Fluidic microneedle fluid delivery device, compositions for local administration to tumors, combination products and uses

Abstract

This invention relates to a jet microneedle delivery device capable of achieving controllable initial diffusion and precise targeted drug delivery, compositions for local tumor injection, drug-device combination products, and their use in the preparation of drugs for local tumor injection. The jet microneedle delivery device uses a conventional needle-free jet injection power source, combined with one or more microneedles to achieve diffusion and precise delivery. The composition includes a boron compound drug component, an immune adjuvant, and a drug carrier. Through a specially designed jet microneedle delivery device, boron compound radiotherapy drugs can be delivered locally to the tumor, avoiding the problems of traditional intravenous administration where drugs struggle to reach the tumor interior and surface, and where systemic toxicity or overdose radioactivity limits the maximum drug dose and therapeutic effect. The high-concentration local delivery of the composition not only improves the local therapeutic effect on the tumor but also effectively generates tumor-specific antibodies through neoantigens produced during treatment, assisted by the immune adjuvant.

Description

Technical Field

[0001] This invention relates to the medical field, particularly to the field of tumor treatment, and specifically to jet microneedle fluid delivery devices, compositions for local tumor drug delivery, drug-device combination products, and their uses. Background Technology

[0002] Malignant tumors are one of the major diseases threatening human health and life. Although there are currently various treatment methods such as surgery, radiotherapy, chemotherapy, and targeted therapy, the efficacy is still very limited for patients with advanced tumors, and there is an urgent need to develop new treatment strategies.

[0003] In the field of radiotherapy, boron neutron capture therapy (BNCT) is considered an effective potential treatment due to its ability to utilize the property of boron-10 nuclei to absorb neutrons and release high-energy particles to kill tumor cells. However, the practical application of BNCT often depends on the distribution and residence of boron-containing drugs in the body. In conventional BNCT, boron-containing drugs are usually administered intravenously, resulting in insufficient concentrations of boron to accumulate at the tumor site, making it difficult to achieve ideal therapeutic effects. Moreover, if intravenously administered boron-containing drugs are distributed too highly in blood vessels and normal tissues, they may produce unnecessary toxic side effects or radiation damage after irradiation by a neutron source.

[0004] The background description is provided for the purpose of understanding the relevant technologies in this field and is not intended as an admission of prior art. Summary of the Invention

[0005] In a first aspect, a jet microneedle fluid delivery device is provided, comprising:

[0006] (i) A tube having a storage cavity for containing a drug or drug component.

[0007] (ii) An injection head fixedly connected to the tube or detachably connected to the tube, preferably the injection head is integrally injection molded with the tube, wherein the injection head includes one or more needle components, each needle component having at least one drug outlet hole, preferably the length of the needle component is greater than 1 mm, and the diameter of the drug outlet hole is 0.05-2 mm.

[0008] (iii) A motorized power mechanism for accelerating a drug or drug component into a high-speed jet, preferably, the motorized power mechanism is selected from one or more of compressed gas drive, spring drive, and electromagnetic drive;

[0009] Preferably, the fluid delivery device further includes (iv) an interventional soft needle, one end of which is connected to or integrated into the tube, and the other end of which is connected to or integrated with the injection head;

[0010] Preferably, the jet microneedle fluid delivery device is used to deliver drugs into the body, achieving controllable initial diffusion and precise targeted drug delivery;

[0011] Optionally, the drug delivery site of this jet microneedle fluid delivery device can be used for, but is not limited to, extravascular drug delivery sites and tumor sites;

[0012] Optionally, the extravascular administration site includes at least one of the following sites: intradermal, subcutaneous, muscle, or organ;

[0013] Optionally, the tumor site includes at least one of the following locations: within the tumor, around the tumor, and local lymph nodes.

[0014] Optionally, the needle tip has a sidewall drug outlet hole; preferably, the needle tip has a plurality of sidewall drug outlet holes; preferably, the plurality of sidewall drug outlet holes are arranged around the needle tip; preferably, the plurality of sidewall drug outlet holes include sidewall drug outlet holes located at different heights; preferably, the needle tip has multiple sets of sidewall drug outlet holes, each set of sidewall drug outlet holes is arranged around the needle tip and different sets of sidewall drug outlet holes are set at different heights.

[0015] Optionally, the needle tip also has a needle tip dispensing hole.

[0016] Optionally, the tube of the fluid delivery device is a dual-lumen or multi-lumen tube, the dual-lumen or multi-lumen being separated by a destructible interface element. Preferably, the interface element is configured to be destroyed by a drug or drug component when the motor power mechanism is triggered. Preferably, the dual-lumen or multi-lumen is used to contain a composition, and preferably at least two of the dual-lumen or multi-lumen is used to contain different components of an in-situ formed sustained-release hydrogel.

[0017] In a second aspect, a composition for local injection into a tumor is provided, comprising:

[0018] (a) A boron compound pharmaceutical ingredient, wherein the content of the boron compound pharmaceutical ingredient is preferably from 0.05% to 5% by weight, and the concentration of the boron compound pharmaceutical ingredient is preferably 0.1-20 mg / mL. The boron compound pharmaceutical ingredient preferably includes or is composed of a pharmaceutical ingredient containing the isotope boron-10. Preferably, the boron compound pharmaceutical ingredient is selected from one or more of inorganic boron compounds, organoboron compounds, polymerically linked boron compounds, and organometallic boron compounds. The boron compound pharmaceutical ingredient preferably includes or is selected from one or more of the following:

[0019] - Boron-cage phenylalanine (BPA) and its derivatives;

[0020] - Sodium boron cage compound (BSH);

[0021] - Dodecoborate cluster lipid derivatives;

[0022] -Carborane nucleoside;

[0023] -GB10(Na2B10H10);

[0024] -Porphyrin cholesterol ester;

[0025] - Cholesterol ester analogues;

[0026] - Boronized epidermal growth factor or anti-epidermal growth factor receptor monoclonal antibody;

[0027] - Boronized DNA metal intercalators;

[0028] - Boron-containing nanoparticles;

[0029] -Transferoglossin-polyethylene glycol (TF-PEG) liposomes;

[0030] -Carborane tetranitroporphyrin;

[0031] -Non-natural amino acids;

[0032] -Borated DNA cyclic peptide;

[0033] - Dodecyl hydrogen cage type dodecyl borate cluster;

[0034] - Boron carbide particles;

[0035] More preferably, the boron compound pharmaceutical ingredient includes BPA, BSH or derivatives thereof, or is composed of at least one of BPA, BSH or derivatives thereof;

[0036] (b) An immune adjuvant, preferably in an amount of 0.05% to 5% by weight, preferably at a concentration of 10-1,000 μg / mL, and preferably an adjuvant capable of stimulating T cells, NK cells and / or dendritic cells, preferably comprising or selected from one or more of the following:

[0037] - Saponin adjuvants, preferably QS-21 and GPI-0100;

[0038] - Mycoglycolipid adjuvants, preferably MPL and RC-529;

[0039] - Cyclic guanosine adjuvants, preferably cyclic guanosine (CDG) and its derivatives;

[0040] - Polymer I:C and its derivatives;

[0041] -MDP derivatives, preferably MDP and Nor-MDP;

[0042] - Cytokines, preferably GM-CSF, IL-2, and IL-12;

[0043] -More preferably, it is selected from at least one of AS01B and GM-CSF, wherein AS01B is a complex adjuvant composed of MPL and saponin QS-21;

[0044] (c) The drug carrier may be selected from one or more of physiological saline, polymer materials, emulsions and liposomes, and the drug carrier preferably includes a sustained-release agent.

[0045] Optionally, the drug carrier comprises:

[0046] The erodeable slow-release agent is preferably composed of 45% to 95% by weight, more preferably 75% to 95% by weight, and preferably composed of polyorthoester polymers.

[0047] The viscosity reducer is preferably composed of 5% to 55% by weight, more preferably 5% to 25% by weight, and preferably composed of glyceryl ester compounds, preferably triacetic acid esters.

[0048] Preferably, the viscosity of the composition, measured at 25°C, is from 100 mPa·s to 10000 mPa·s, more preferably from 1000 mPa·s to 10000 mPa·s, and even more preferably from 2000 mPa·s to 10000 mPa·s.

[0049] Preferably, the number average molecular weight of the polyorthoester is 1,000 to 20,000 Daltons, more preferably 2,000 to 10,000 Daltons, and most preferably 4,000 to 7,000 Daltons.

[0050] Optionally, the drug carrier comprises:

[0051] A thermosensitive sustained-release agent is a deliverable fluid at low temperatures that transforms into a sustained-release hydrogel upon in vivo above its phase transition temperature. The content of the thermosensitive sustained-release agent is preferably from 45% to 99.9% by weight, more preferably from 75% to 99.5% by weight; preferably, the curing temperature of the thermosensitive sustained-release agent is from 10°C to 35°C, and the thermosensitive sustained-release agent is selected from at least one of the following:

[0052] Polyethylene oxide-polypropylene oxide-polyethylene oxide triblock copolymer (PEO-PPO-PEO) (Poloxamer 407)

[0053] Lactic acid-glycolic acid copolymer-polyethylene glycol-lactic acid-glycolic acid triblock copolymer (PLGA-PEG-PLGA);

[0054] Preferably, the thermosensitive sustained-release agent is composed of PEO-PPO-PEO or PLGA-PEG-PLGA.

[0055] Optionally, the drug carrier comprises a multi-component polymer-nanoparticle (PNP) hydrogel, including or consisting of the following components:

[0056] (c1) A first component, wherein the first component is selected from hydrophobically modified water-soluble polymers, preferably selected from hydrophobically modified cellulose derivatives, chitosan derivatives, and alginate derivatives, and more preferably including HPMC-C. 12 Or by HPMC-C 12 composition;

[0057] (c2) The second component is selected from polymer nanoparticles or inorganic nanoparticles, preferably including PEG-PLA, PLGA, PCL nanoparticles or composed thereof;

[0058] Preferably, the content of the first component is 0.5-5 wt%, more preferably 1-2 wt%, and the content of the second component is 5-20 wt%, more preferably about 10 wt%. Preferably, the weight ratio of the first component to the second component is in the range of 1:2 to 1:40, more preferably in the range of 1:10 to 1:20.

[0059] Optionally, the drug carrier further includes an interface material, which preferably comprises or is composed of physiological saline; preferably, the interface material is located between different components of the multi-component polymer-nanoparticle (PNP) hydrogel.

[0060] Optionally, the drug carrier comprises:

[0061] The non-sustained-release agent is preferably present in an amount of 45% to 99.95% by weight, more preferably in an amount of 55% to 99.5% by weight, and is composed of liposomes, physiological saline or glucose solution.

[0062] Optionally, the composition is a prefilled injectable, preferably prefilled into a fluid delivery device in the form of a syringe or injection pen, preferably in which at least two materials for forming an in-situ sustained-release hydrogel are separated by an interface material, and the fluid delivery device is preferably as described in the first aspect.

[0063] Thirdly, a drug-device combination product is provided, comprising:

[0064] (a) The composition according to the second aspect;

[0065] (b) The fluid delivery device according to the first aspect.

[0066] Optionally, the use of the composition described in the second aspect or the pharmaceutical device combination product described in the third aspect in the preparation of a medicament for administration by local injection into a tumor.

[0067] Optionally, the use of a composition containing a boron compound, preferably a composition containing a boron compound and an immune adjuvant, preferably a composition according to the second aspect, in the preparation of a medicament for local injection into a tumor, wherein the composition is injected into the tumor site and subjected to neutron irradiation after injection, thereby preferably killing tumor cells through a neutron capture reaction and synergistically inducing the production of tumor antigens, while preferably the immune adjuvant enhances the activity of tumor-specific in vivo immune cells activated by the produced tumor antigens.

[0068] Optionally, the composition is administered by injection using the fluid delivery device according to the first aspect.

[0069] Optionally, the tumor is selected from at least one of the following tumors: melanoma, non-small cell lung cancer, small cell lung cancer, breast cancer, kidney cancer, liver cancer, pancreatic cancer, colorectal cancer, prostate cancer, ovarian cancer, glioma, or bladder cancer.

[0070] Fourthly, a method for treating tumors is provided, comprising the following steps:

[0071] (a) Preferably, the fluid delivery device according to the first aspect is used to inject the composition according to the second aspect into the tumor site;

[0072] (b) After injection, the tumor site is subjected to neutron irradiation;

[0073] The composition preferably kills tumor cells through a neutron capture reaction and synergistically induces the production of tumor antigens, while preferably an immune adjuvant enhances the activity of tumor-specific in vivo immune cells activated by the produced tumor antigens;

[0074] Preferably, the composition has a drug carrier for confining the boron compound and the immune adjuvant to the tumor site, thereby providing a prolonged retention time of the boron compound and the immune adjuvant at the tumor site.

[0075] Other optional features and technical effects of the embodiments of the present invention are partly described below and partly apparent from reading this document. Attached Figure Description

[0076] Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings. The elements shown are not limited to the scale shown in the drawings, and the same or similar reference numerals in the drawings denote the same or similar elements, wherein:

[0077] Figure 1 A schematic structural diagram of a fluid delivery device according to an embodiment of the present invention is shown; and

[0078] Figures 2A to 2E A schematic structural diagram of a fluid delivery device according to different embodiments of the present invention is shown. Detailed Implementation

[0079] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments and accompanying drawings. Here, the illustrative embodiments and descriptions of this invention are used to explain the invention, but are not intended to limit the invention.

[0080] The term "comprising" and its variations as used herein signify open inclusion, i.e., "including but not limited to". Unless otherwise stated, the term "or" means "and / or". The term "based on" means "at least partially based on". The terms "one example implementation" and "one implementation" mean "at least one example implementation". The term "another implementation" means "at least one additional implementation". The terms "first", "second", etc., may refer to different or the same objects. Other explicit and implicit definitions may also be included below.

[0081] Where numerical ranges are provided herein, it is meant that every intermediate value between the upper and lower limits of that range, and any other specified or intermediate value within that range, is included in the disclosure. For example, if a range of 10 to 20 weight percentages (wt%), such as 11, 12, 13, 14, 15, 16, 17, 18, and 19 wt%, is indicated, as are value ranges greater than or equal to 10 wt% up to about 20 wt% and value ranges less than or equal to 20 wt% down to about 10 wt%, these are also explicitly disclosed.

[0082] The term “basically” means to a great extent or close to complete with respect to a feature or entity, that is, 85% or more.

[0083] The term “about,” especially when modifying a quantity, means including a deviation of plus or minus 5%, 10%, 15%, or 20%.

[0084] The terms “preferred,” “preferred,” “optional,” or “optionally” mean that the situation described below may or may not occur, such that the description includes both the occurrence and non-occurrence of such situation.

[0085] definition

[0086] In this context, the “molecular weight” of a polymer refers to its nominal average molecular weight, typically determined by size exclusion chromatography, light scattering, or sedimentation rate methods. Molecular weight can be expressed as number-average molecular weight or weight-average molecular weight. Unless otherwise stated, all molecular weights mentioned herein are exponential-average molecular weights. Both number-average and weight-average molecular weights can be determined using gel permeation chromatography or other liquid chromatography techniques. Other methods for measuring molecular weight values ​​can also be used to determine the number-average molecular weight, such as colligative measurements (e.g., freezing point depression, boiling point elevation, or osmotic pressure), or to determine the weight-average molecular weight using light scattering, ultracentrifugation, or viscometry.

[0087] In this document, "pharmaceutical ingredient" or "active ingredient" refers to any compound or mixture of compounds that produces beneficial or useful results. Generally, "active pharmaceutical agent" or "pharmaceutical" refers to any organic or inorganic compound or substance that is biologically active and suitable for or intended for therapeutic purposes. As used herein, reference to a pharmaceutical agent, and to other chemical compounds mentioned herein, is intended to include any pharmaceutically acceptable salt form of the compound, including isomers of applicable compounds of this invention such as diastereomers and enantiomers, salts, solvates, polymorphs, specific crystalline forms, and racemic mixtures and pure isomers. An active pharmaceutical agent is distinct from components such as carriers, diluents, lubricants, binders, and other formulation aids, encapsulation agents, or other protective ingredients. An example of an active pharmaceutical agent is a pharmaceutical product. Suitable pharmaceutical agents include locally or systemically acting active pharmaceutical agents that can be administered to the subject by injection, such as subcutaneous, intradermal, intramuscular, intraocular, or intra-articular injection, either locally or intralesionally (including, for example, application to abrasions, lacerations, puncture wounds, etc., and entry into surgical wounds or incisions). Prodrugs and pharmaceutically acceptable salts of the active pharmaceutical agent are also included within the scope of this application.

[0088] In this article, "pharmaceutically acceptable salt" means a salt form of a drug having at least one suitable salt-forming group that does not cause significant adverse toxicological effects on patients.

[0089] In this paper, "biodegradable" refers to the degradation, decomposition, or digestion of polymers through biological environmental processes, including those of living organisms, particularly at physiological pH and temperature. As an example, the primary mechanism of polyorthoester biodegradation is the hydrolysis of bonds between and within polyorthoester units.

[0090] In this article, “treatment” for a disease or condition includes preventing the disease or condition from occurring in a person or animal who may be predisposed to having the disease or condition but has not yet experienced or shown symptoms of the disease or condition (preventive treatment), suppressing the disease or condition (slowing down or stopping its development), providing relief from the symptoms or side effects of the disease or condition, and alleviating the disease or condition.

[0091] Currently, boron-containing drugs commonly used in boron neutron capture therapy (BNCT) are mostly administered via intravenous delivery due to limitations in systemic toxicity, resulting in insufficient local drug concentrations at the tumor site and limited therapeutic efficacy.

[0092] Accordingly, embodiments of the present invention provide a composition for local injection into a tumor, the composition comprising a boron-containing compound pharmaceutical ingredient, an immune adjuvant, and a drug carrier. Embodiments of the present invention also provide a pharmaceutical device combination product comprising the aforementioned composition and a fluid delivery device. Embodiments of the present invention further provide the use of the above-described composition, the composition comprising a boron-containing compound pharmaceutical ingredient, and the composition comprising a boron-containing compound pharmaceutical ingredient and an immune adjuvant in the preparation of a medicament for local injection into a tumor. Embodiments of the present invention further provide a method for treating tumors using the above-described composition.

[0093] Furthermore, embodiments of the present invention also provide a jet microneedle fluid delivery device, which can be used to deliver the composition to a tumor site, or to deliver any suitable drug.

[0094] Composition and preparation method

[0095] This invention relates to a composition for local injection into a tumor, the composition comprising a boron compound pharmaceutical ingredient, an immune adjuvant, and a drug carrier.

[0096] The boron compound is the key active ingredient in boron neutron capture therapy (BNCT) of this invention. When this composition is delivered to the tumor site and subsequently irradiated with neutrons, the boron-10 isotope in the boron compound can capture thermal neutrons, triggering a high-energy fission reaction, thereby precisely killing tumor cells. The inventors have discovered that, compared to traditional intravenous administration, the local tumor injection method of this invention significantly increases the concentration of the boron compound at the tumor site and reduces its distribution in normal tissues, thereby improving therapeutic efficacy and reducing off-target toxicity. Optionally, the use of a jet microneedle fluid delivery device can further optimize the distribution of the boron compound at the tumor site, achieving more precise targeted therapy.

[0097] The inventors have also discovered that by combining boron compound drug components with immune adjuvants in the same formulation for local tumor administration, a unique synergistic mechanism can be formed: the boron compound drug components, under subsequent neutron irradiation, not only effectively kill tumor cells, but more importantly, actively induce the production of a large number of tumor antigens, while the simultaneously present immune adjuvants can immediately enhance the immune response to these newly generated antigens. This combination not only overcomes the limitation of insufficient local tumor drug concentration caused by the intravenous administration of traditional anti-tumor drugs, but also achieves spatiotemporal synergy between drug therapy and immune response, and significantly improves the therapeutic effect.

[0098] In one embodiment, the composition for local tumor administration provided by the present invention can be in the form of a solution, suspension, or emulsion, whereby the components of the composition can be injected (e.g., diffusely injected) onto the tumor site. Boron compound drug components can be dissolved in a carrier to form a solution or dispersed in a carrier to form a suspension, while immune adjuvants can form a homogeneous mixture with the carrier. When liposomes are used as a carrier, an emulsion system can be formed. The present invention is not limited in this respect.

[0099] In one embodiment of the present invention, the boron compound pharmaceutical component preferably comprises or is composed of a pharmaceutical component containing the isotope boron-10. The boron-10 isotope has a high neutron capture cross-section, and under subsequent neutron irradiation, it can efficiently generate alpha particles and lithium ions, thereby killing tumor cells. The boron compound pharmaceutical component is preferably selected from one or more of inorganic boron compounds, organoboron compounds, polymerically linked boron compounds, and organometallic boron compounds; the present invention does not limit the specific structure of the boron compound.

[0100] More preferably, the boron compound pharmaceutical ingredient includes or is selected from one or more of the following: boron cage phenylalanine (BPA) and its derivatives, sodium boron cage compound (BSH), dodecoborate cluster lipid derivatives, carborane nucleosides, GB10 (Na2B10H10), porphyrin cholesterol esters, cholesterol ester analogs, boronized epidermal growth factor or anti-epidermal growth factor receptor monoclonal antibodies, boronized DNA metal intercalators, boron-containing nanoparticles, transferrin-polyethylene glycol (TF-PEG) liposomes, carborane tetrazole porphyrin, non-natural amino acids, boronized DNA cyclic peptides, dodecoborate clusters, and boron carbide particles.

[0101] More preferably, the boron compound pharmaceutical ingredient includes BPA, BSH, or derivatives thereof, or is composed of at least one of BPA, BSH, or derivatives thereof. BPA is an amino acid derivative with good tumor cell uptake ability. BSH is a simple boron cluster compound with good water solubility and tumor targeting, and both BPA and its derivatives are commonly used boron drugs in boron neutron capture therapy (BNCT).

[0102] In one embodiment, the content of the boron compound pharmaceutical ingredient is preferably from 0.05% to 5% by weight. More specifically, the content of the boron compound pharmaceutical ingredient can be any of the following values: 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.12%, 0.15%, 0.18%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.1%, 1.2%. 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5%.Alternatively, the content of the boron compound pharmaceutical component can be a range between any two adjacent values, for example: 0.05%-0.06%, 0.06%-0.07%, 0.07%-0.08%, 0.08%-0.09%, 0.09%-0.1%, 0.1%-0.12%, 0.12%-0.15%, 0.15%-0.18%, 0.18%-0.2%, 0.2%-0.25%, 0.25%-0.3%, 0.3%-0.35%, 0.35%-0.4%, 0.4%-0.45%. 0.45%-0.5%, 0.5%-0.55%, 0.55%-0.6%, 0.6%-0.65%, 0.65%-0.7%, 0.7%-0.75%, 0.75%-0.8%, 0.8%-0.85%, 0.85%-0.9%, 0.9%-0.95%, 0.95%-1%, 1%-1.1%, 1.1%-1.2%, 1.2%-1.3%, 1.3%-1.4%, 1.4%-1.5%, 1.5%-1.6%, 1.6%-1.7%, 1.7%-1.8% 1.8%-1.9%, 1.9%-2%, 2%-2.1%, 2.1%-2.2%, 2.2%-2.3%, 2.3%-2.4%, 2.4%-2.5%, 2.5%-2.6%, 2.6%-2.7%, 2.7%-2.8%, 2.8%-2.9%, 2.9%-3%, 3%-3.1%, 3.1%-3.2%, 3.2%-3.3%, 3.3%-3.4%, 3.4%-3.5%, 3.5%-3.6%, 3.6%-3.7%, 3.7%-3.8%, 3.8% -3.9%, 3.9%-4%, 4%-4.1%, 4.1%-4.2%, 4.2%-4.3%, 4.3%-4.4%, 4.4%-4.5%, 4.5%-4.6%, 4.6%-4.7%, 4.7%-4.8%, 4.8%-4.9%, 4.9%-5%; or it can be a range between any two values ​​within the above ranges, such as: 0.05%-0.15%, 0.1%-0.5%, 0.3%-1%, 1%-2%, 1.5%-3.5%, 2%-4%, 3%-5%, etc.

[0103] In another embodiment, the concentration of the boron compound pharmaceutical component is preferably 0.1-20 mg / mL. More specifically, the concentration of the boron compound pharmaceutical component can be any of the following values: 0.1 mg / mL, 0.15 mg / mL, 0.2 mg / mL, 0.25 mg / mL, 0.3 mg / mL, 0.35 mg / mL, 0.4 mg / mL, 0.45 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1 mg / mL, 1.2 mg / mL, 1.4 mg / mL, 1.6 mg / mL, 1.8 mg / mL, 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 3.5 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 5.5 mg / mL. mL, 6mg / mL, 6.5mg / mL, 7mg / mL, 7.5mg / mL, 8mg / mL, 8.5mg / mL, 9mg / mL, 9.5mg / mL, 10mg / mL, 10.5mg / mL, 11mg / mL, 11.5mg / mL, 12mg / mL, 12.5mg / mL, 13mg / m L, 13.5mg / mL, 14mg / mL, 14.5mg / mL, 15mg / mL, 15.5mg / mL, 16mg / mL, 16.5mg / mL, 17mg / mL, 17.5mg / mL, 18mg / mL, 18.5mg / mL, 19mg / mL, 19.5mg / mL, 20mg / mL.Alternatively, the concentration of the boron compound pharmaceutical component can be within any range of any two adjacent values, for example: 0.1-0.15 mg / mL, 0.15-0.2 mg / mL, 0.2-0.25 mg / mL, 0.25-0.3 mg / mL, 0.3-0.35 mg / mL, 0.35-0.4 mg / mL, 0.4-0.45 mg / mL, 0.45-0.5 mg / mL, 0.5-0.6 mg / mL, 0.6-0.7 mg / mL, 0.7-0.8 mg / mL, 0.8-0.9 mg / mL, 0. 9-1mg / mL, 1-1.2mg / mL, 1.2-1.4mg / mL, 1.4-1.6mg / mL, 1.6-1.8mg / mL, 1.8-2mg / mL, 2-2.5mg / mL, 2.5-3mg / mL, 3-3.5mg / mL , 3.5-4mg / mL, 4-4.5mg / mL, 4.5-5mg / mL, 5-5.5mg / mL, 5.5-6mg / mL, 6-6.5mg / mL, 6.5-7mg / mL, 7-7.5mg / mL, 7.5-8mg / mL, 8- 8.5mg / mL, 8.5-9mg / mL, 9-9.5mg / mL, 9.5-10mg / mL, 10-10.5mg / mL, 10.5-11mg / mL, 11-11.5mg / mL, 11.5-12mg / mL, 12-12.5 mg / mL, 12.5-13mg / mL, 13-13.5mg / mL, 13.5-14mg / mL, 14-14.5mg / mL, 14.5-15mg / mL, 15-15.5mg / mL, 15.5-16mg / mL, 16-16 0.5 mg / mL, 16.5-17 mg / mL, 17-17.5 mg / mL, 17.5-18 mg / mL, 18-18.5 mg / mL, 18.5-19 mg / mL, 19-19.5 mg / mL, 19.5-20 mg / mL; or it can be a range between any two values ​​within the above ranges, such as: 0.1-1 mg / mL, 0.2-0.8 mg / mL, 0.5-2 mg / mL, 1-5 mg / mL, 5-10 mg / mL, 8-15 mg / mL, 10-20 mg / mL, etc.

[0104] In embodiments of the present invention, the immune adjuvant may be an adjuvant capable of stimulating T cells, NK cells, and / or dendritic cells, and may be selected from one or more of saponin adjuvants, mycoglycolipid adjuvants, cyclic guanosine monophosphate adjuvants, poly(I:C) and its derivatives, MDP derivatives, and cytokines.

[0105] The saponin adjuvant is optionally selected from QS-21 and GPI-0100; the mycoglycolipid adjuvant is optionally selected from MPL and RC-529; the cyclic guanosine monophosphate adjuvant is optionally selected from cyclic guanosine monophosphate (CDG) and its derivatives; the MDP derivative is optionally selected from MDP and Nor-MDP; and the cytokines are optionally selected from GM-CSF, IL-2, and IL-12.

[0106] In some embodiments of the present invention, the immune adjuvant is optionally selected from at least one of ASO1B and GM-CSF, wherein ASO1B is a composite adjuvant composed of MPL and saponin QS-21.

[0107] In one embodiment of the present invention, the content of the immune adjuvant is preferably from 0.05% to 5% by weight. More specifically, the content of the immune adjuvant can be any of the following values: 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.12%, 0.15%, 0.18%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.1%, 1.2%, 1 0.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5%.Alternatively, the content of the immune adjuvant can be a range between any two adjacent values, for example: 0.05%-0.06%, 0.06%-0.07%, 0.07%-0.08%, 0.08%-0.09%, 0.09%-0.1%, 0.1%-0.12%, 0.12%-0.15%, 0.15%-0.18%, 0.18%-0.2%, 0.2%-0.25%, 0.25%-0.3%, 0.3%-0.35%, 0.35%-0.4%, 0.4%-0.45%, 0. 45%-0.5%, 0.5%-0.55%, 0.55%-0.6%, 0.6%-0.65%, 0.65%-0.7%, 0.7%-0.75%, 0.75%-0.8%, 0.8%-0.85%, 0.85%-0.9%, 0.9%-0.95%, 0.95%-1%, 1%-1.1%, 1.1%-1.2%, 1.2%-1.3%, 1.3%-1.4%, 1.4%-1.5%, 1.5%-1.6%, 1.6%-1.7%, 1.7%-1.8%, 1 0.8%-1.9%, 1.9%-2%, 2%-2.1%, 2.1%-2.2%, 2.2%-2.3%, 2.3%-2.4%, 2.4%-2.5%, 2.5%-2.6%, 2.6%-2.7%, 2.7%-2.8%, 2.8%-2.9%, 2.9%-3%, 3%-3.1%, 3.1%-3.2%, 3.2%-3.3%, 3.3%-3.4%, 3.4%-3.5%, 3.5%-3.6%, 3.6%-3.7%, 3.7%-3.8%, 3.8%- 3.9%, 3.9%-4%, 4%-4.1%, 4.1%-4.2%, 4.2%-4.3%, 4.3%-4.4%, 4.4%-4.5%, 4.5%-4.6%, 4.6%-4.7%, 4.7%-4.8%, 4.8%-4.9%, 4.9%-5%; or it can be a range between any two values ​​within the above ranges, such as: 0.05%-0.15%, 0.1%-0.5%, 0.3%-1%, 1%-2%, 1.5%-3.5%, 2%-4%, 3%-5%, etc.

[0108] The concentration of the immune adjuvant is preferably 10-1000 μg / mL. More specifically, the concentration of the immune adjuvant can be any of the following values: 10 μg / mL, 20 μg / mL, 30 μg / mL, 40 μg / mL, 50 μg / mL, 60 μg / mL, 70 μg / mL, 80 μg / mL, 90 μg / mL, 100 μg / mL, 120 μg / mL, 150 μg / mL, 180 μg / mL, 200 μg / mL, 2... 50μg / mL, 300μg / mL, 350μg / mL, 400μg / mL, 450μg / mL, 500μg / mL, 550μg / mL, 600μg / mL, 6 50μg / mL, 700μg / mL, 750μg / mL, 800μg / mL, 850μg / mL, 900μg / mL, 950μg / mL, 1000μg / mL. Alternatively, the concentration of the immunoadjuvant can be a range between any two adjacent values, for example: 10-20 μg / mL, 20-30 μg / mL, 30-40 μg / mL, 40-50 μg / mL, 50-60 μg / mL, 60-70 μg / mL, 70-80 μg / mL, 80-90 μg / mL, 90-100 μg / mL, 100-120 μg / mL, 120-150 μg / mL, 150-180 μg / mL, 180-200 μg / mL, 200-250 μg / mL, 250-300 μg / mL, 300-350 μg / mL, 350-400 μg / mL, 400-450 μg / mL. 450-500μg / mL, 500-550μg / mL, 550-600μg / mL, 600-650μg / mL, 650-700μg / mL, 700-750μg / mL, 750-800μg / mL, 800-850μg / mL, 850-900μg / mL, 900-950μg / mL, 950-1000μg / mL; or it can be a range between any two values ​​within the above ranges, such as: 10-100μg / mL, 50-200μg / mL, 100-300μg / mL, 200-500μg / mL, 300-700μg / mL, 500-1000μg / mL, etc.

[0109] In embodiments of the present invention, the drug carrier may optionally include one or more of physiological saline, polymer materials, emulsions, and liposomes. Preferably, the drug carrier may include a sustained-release agent or a non-sustained-release agent.

[0110] In some embodiments of the present invention, the mass ratio of the boron compound drug component to the immune adjuvant is 1:0.1-1:10, and the mass ratio of the boron compound drug component to the drug carrier is 1:100-1:10000.

[0111] In a specific embodiment of the present invention, the mass ratio of the boron compound drug component to the immune adjuvant can be flexibly adjusted according to the desired immune response intensity. Optionally, the mass ratio of the boron compound drug component to the immune adjuvant is 1:0.1-1:10. Optional mass ratios include, but are not limited to, 1:0.1, 1:0.15, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.7, 1:2, 1:2.2, 1:2.5, 1:2.8, 1:3, 1:3.3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, and 1:10. Furthermore, this invention also covers all sub-ranges within the aforementioned mass ratio range, such as 1:0.1-1:0.5, 1:0.5-1:1, 1:1-1:2, 1:2-1:3, 1:3-1:5, 1:5-1:7, 1:7-1:10, etc. Even further, any intermediate values ​​within the aforementioned mass ratio range, such as 1:0.12, 1:0.18, 1:0.23, 1:0.42, 1:0.65, 1:0.85, 1:1.25, 1:1.75, 1:2.3, 1:2.6, 1:3.1, 1:3.7, 1:4.2, 1:5.3, 1:6.8, 1:8.2, 1:9.3, etc., are also considered part of this invention and fall within its protection scope.

[0112] Similarly, the mass ratio of the boron compound drug component to the drug carrier can be adjusted according to specific application requirements, and the mass ratio range is 1:100-1:10000. Specific numerical points that can be selected include, but are not limited to, 1:100, 1:120, 1:150, 1:180, 1:200, 1:250, 1:300, 1:350, 1:400, 1:450, 1:500, 1:600, 1:700, 1:800, 1:900, 1:1000, 1:1200, 1:1500, 1:1800, 1:2000, 1:2500, 1:3000, 1:3500, 1:4000, 1:4500, 1:5000, 1:6000, 1:7000, 1:8000, 1:9000, and 1:10000. Furthermore, this invention covers all sub-ranges within the aforementioned mass ratio range, such as 1:100-1:500, 1:500-1:1000, 1:1000-1:2500, 1:2500-1:5000, 1:5000-1:8000, 1:8000-1:10000, etc. Even further, any intermediate values ​​within the aforementioned mass ratio range, such as 1:110, 1:135, 1:175, 1:230, 1:340, 1:560, 1:890, 1:1340, 1:2750, 1:4700, 1:6700, 1:8800, etc., are also considered part of this invention and fall within its protection scope.

[0113] Furthermore, the numerical range of the aforementioned mass ratio and all sub-ranges or specific points within that range can be selected according to actual application requirements. Further, all numerical ranges, sub-ranges, and their intermediate values ​​described in this invention are considered integral parts of this invention and can be arbitrarily selected during implementation. Regardless of the chosen combination of sub-ranges or numerical points, it should be considered to fall within the protection scope of this invention. Therefore, any adjustment or selection of these ranges or points is considered an equivalent modification of this invention and falls within the protection scope of this invention.

[0114] In one embodiment, the sustained-release agent is an aggressive sustained-release agent, preferably composed of polyorthoester polymers, more preferably polyorthoesters. Polyorthoester polymers include homopolymers, copolymers (including random copolymers, block copolymers, alternating copolymers, and graft copolymers), and mixtures thereof. As an example, polyorthoesters may include polylactic acid (PLA, CAS No.: 26100-51-6), polyglycolic acid (PGA, CAS No.: 26247-02-5), or copolymers thereof, such as polylactic acid-glycolic acid copolymer (PLGA, CAS No.: 26780-50-7). These materials have good biocompatibility and degradability, and their molecular weight and degradation rate can be adjusted according to specific application requirements.

[0115] Polyorthoesters used in the compositions provided by the present invention are typically composed of alternating residues derived from the reaction of diene acetals and diols, wherein the adjacent diol residues of each diene acetal-derived residue are separated from the reacted diol residues. Polyorthoesters include subunits containing α-hydroxy acids, i.e., subunits derived from α-hydroxy acids or their cyclic diesters, such as subunits containing glycolide, lactide, or combinations thereof (i.e., poly(glycol-co-lactide)), comprising all lactide and glycolide in ratios such as 75:25, 65:35, 50:50, etc. Such subunits are also referred to as latent acid subunits; due to their terminal hydroxyl groups, these latent acid subunits also fall into the more general class of "diols" used in the present invention. Polyorthoesters can be prepared as described, for example, in U.S. Patent Nos. 4,549,010 and 5,968,543. Polyorthoesters suitable for use in the compositions provided by the present invention are described in U.S. Patent No. 8,252,304.

[0116] Contains α-hydroxy acid subunit (R 1 The molar percentage of ) typically ranges from approximately 0 to 20 mol% of the total diol component (R). 1 and R 3 (As provided below). In one or more embodiments, the polyorthoester formulation contains at least about 0.01 molar percentage of α-hydroxy acid subunits. Exemplary percentages of α-hydroxy acid subunits in the polymer range from about 0 to about 50 molar percentages, or from about 0 to about 25 molar percentages, or from about 0.05 to about 30 molar percentages, or from about 0.1 to about 25 molar percentages. For example, in one embodiment, the polymer contains about 0 to about 50 molar percentages of α-hydroxy acid subunits. In another embodiment, the polymer contains about 0 to about 25 molar percentages of α-hydroxy acid subunits. In yet another embodiment, the polymer contains about 0.05 to about 30 molar percentages of α-hydroxy acid subunits. In yet another embodiment, the polymer contains about 0.1 to about 25 molar percentages of α-hydroxy acid subunits. As an example, the percentage containing the α-hydroxy acid subunit can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 24, 26, 27, 28, 29, or 30 molar percentages, including any and all ranges formed by combining any lower molar percentage figure with any higher molar percentage figure.

[0117] More specifically, the polyorthoester used in the compositions provided by the present invention is described by the following formula:

[0118]

[0119] Where R* is C 1-4 Alkyl (e.g., C1, C2, C3, or C4 alkyl), n is an integer ranging from 5 to 400, and A in each subunit is R. 1 Or R 3 That is, any monomer unit of the polymer of formula I. In this context, A can be R. 1 Or R 3 .

[0120] In a particular embodiment, R* is an ethyl (i.e., C2 alkyl) subunit according to Formula I, wherein R* is an ethyl, corresponding to the subunit obtained by reacting the diol provided in this invention with 3,9-bis(acetal)-2,4,8,10-tetraoxospiro[5.5]undecane (DETOSU), having the following structure.

[0121]

[0122] For equation I, as mentioned above, A can correspond to R. 1 R 1 for

[0123]

[0124] Where p and q are each independently an integer ranging from approximately 1 to 20 (e.g., each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20), and each R 5 Independently hydrogen or C 1-4 Alkyl (e.g., hydrogen, or C1, C2, C3, or C4 alkyl); and R 6 for:

[0125]

[0126] Where s is an integer from 0 to 10 (e.g., selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); t is an integer from 2 to 30; and R 7 It is hydrogen or C 1-4 Alkyl (e.g., hydrogen, or C1, C2, C3, or C4 alkyl); in one or more specific embodiments, R 7 It is hydrogen. R 1 The subunit is a subunit containing an α-hydroxy acid, that is, a subunit derived from an α-hydroxy acid and its cyclic diester.

[0127] For equation I, A can also correspond to R. 3 , where R 3 for

[0128]

[0129] x is an integer from 1 to 100, and in certain specific cases, selected from 1, 2, 3, 4, and 5. y is an integer from 2 to 30; and R 8 It is hydrogen or C 1-4 Alkyl (C1, C2, C3, or C4 alkyl).

[0130] In a particular implementation, R 8 It is hydrogen.

[0131] In some embodiments, the polyorthoester is wherein A is R 1 Or R 3 , of polyorthoester, where R 1 for

[0132]

[0133] Where p and q are each independently an integer ranging from about 1 to 20, where R is present in the polyorthoester polymer. 1 The mean of p or the mean of the sum of p and q (p+q) is approximately between 1 and 7 (e.g., 1, 2, 3, 4, 5, 6, 7); x and s are each independently an integer from 0 to 10; and t and y are each independently an integer from 2 to 30. In one or more specific implementations, R 5 It is hydrogen.

[0134] Another specific polyorthoester is in which A is R 1 Or R 3， Of those, R 1 for

[0135]

[0136] Where p and q are each independently an integer varying from about 1 to 20, or from about 1 to 15, or from about 1 to 10, where R is present in the polyorthoester polymer. 1 The average of p, or the average of the sum of p and q (i.e., p+q), is approximately between 1 and 7. Additionally, specific ranges for x and s (for the specific embodiments described above or for any polyorthoester provided according to the invention) are those where each is an integer ranging from 0 to 7 or from 1 to 5 independently. Similarly, specific ranges for t and y are those where each varies independently from 2 to 10.

[0137] The specific polyorthoester is R 5 Those that are hydrogen or methyl.

[0138] In some specific embodiments, s and x are each independently selected from 1, 2, 3, 4, 5, 6, 7, and 8. In some specific embodiments, s is 2. In some other specific embodiments, x is 2.

[0139] Exemplary polyorthoesters contain alternating residues of 3,9-diethyl-3,9-2,4,8,10-tetraoxohelic[5.5]undecane-3,9-diyl and A.

[0140]

[0141] A is as described above.

[0142] Polyorthoesters, such as those described in this invention, can be produced by adding a demonstrative diene acetal, 3,9-di(acetal)-2,4,8,10-tetraoxospiro[5.5]undecane (DETOSU).

[0143]

[0144] With one or more of the diols described above, such as HO-R 1 -OH or HO-R 3 Prepared via a -OH reaction. Exhibitory diols include oligoethylene glycols, such as triethylene glycol (TEG), oligoethylene glycols modified with one or more α-hydroxy acids at one or more ends, such as oligoethylene glycol glycolide or oligoethylene glycol lactide, and organic diols having a hydrocarbon core of 2 to 30 carbon atoms, such as 1,6-hexanediol, 1,10-decanediol, cis / trans-1,4-cyclohexanediol, p-menthane-3,8-diol, 1,4-butanediol, 1,5-pentanediol, 1,7-heptanediol, 1,8-octanediol, 1,10-decanediol, 1,12-dodecanediol, and their cyclic equivalents, wherein the hydroxyl group can be at any two positions on a cycloalkyl or alkylene ring. Organic diols can have 2 to 20 carbon atoms. Organic diols can be linear, branched, or cyclic, and can be saturated or unsaturated. Typically, unsaturated diols will have 1-3 unsaturated elements. A particular polyorthoester may contain from about 10 to 50 total molar percentages of subunits derived from one or more organic diols with a hydrocarbon core.

[0145] The preparation of diols, as described in U.S. Patent No. 5,968,543 and Heller et al., J. Polymer Sci., Polymer Letters Ed. 18:293-297 (1980), such as HO-R 1 -OH. For example, this can be achieved by using the formula HO-R 3The -OH diol reacts with 0.5 to 10 molar equivalents of α-hydroxy acid cyclic diesters, such as lactide and glycolide, and the reaction is allowed to proceed at 100-200°C for approximately 12 to 48 hours to prepare HO-R compounds containing polyester groups. 1 -OH diols. Suitable solvents for the reaction include organic solvents such as dimethylacetamide, dimethyl sulfoxide, dimethylformamide, acetonitrile, pyrrolidone, tetrahydrofuran, and methyl butyl ether. Although diol products in this invention generally refer to isolated and simplified entities, such as TEG glycolide (and diol reaction products such as TEG glycolide), those skilled in the art will understand that due to the reactivity of the reactants, such as the ring-opening of glycolide, diols are actually derived from complex mixtures of reactants, which makes the term TEG glycolide (or any other term for similar products) generally refer to the average or overall properties of the products.

[0146] Specific polyorthoesters are prepared by reacting 3,9-bis(acetal)-2,4,8,10-tetraoxospiro[5.5]undecane (DETOSU) with one or more reactive diols. Polyorthoesters are typically prepared by reacting DETOSU with two or more reactive diols under anhydrous conditions. Specific polyorthoesters are also prepared, as described in U.S. Patent No. 8,252,305, by reacting DETOSU with polyethylene glycol and polyethylene glycol glycolide. Specific polyorthoesters prepared from DETOSU-polyethylene glycol-polyethylene glycol glycolide have the following molar ratio: 90:80:20, although the component ratios can be appropriately modified as described above.

[0147] Polyorthoesters formed by the reaction of DETOSU with TEG and TEG glycolide can generally be described as having the following subunits, where R 1 This corresponds to the glycol ester portion derived from polyethylene glycol glycolide (formed by the reaction of glycolide and TEG), while R 3 Corresponding to the glycol ester portion derived from polyethylene glycol:

[0148] Where A is R 1 , and R 1 for Where R 5 For hydrogen and R 6 for

[0149] The polyorthoester composition obtained is as follows:

[0150]

[0151] The sum of p and q averages 2, while s is 2; and when A is R 3 At that time, R 3 for Where x is 2, the resulting polyorthoester subunit or component is:

[0152]

[0153] The structures of corresponding polyorthoesters prepared from the various α-hydroxy acid subunits and other diols described in this invention can be readily envisioned.

[0154] In one particular embodiment of the polyorthoester, the polyorthoester has a molecular weight ranging from about 1,000 Daltons to 20,000 Daltons.

[0155] In one embodiment, the polyorthoester described in this section is a semi-solid at room temperature and above room temperature. In one embodiment, it contains 80 to 100 mol% R 3 , where R 3 for Polyorthoesters with x = 2 are semi-solid at room temperature and above. Semi-solid polymers exist in a glassy or viscous liquid state. Semi-solid polymers typically exhibit a glass transition temperature (Tg) below room temperature. Below Tg, the semi-solid polymer can be considered to exist in a glassy state, while above Tg, the polyorthoester can be considered to exist in a liquid state. Semi-solid polyorthoester polymers are not thermoplastic polymers.

[0156] Generally, polyorthoesters according to any of the following formulas, Formula I, Formula II, Formula III, or Formula IV, are suitable for the compositions and / or delivery carriers provided by the present invention:

[0157]

[0158] For equations I-IV,

[0159] R represents a bond, -(CH2) a -, or -(CH2) b -O-(CH2) c -; where a is an integer from 1 to 12 (e.g., selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12), while b and c are independently integers from 1 to 5 (e.g., selected from 1, 2, 3, 4, and 5);

[0160] R* is C 1-4 alkyl;

[0161] R o R” and R”' are independently H or C 1-4 alkyl;

[0162] n is an integer of at least 5; and

[0163] A is a diol.

[0164] For example, the carrier described in this invention may be composed of polyorthoesters of formula I, II, III, or IV, wherein

[0165] R represents a bond, -(CH2) a -, or -(CH2) b -O-(CH2) c -; where a is an integer from 1 to 12, while b and c are independently integers from 1 to 5;

[0166] R* is C 1-4 alkyl;

[0167] R o R” and R”' are independently H or C 1-4 alkyl;

[0168] n is an integer of at least 5; and

[0169] A is R 1 R 2 R 3 , or R 4 ,in

[0170] R 1 It is a subunit containing an α-hydroxy acid, as described in the preceding paragraphs;

[0171] R 5 For H or C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl); and R 6 Selected from the following groups:

[0172]

[0173] in:

[0174] s is an integer from 0 to 10;

[0175] t is an integer from 2 to 30; and

[0176] R 7 For H or C 1-4 alkyl;

[0177] R 2 for:

[0178]

[0179] R 3 for:

[0180]

[0181] in:

[0182] x is an integer ranging from 0 to 200;

[0183] y is an integer ranging from 2 to 30;

[0184] R 8 For H or C 1-4 alkyl;

[0185] R 9 and R 10 Independently for C 1-12 Alkylene;

[0186] R 11 For H or C 1-6 Alkyl and R 12 C 1-6 Alkyl; or R 11 and R 12 Together for C 3-10 Alkylene; and

[0187] R 4 It is a diol residue containing at least one functional group independently selected from amide, imide, urea, and carbmate groups.

[0188] In some cases, the polyorthoester is a polyorthoester according to any one of formulas I-IV, where A is R 1 R 3 , or R 4 , where R 3 Selected from

[0189]

[0190] in

[0191] x is an integer from 0 to 100;

[0192] y is an integer from 2 to 30;

[0193] R 8 For H or C 1-4 alkyl;

[0194] R 9 and R 10 Independently for C 1-12 Alkylene;

[0195] R 11 For H or C 1-6 Alkyl and R 12 C 1-6 Alkyl; or R 11 and R 12 Together for C 3-10 Alkylene;

[0196] R4 It is a diol residue containing at least one functional group independently selected from amide, imide, urea, and polyurethane groups; and R 5 For H or C 1-4 alkyl.

[0197] In a specific embodiment of a polyorthoester, formula R 1 The fraction of Unit A is between 0 and 20 mole percentages.

[0198] An exemplary polyorthoester is described by formula I, II, III or IV, wherein

[0199] No unit has an equivalent to R 2 A;

[0200] R 3 for:

[0201]

[0202] in

[0203] x is an integer from 1 to 100;

[0204] y is an integer from 2 to 30; and

[0205] R 6 for:

[0206]

[0207] in:

[0208] s is an integer from 1 to 10;

[0209] t is an integer from 2 to 30; and

[0210] R 5 R 7 , and R 8 It can be hydrogen or methyl on its own.

[0211] Another representative polyorthoester of formula I, II, III or IV is R. 3 and R 6 Both are -(CH2-CH2-O)2-(CH2-CH2)-; R 5 is methyl; and wherein each of p and q is independently selected from polyorthoesters of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0212] In another polyorthoester embodiment of formula I, II, III or IV, R 3 and R 6Both are -(CH2-CH2-O)9-(CH2-CH2)-; R 5 It is methyl; and the sum of p or p and q is 2.

[0213] In another variant, the polyorthoester is of formula I, II, III, or IV, and R is -(CH2). b -O-(CH2) c -; where b and c are both 2; R* is a C2 alkyl group.

[0214] Other representative polyorthoesters of formulas I, II, III, or IV, wherein R 5 It is hydrogen or methyl; R 6 for Where s is an integer from 1 to 10, or in some embodiments s is selected from 1, 2, 3, or 4; t is an integer from 2 to 30, particularly selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10; R 7 It is hydrogen or methyl; while R 3 for Where x is an integer from 1 to 10, or in some embodiments selected from 1, 2, 3, or 4; y is an integer from 2 to 30, particularly selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10; R 8 It is hydrogen or methyl; R 4 Selected from aliphatic diol residues having 2-20 carbon atoms (e.g., selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 carbon atoms), while in some embodiments R 4 It has 2-10 carbon atoms, broken by one or two amide, imide, urea, or polyurethane groups. In some cases, A in polyorthoester is R. 1 The subunit ratio ranges from approximately 0.01 to 50 molar percentages. In some cases, A in polyorthoester is R. 1 The subunit ratio ranges from about 0 to 30 mole percentages, or from about 0.1 to 25 mole percentages. Demonstrative mole percentages include 10, 15, 20, and 25 mole percentages of polyorthoesters in which A is R. 1 The subunit. In one embodiment, the molar percentage is 20. Alternatively, in one or more embodiments, where A is R 2 The proportion of subunits is less than approximately 20%, less than approximately 10%, or less than approximately 5%, and A is R. 4 The proportion of subunits is less than about 20 percent, less than about 10 percent, or less than about 5 percent.

[0215] In some embodiments, the polyorthoesters shown as Formula I, Formula II, Formula III and Formula IV are polyorthoesters with alternating diene acetal and diol residues, each adjacent diene acetal residue pair being separated by a polyol residue, such as a diol.

[0216] Methods for manufacturing polyorthoesters are well known in the art and are described, for example, in U.S. Patent Nos. 6,613,355 and 8,252,304.

[0217] In one embodiment, the sustained-release agent is used to control the sustained-release effect of the boron compound pharmaceutical ingredient and / or the immunoadjuvant. The content of the sustained-release agent is preferably from 45% to 95% by weight, more preferably from 75% to 95% by weight. More specifically, the content of the sustained-release agent can be any of the following values: 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%. Alternatively, the content of the sustained-release agent can be a range between any two adjacent values, such as: 45%-50%, 50%-55%, 55%-60%, 60%-65%, 65%-70%, 70%-75%, 75%-80%, 80%-85%, 85%-90%, 90%-95%; or it can be a range between any two values ​​within the above ranges, such as: 45%-55%, 50%-65%, 60%-75%, 70%-85%, 75%-90%, 80%-95%, etc.

[0218] The number average molecular weight of the polyorthoester is approximately 1,000 to 20,000 Daltons, preferably 2,000 to 10,000 Daltons, and more preferably 4,000 to 7,000 Daltons. The number average molecular weight can be determined by gel permeation chromatography (GPC) using polystyrene as a standard and tetrahydrofuran as the mobile phase.

[0219] In one embodiment, to adjust the rheological properties of the composition and make it suitable for injection, the composition further includes a viscosity reducer. The content of the viscosity reducer is preferably from 5% to 55% by weight, more preferably from 5% to 25% by weight. More specifically, the content of the viscosity reducer can be any of the following values: 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%. Alternatively, the content of the viscosity reducer can be a range between any two adjacent values, for example: 5%-10%, 10%-15%, 15%-20%, 20%-25%, 25%-30%, 30%-35%, 35%-40%, 40%-45%, 45%-50%, 50%-55%; or it can be a range encompassing any two values ​​within the above ranges, for example: 5%-15%, 10%-25%, 15%-35%, 25%-45%, 30%-50%, 40%-55%, etc. Preferably, the viscosity reducer is triacetin (CAS No.: 102-76-1, molecular formula: C9H). 14 O6) composition. Triacetin can significantly reduce the viscosity of the composition, thereby improving injection fluidity.

[0220] In a preferred embodiment of the present invention, the proportions of each component in the composition should be understood as approximate values. Taking a preferred proportion as an example, when the active ingredient is 0.2% by weight, the sustained-release agent is about 65% by weight, and the viscosity reducer is about 35% by weight, the content of each component may fluctuate within an approximate range (e.g., ±1%). Considering that the content of the active ingredient is relatively low (typically 0.05-0.5% by weight), this expression is clear and reasonable to those skilled in the art.

[0221] Preferably, the viscosity of the composition, measured at 25°C, is from 100 mPa·s to 10000 mPa·s, more preferably from 1000 mPa·s to 10000 mPa·s, and even more preferably from 2000 mPa·s to 10000 mPa·s. More specifically, the viscosity of the composition measured at 25°C can be any of the following values: 100 mPa·s, 200 mPa·s, 300 mPa·s, 400 mPa·s, 500 mPa·s, 600 mPa·s, 700 mPa·s, 800 mPa·s, 900 mPa·s, 1000 mPa·s, 1200 mPa·s, 1500 mPa·s, 1800 mPa·s, 2000 mPa·s, 2500 mPa·s, 3000 mPa·s, 3500 mPa·s, 4000 mPa·s, 4500 mPa·s, 5000 mPa·s, 6000 mPa·s, 7000 mPa·s, 8000 mPa·s, 9000 mPa·s, or 10000 mPa·s. Alternatively, the viscosity of the composition measured at 25°C can be a range between any two adjacent values, for example: 100-200 mPa·s, 200-300 mPa·s, 300-400 mPa·s, 400-500 mPa·s, 500-600 mPa·s, 600-700 mPa·s, 700-800 mPa·s, 800-900 mPa·s, 900-1000 mPa·s, 1000-1200 mPa·s, 1200-1500 mPa·s, 1500-1800 mPa·s, 1800-2000 mPa·s, 2000-2500 mPa·s, 2500-3000 mPa·s, 300... 0-3500 mPa·s, 3500-4000 mPa·s, 4000-4500 mPa·s, 4500-5000 mPa·s, 5000-6000 mPa·s, 6000-7000 mPa·s, 7000-8000 mPa·s, 8000-9000 mPa·s, 9000-10000 mPa·s; or it can be a range between any two values ​​within the above ranges, such as: 100-500 mPa·s, 500-1000 mPa·s, 1000-2000 mPa·s, 2000-5000 mPa·s, 5000-8000 mPa·s, 8000-10000 mPa·s, etc. The viscosity measurement can be performed using a rotational rheometer at 25±0.5℃, or using a Brinell conical viscometer under the same conditions, with a rotational speed of 2.5 rpm.

[0222] In one embodiment, the density of the composition is 1.1-1.4 g / mL, preferably 1.2-1.3 g / mL, and more preferably 1.24-1.26 g / mL. Specifically, it can be any value from 1.10, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, and 1.40 g / mL, or a range between any two adjacent values.

[0223] In one specific embodiment, the drug carrier of the present invention includes a thermosensitive sustained-release agent, wherein the content of the thermosensitive sustained-release agent is preferably from 45% to 99.95% by weight, more preferably from 55% to 99.5% by weight. Specifically, the content of the thermosensitive sustained-release agent can be any one of 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 97, 98, 99, and 99.5% by weight, or a range between any two adjacent values.

[0224] The thermosensitive sustained-release agent exhibits reversible sol-gel transition behavior with temperature changes. It is liquid at low temperatures (e.g., 0-8°C), suitable for injection administration; as the temperature rises, it undergoes a solidification (including semi-solidification or gelation) transition. Specifically, the solidification (including semi-solidification or gelation) temperature (the transition temperature from liquid to solid (including semi-solid or gel)) of the thermosensitive sustained-release agent is 10°C to 45°C, preferably 35°C to 39°C, more preferably 36°C to 38°C, and even more preferably 36°C-37°C. Specifically, the solidification temperature can be any value from 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45°C, or a range between any two adjacent values.

[0225] The thermosensitive sustained-release agent may be a polyethylene oxide-polypropylene oxide-polyethylene oxide triblock copolymer (PEO-PPO-PEO, poloxamer 407) or a lactic acid-glycolic acid copolymer-polyethylene glycol-lactic acid-glycolic acid triblock copolymer (PLGA-PEG-PLGA). Preferably, the thermosensitive sustained-release agent is composed of poloxamer 407 or PLGA-PEG-PLGA.

[0226] The chemical structure of the PLGA-PEG-PLGA thermosensitive hydrogel is shown in the figure:

[0227]

[0228] Poloxamer 407 is a chemically stable triblock copolymer whose chemical stability gives it high stability in oxidizing, reducing, and acid / alkali environments.

[0229] In a preferred embodiment of the present invention, the thermosensitive sustained-release agent poloxamer 407 can be used as an in-situ gel for local injection. Its gel is transparent and highly hydrophilic, forming a three-dimensional mesh structure that firmly binds the drug within, thereby prolonging the drug's residence time at the affected area and improving bioavailability. Poloxamer 407 gel exhibits good tissue compatibility and significantly reduces the irritation of surrounding tissues caused by the drug dosage. Poloxamer 407 can have any of the aforementioned curing temperatures.

[0230] In another specific embodiment, the thermosensitive sustained-release agent PLGA-PEG-PLGA remains in a liquid state (sol state) below the phase transition temperature; when the temperature reaches the phase transition temperature, it rapidly gels to form a solid structure. PLGA-PEG-PLGA hydrogels are particularly suitable for local chemotherapy applications, enabling precise drug delivery to the target site and prolonging drug release time through gel formation, thereby reducing systemic side effects. By adjusting the molecular weight and copolymerization ratio of PLGA-PEG-PLGA, precise control of the drug release rate can be achieved. The thermosensitive sustained-release agent PLGA-PEG-PLGA can have any of the aforementioned curing temperatures.

[0231] Specifically, the composition of the PLGA-PEG-PLGA hydrogel can be further optimized to meet the delivery requirements of different drugs. For the PLGA-PEG-PLGA thermosensitive hydrogel, it is preferred that its purity is above 95%, its storage conditions are -20°C, and it exhibits phase transition behavior at a specific temperature.

[0232] To meet diverse drug and therapeutic needs, the thermosensitive sustained-release formulation of this invention can be combined with other types of drug carriers, such as saline, emulsions, and liposomes. The composition is designed to achieve precise release and sustained retention of the drug at the tumor site, ensuring therapeutic efficacy and reducing side effects.

[0233] In some embodiments, the drug carrier comprises a multi-component polymer-nanoparticle (PNP) hydrogel. The PNP hydrogel consists of the following components: a first component selected from hydrophobically modified water-soluble polymers, preferably selected from hydrophobically modified cellulose derivatives, chitosan derivatives, and alginate derivatives, and more preferably including HPMC-C. 12 Or by HPMC-C 12The composition includes a second component, which is selected from polymer nanoparticles or inorganic nanoparticles, preferably including PEG-PLA, PLGA, PCL nanoparticles, or a combination thereof. The PNP hydrogel is formed through non-covalent supramolecular interactions between the first and second components. The first component (HPMC-C12), as a hydrophobically modified water-soluble polymer, has a hydrophobic portion that can form supramolecular interactions with the hydrophobic portion of the nanoparticles in the second component. The first component is preferably hydrophobically modified hydroxypropyl methylcellulose (HPMC-C12); the second component is preferably polyethylene glycol-polylactic acid (PEG-PLA), polylactic acid-glycolic acid copolymer (PLGA), or polycaprolactone (PCL) nanoparticles. These nanoparticles exhibit good biocompatibility and biodegradability, and can be used as drug carriers.

[0234] The content of the first component is preferably 0.5-5 wt%, more preferably 1-2 wt%. More specifically, the content of the first component can be any of the following values: 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1.0 wt%, 1.1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.7 wt%, 1.8 wt%, 1.9 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, or 5.0 wt%. Alternatively, the content of the first component can be a range between any two adjacent values, such as: 0.5-0.8 wt%, 0.8-1.0 wt%, 1.0-1.2 wt%, 1.2-1.5 wt%, 1.5-2.0 wt%, 2.0-2.5 wt%, 2.5-3.0 wt%, 3.0-3.5 wt%, 3.5-4.0 wt%, 4.0-4.5 wt%, 4.5-5.0 wt%; or it can be a range between any two values ​​within the above ranges, such as: 0.5-1.5 wt%, 1.0-2.0 wt%, 1.0-3.0 wt%, 2.0-4.0 wt%, 3.0-5.0 wt%, etc.

[0235] The content of the second component is preferably 5-20 wt%, more preferably about 10 wt%. More specifically, the content of the second component can be any of the following values: 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%. Alternatively, the content of the second component can be a range between any two adjacent values, for example: 5-7 wt%, 7-9 wt%, 9-11 wt%, 11-13 wt%, 13-15 wt%, 15-17 wt%, 17-19 wt%, 19-20 wt%; or it can be a range including any two values ​​within the above ranges, for example: 5-10 wt%, 8-12 wt%, 10-15 wt%, 12-18 wt%, 15-20 wt%, etc.

[0236] The weight ratio of the first component to the second component is preferably in the range of 1:2 to 1:40, more preferably in the range of 1:10 to 1:20. This range is chosen because a lower content of the first component ensures the injectability of the hydrogel, while a higher content of the second component provides better drug encapsulation and release. More specifically, the weight ratio of the first component to the second component can be any of the following values: 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:25, 1:30, 1:35, or 1:40. Alternatively, the weight ratio of the first component to the second component can be a range between any two adjacent values, such as: 1:2-1:5, 1:5-1:10, 1:10-1:15, 1:15-1:20, 1:20-1:25, 1:25-1:30, 1:30-1:35, 1:35-1:40; or it can be a range between any two values ​​within the above ranges, such as: 1:2-1:10, 1:5-1:20, 1:10-1:30, 1:15-1:40, etc.

[0237] With the help of the PNP hydrogel, a sufficiently high yield stress forms a robust reservoir under normal pressure in the subcutaneous space after drug administration.

[0238] Optionally, the drug carrier further includes an interface material, which preferably comprises or is composed of physiological saline. The interface material is located between the different components of the multi-component polymer-nanoparticle (PNP) hydrogel during storage, contributing to the stability of the multi-component structure during storage. Alternatively, a destructible physical interface structure can be provided to achieve component separation during storage.

[0239] In one specific embodiment, the drug carrier of the present invention comprises a non-sustained-release agent. The content of the non-sustained-release agent is preferably from 45% to 99.95% by weight, more preferably from 55% to 99.5% by weight. More specifically, the content of the non-sustained-release agent can be any of the following values: 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, ... 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%. Alternatively, the content of the non-sustained-release agent can be a range between any two adjacent values, such as: 45%-50%, 50%-55%, 55%-60%, 60%-65%, 65%-70%, 70%-75%, 75%-80%, 80%-85%, 85%-90%, 90%-95%, 95%-97%, 97%-98%, 98%-99%, 99%-99.5%, 99.5%-99.95%; or it can be a range encompassing any two values ​​within the above ranges, such as: 45%-55%, 50%-65%, 60%-75%, 70%-85%, 75%-90%, 80%-95%, 90-99.95%, etc. The non-sustained-release agent includes liposomes, physiological saline, or glucose solution, preferably liposomes.

[0240] In specific embodiments of liposomes, liposomes can be further classified into cationic liposomes and neutral liposomes. The cationic liposomes may include any one or more of DOTAP (1,2-dioleoyl-3-trimethylammonium chloride propaneuryl chloride), DOTMA (1,2-dioleoyl-3-trimethylammonium chloride methacrylate), and DC-Chol (a cholesterol derivative, DC-Cholesterol). Cationic liposomes are commonly used to enhance the cellular uptake efficiency and targeting of drugs.

[0241] Neutral liposomes can include any one or more of DOPC (1,2-dioleoyl-sn-glycerol-3-phosphorylcholine), DSPC (1,2-distearatel-sn-glycerol-3-phosphorylcholine), and DPPC (1,2-dipalmitoyl-sn-glycerol-3-phosphorylcholine). Neutral liposomes are widely used in drug delivery systems due to their stability and good biocompatibility.

[0242] In a preferred embodiment, the mass ratio of cationic liposomes to neutral liposomes is preferably from 1:8 to 1:12. Specifically, it can be any one of 1:8, 1:9, 1:10, 1:11, and 1:12, or a range between any two. This mass ratio improves the distribution and retention time of the drug in vivo by optimizing the charge characteristics and equilibrium stability of the liposome carrier.

[0243] In some embodiments, the particle size of the cationic liposomes is preferably between 100 nm and 300 nm. More specifically, the particle size of the cationic liposomes can be any of the following values: 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 210 nm, 220 nm, 230 nm, 240 nm, 250 nm, 260 nm, 270 nm, 280 nm, 290 nm, or 300 nm. Alternatively, the particle size of the cationic liposomes can be a range between any two adjacent values, such as: 100-120 nm, 120-140 nm, 140-160 nm, 160-180 nm, 180-200 nm, 200-220 nm, 220-240 nm, 240-260 nm, 260-280 nm, 280-300 nm; or it can be a range encompassing any two values ​​within the above ranges, such as: 100-150 nm, 150-200 nm, 200-250 nm, 250-300 nm, etc. Choosing the right particle size helps optimize drug distribution characteristics and improve drug stability and targeting.

[0244] In one embodiment, the balance of the composition may include excipients, unavoidable impurities, and / or residual solvents from preparation. To further improve the stability and processing performance of the compositions of the present invention, one or more pharmaceutical excipients may be added to the compositions, including but not limited to dissolving agents, osmotic pressure regulators, pH regulators, or maintenance agents. The specific amounts of these excipients can be adjusted according to actual needs.

[0245] It should be understood that the content ranges of each component in the compositions described in this specification are described independently, and the sum of their upper limits may exceed 100%. When actually formulating the compositions of this invention, the content of each component will be adjusted based on a total weight of 100%, that is, the sum of the weight percentages of each component should be 100%. For example, when the composition simultaneously contains boron compound pharmaceutical ingredients, immune adjuvants, sustained-release agents, and viscosity reducers, adjustments should be made within the aforementioned component content ranges according to the characteristics and proportioning requirements of each component to ensure that the total content of each component in the final composition is 100%. Any adjustment to any component should be made within the understanding of a person skilled in the art to achieve the technical effects of this invention.

[0246] Those skilled in the art will understand that, in addition to the explicitly listed active ingredients and carrier components, the composition may also contain excipients, trace impurities, and / or residual solvents from the preparation process. These additional components are typically present in the balance and their content should be included in the total weight percentage (100%).

[0247] In some embodiments, the composition can be prepared as an injection.

[0248] In some embodiments, the injectable may be a single-dose injectable, such as an ampoule injectable, a vial injectable, or a pre-filled syringe injectable; or it may be a multi-dose injectable, such as a multi-dose vial injectable. Preferably, the injectable is a pre-filled injectable. More preferably, the injectable is a pre-filled injectable pre-loaded in a pre-filled pen delivery device. In particular, when the composition of the present invention contains components that require in-situ formation of a sustained-release hydrogel, in the pre-filled injectable, at least two materials for forming the in-situ sustained-release hydrogel are preferably separated by an interface material or a destructible interface structure described below to avoid mixing or premature gelation before injection.

[0249] Delivery device

[0250] In various embodiments of the present invention, such as Figure 1 As shown, a jet microneedle fluid delivery device is provided. This jet microneedle fluid delivery device can be used to deliver drugs into the body, achieving controllable initial diffusion and precise targeted drug delivery. Optionally, the drug delivery site of this jet microneedle fluid delivery device is used for, but is not limited to, extravascular drug delivery sites and tumor sites. Optionally, the extravascular drug delivery site includes at least one of the following sites: intradermal, subcutaneous, muscle, and organ. Optionally, the tumor site includes at least one of the following sites: intratumoral, peritumoral, and local lymph node. Preferably, this jet microneedle fluid delivery device can be used to deliver the composition described in the embodiments of the present invention.

[0251] The jet microneedle fluid delivery device may include a tube 100 for containing fluid, the tube 100 having a storage cavity for storing the fluid, and the tube 100 having a first end 110 and a second end 120. For example... Figure 1 As shown, the second end 120 may be provided with a hole 121 for distributing fluid in the pipe.

[0252] In some embodiments of the present invention, the fluid delivery device further includes an interventional soft needle, one end of which is connected to the tube and the other end to or integrated with the injection head. The interventional soft needle can improve the accuracy and flexibility of drug delivery, and is particularly suitable for local drug delivery to deep tumors. The interventional soft needle can be flexible, capable of reaching the target location along a curved path.

[0253] The fluid delivery device may also include an injection head 200 detachably connected to the tube 100, the injection head 200 including one or more needle elements 210. The one or more needle elements 210 are configured to removably engage with a self-closing resilient portion in the second end 120 or an aperture 121 for dispensing fluid 130 within the tube 100. In some embodiments, the injection head may be fixedly connected to the tube.

[0254] The fluid delivery device may further include a power mechanism 300. The power mechanism is a motorized power mechanism, meaning that, in the context of this disclosure, the power mechanism does not include manually operated components. The power mechanism 300 includes a piston 310 disposed in the first end 110 of the tube 100, capable of pushing the fluid 130, or operatively connected to the piston 310 to apply delivery pressure to the piston 310 pushing the fluid 130.

[0255] In some embodiments of the present invention, such as Figure 1 As shown, the piston 310 can be provided as a separate component, and the power mechanism 300 is configured to operate connected to the piston 310 to apply delivery pressure to the piston 310. It is also conceivable that, in other embodiments of the invention, the power mechanism 300 may be integrally integrated with the piston 310.

[0256] In some embodiments of the present invention, the driving method of the power mechanism 300 may include any one of compressed gas driving, spring driving, electromagnetic driving, or a combination of the above driving methods. For example, in some embodiments, the power mechanism 300 may be driven by compressed gas, such as compressed nitrogen or compressed carbon dioxide gas, or by compressed mechanical spring, or by piezoelectric actuator, without limitation.

[0257] In some embodiments of the present invention, compared to manual needle injection (where the piston inside the needle tube has a pushing speed of approximately 0.01 m / s), the piston speed of the piston 310 of the fluid delivery device of the present invention when pushing the fluid 130 in the tube 100 is greater than or equal to 10 times the piston speed of manual needle injection. The piston speed of the piston 310 when pushing the fluid 130 is 0.05 m / s to 0.50 m / s, preferably 0.09 m / s to 0.25 m / s, and even more preferably 0.14 to 0.20 m / s.

[0258] In some embodiments of the present invention, compared to manual needle injection (where the outlet jet velocity of the fluid ejected from the needle is approximately 2 m / s), the outlet jet velocity of the fluid 130 of the fluid delivery device of the present invention, when pushed away by the piston 310 from the plurality of holes 121 in the second end 120 or one or more needle parts 210 of the injection head 200, is greater than or equal to 10 m / s, preferably greater than or equal to 50 m / s, more preferably greater than or equal to 100 m / s, and more preferably greater than or equal to 150 m / s.

[0259] In some embodiments of the present invention, at least one of the one or more needle elements 210 is substantially inserted into a human or animal body.

[0260] In some embodiments of the present invention, at least one of the one or more needle components has an aperture in the range of 0.06 mm to 1.50 mm, more preferably in the range of 0.11 mm to 1.00 mm, and even more preferably in the range of 0.11 mm to 0.50 mm.

[0261] In some embodiments of the present invention, at least one of the self-sealing elastic part or the hole for distributing fluid in the pipe has a diameter in the range of 0.06 mm to 1.50 mm, more preferably in the range of 0.11 mm to 1.00 mm, and even more preferably in the range of 0.11 mm to 0.50 mm.

[0262] In some embodiments of the present invention, the total fluid delivery area of ​​the plurality of needle elements or the plurality of orifices for dispensing fluid within the tube is 0.009 mm. 2 The above is preferably 0.020 mm. 2 The above, more preferably, is 0.053mm. 2 The above, more preferably 0.28mm 2 The area of ​​a single hole in the aforementioned needle or hole is 0.0028–0.035 mm². 2 Preferably, the diameter is 0.0028–0.020 mm. 2 More preferably, it is 0.0028–0.009 mm. 2The single-hole area of ​​the needle tip refers to the single-hole area calculated from the inner diameter of the needle tip.

[0263] In some embodiments of the present invention, the fluid delivery device is configured such that the diffusion volume of the fluid 130 within the body is greater than the undelivered volume. Preferably, the diffusion volume of the fluid within the body is at least 1.50 times the undelivered volume, more preferably at least 1.80 times, even more preferably at least 2.40 times, more preferably at least 3.00 times, and even more preferably at least 3.60 times. Specifically, the diffusion volume ratio can be from 3.00 times to 10.00 times, from 4.00 times to 10.00 times, more preferably from 4.40 times to 8.00 times, and even more preferably from 5.0 times to 6.50 times. The specific values ​​listed include, but are not limited to: 4.00 times, 4.40 times, 4.60 times, 4.80 times, 5.00 times, 5.10 times, 5.20 times, 5.30 times, 5.40 times, 5.50 times, 5.60 times, 5.80 times, 5.90 times, 6.00 times, 6.50 times, 7.00 times, 8.00 times, 9.00 times, and 10.00 times, or any range between these values.

[0264] In some embodiments of the present invention, the dispersion volume ratio refers to the ratio of the volume of the dispersion region of the fluid delivered by the fluid delivery device in the body to the original volume of the undelivered fluid, that is:

[0265]

[0266] In other embodiments of the present invention, the diffusion volume ratio may also refer to the ratio of the diffusion volume of fluid delivered by the fluid delivery device of the present invention in the body to the diffusion volume of fluid delivered by manual needle injection in the body, that is:

[0267]

[0268] The diffusion volume of the delivery fluid can be calculated in various ways, without limitation. For example, in some embodiments of the present invention, a fluorescent marker can be added to the drug or vaccine in advance, and then the volume of the diffusion region can be calculated by scanning with medical imaging technology and using image analysis software, such as calculating the envelope map of the diffusion region to estimate the volume of the diffusion region.

[0269] It is understandable that when a delivery fluid enters the body through a fluid delivery device, its three-dimensional spatial distribution area increases due to the diffusion effect of the fluid within the body. This diffusion process increases the surface area of ​​the fluid, especially drugs or vaccines, in contact with tissues in the body, thereby improving the bioavailability and efficacy of the drug.

[0270] In some embodiments of the present invention, the outlet jet velocity v of the one or more needle elements can be configured such that the fluid jet passing through the one or more needle elements has a variety of different bulk dispersions, i.e., different dispersion volume ratios, dispersion depths, or dispersion extents; thereby, in some embodiments of the present invention, the outlet jet velocities v of the one or more needle elements can be equal and have a first outlet jet velocity v1, the magnitude of which is configured such that the fluid jet passing through the one or more needle elements has different dispersions.

[0271] In several embodiments of the present invention, the fluid delivery device may include an interventional soft needle. One end of the interventional soft needle is connected to the tube, and the other end is connected to or integrated with the injection head. The interventional soft needle is primarily used for drug delivery to specific tumor sites, particularly when the tumor is located deep or inaccessible. Its flexible structure allows it to reach the target location along a curved path, thereby improving the flexibility and adaptability of drug administration and ensuring better drug distribution within the tumor area. The interventional soft needle is an optional component in the present invention, depending primarily on the specific location of the tumor and treatment needs. When the tumor is located on the body surface or in other easily accessible areas, drug delivery can be achieved directly using the injection head without the need for an interventional soft needle. This flexibility allows the multimodal fluid delivery device to be adapted to different clinical scenarios, thereby simplifying the device structure and reducing operational complexity and cost.

[0272] In specific applications, interventional soft needles can be made of flexible biocompatible materials, such as medical-grade polyurethane, polyethylene, or silicone. These materials provide sufficient flexibility while ensuring safety and stability during use. Furthermore, the outer diameter of the interventional soft needle is preferably between 0.50 mm and 1.50 mm, and the length is preferably between 10 mm and 50 mm, more preferably between 15 mm and 30 mm, to allow for adjustment based on the depth and location of the tumor.

[0273] Apart from Figure 1 In addition to the fluid delivery device embodiments shown, the present invention also provides other optional embodiments, such as... Figures 2A to 2E As shown. Figures 2A to 2E The embodiments shown primarily demonstrate the design of different needle tip structures, and have similar characteristics to... Figure 1 The similar working principle shown, and Figures 2A to 2E Features, parameters, etc., not described in detail in the illustrated embodiments can be found by referring to Figure 1 All of the above are applicable to the local injection treatment of tumors using the composition of boron compound drugs and immune adjuvants described in this invention.

[0274] Figure 2AAn embodiment of a jet microneedle fluid delivery device and its injection head structure is shown, wherein the injection head 200 is fixedly connected to the tube 100, for example by integral injection molding. The injection head 200 includes an integral needle tip 210 having a single drug outlet 211 located at the needle tip for delivering drugs or compositions to the tumor site in the form of a high-speed jet. This design is simple in structure, easy to manufacture, and suitable for local tumor drug delivery without complex diffusion. The dimensions and outlet jet velocity of the needle tip and its components in this embodiment can be found in [reference needed]. Figure 1 The implementation method shown.

[0275] Figure 2B An embodiment of a jet microneedle fluid delivery device and its injection head structure is shown, wherein the injection head 200 is fixedly connected to the tube 100, for example, by integral injection molding. The injection head 200 includes an integral needle tip 210. The needle tip 210 has at least one sidewall drug outlet 212. Preferably, the needle tip 210 has a plurality of sidewall drug outlets 212 arranged around the needle tip 210, and these sidewall drug outlets can be located at different heights of the needle tip, thereby enabling the drug or composition to achieve a wider diffusion range and more effectively cover the tumor area after entering the tumor tissue. The needle tip also has a needle tip drug outlet 211. The dimensions and outlet jet velocity of the needle tip and its components in this embodiment are described in reference. Figure 1 The implementation method shown.

[0276] Figure 2C An embodiment of a jet microneedle fluid delivery device and its injection head structure is shown, wherein the injection head 200 is fixedly connected to the tube 100, for example by integral injection molding. The injection head 200 includes an integral needle tip 210. The needle tip 210 has at least one sidewall drug outlet 212. Preferably, the needle tip 210 has a plurality of sidewall drug outlets 212 arranged around the needle tip 210, and these sidewall drug outlets can be located at different heights of the needle tip, thereby enabling the drug or composition to achieve a wider diffusion range and more effectively cover the tumor area after entering the tumor tissue. In this embodiment, the needle tip does not have a needle tip drug outlet. The dimensions and outlet jet velocity of the needle tip and its components in this embodiment can be found in reference... Figure 1 The implementation method shown.

[0277] Figure 2D An embodiment of a jet microneedle fluid delivery device and its injection head structure are shown, wherein the injection head 200 is fixedly connected to the tube 100, for example by integral injection molding. The injection head 200 includes an integral needle tip 210. Figure 2B compared to, Figure 2DThe injection head structure of this jet microneedle fluid delivery device differs in that the sidewall drug outlet holes 212 are arranged in groups, meaning that sidewall drug outlet holes 212 are respectively provided at different heights of the needle tip 210. Preferably, each group of sidewall drug outlet holes 212 is arranged around the needle tip, and different groups of sidewall drug outlet holes 212 are set at different heights. This design further optimizes the diffusion range and uniformity of the drug within the tumor, and allows for adjustment of the drug delivery method according to the morphology and location of the tumor, thereby better adapting to different treatment needs. Furthermore, the needle tip also has a needle tip drug outlet hole 211. The dimensions and outlet jet velocity of the needle tip and its components in this embodiment can be found in [reference needed]. Figure 1 The implementation method shown.

[0278] Figure 2E An embodiment of a jet microneedle fluid delivery device and its injection head structure are shown, wherein the injection head 200 is fixedly connected to the tube 100, for example by integral injection molding. The injection head 200 includes an integral needle tip 210. Figure 2E In the injection head structure of the jet microneedle fluid delivery device, the sidewall drug outlet holes 212 are also arranged in groups, that is, sidewall drug outlet holes 212 are respectively provided at different heights of the needle tip 210. Preferably, each group of sidewall drug outlet holes 212 is arranged around the needle tip, and the sidewall drug outlet holes 212 of different groups are set at different heights. This design further optimizes the diffusion range and uniformity of the drug in the tumor, and the drug delivery method can be adjusted according to the morphology and location of the tumor, thereby better adapting to different treatment needs. In this embodiment, the needle tip does not have a needle tip drug outlet hole. The dimensions and outlet jet velocity of the needle tip and its components in this embodiment can be referred to Figure 1 The implementation method shown.

[0279] This design offers flexibility for different tumor locations, enabling the fluid delivery device to adapt to a variety of treatment needs, providing effective drug delivery solutions for both superficial and deep tumors.

[0280] The present invention also provides a drug-device combination product, the drug-device combination product comprising:

[0281] (a) The composition comprising the embodiments described above.

[0282] (b) A fluid delivery device according to the embodiments described above.

[0283] The present invention also provides the use of the above-described composition or pharmaceutical-device combination product in the preparation of a medicament for local injection administration to tumors.

[0284] These approaches can effectively address the problems of drugs failing to reach the tumor site effectively and insufficient drug concentrations in traditional cancer treatments.

[0285] Furthermore, the present invention also provides the use of compositions comprising boron compounds, preferably compositions comprising boron compounds and immune adjuvants, and preferably compositions as described above, in the preparation of medicaments for local injection into tumor sites, wherein the compositions are injected into the tumor site and subsequently subjected to neutron irradiation, thereby preferably killing tumor cells through a neutron capture reaction and synergistically inducing the production of tumor antigens, while preferably the immune adjuvant enhances the activity of tumor-specific in vivo immune cells activated by the produced tumor antigens.

[0286] This application enables the synergistic effect of chemotherapy, neutron capture therapy, and immunotherapy, providing a novel strategy for cancer treatment.

[0287] In some embodiments, the composition as described above is administered via injection using the fluid delivery device, characterized by: the ability to achieve high-speed jet injection, ensuring drug delivery to the tumor site; optional interventional soft needles for deep tumor delivery; and a dual- or multi-chamber design with interfacial materials or destructible interfacial elements that allows for the separate storage of sustained-release formulation components before injection, followed by re-mixing and injection when needed, thus providing better control over drug release kinetics. Compared to manual needle injection, the jet microneedle fluid delivery device of the present invention exhibits higher piston speeds when the piston pushes the fluid and higher outlet jet speeds, achieving excellent in vivo diffusion.

[0288] The present invention also provides a method for treating tumors, the method comprising the following steps:

[0289] (a) Preferably, the fluid delivery device of the embodiments described above is used to inject the composition of the embodiments described above into the tumor site. The composition includes a boron compound drug component, an immune adjuvant, and a drug carrier, which may contain different drug carriers such as sustained-release agents or non-sustained-release agents.

[0290] (b) After injection, the tumor site is irradiated with neutrons.

[0291] In this method, the boron compound drug component in the composition kills tumor cells through a neutron capture reaction and induces the production of tumor antigens, while the immune adjuvant enhances the immune response to these tumor antigens. Preferably, the composition has a drug carrier for confining the boron compound and the immune adjuvant to the tumor site, thereby prolonging the residence time of the boron compound and the immune adjuvant at the tumor site and improving the therapeutic effect.

[0292] The method of this invention utilizes the triple synergistic effect of local tumor injection, neutron capture reaction, and immune adjuvant, enabling more effective and safer tumor treatment while reducing side effects. To ensure the therapeutic efficacy of BNCT, it is preferable to perform imaging evaluation before treatment to understand the tissue distribution of boron drugs and to use multi-timepoint or dynamic imaging to study the dynamic distribution of the drug in vivo.

[0293] The compositions, drug-device combinations, uses, and methods described in this invention can be used to treat various types of tumors, including but not limited to: melanoma, non-small cell lung cancer, small cell lung cancer, breast cancer, kidney cancer, liver cancer, pancreatic cancer, colorectal cancer, prostate cancer, ovarian cancer, glioma, or bladder cancer, especially locally recurrent tumors such as central nervous system tumors, head and neck tumors, and malignant melanoma of the skin.

[0294] Currently, traditional boron neutron capture therapy (BNCT) mainly relies on intravenous administration. However, this route of administration often results in insufficient accumulation of boron-containing drugs at the tumor site due to systemic toxicity limitations, affecting treatment efficacy. Although there have been some attempts to utilize tumor autoantigens through intratumoral injection of adjuvants, this passive approach of utilizing existing antigens has certain limitations in efficacy.

[0295] The inventors have discovered that by directly injecting boron-containing compounds into the tumor site (e.g., the tumor itself, peritumoral area, or local lymph nodes), the boron concentration at the tumor site can be significantly increased, thereby achieving highly efficient killing of the tumor area during neutron irradiation. Compared to conventional intravenous administration, local injection can significantly increase the boron concentration at the tumor site while reducing the off-target distribution of boron-containing drugs in normal tissues or blood vessels, thus reducing potential systemic toxicity.

[0296] To address this, embodiments of the present invention achieve highly efficient tumor killing during neutron irradiation by directly injecting boron-containing compounds into the tumor site (e.g., the tumor itself, peritumoral area, or local lymph nodes). Compared to conventional intravenous administration, local injection significantly increases the local boron concentration in the tumor, reducing excessive distribution of boron-containing drugs in normal tissues or blood vessels. Optionally, by employing a jet microneedle fluid delivery device, the limitations of traditional needles or catheters can be overcome to some extent, achieving controllable initial diffusion and targeted drug delivery depth, thereby improving operational flexibility and the accuracy of drug distribution in the tumor site. Thus, through this local tumor injection, optionally combined with a diffuse jet microneedle-based fluid delivery device, a higher concentration of boron-containing drugs can be delivered to the tumor area, reducing radiation damage to normal tissues.

[0297] A further embodiment of the present invention incorporates an immune adjuvant (such as an adjuvant that stimulates T cells, NK cells, and / or dendritic cells) to trigger or enhance the body's anti-tumor immune response while neutron irradiation kills tumor cells. When tumor cells are locally destroyed by BNCT, their fragments and released tumor-associated antigens can be more effectively recognized by the immune system with the synergistic effect of the immune adjuvant, thereby stimulating or amplifying a tumor-specific immune response. Compared to radiotherapy or immunotherapy alone, this combined approach can effectively reduce the tumor burden locally while preserving or activating the patient's own immune function. Thus, by utilizing the synergistic effect of BNCT and immune adjuvants, the local killing of tumors and the systemic immune response are mutually promoted, slowing or preventing tumor regrowth.

[0298] As a supplement or alternative, further embodiments of the present invention incorporate the use of a sustained-release carrier (such as an erosive sustained-release agent, a thermosensitive sustained-release agent, or a multi-component cross-linked PNP hydrogel) at the tumor site. This allows the boron-containing compound and optional immune adjuvant to maintain an effective concentration locally for a longer period, and enables neutron irradiation to be performed as needed, thereby reducing the cumulative radioactivity or toxic side effects caused by frequent drug administration. This achieves precise localization and long-lasting effect of the drug at the tumor site, effectively avoiding the problem of boron compounds diffusing to other sites due to metabolism and affecting the efficacy of neutron irradiation, thus significantly improving the specificity and safety of local tumor treatment.

[0299] In specific embodiments using PNP crosslinked hydrogels, interfacial materials or physical interfacial structures are also provided to separate the multiple components of the PNP hydrogel before drug administration. Specifically, for the physical interfacial structure, multi-lumen tubes and destructible interfacial elements can be provided as separation and storage means, thereby allowing boron-containing drugs, immune adjuvants, or different components of the hydrogel to be packaged in multiple chambers. Thus, once the motorized mechanism (such as compressed gas or spring drive) is triggered, the interfacial material no longer provides interfacial interaction or the interfacial element is destroyed, and the components of the PNP hydrogel mix in the channels of the jet microneedle fluid delivery device and are ultimately injected into the tumor site, forming an in-situ gel enriched locally in the tumor. This operating mode effectively preserves the multiple components of the PNP hydrogel while allowing the multiple components of the PNP hydrogel to be fully mixed and crosslinked and solidified locally in the tumor.

[0300] This invention also provides a jet microneedle fluid delivery device. By combining a storage cavity, an injection head, and a motorized power mechanism, the device can efficiently convert drugs or drug components into high-speed jets for direct delivery to the target area, thereby achieving controllable initial diffusion and precise targeted drug delivery. In tumor local drug delivery applications, the jet microneedle device can achieve precise drug delivery, significantly increase the drug concentration at the tumor site, and effectively reduce the distribution of drugs in normal tissues by controlling initial diffusion and delivery depth, thereby reducing systemic toxicity and side effects. A further embodiment of this invention provides a jet microneedle fluid delivery device comprising an integrally injection-molded structure and / or multiple storage cavities with destructible interface elements. In tumor local drug delivery applications, the jet microneedle fluid delivery device, with its multiple storage cavities featuring destructible interface elements, further supports the dispensing and on-site mixing of complex drugs (e.g., different components of a multi-component cross-linked PNP hydrogel), ensuring drug stability during storage and reliable cross-linking in vivo.

[0301] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A jet microneedle fluid delivery device, characterized in that, include: (i) A tube having a storage cavity for containing a drug or drug component. (ii) An injection head fixedly connected to the tube or detachably connected to the tube, preferably the injection head is integrally injection molded with the tube, wherein the injection head includes one or more needle components, each needle component having at least one drug outlet hole, preferably the length of the needle component is greater than 1 mm, and the diameter of the drug outlet hole is 0.05-2 mm. (iii) A motorized power mechanism for accelerating a drug or drug component into a high-speed jet, preferably, the motorized power mechanism is selected from one or more of compressed gas drive, spring drive, and electromagnetic drive; Preferably, the fluid delivery device further includes (iv) an interventional soft needle, one end of which is connected to or integrated into the tube, and the other end of which is connected to or integrated with the injection head; Preferably, the jet microneedle fluid delivery device is used to deliver drugs into the body, achieving controllable initial diffusion and precise targeted drug delivery; Optionally, the drug delivery site of this jet microneedle fluid delivery device can be used for, but is not limited to, extravascular drug delivery sites and tumor sites; Optionally, the extravascular administration site includes at least one of the following sites: intradermal, subcutaneous, muscle, or organ; Optionally, the tumor site includes at least one of the following locations: within the tumor, around the tumor, and local lymph nodes.

2. The jet microneedle fluid delivery device according to claim 1, characterized in that, The needle tip has a sidewall drug outlet hole. Preferably, the needle tip has multiple sidewall drug outlet holes. Preferably, the multiple sidewall drug outlet holes are arranged around the needle tip. Preferably, the multiple sidewall drug outlet holes include sidewall drug outlet holes located at different heights. Preferably, the needle tip has multiple sets of sidewall drug outlet holes, each set of sidewall drug outlet holes is arranged around the needle tip, and different sets of sidewall drug outlet holes are set at different heights.

3. The jet microneedle fluid delivery device according to claim 1 or 2, characterized in that, The needle also has a needle tip dispensing hole.

4. The jet microneedle fluid delivery device according to any one of claims 1 to 3, characterized in that, The tube of the fluid delivery device is a dual-lumen or multi-lumen tube, the dual-lumen or multi-lumen being separated by a destructible interface element, preferably configured to be destroyed by a drug or drug component when the motor power mechanism is triggered, preferably, the dual-lumen or multi-lumen is used to contain a composition, preferably at least two of the dual-lumen or multi-lumen is used to contain different components of an in-situ formed sustained-release hydrogel.

5. A composition for local injection into a tumor, characterized in that, include: (a) A boron compound pharmaceutical ingredient, wherein the content of the boron compound pharmaceutical ingredient is preferably from 0.05% to 5% by weight, and the concentration of the boron compound pharmaceutical ingredient is preferably 0.1-20 mg / mL. The boron compound pharmaceutical ingredient preferably includes or is composed of a pharmaceutical ingredient containing the isotope boron-10. Preferably, the boron compound pharmaceutical ingredient is selected from one or more of inorganic boron compounds, organoboron compounds, polymerically linked boron compounds, and organometallic boron compounds. The boron compound pharmaceutical ingredient preferably includes or is selected from one or more of the following: - Boron-cage phenylalanine (BPA) and its derivatives; - Sodium boron cage compound (BSH); - Dodecoborate cluster lipid derivatives; -Carborane nucleoside; -GB10(Na2B10H10); -Porphyrin cholesterol ester; - Cholesterol ester analogues; - Boronized epidermal growth factor or anti-epidermal growth factor receptor monoclonal antibody; - Boronized DNA metal intercalators; - Boron-containing nanoparticles; -Transferoglossin-polyethylene glycol (TF-PEG) liposomes; -Carborane tetranitroporphyrin; -Non-natural amino acids; -Borated DNA cyclic peptide; - Dodecyl hydrogen cage type dodecyl borate cluster; - Boron carbide particles; More preferably, the boron compound pharmaceutical ingredient includes BPA, BSH or derivatives thereof, or is composed of at least one of BPA, BSH or derivatives thereof; (b) An immune adjuvant, preferably in an amount of 0.05% to 5% by weight, preferably at a concentration of 10-1,000 μg / mL, and preferably an adjuvant capable of stimulating T cells, NK cells and / or dendritic cells, preferably comprising or selected from one or more of the following: - Saponin adjuvants, preferably QS-21 and GPI-0100; - Mycoglycolipid adjuvants, preferably MPL and RC-529; - Cyclic guanosine adjuvants, preferably cyclic guanosine (CDG) and its derivatives; - Polymer I:C and its derivatives; -MDP derivatives, preferably MDP and Nor-MDP; - Cytokines, preferably GM-CSF, IL-2, and IL-12; -More preferably, it is selected from at least one of AS01B and GM-CSF, wherein AS01B is a complex adjuvant composed of MPL and saponin QS-21; (c) The drug carrier may be selected from one or more of physiological saline, polymer materials, emulsions and liposomes, and the drug carrier preferably includes a sustained-release agent.

6. The composition according to claim 5, characterized in that, The drug carrier includes: The erodeable slow-release agent is preferably composed of 45% to 95% by weight, more preferably 75% to 95% by weight, and preferably composed of polyorthoester polymers. The viscosity reducer is preferably present in a content of 5% to 55% by weight, more preferably 5% to 25% by weight, and preferably composed of a glycerol ester compound, more preferably composed of a glycerol triacetate.

7. The composition according to claim 5, characterized in that, The drug carrier includes: A thermosensitive sustained-release agent is a deliverable fluid at low temperatures that transforms into a sustained-release hydrogel upon in vivo above its phase transition temperature. The content of the thermosensitive sustained-release agent is preferably from 45% to 99.9% by weight, more preferably from 75% to 99.5% by weight; preferably, the curing temperature of the thermosensitive sustained-release agent is from 10°C to 35°C, and the thermosensitive sustained-release agent is selected from at least one of the following: Polyethylene oxide-polypropylene oxide-polyethylene oxide triblock copolymer (PEO-PPO-PEO) (Poloxamer 407) Lactic acid-glycolic acid copolymer-polyethylene glycol-lactic acid-glycolic acid triblock copolymer (PLGA-PEG-PLGA); Preferably, the thermosensitive sustained-release agent is composed of PEO-PPO-PEO or PLGA-PEG-PLGA.

8. The composition according to claim 5, characterized in that, The drug carrier comprises a multi-component polymer-nanoparticle (PNP) hydrogel, including or consisting of the following components: (c1) A first component, wherein the first component is selected from hydrophobically modified water-soluble polymers, preferably selected from hydrophobically modified cellulose derivatives, chitosan derivatives, and alginate derivatives, and more preferably including HPMC-C. 12 Or by HPMC-C 12 composition; (c2) The second component is selected from polymer nanoparticles or inorganic nanoparticles, preferably including PEG-PLA, PLGA, PCL nanoparticles or composed thereof; Preferably, the content of the first component is 0.5-5 wt%, more preferably 1-2 wt%, and the content of the second component is 5-20 wt%, more preferably about 10 wt%. Preferably, the weight ratio of the first component to the second component is in the range of 1:2 to 1:40, more preferably in the range of 1:10 to 1:

20. Optionally, the drug carrier further includes an interface material, which preferably comprises or is composed of physiological saline; preferably, the interface material is located between different components of the multi-component polymer-nanoparticle (PNP) hydrogel.

9. The composition according to claim 5, characterized in that, The drug carrier includes: The non-sustained-release agent is preferably present in an amount of 45% to 99.95% by weight, more preferably in an amount of 55% to 99.5% by weight, and is composed of liposomes, physiological saline or glucose solution.

10. The composition according to any one of claims 5 to 9, characterized in that, The composition is a prefilled injectable, preferably prefilled into a fluid delivery device in the form of a syringe or injection pen, preferably, in the prefilled injectable, at least two materials for forming an in-situ sustained-release hydrogel are separated by an interface material, and the fluid delivery device is preferably a fluid delivery device according to any one of claims 1 to 4.

11. A combination drug and medical device product, characterized in that, include: (a) The composition according to any one of claims 5 to 10; (b) The fluid delivery device according to any one of claims 1 to 4.

12. Use of the composition of any one of claims 5 to 10 or the pharmaceutical-device combination product of claim 11 in the preparation of a medicament for administration by local injection into a tumor.

13. Use of a composition containing a boron compound, preferably a composition containing a boron compound and an immune adjuvant, preferably a composition according to any one of claims 5 to 10, in the preparation of a medicament for local injection into a tumor, wherein the composition is injected into the tumor site and subjected to neutron irradiation after injection, thereby preferably killing tumor cells by a neutron capture reaction and synergistically inducing the production of tumor antigens, while preferably the immune adjuvant enhances the activity of tumor-specific in vivo immune cells activated by the produced tumor antigens.

14. The use according to claim 13, characterized in that, The composition is administered by injection using a fluid delivery device according to any one of claims 1 to 4.

15. The use according to any one of claims 12 to 14, characterized in that, The tumor is selected from at least one of the following tumors: melanoma, non-small cell lung cancer, small cell lung cancer, breast cancer, kidney cancer, liver cancer, pancreatic cancer, colorectal cancer, prostate cancer, ovarian cancer, glioma, or bladder cancer.

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