure. The tablet absorbs fluid, subsequently undergoing a cross-linking reaction to form a gel, and cross-links with the tumor surface and surrounding tissue.

[0048] In some embodiments, this disclosure relates to a method of delivering a drug to a patient via intraperitoneal injection. The method includes applying the system into the peritoneal cavity. All components required for the system are compressed into rods for containment within a suitable intraperitoneal injection needle. The rods are designed to absorb fluid and subsequently cross-link with tissues upon delivery into the peritoneal cavity.

[0049] This system offers numerous advantages. PEG-SG reacts with primary amino groups in proteins. It can adhere to the surface of any organ or tissue in the body without the need for sutures or staples. It is suitable for organs or tissues such as the lungs, kidneys, stomach, esophagus, intestines, and bladder. This system achieves true local drug delivery without the need for implantation (embedding) into organs or tissues. It reduces the need for systemic administration of high drug concentrations, while significantly improving therapeutic efficacy by maintaining the minimum effective drug concentration locally for more than 30 days and keeping the drug concentration in the systemic circulation at extremely low levels. Therefore, the risk of systemic adverse reactions (if any) is extremely low. This system is biocompatible and non-toxic and non-immunogenic.

[0050] Unless otherwise expressly defined, all technical terms, symbols and other scientific terms used herein shall have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0051] The singular forms “a”, “an” and “the” used in this article all contain plural references (and vice versa, that is, any plural form also contains singular references), unless the context explicitly states otherwise.

[0052] The term "about," unless otherwise explicitly defined, typically refers to a range within plus or minus 10% of the indicated value. For example, "about 10%" could represent a range of 9% to 11%. Sometimes, preferably, "about" includes within plus or minus 5% of the indicated value. Alternatively, "about" includes within plus or minus 5% of the indicated value. When "about" precedes a range, the modifier applies to both the lower and upper limits of that range.

[0053] The term "multiple" as used herein means "a plurality of," and these two terms are generally used interchangeably. When the terms "multiple" or "a plurality of" are applied to "electron groups" or "nucleophiles," they mean: in some embodiments, "at least two" or "two or more"; in some embodiments, "at least three" or "three or more"; in some embodiments, "at least four" or "four or more." In some embodiments, it is sometimes preferred that "multiple" refers to 2, 3, 4, 5, or 6. In some embodiments, it refers to 2 to 4. In some embodiments, it is sometimes preferred that it refers to 2 to 3. In some embodiments, it is sometimes preferred that it refers to 2.

[0054] As used in this article, the term "body cavity" refers to a cavity in the body that houses vital organs. Examples of body cavities include, but are not limited to: the thoracic cavity, which houses the heart and lungs; the abdominal cavity, which houses digestive organs such as the stomach, liver, and intestines; the pelvic cavity, which contains the reproductive organs, bladder, and rectum; the cranial cavity, which houses the brain; and the spinal canal, which surrounds the spinal cord.

[0055] As used herein, the term "electrophilic group" refers to a functional group within a molecule that acts as an electrophile; this means that the group can readily accept a pair of electrons from another molecule (i.e., the nucleophile), thereby forming a covalent bond. Such groups are typically positively charged due to the attachment of electron-withdrawing groups or contain atoms with a partially positive charge. Examples of electrophilic groups include, but are not limited to: activated esters (such as N-hydroxysuccinimide (NHS) esters), carbonyl compounds (including aldehydes and ketones), haloalkanes (such as bromomethane (CH3Br)), isothiocyanates, and epoxides.

[0056] As used herein, the term "nucleophile" refers to a functional group that contains an electron-rich atom and can act as a nucleophile, providing a pair of electrons to form a new covalent bond. Examples of nucleophilic atoms include oxygen, nitrogen, and sulfur; common examples of nucleophilic functional groups include, but are not limited to: amines (such as primary, secondary, and tertiary amines), alcohols (containing hydroxyl groups -OH), thiols (also known as mercapto groups, containing -SH), carboxylates (such as carboxylic acids -COOH and their derivatives), and phosphates.

[0057] As used herein, the term "biocompatible polymer" refers to a polymeric material that is compatible with living tissues, can be used in vivo or peripherally, and does not cause any serious side effects. Such polymers can be synthetic or natural. Examples of biocompatible polymers include, but are not limited to: polyethylene glycol (PEG), polyethylene oxide (PEO), polyethylene oxide-co-propylene oxide (PPO), polyethylene oxide block or random copolymers, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), polyamino acids, dextran, etc.

[0058] As used herein, the term "multi-arm polyethylene glycol-succinimide glutarate (PEG-SG)" or similar term refers to a compound having a PEG core and multiple electrophilic groups, such as multi-arm PEG-SG. The number of said multiple electrophilic groups can be 2 to 12, sometimes preferably 2 to 8, sometimes preferably 4 to 8 (e.g., 4, 5, 6, 7 or 8), and sometimes preferably 4, 6 or 8.

[0059] The term "multi-arm polyethylene glycol-succinimide glutarate" or similar term refers to a multi-arm polyethylene glycol (PEG) derivative in which each arm is terminated with a succinimide ester group.

[0060] The terms "8-arm polyethylene glycol-succinimide glutarate", "8-arm PEG-SG", or similar terms refer to an eight-arm polyethylene glycol (PEG) derivative, wherein each of the eight arms is terminated with a succinimide NHS ester group. These arms are linked to a hexaglycerol core.

[0061] For example, the term "multi-arm polyethylene glycol-nucleophile" or similar term as used herein refers to a compound having a PEG core and multiple nucleophilic groups, such as a multi-arm PEG-amine. The number of said multiple nucleophilic groups may be 2 to 12, sometimes preferably 2 to 8, sometimes preferably 4 to 8 (e.g., 4, 5, 6, 7 or 8), and sometimes preferably 4, 6 or 8.

[0062] The term "multi-arm polyethylene glycol-amine" or similar terms refer to a multi-arm polyethylene glycol (PEG) derivative in which each arm is terminally end in an amino group. For example, the terms "4-arm polyethylene glycol-amine," "4-arm-PEG-amine," or similar terms refer to a multi-arm PEG derivative having a pentaerythritol core and each of its four arms terminally end in a primary amine group.

[0063] In this disclosure, terms such as “PEG-SG20k” refer to polyethylene glycol-succinimide glutarate with a molecular weight of 20 kDa; terms such as “PEG-Amine5k” refer to polyethylene glycol-amine with a molecular weight of 5 kDa; and other similar terms will be understood by those skilled in the art accordingly.

[0064] As used herein, the terms “drug,” “therapeutic agent,” “pharmaceutical formulation,” or similar terms refer to an active pharmaceutical ingredient, and sometimes to a composition containing that ingredient. These terms are sometimes used interchangeably in this application. Medicines suitable for delivery according to this disclosure include, but are not limited to: chemotherapy drugs such as cyclophosphamide, cisplatin, carboplatin, melphalan, methotrexate, 5-fluorouracil (5-FU), gemcitabine, cytarabine, vincristine, vincaine, paclitaxel, docetaxel, etoposide, irinotecan, doxorubicin, bleomycin, mitomycin, prednisone, dexamethasone, bevacizumab, trabectedin, pemetrexed; analgesics such as ibuprofen, naproxen, diclofenac, celecoxib, acetaminophen, morphine, oxycodone, hydrocodone, fentanyl, lidocaine, bupivacaine, amitriptyline, duloxetine, gabapentin, pregabalin, capsaicin, prednisone, dexamethasone; and antipsychotic drugs such as haloperidol, chlorpromazine, and fluphenazine. Intravenous, thioridazine, loxapine, perphenazine, trifluoperazine, thiothoxan, prochlorperazine, cloprothoxan, risperidone, olanzapine, quetiapine, aripiprazole, clozapine, ziprasidone, paliperidone, lurasidone, ipraridone, and asenapine; and antibiotics used for anti-infective purposes, such as amoxicillin, penicillin V, flucloxacillin, cephalexin, cefuroxime, ceftriaxone, doxycycline, tetracycline, minocycline, azithromycin, erythromycin, clarithromycin, gentamicin, tobramycin, amikacin, ciprofloxacin, levofloxacin, moxifloxacin, trimethoprim / sulfamethoxazole, sulfamethoxazole, clindamycin, lincomycin, vancomycin, teicoplanin, linezolid, terdizolid, imipenem / cilastatin, meropenem, ertapenem, and aztreonam. As used herein, the term "filler" refers to an inert substance used to increase the volume of a tablet or capsule. Examples of fillers suitable for use in this disclosure include, but are not limited to, mannitol, sucrose, lactose, microcrystalline cellulose (MCC), calcium hydrogen phosphate dihydrate, starch, glucose, and sodium bicarbonate.

[0065] The term "topical administration" as used in this article refers to the direct application of the drug in the gel to a specific part of the body, rather than through intravenous injection or into the stomach via the mouth and esophagus.

[0066] The term "sustained release" as used in this article refers to a drug delivery system designed to gradually release a drug over time.

[0067] As used herein, the term "binding agent" refers to an excipient used to bind the components together and impart the desired mechanical strength to a tablet. Examples of binding agents suitable for use in this disclosure include, but are not limited to, starch, gelatin, polyvinylpyrrolidone (PVP), microcrystalline cellulose (MCC), sucrose, hydroxypropyl methylcellulose (HPMC), and ethyl cellulose.

[0068] The terms “comprising,” “having,” “including,” and “containing,” or similar terms, unless otherwise stated, shall be interpreted as open-ended terms (i.e., meaning “including but not limited to”).

[0069] The terms “subject,” “patient,” or similar terms used in this article are intended to encompass both human and non-human animals, such as non-human primates, domesticated animals, and / or agriculturally useful animals (e.g., horses, sheep, dogs, cats, cattle, pigs, etc.).

[0070] As used herein, “treatment,” “curing,” or “manipulation” in relation to a subject suffering from a disease or condition means implementing a protocol (e.g., administering a therapeutic agent using the delivery system of this disclosure) on the subject so as to cure, heal, alleviate, relieve, alter, remedy, improve, or enhance at least one symptom of the disease or condition.

[0071] This disclosure is intended to cover any reasonable combination of the disclosed embodiments.

[0072] The following examples are for illustrative purposes only and are not intended to limit the scope of this disclosure as defined by the appended claims.

[0073] Example

[0074] Material

[0075] PLGA: The Resomer RG series poly(lactic-co-glycolic acid) copolymer produced by Evonik Industries AG is selected, with a molar ratio of lactol to glycolol ranging from 50:50 to 85:15.

[0076] PEG-SG20k: 8-arm poly(ethyleneglycol)-succinimidyl glutarate, with a molecular weight (MW) of 20 kDa, manufactured by JenKem Technologies.

[0077] PEG-Amine5k: 4-arm poly(ethylene glycol)-Amine, with a molecular weight (MW) of 5 kDa, is manufactured by JenKem Technologies.

[0078] PEG10k: Poly(ethylene glycol) with a molecular weight (MW) of 10 kDa.

[0079] Example 1: PEG0PLGA0

[0080] All components and their respective weights are recorded in Table 1. All components, namely 1200 mg PEG-SG20kJ, 600 mg PEG-Amine5kJ, 60 mg cisplatin, and 200 mg mannitol, were mixed together. This mixture was processed into tablets using a tableting machine. A total of 10 tablets were prepared from this mixture, each containing 6 mg of cisplatin. These tablets underwent in vitro release studies, and the results are presented in Table 1. Figure 1 middle.

[0081]

[0082] Example 2 PEG80PLGA0

[0083] All components and their respective weights are recorded in Table 1. To prepare the mixture, 2 mL of dichloromethane was added to a test tube containing 240 mg of PEG10k. The test tube was then shaken until the PEG was completely dissolved. Immediately afterwards, 60 mg of cisplatin was added to the PEG test tube. The resulting suspension was then homogenized using a small homogenizer at 10,000 rpm for 2 minutes. The mixture was then transferred to an aluminum weighing dish and placed in a fume hood to allow the solvent to evaporate naturally overnight. The weighing dish containing the mixture was then transferred to a vacuum oven to ensure complete solvent removal. The resulting PEG-cisplatin flakes were then cut into small pieces with scissors. These small pieces were then pulverized using a high-speed grinder at 10,000 rpm for 5 minutes. The pulverized PEG-cisplatin material was then mixed with other components, namely 1200 mg PEG-SG20kJ, 600 mg PEG-Amine5kJ, and 200 mg mannitol. The mixture was then processed using a tableting machine to form tablets. A total of 10 tablets were prepared, each containing 6 mg of cisplatin. In vitro release tests were then performed on these tablets, and the results are as follows: Figure 1 As shown.

[0084] Example 3 PEG70PLGA10

[0085] All components and their respective weights are recorded in Table 1. To prepare the mixture, 2 mL of dichloromethane was added to a test tube containing 210 mg PEG10k and 30 mg PLGA (polylactic acid-glycolic acid copolymer). The test tube was then shaken until both PEG and PLGA were completely dissolved. Next, 60 mg cisplatin was added to the PEG-PLGA test tube. The resulting suspension was then homogenized using a small homogenizer at 10,000 rpm for 2 minutes. The mixture was then transferred to an aluminum weighing dish and placed in a fume hood overnight to allow solvent evaporation. The weighing dish containing the mixture was then transferred to a vacuum oven to ensure complete solvent removal. The resulting PEG-cisplatin-PLGA flakes were then cut into small pieces. These small pieces were then pulverized using a high-speed grinder at 10,000 rpm for 5 minutes. The pulverized PEG-cisplatin-PLGA material was then mixed with other components, namely 1200 mg PEG-SG20kJ, 600 mg PEG-Amine5kJ, and 200 mg mannitol. The mixture was then processed using a tableting machine to form tablets. A total of 10 tablets were prepared, each containing 6 mg of cisplatin. In vitro release studies were then conducted on these tablets, and the results are presented below. Figure 1 middle.

[0086] Example 4 PEG50PLGA30

[0087] All components and their respective weights are recorded in Table 1. To prepare the mixture, 2 mL of dichloromethane was added to a test tube containing 150 mg PEG10k and 90 mg PLGA. The test tube was shaken until both PEG and PLGA were completely dissolved. Subsequently, 60 mg cisplatin was added to the PEG-PLGA test tube. The resulting suspension was then homogenized using a small homogenizer at 10,000 rpm for 2 minutes. The mixture was then transferred to an aluminum weighing dish and placed in a fume hood to allow the solvent to evaporate overnight. The weighing dish containing the mixture was then transferred to a vacuum oven to ensure complete solvent removal. The resulting PEG-cisplatin-PLGA flakes were then cut into small pieces with scissors. These small pieces were then pulverized using a high-speed grinder at 10,000 rpm for 5 minutes. The pulverized PEG-cisplatin-PLGA material was then mixed with other components, namely 1200 mg PEG-SG20k, 600 mg PEG-Amine5k, and 200 mg mannitol. This mixture was then processed into tablets using a tableting machine. A total of 10 tablets were prepared from this mixture, each containing 6 mg of cisplatin. In vitro release studies were subsequently performed on these tablets, and the results are shown in Figure 1 and Table 2.

[0088] Example 5 PEG30PLGA50

[0089] All components and their respective weights are recorded in Table 1. To prepare the mixture, 2 mL of dichloromethane was added to a test tube containing 90 mg of PEG10k and 150 mg of PLGA. The test tube was shaken until both PEG and PLGA were completely dissolved. Subsequently, 60 mg of cisplatin was added to the PEG-PLGA test tube. The resulting suspension was then homogenized using a small homogenizer at 10,000 rpm for 2 minutes. The mixture was then transferred to an aluminum weighing dish and placed in a fume hood overnight to allow the solvent to evaporate. Next, the weighing dish containing the mixture was transferred to a vacuum oven to ensure complete solvent removal. The resulting PEG-cisplatin-PLGA sheet was then cut into small pieces using scissors. These small pieces were then pulverized in a high-speed grinder at 10,000 rpm for 5 minutes. Subsequently, the pulverized PEG-cisplatin-PLGA material was mixed with other components, specifically 1200 mg PEG-SG20kJ, 600 mg PEG-Amine5kJ, and 200 mg mannitol. This mixture was then compressed into tablets using a tableting machine. A total of 10 tablets were prepared from this mixture, each containing 6 mg of cisplatin. In vitro release studies were then conducted on these tablets, and the results are presented below. Figure 1 And in Table 2.

[0090] Example 6 PEG10PLGA70

[0091] All components and their respective weights are recorded in Table 1. To prepare the mixture, 2 mL of dichloromethane was added to a test tube containing 30 mg PEG10k and 210 mg PLGA. The test tube was shaken until both PEG and PLGA were completely dissolved. Subsequently, 60 mg cisplatin was added to the PEG-PLGA test tube. The resulting suspension was then homogenized using a small homogenizer at 10,000 rpm for 2 minutes. The mixture was then transferred to an aluminum weighing dish and placed in a fume hood to allow the solvent to evaporate overnight. The weighing dish containing the mixture was then transferred to a vacuum oven to ensure complete solvent removal. The resulting PEG-cisplatin-PLGA flakes were then cut into small pieces with scissors. These small pieces were then pulverized using a high-speed grinder at 10,000 rpm for 5 minutes. The pulverized PEG-cisplatin-PLGA material was then mixed with other components, namely 1200 mg PEG-SG20k, 600 mg PEG-Amine5k, and 200 mg mannitol. The mixture was then compressed into tablets using a tablet press. A total of 10 tablets were prepared, each containing 6 mg of cisplatin. In vitro release studies were subsequently performed on these tablets, and the results are shown in Figure 1 and Table 2.

[0092] Example 7 PEG5PLGA75

[0093] All components and their respective weights are recorded in Table 1. To prepare the mixture, 2 mL of dichloromethane was added to a test tube containing 15 mg of PEG10k and 225 mg of PLGA. The test tube was shaken until both PEG and PLGA were completely dissolved. Subsequently, 60 mg of cisplatin was added to the PEG-PLGA test tube. The resulting suspension was then homogenized using a small homogenizer at 10,000 rpm for 2 minutes. The mixture was then transferred to an aluminum weighing dish and placed in a fume hood overnight to allow the solvent to evaporate. The weighing dish containing the mixture was then transferred to a vacuum oven to ensure complete solvent removal. The resulting PEG-cisplatin-PLGA sheet was then cut into small pieces using scissors. These small pieces were then pulverized in a high-speed grinder at 10,000 rpm for 5 minutes. Subsequently, the pulverized PEG-cisplatin-PLGA material was mixed with other components, specifically 1200 mg PEG-SG20kJ, 600 mg PEG-Amine5kJ, and 200 mg mannitol. This mixture was then compressed into tablets using a tableting machine. A total of 10 tablets were prepared from this mixture, each containing 6 mg of cisplatin. In vitro release studies were then conducted on these tablets, and the results are presented below. Figure 1 And in Table 2.

[0094] Example 8 PEG0PLGA80

[0095] All components and their respective weights are recorded in Table 1. To prepare the mixture, 2 mL of dichloromethane was added to a test tube containing 240 mg of PLGA. The test tube was shaken until the PLGA was completely dissolved. Subsequently, 60 mg of cisplatin was added to the PLGA test tube. The resulting suspension was then homogenized using a small homogenizer at 10,000 rpm for 2 minutes. The mixture was then transferred to an aluminum weighing dish and placed in a fume hood to allow the solvent to evaporate naturally overnight. The weighing dish containing the mixture was then transferred to a vacuum oven to ensure complete solvent removal. The resulting cisplatin-PLGA flakes were then cut into small pieces with scissors. These small pieces were then pulverized using a high-speed grinder at 10,000 rpm for 5 minutes. The pulverized cisplatin-PLGA material was then mixed with other components, namely 1200 mg PEG-SG20k, 600 mg PEG-Amine5k, and 200 mg mannitol. The mixture was then compressed into tablets using a tablet press. A total of 10 tablets were prepared, each containing 6 mg of cisplatin. In vitro release studies were subsequently performed on these tablets, and the results are shown in Figure 1 and Table 2.

[0096] Example 9 In vitro drug release test

[0097] In vitro drug release tests were conducted on the tablets prepared in Examples 1 to 8. One tablet was placed in a 2 mL test tube containing 1.2 mL of physiological saline. The next day, all the saline solution was collected, and 0.8 mL of fresh physiological saline was added. This procedure was repeated for a total of 42 days. The cisplatin content was quantitatively determined by LC-MS. The results are shown in Figure 1 and Table 2.

[0098] Table 2. Cumulative release of cisplatin

[0099]

[0100] The hydrophilic properties of PEG polymers enable the sustained release of cisplatin via diffusion, induced by the swelling of PEG upon absorbing water. Introducing additional PEG10k leads to partial blockage of the micropores within the PEG gel, significantly reducing the diffusion rate of cisplatin. Adding PLGA can further reduce the diffusion rate. Optimal drug release rates can be achieved by adjusting the amounts of PEG10k and PLGA in the drug delivery system.

[0101] Example 10 PEG0PLGA0V10

[0102] All components and their respective weights are listed in Table 3. All components—1200 mg PEG-SG20kJ, 600 mg PEG-Amine5kJ, 20 mg vinorelbine, and 200 mg mannitol—were mixed together. The mixture was then processed using a tableting machine to produce tablets. A total of 10 tablets were prepared from this mixture, each containing 2 mg of vinorelbine.

[0103] Table 3. Examples 10-17 (Changchun Ruibin Formula)

[0104]

[0105] Example 11 PEG80PLGA0V11

[0106] All components and their respective weights are recorded in Table 3. To prepare the mixture, 2 mL of dichloromethane was added to a test tube containing 240 mg PEG-10k and 20 mg vinorelbine. The test tube was shaken until the PEG and vinorelbine were completely dissolved. The resulting mixture was then transferred to an aluminum weighing dish and placed in a fume hood to allow the solvent to evaporate naturally overnight. Next, the weighing dish containing the mixture was transferred to a vacuum oven to ensure complete solvent removal. The resulting PEG-vinorelbine flakes were then cut into small pieces using scissors. These small pieces were then pulverized using a high-speed grinder at 10,000 rpm for 5 minutes. The pulverized PEG-vinorelbine material was then mixed with the other components: 1200 mg PEG-SG20k, 600 mg PEG-Amine5k, and 200 mg mannitol. The mixture was then processed using a tableting machine to form tablets. The mixture was used to prepare 10 tablets, each containing 2 mg of vinorelbine.

[0107] Example 12 PEG70PLGA10V12

[0108] All components and their respective weights are recorded in Table 3. To prepare the mixture, 2 mL of dichloromethane was added to a test tube containing 210 mg PEG10k, 20 mg vinorelbine, and 30 mg PLGA. The test tube was shaken until the PEG, vinorelbine, and PLGA were completely dissolved. The resulting mixture was then transferred to an aluminum weighing dish and placed in a fume hood to allow the solvent to evaporate naturally overnight. Next, the weighing dish containing the mixture was transferred to a vacuum oven to ensure complete solvent removal. The resulting PEG-vinorelbine-PLGA flakes were then cut into small pieces using scissors. These small pieces were then pulverized using a high-speed grinder at 10,000 rpm for 5 minutes. The pulverized PEG-vinorelbine-PLGA material was then mixed with the other components: 1200 mg PEG-SG20k, 600 mg PEG-Amine5k, and 200 mg mannitol. The mixture was processed using a tableting machine to produce tablets. A total of 10 tablets were prepared from the mixture, each containing 2 mg of vinorelbine.

[0109] Example 13 PEG50PLGA30V13

[0110] All components and their respective weights are recorded in Table 3. To prepare the mixture, 2 mL of dichloromethane was added to a test tube containing 150 mg PEG10k, 20 mg vinorelbine, and 90 mg PLGA. The test tube was shaken until the PEG, vinorelbine, and PLGA were completely dissolved. The resulting mixture was then transferred to an aluminum weighing dish and placed in a fume hood to allow the solvent to evaporate naturally overnight. Next, the weighing dish containing the mixture was transferred to a vacuum oven to ensure complete solvent removal. The resulting PEG-vinorelbine-PLGA flakes were then cut into small pieces using scissors. These small pieces were then pulverized using a high-speed grinder at 10,000 rpm for 5 minutes. The pulverized PEG-vinorelbine-PLGA material was then mixed with the other components: 1200 mg PEG-SG20k, 600 mg PEG-Amine5k, and 200 mg mannitol. The mixture was processed using a tableting machine to produce tablets. A total of 10 tablets were prepared from the mixture, each containing 2 mg of vinorelbine.

[0111] Example 14 PEG30PLGA50V14

[0112] All components and their respective weights are recorded in Table 3. To prepare the mixture, 2 mL of dichloromethane was added to a test tube containing 90 mg PEG10k, 20 mg vinorelbine, and 150 mg PLGA. The test tube was shaken until the PEG, vinorelbine, and PLGA were completely dissolved. The resulting mixture was then transferred to an aluminum weighing dish and placed in a fume hood to allow the solvent to evaporate naturally overnight. Next, the weighing dish containing the mixture was transferred to a vacuum oven to ensure complete solvent removal. The resulting PEG-vinorelbine-PLGA flakes were then cut into small pieces using scissors. These small pieces were then placed in a high-speed grinder set at 10,000 rpm and ground for 5 minutes. Subsequently, the resulting PEG-vinorelbine-PLGA pulverizer was mixed with other components, specifically 1200 mg PEG-SG20kJ, 600 mg PEG-Amine5kJ, and 200 mg mannitol. This mixture was then processed in a tableting machine to form tablets. Ultimately, a total of 10 tablets were produced from this mixture, each containing 2 mg of vinorelbine.

[0113] Example 15 PEG10PLGA70V15

[0114] All components and their respective weights are recorded in Table 3. To prepare the mixture, 2 mL of dichloromethane was added to a test tube containing 30 mg PEG10k, 20 mg vinorelbine, and 210 mg PLGA. The test tube was shaken until the PEG, vinorelbine, and PLGA were completely dissolved. The resulting mixture was then transferred to an aluminum weighing dish and placed in a fume hood to allow the solvent to evaporate naturally overnight. Next, the weighing dish containing the mixture was transferred to a vacuum oven to ensure complete solvent removal. The resulting PEG-vinorelbine-PLGA flakes were then cut into small pieces using scissors. These small pieces were then pulverized using a high-speed grinder at 10,000 rpm for 5 minutes. The pulverized PEG-vinorelbine-PLGA material was then mixed with the other components: 1200 mg PEG-SG20k, 600 mg PEG-Amine5k, and 200 mg mannitol. The mixture was compressed using a tablet press to produce tablets. A total of 10 tablets were prepared from the mixture, each containing 2 mg of vinorelbine.

[0115] Example 16 PEG5PLGA75V16

[0116] All components and their respective weights are recorded in Table 3. To prepare the mixture, 2 mL of dichloromethane was added to a test tube containing 15 mg PEG10k, 20 mg vinorelbine, and 225 mg PLGA. The test tube was shaken until the PEG, vinorelbine, and PLGA were completely dissolved. The resulting mixture was then transferred to an aluminum weighing dish and placed in a fume hood to allow the solvent to evaporate naturally overnight. Next, the weighing dish containing the mixture was transferred to a vacuum oven to ensure complete solvent removal. The resulting PEG-vinorelbine-PLGA flakes were then cut into small pieces using scissors. These small pieces were then placed in a high-speed grinder set at 10,000 rpm and ground for 5 minutes. Subsequently, the resulting PEG-vinorelbine-PLGA pulverizer was mixed with other components, specifically 1200 mg PEG-SG20kJ, 600 mg PEG-Amine5kJ, and 200 mg mannitol. This mixture was then processed in a tableting machine to form tablets. Ultimately, a total of 10 tablets were produced from this mixture, each containing 2 mg of vinorelbine.

[0117] Example 17 PEG0PLGA80V17

[0118] All components and their respective weights are recorded in Table 3. To prepare the mixture, 2 mL of dichloromethane was added to a test tube containing 20 mg vinorelbine and 240 mg PLGA. The test tube was shaken until the vinorelbine and PLGA were completely dissolved. The resulting mixture was then transferred to an aluminum weighing dish and placed in a fume hood to allow the solvent to evaporate naturally overnight. Next, the weighing dish containing the mixture was transferred to a vacuum oven to ensure complete solvent removal. The resulting vinorelbine-PLGA flakes were then cut into small pieces with scissors. These small pieces were then pulverized using a high-speed grinder set to 10,000 rpm for 5 minutes. The pulverized vinorelbine-PLGA material was then mixed with other components, including 1200 mg PEG-SG20kJ, 600 mg PEG-Amine5kJ, and 200 mg mannitol. The mixture was processed using a tableting machine to produce tablets. A total of 10 tablets were prepared from the mixture, each containing 2 mg of vinorelbine.

[0119] Example 18: Delivery of cisplatin and vinorelbine

[0120] To prepare a mixture of cisplatin and vinorelbine, 2 mL of dichloromethane was added to a test tube containing 20 mg vinorelbine, 30 mg PEG10k, and 210 mg PLGA. The test tube was shaken until the vinorelbine, PEG, and PLGA were completely dissolved. Then, 60 mg of cisplatin was added to the test tube containing the PEG-vinorelbine-PLGA mixture. The resulting suspension was then homogenized using a small homogenizer at 10,000 rpm for 2 minutes. The mixture was then transferred to an aluminum weighing dish and placed in a fume hood to allow the solvent to evaporate naturally overnight. Finally, the weighing dish containing the mixture was transferred to a vacuum oven to ensure complete solvent removal. The resulting PEG-vinorelbine-cisplatin-PLGA sheet was then cut into small pieces. These small pieces were then placed in a high-speed grinder and ground at 10,000 rpm for 5 minutes. Subsequently, the pulverized PEG-vinorelbine-cisplatin-PLGA material was mixed with other components, namely 1200 mg of PEG-SG20k, 600 mg of PEG-Amine5k, and 200 mg of mannitol. This mixture was then compressed into tablets using a tableting machine. Ultimately, a total of 10 tablets were prepared from this mixture, each containing 2 mg of vinorelbine and 6 mg of cisplatin.

[0121] Example 19 Intraperitoneal injection (ovarian cancer treatment)

[0122] The tablets are formed into rods approximately 2 mm in diameter. They can be injected intraperitoneally using a 12-gauge needle. The rods absorb bodily fluids and cross-link with tissues within the peritoneal cavity. In the treatment of ovarian cancer, intraperitoneal administration of chemotherapy drugs has become a standard treatment regimen.

[0123] Example 20: Bronchoscope Delivery (Lung Cancer Treatment)

[0124] A tablet (or smaller tablets) can be delivered to the tracheal tumor via bronchoscopy or robot-assisted bronchoscopy. The tablet absorbs bodily fluids and cross-links with the tumor and surrounding tissues. This localized, sustained-release effect of chemotherapy drugs inhibits the growth of cancer cells, ultimately leading to their complete eradication.

[0125] Example 21: Delivery of the patch

[0126] Eighteen tablets are placed on a 4 x 6 cm woven fiber matrix (e.g., sodium carboxymethyl cellulose) (see Figure 2). A pressure of 100 to 10,000 kg is then applied to the tablets, pressing them into the matrix for one minute. The patch is folded into four layers along the dotted line. The folded patch is then delivered into a body cavity (e.g., the lung cavity) through a cannula with a diameter of 10 mm or larger. Once inside the body cavity, the patch is unfolded and applied to the surface of an organ (e.g., the lung, kidney, stomach, esophagus, prostate, bladder, body cavity wall, etc.) (i.e., the tumor site or adjacent area). The patch is moistened with saline solution. The patch is then pressed for three minutes. The PEG-SG component cross-links with the tissue surface. PEG-SG and PEG-Amine cross-link through their respective multi-arm structures to form a PEG gel. Chemotherapy drugs (cisplatin and vinorelbine) are released locally and sustained for an extended period (over 30 days).

[0127] Example 22 Insulin Delivery System

[0128] To prepare the insulin solution, 100 mg of insulin, 240 mg of PEG10k, and 200 mg of mannitol were added to a glass vial containing 2 mL of water. The vial was shaken until the insulin, PEG10k, and mannitol were completely dissolved, and then the solution was lyophilized. The resulting lyophilized powder was then mixed with 1200 mg of PEG-SG20k and 600 mg of PEG-Amine5k. The mixture was processed using a tablet press to form tablets. A total of 10 tablets were prepared, each containing 10 mg of insulin. Each tablet could be processed into a rod with a diameter of approximately 2 mm. Intraperitoneal injection was possible using a 12-gauge needle. The rod absorbs fluid in the peritoneal cavity and cross-links with tissues.

[0129] Example 23 Intravesical Delivery Device

[0130] To prepare a mixture of mitomycin and doxorubicin, 4 mL of dichloromethane was added to a test tube containing 30 mg of PEG10k and 210 mg of PLGA. The test tube was shaken until the PEG and PLGA were completely dissolved. Then, 30 mg of mitomycin and 30 mg of doxorubicin were added to the PEG-PLGA solution. The resulting suspension was then transferred to an aluminum weighing dish and placed in a fume hood overnight to allow the solvent to evaporate. The weighing dish containing the mixture was then transferred to a vacuum oven to ensure complete solvent removal. The resulting PEG-mitomycin-doxorubicin-PLGA flakes were then cut into small pieces using scissors. These small pieces were then pulverized using a high-speed grinder at 10,000 rpm for 5 minutes. Finally, the pulverized PEG-mitomycin-doxorubicin-PLGA material was mixed with other components, namely 1200 mg PEG-SG20k, 600 mg PEG-Amine5k, and 200 mg mannitol. This mixture was then processed in a tablet press to produce tablets with a diameter of 3.5 mm. A total of 10 to 20 tablets were produced from this mixture. These tablets were then loaded into a 3.5 mm inner diameter catheter. The catheter wall had perforations with a diameter of 1.0 to 1.5 mm, spaced 1.5 to 2.0 mm apart. This catheter was inserted into the bladder through the urethra. The medication within the catheter was released into the urine through these perforations, thus treating bladder cancer.

[0131] It will be apparent to those skilled in the art that various modifications and variations can be made to the methods disclosed herein without departing from the spirit and scope of this disclosure. Therefore, this disclosure is intended to cover such modifications and variations made to this disclosure, provided they fall within the scope of the appended claims and their equivalents. All patent or non-patent documents cited herein are incorporated herein by reference in their entirety and are not construed as an admission that they constitute prior art.

Claims

1. A biocompatible delivery system for local and sustained-release drug administration, comprising: (i) A biocompatible polymer having multiple electrophilic groups; (ii) A biocompatible polymer having multiple nucleophilic groups; as well as (iii) A drug.

2. The biocompatible delivery system according to claim 1, further comprising polyethylene glycol.

3. The biocompatible delivery system according to claim 2, further comprising polylactic acid-glycolic acid copolymer.

4. The biocompatible delivery system according to claim 1, further comprising polylactic acid-glycolic acid copolymer.

5. The biocompatible delivery system according to any one of claims 1 to 4, further comprising a filler and / or a binder.

6. The biocompatible delivery system according to any one of claims 1 to 5, wherein all components are in powder form and are compressed into tablets.

7. The biocompatible delivery system according to any one of claims 1 to 6, wherein the biocompatible polymer having a plurality of electrophilic groups is multi-arm polyethylene glycol-succinimide glutarate, and the biocompatible polymer having a plurality of nucleophilic groups is multi-arm polyethylene glycol amine.

8. The biocompatible delivery system according to any one of claims 1 to 7, which is in tablet form and can be applied directly to the lesion site by mechanical means.

9. The biocompatible delivery system according to any one of claims 1 to 8, wherein the drug is selected from cyclophosphamide, cisplatin, carboplatin, melphalan, methotrexate, 5-fluorouracil (5-FU), gemcitabine, cytarabine, vincristine, vinblastine, paclitaxel, docetaxel, etoposide, irinotecan, doxorubicin, bleomycin, mitomycin, prednisone, dexamethasone, bevacizumab, trabectedin, pemetrexed; analgesics such as ibuprofen, naproxen, diclofenac, celecoxib, acetaminophen, morphine, oxycodone, hydrocodone, fentanyl, lidocaine, bupivacaine, amitriptyline, duloxetine, gabapentin, pregabalin, capsaicin, prednisone, dexamethasone; and antipsychotics such as haloperidol, chlorpromazine, fluphenazine. Thioridazine, loxapine, perphenazine, trifluoperazine, thiothoxane, prochlorperazine, cloprothoxane, risperidone, olanzapine, quetiapine, aripiprazole, clozapine, ziprasidone, paliperidone, lurasidone, ilopiperidone, and asenapine; and anti-infective antibiotics such as amoxicillin, penicillin V, flucloxacillin, cephalexin, cefuroxime, ceftriaxone, doxycycline, tetracycline, minocycline, azithromycin, erythromycin, clarithromycin, gentamicin, tobramycin, amikacin, ciprofloxacin, levofloxacin, moxifloxacin, trimethoprim / sulfamethoxazole, sulfamethoxazole, clindamycin, lincomycin, vancomycin, teicoplanin, linezolid, terdizolid, imipenem / cilastatin, meropenem, ertapenem, and aztreonam.

10. The biocompatible delivery system of claim 8, wherein the lesion area is a tumor site.

11. The biocompatible delivery system of any one of claims 1 to 10, wherein it is in tablet form and can be converted into a rod for injection into a body cavity.

12. A patch comprising a plurality of biocompatible delivery systems as claimed in any one of claims 1 to 11.

13. The patch of claim 12, wherein the biocompatible delivery system is in tablet form, arranged and pressed onto the patch.

14. The patch as described in claim 12 or 13, which is folded into multiple layers and can be delivered into a body cavity via a cannula.

15. The patch as claimed in claim 14, which unfolds within a body cavity and adheres to a tissue surface.

16. The patch of claim 15, wherein the tissue surface is located at or near the tumor site.

17. A method of treating a disease or condition, selected from cancer, pain, mental health, and infection, comprising administering a therapeutically effective amount of a therapeutic agent to a patient in need of treatment via a biocompatible delivery system according to any one of claims 1 to 11 or a patch according to any one of claims 12 to 16.

18. The method of claim 17, wherein the disease or condition is cancer.

19. The method of claim 18, wherein the cancer is selected from lung cancer, kidney cancer, stomach cancer, esophageal cancer, intestinal cancer, bladder cancer, prostate cancer, liver cancer, pancreatic cancer, heart cancer, ovarian cancer, uterine cancer, and tumors / cancers of any organ within a body cavity.

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