Anesthetic pharmaceutical compositions, kits and uses thereof for slow release of an anesthetic agent and concurrent medical imaging of its distribution

Abstract

Described is a pharmaceutical compositions for slow release and concurrent tracking of a local anesthetic during medical procedures. Particularly there is a provided an anesthetic pharmaceutical composition comprising an anesthetic agent and a contrast agent, both embedded in a gel. Also provided are kits and methods of uses for concurrent anaesthesia 5 and medical imaging of distribution of an anesthetic agent in a subject.

Description

ANESTHETIC PHARMACEUTICAL COMPOSITIONS, KITS AND USES THEREOF FOR SLOW RELEASE OF AN ANESTHETIC AGENT AND CONCURRENT MEDICAL IMAGING OF ITS DISTRIBUTION CROSS REFERENCE TO RELATED APPLICATION

[0001] The present application claims priority to U.S. provisional patent application US 63 / 636,276 filed on April 19, 2024, which content is incorporated herein in its entirety. FIELD OF THE INVENTION

[0002] The invention relates to the field of anesthesia, and more particularly to pharmaceutical compositions for slow release and concurrent tracking of a local anesthetic during medical procedures. BACKGROUND OF THE INVENTION

[0003] The use of anesthetic for nerve blocks is a common practice in the field of interventional pain management for temporary pain relief. The injection of such medication can be used either for a diagnostic purpose (e.g., for confirming the location of the pain by providing relief) or it can be used for a therapeutic purpose by providing relief prior to, during and / or after a painful medical procedure.

[0004] Anesthetic hydrogels are well-known, particularly for dentistry applications and for skin surgical incisions. However, these hydrogels are often not sterile and typically not compatible with injection inside the body. Also, none of them comprise a contrast agent for medical imaging of the vertebral body. Currently there are over 30 injectable hydrogel- based products that have been approved by the FDA and / or EMA (Mandal A, et al., Bioeng Tranl Med.2020; 5:e10158; DOI: 10.1002 / btm2.10158).

[0005] Unlike the gum or skin, the vertebral body is a heavily perfused structure with multiple connections with adjacent veins, venous plexus and arteries. Therefore, injecting conventional anesthetic (i.e., lidocaine or other) within the vertebral body is not ideal since it results in medication diffusion in the intravascular compartment. Such diffusion is undesirable because it does not provide any pain relief at the site of the medical procedure and because it can very quickly cause systemic toxicity (i.e., drowsiness, oral paresthesia,tinnitus, muscle spasm, seizure, coma, respiratory arrest, cardiac arrest, among other symptoms).

[0006] Today there is still no effective solution for a “direct” intraosseous vertebral body block with the intent to anesthetize the basivertebral nerve prior to a basivertebral nerve ablation. The existing alternatives for that procedure or similar painful medical procedures are a moderate sedation, a deep sedation or a general anesthesia. However, all these have significant mortality / morbidity and are quite costly because of the patient monitoring and recovery post sedation / anesthetic induction. There are also limited operating room, time and space available in most healthcare systems for these.

[0007] In international PCT publication WO 2025 / 032530 Applicant describes novel devices, systems and methods for basivertebral nerve (BVN) ablation, a nerve that mediates pain within the spinal vertebral bodies. That technology provides, among other things, the benefit of being simpler and less invasive than current BVN ablation procedures.

[0008] Therefore, there is a need for an anesthetic pharmaceutical composition providing the possibility to perform, safely and at lower costs, many different types of painful medical procedures outside of hospitals.

[0009] There is particularly a need for an anesthetic pharmaceutical composition useful in the technology described in WO 2025 / 032530 for the treatment / ablation of the basivertebral nerve.

[0010] There is further a need for an anesthetic pharmaceutical composition comprising an anesthetic agent and a contrast agent embedded in a gel, the composition which is capable of releasing slowly and locally the anesthetic to the neural structures within bones.

[0011] The present invention addresses these needs and other needs as it will be apparent from the review of the disclosure and description of the features of the invention hereinafter.BRIEF SUMMARY OF THE INVENTION

[0012] According to one aspect, the invention relates to an anesthetic pharmaceutical composition comprising an anesthetic agent and a contrast agent, both embedded in a gel.

[0013] According to a particular aspect, the invention relates to an anesthetic pharmaceutical composition, comprising: - an anesthetic agent; and - a contrast agent; - an hydrogel embedding the anesthetic agent and the contrast agent; wherein said hydrogel has a viscosity providing for a slow-release of the anesthetic agent in osseous tissues; wherein the anesthetic agent is selected from the group consisting of lidocaine, benzocaine, tetracaine, bupivacaine, ropivacaine, mepivacaine, procaine, chloroprocaine, articaine prilocaine, dexamethasone and mixtures thereof; and wherein the contrast agent is selected from the group consisting of iodinated contrast agents, gadolinium-based contrast agents, barium sulfate, iron oxide nanoparticles, silver nanoparticles, nanomaterials, metal-based nanoparticles, microbubbles, gold nanoparticles, bismuth-containing compounds, zirconium compounds and phosphocalcic apatite.

[0014] According to another aspect, the invention relates to an anesthetic pharmaceutical composition, comprising: - an anesthetic agent; and - a contrast agent; - an hydrogel embedding the anesthetic agent and the contrast agent; wherein said composition has viscosity sufficient for the composition to remain at a deposition site for an extended duration and not be washed out by blood perfusion; wherein the anesthetic agent is selected from the group consisting of lidocaine, benzocaine, tetracaine, bupivacaine, ropivacaine, mepivacaine, procaine, chloroprocaine, articaine prilocaine, dexamethasone and mixtures thereof; andwherein the contrast agent is selected from the group consisting of iodinated contrast agents, gadolinium-based contrast agents, barium sulfate, iron oxide nanoparticles, silver nanoparticles, nanomaterials, metal-based nanoparticles, microbubbles, gold nanoparticles, bismuth-containing compounds and zirconium compounds.

[0015] According to another aspect, the invention relates to a kit for concurrent anaesthesia and medical imaging of distribution of an anesthetic agent in a subject, comprising: (i) an anesthetic pharmaceutical composition as defined herein; and (ii) a trocar and at least one stylet.

[0016] According to another aspect, the invention relates to a method for concurrent anaesthesia and medical imaging of distribution of an anesthetic agent in a subject, comprising: - providing an anesthetic pharmaceutical composition, and / or a kit, as defined herein; - injecting said anesthetic pharmaceutical composition into said subject; - visualizing injection of the anesthetic pharmaceutical composition using a medical imaging technology allowing for visualization of the contrast agent.

[0017] According to another aspect, the invention relates to the use of an anesthetic pharmaceutical composition as defined herein for concurrent anaesthesia and medical imaging of distribution of the anesthetic agent in a subject in need of a painful medical procedure.

[0018] According to another aspect, the invention relates to a system for concurrent anaesthesia and medical imaging of distribution of an anesthetic agent in a subject, comprising: (i) an anesthetic pharmaceutical composition as defined herein; and (ii) a medical imaging device allowing for visualization of the contrast agent.

[0019] According to another aspect, the invention relates to a method for the manufacture of an anesthetic pharmaceutical composition as defined herein, comprising: - providing at least one anesthetic agent, at least one contrast agent and a biocompatible hydrogel matrix material;- preparing a hydrogel precursor solution by dissolving or dispersing the hydrogel matrix material in a biocompatible solvent or buffer; - incorporating the at least one anesthetic agent and the at least one contrast agent into the hydrogel precursor solution; - initiating gelation or crosslinking of the hydrogel precursor solution to lead to the formation of a hydrogel network incorporating the at least one anesthetic agent and the at least one contrast agent.

[0020] Additional aspects, advantages and features of the present invention will become more apparent upon reading of the following non-restrictive description of preferred embodiments which are exemplary and should not be interpreted as limiting the scope of the invention. DETAILED DESCRIPTION OF EMBODIMENTS

[0021] In the following description of the embodiments, it will be understood that other embodiments may be made without departing from the scope of the invention disclosed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. General overview

[0022] The invention aims to address problems associated with local administration of anesthetic agents during painful medical procedures. Particularly, certain aspects of the invention concern pharmaceutical compositions and methods for concurrent anaesthesia of a subject and medical imaging of the distribution of an anesthetic agent in the subject. Additional aspects concerns monitoring and slow release of the anesthetic agent to provide a controlled and moderate local anesthesia, instead of an undesirable distribution inside the whole body.Anesthetic pharmaceutical compositions

[0023] One aspect of the invention concerns an anesthetic pharmaceutical composition comprising an anesthetic agent and a contrast agent embedded in a gel.

[0024] As used herein, the term “anesthetic pharmaceutical composition” refers to a composition which purpose is to provide a local anesthesia, i.e., to provide a temporary loss of sensation in a specific area of the body by blocking the transmission of nerve impulses in the area where the composition is applied or injected.

[0025] As used herein, the term “anesthetic agent” encompasses one or more compounds that may be used to provide a local anesthesia by eliminating pain sensation during painful medical procedures, such as minor surgeries, dental procedures, and certain diagnostic tests, without inducing unconsciousness or affecting other bodily functions. Examples of possible anesthetic agent include, but are not limited to, amylocaine (Stovaine), ambucaine, articaine (Septocaine™), benzocaine, benzonatate (Tessalon™), bupivacaine (Marcaine™), butacaine, butanilicaine, chloroprocaine (Nesacaine™), cinchocaine, cocaine, dibucaine, diperodon, dimethocaine, eucaine, etidocaine, hexycaine, fomocaine, fotocaine, hydroxyprocaine, isobucaine, levobupivacaine, lidocaine (Xylocaine™), mepivacaine (Carbocaine™), meprylcaine, metabutoxycaine, nitracaine, orthocaine, oxybuprocaine, paraethoxycaine, phenacaine, piperocaine, piridocaine, pramocaine, prilocaine (Citanest™), primacaine, procaine (Novocain™), procainamide, proparacaine, propoxycaine, pyrrocaine, quinisocaine, ropivacaine (Naropin™), trimecaine, tetracaine, tolycaine, and tropacocaine. In particular embodiments, the anesthetic agent is selected from lidocaine (Xylocaine™), benzocaine, tetracaine, bupivacaine (Marcaine™), ropivacaine (Naropin™), mepivacaine (Carbocaine™), procaine (Novocain™), chloroprocaine (Nesacaine™), articaine (Septocaine™), prilocaine (Citanest™), corticosteroids (e.g., dexamethasone) and mixtures thereof. It may also be envisionable to use other corticosteroids such as prednisone, prednisolone, hydrocortisone, cortisone cetamethasone, triamcinolone, methylprednisolone, and fludrocortisone. The corticosteroid(s) may be used individual or combination with lidocaine (e.g., to offer short and long-term pain relief).

[0026] In one particular embodiment the anesthetic agent comprises lidocaine. In one particular embodiment the anesthetic agent comprises both lidocaine and tetracaine.

[0027] In one particular embodiment the anesthetic agent is combined with one or more other pharmaceutical. Therefore the anesthetic pharmaceutical composition may further comprise one or more vasoconstrictor agents. In one particular embodiment the anesthetic pharmaceutical composition comprises at least one vasoconstrictor agent such as epinephrine. It is within the skills of those in the art to select the proper anaesthetic agent (or combination(s) thereof) according to various factors such as, the type of medical procedure, the clinical scenario, the patient’s condition, the local physiological environment in which the anaesthetic agent(s) will be released, the gel properties, (viscosity, porosity, etc.) and the like.

[0028] In embodiments, the anesthetic agent is present in the composition at a concentration of about 0.01 wt% to about 30 wt%, or about 0.1 wt% to about 25 wt%, preferably about 0.2 wt% to about 10 wt%.

[0029] As used herein, the term “contrast agent” encompasses one or more compounds that may be used to improve visibility and / or diagnostic accuracy of medical imaging studies. In this case, the contrast agent will confirm the anatomical location of the injection and ensure safe delivery. Suitable contrast agents may be visualized using medical imaging devices and procedures including, but not limited to, computed tomography (CT) scans, magnetic resonance imaging (MRI) scans, X-rays (e.g., fluoroscopy), and ultrasound. Examples of possible contrast agent include, but are not limited to: (i) iodinated contrast agents such as iohexol (Omnipaque™), iopamidol (Isovue™), ioversol (Optiray™), iodixanol (Visipaque™), iopromide (Ultravist™); (ii) gadolinium-based contrast agents (GBCAs) such as gadopentetate dimeglumine (Magnevist™), gadobutrol (Gadavist™), gadoterate meglumine (Dotarem™), gadobenate dimeglumine (MultiHance™), gadoteridol (ProHance™); (iii) barium sulfate (BaSO4); (iv) nanoparticles including but not limited to, iron oxide nanoparticles, silver nanoparticles, nanomaterials, metal-based nanoparticles; (v) microbubbles (e.g., microspheres filed with air, nitrogen or perfluorocarbon); (vi) gold nanoparticles; (vii) bismuth-containing compounds (e.g., bismuth chelate, bismuth nanoparticles, bismuth–gadolinium,nanoparticles, Bi-HPDO3A, etc.); and (viii) zirconium compounds such as ZrO2, Zr(SO4)2, and H2ZrO3). In one particular embodiment, the contrast agent is iohexol (Omnipaque™). A list of FDA approved contrast agents is available on the web site of the National Institute of Health (NIH).

[0030] In embodiments, the contrast agent is present in the composition at a concentration of about 0.1 wt% to about 50 wt%, or about 1 wt% to about 30 wt%, preferably about 3 wt% to about 25 wt%.

[0031] One essential aspect of the invention relates to the fact the anesthetic agent(s) and contrast agent(s) are embedded in a gel. As used herein, the term “embedded in a gel” means that the agents are incorporated or contained within a gel matrix or structure. In accordance with the present invention, the gel serves as a medium or carrier for the embedded anesthetic agent(s) and the contrast agent(s), thereby providing support and containment for these agents.

[0032] As is known, hydrogel biomaterials are either natural or synthetic in material origin. Natural hydrogels are typically derived from polypeptides (e.g., fibrin, collagen, gelatin) or polysaccharides (e.g., hyaluronic acid, alginate, cellulose, chitosan). On the other hand, examples of synthetic hydrogels include poly(ethylene glycol), poly(acrylate) derivatives, poly(methacrylate) derivatives, poly(acrylamide), poly(lactic-co-glycolic acid), poly(vinyl alcohol), and poly(urethane).

[0033] Preferably, the gel is biocompatible with medical and biological applications, i.e., the gel can coexist with living tissues without causing harm, adverse reactions, or immune responses. In one particular embodiment the gel consists of a hydrogel. The Hydrogel biomaterials may be of natural or synthetic in material origin.

[0034] In embodiments, the gel is viscous. In embodiments the gel comprises polypeptides (e.g., fibrin, collagen, gelatin), polymers, hyaluronic acid (e.g., a hyaluronic acid viscous gel), guanosine derivatives (e.g., guanosine-derived hydrogels), TRI-726, Pluronics such as F68 (Polaxamer-188), F38 (Poloxamer-108), and F127 (Poloxamer- 407), P85, L61, and carboxymethyl cellulose.

[0035] Gels that are suitable for the present invention includes gels obtained following to modification(s) of existing anesthetic gels that are commonly used for dentistry applications and / or for skin surgical incisions (e.g., lidocaine hydrochloride jelly USP, 2%). A list of clinically approved injectable hydrogels is available in paper published by Mandal A, et al., Bioeng Tranl Med. 2020; incorporated herein by reference in its entirety). It is within the skills of those in the art to select proper material(s) for obtaining an anesthetic pharmaceutical composition in accordance with the present invention, based on parameters including, but not limited to, biocompatibility, porosity, degradability, release of therapeutic agents, the local physiological environment in which the hydrogel will be deployed, etc.

[0036] In embodiments, the anesthetic pharmaceutical composition and / or gel comprises a viscosity that is compatible with an injection within bones, tooth and / or soft tissues. In embodiments, the composition and / or gel comprises a viscosity allowing the release of the anesthetic agent over time gradually and in a controlled manner, when injected into a bone structure. In embodiments, the composition and / or gel comprises a viscosity allowing the composition and / or gel to remain at a deposition site for an extended duration, and not be washed out by blood perfusion. In embodiments, the composition is formulated to provide for a release of the anesthetic agent at about 5 mg / h to about 5000 mg / h, or about 50 mg / h to about 2000 mg / h, preferably about 100 mg / h to about 1500 mg / h.

[0037] In embodiments, the composition comprises a viscosity of about 1 to about 10 000 poise, or about 1 to about 1000 poise, about 1 to about 500 poise, or about 5 to about 100 poise.

[0038] The anesthetic pharmaceutical composition of the invention may further comprise additional components useful in the medical procedure(s) of interest, including, but not limited to, compounds that affect electrical and / or thermal conductivity. Examples of compounds that could affect the electrical conductivity include, but are not limited to, salts, metallic and nonmetallic nanoparticles (e.g. gold, Al2O3, TiO2, SiO2, etc.), polyethylene glycol (PEG), Polypyrrole (PPy), Polyaniline (PANI), etc.

[0039] For example, it may be useful during the course of a radiofrequency ablation (RFA) to provide an anesthetic pharmaceutical composition further comprising compound(s) that affect electrical and / or thermal conductivity in order to increase, decrease, maintain or influence electrical and / or thermal properties of the surrounding tissue and / or to enhance the performance characteristics of the ablation. Additional compound(s) may also be present in the composition to positively influence the ablation zone, to provide a better control of the size of the ablation zone, to shorten the required ablation time, to provide a more uniform environment for ablation, etc. Additional compound(s) in the anesthetic pharmaceutical composition of the invention may also include medication(s) that could be distributed locally, such as ablation medication (e.g. alcohol, phenol, etc.), a chemotherapeutic agent, etc.

[0040] Preferably the anesthetic pharmaceutical composition consists of a sterile composition that is compatible with usage in humans. The composition may also be formulated (i.e., components, viscosity, buffers, pH, etc.) according to a desired medical use. For instance, the anesthetic pharmaceutical composition may be formulated specifically for diagnostic testing, for an intraosseous procedure, for cancer therapy and / or tumor ablation, for bone biopsy, for a surgical procedure of the vertebral body, for an injection within soft tissue, and / or for an image guided medical procedure, etc. It is also envisionable to formulate and use composition of the invention for some dentistry procedures. It is within the skills of those in the art to prepare proper formulations in accordance with a desired particular use. Methods of manufacture

[0041] Another aspect of the invention concerns methods for the manufacture of a anesthetic pharmaceutical composition as defined herein.

[0042] Anesthetic pharmaceutical compositions in accordance with the present invention may be manufactured using known methods and techniques, e.g. methods and techniques for the manufacture of hydrogels incorporating compounds and pharmaceutical agents.

[0043] Example 1: A general outline of a manufacturing process may comprise the following steps.

[0044] 1. Procurement of compounds. Obtain high-quality medical grade compounds (e.g., hyaluronic acid, contrast agent, etc.) through synthesis or purchase from a reputable supplier. Ensure that the compounds meet the required specifications for medical use (e.g., U.S. FDA; Health Canada).

[0045] 2. Formulation development: Determine the composition of the hydrogel based on the desired properties and intended application of the hydrogel. This may include determining the type and concentration of polymers, crosslinkers, and any additional additives such anesthetic agent(s), contrast agent(s), compounds that affect electrical and / or thermal conductivity, drugs (e.g., ablation medication, chemotherapeutic agents, bioactives) and / or any additional molecule. Further consideration factors such as gelation time, mechanical strength, biocompatibility, and drug release kinetics.

[0046] 3. Preparation of hydrogel precursor solution: Prepare a hydrogel precursor solution by dissolving or dispersing the hydrogel matrix material in a suitable solvent or buffer. Ensure that the solvent is compatible with the anesthetic agent and contrast agent. For instance for hydrogel based on hyaluronic acid, this step may involve dissolving the hyaluronic acid in a suitable aqueous solvent to form a hydrated HA solution.

[0047] 4. Incorporation of the anesthetic agent and contrast agent: Add the desired anesthetic agent(s) and desired contrast agent(s) into the hydrogel precursor solution. Mix thoroughly to achieve a homogeneous distribution of the agents within the hydrogel matrix.

[0048] 5. Gelation / crosslinking: Initiate the gelation or crosslinking of the hydrogel precursor solution to lead to the formation of the hydrogel network (e.g., an injectable hydrogel). Depending on the chosen hydrogel material, this can be achieved through methods such as temperature-induced gelation, chemical crosslinking, or photopolymerization. Follow the recommended protocols and conditions to achieve the desired gelation characteristics.

[0049] 6. Sterilization: Ensure the hydrogel is free from any microbial contaminants by subjecting it to sterilization methods such as autoclaving, ethylene oxide (ETO) sterilization, gamma irradiation, or filtration. Choose a sterilization method that maintains the integrity and functionality of the composition. For instance, it may be preferable to carry out the previous steps under sterile conditions since some sterilization methods such as autoclaving may not be applicable to the compositions of the invention which may comprise heat-sensitive agents and compounds.

[0050] 7. Quality control: Perform thorough testing to ensure the hydrogel meets the required specifications and standards. This may include evaluating mechanical properties, swelling behavior, degradation rate, biocompatibility, drug release kinetics, biocompatibility, and imaging characteristics, among others.

[0051] 8. Packaging and storage: Properly package the hydrogel to maintain its integrity and sterility. Follow appropriate storage conditions to preserve its properties and shelf life.

[0052] Example 2: Another general outline of a manufacturing process may comprises the following steps.

[0053] 1. Procurement of compounds. Obtain high-quality medical grade compounds (e.g., hyaluronic acid, contrast agent, etc.) through synthesis or purchase from a reputable supplier. Ensure that the compounds meet the required specifications for medical use (e.g., U.S. FDA; Health Canada).

[0054] 2. Formulation development: Determine the composition of the hydrogel based on the desired properties and intended application of the hydrogel. This may include determining the type and concentration of polymers, crosslinkers, and any additional additives such anesthetic agent(s), contrast agent(s), compounds that affect electrical and / or thermal conductivity, drugs (e.g., ablation medication, chemotherapeutic agents, bioactives) and / or any additional molecule. Further consideration factors such as gelation time, mechanical strength, biocompatibility, and drug release kinetics.

[0055] 3. Preparation of hydrogel precursor solution: Prepare a hydrogel precursor solution by dissolving or dispersing the hydrogel matrix material in a suitable solvent or buffer. Ensure that the solvent is compatible with the anesthetic agent and contrast agent. For instance for hydrogel based on hyaluronic acid, this step may involve dissolving the hyaluronic acid in a suitable aqueous solvent to form a hydrated HA solution.

[0056] 4. Incorporation of the anesthetic agent and contrast agent: Add the desired anesthetic agent(s) and desired contrast agent(s) into the hydrogel precursor solution. Mix thoroughly to achieve a homogeneous distribution of the agents within the hydrogel matrix.

[0057] 5. Sterilization: Ensure the hydrogel is free from any microbial contaminants by subjecting it to sterilization methods such as autoclaving, ethylene oxide (ETO) sterilization, gamma irradiation, or filtration. Choose a sterilization method that maintains the integrity and functionality of the composition. For instance, it may be preferable to carry out the previous steps under sterile conditions since some sterilization methods such as autoclaving may not be applicable to the compositions of the invention which may comprise heat-sensitive agents and compounds.

[0058] 6. Packaging and storage: Properly package the hydrogel to maintain its integrity and sterility. Follow appropriate storage conditions to preserve its properties and shelf life.

[0059] 7. Quality control: Perform thorough testing to ensure the hydrogel meets the required specifications and standards. This may include evaluating mechanical properties, swelling behavior, degradation rate, biocompatibility, drug release kinetics, biocompatibility, and imaging characteristics, among others. Those skilled in the art will be able to manufacture anesthetic pharmaceutical compositions in accordance with the present using these guidelines, as well as methods and techniques know in the art. If necessary, this may involve consulting with experts in the field, such as formulation scientists, regulatory professionals, polymer scientists. Additional techniques and variations of those above is within the skills of those in the art.Kit

[0060] Another aspect of the invention concerns a kit for concurrent anaesthesia and medical imaging of distribution of an anesthetic agent in a subject.

[0061] In one embodiment the kit comprises an anesthetic pharmaceutical composition as defined herein and a system for basivertebral nerve (BVN) ablation as described in WO 2025 / 032530 (incorporated herein by reference in its entirety), the system comprising preferably a trocar and at least one stylet.

[0062] In one embodiment the kit comprises (i) a hydrogel precursor solution, the solution comprising an hydrogel matrix as defined herein, an anesthetic agent and a contrast agent; and (ii) a crosslinking agent leading to formation of a hydrogel network when mixed with the hydrogel precursor solution.

[0063] In another embodiment, the kit comprises an anesthetic pharmaceutical composition as defined herein and at least one additional component including, but not limited to, a user manual or instructions, a syringe, a mixer, a needle, pen(s), marking sheets, boxes, holders, wipes, a topical anesthetic, disinfecting solutions and a preoperative surgical scrub brush. Methods and Medical uses

[0064] Another aspect of the invention concerns the medical uses of the anesthetic pharmaceutical compositions as defined herein and related methods, particularly for concurrent anaesthesia and medical imaging of distribution of the anesthetic agent in a subject.

[0065] In one particular aspect, the invention relates to a method for concurrent anaesthesia and medical imaging of distribution of an anesthetic agent in a subject. In one embodiment the method comprises: (i) providing an anesthetic pharmaceutical composition as defined herein; (ii) injecting the pharmaceutical composition into the subject; and (iii) visualizing injection of the pharmaceutical composition using a medical imaging technology allowing for visualization of the contrast agent.

[0066] As used herein, the term “subject” refers to any living animals in which nerve pain mitigation may be desirable, including birds, reptiles, amphibians, mammals, etc. The term “subject” includes domestic animals (e.g. cats, dogs, horses, pigs, cows, goats, sheep), rodents (e.g. mice or rats), rabbits, squirrels, bears, primates (e.g., chimpanzees, monkeys, gorillas, and humans), wild animals such as those living in zoos (e.g. lion, tiger, elephant, and the like), and transgenic species thereof. In preferred embodiments the subject is a human, more preferably a human patient in need of treatment. In particular embodiments the human patient is in need of a medical procedure that may be painful, such as a diagnostic testing, an intraosseous procedure, a cancer therapy, a tumor ablation, a bone biopsy, a surgical procedure of the vertebral body, an image guided medical procedure. In one particular embodiment the human patient requires pain mitigation associated with a local anesthetic to mitigate pain that emanates from inside a bone (e.g., intraosseous injection). In a more specific embodiment, the human patient is in need of treatment or ablation of the basivertebral nerve (BVN), including but not limited a BVN ablation.

[0067] According to the invention, the presence of a contrast agent within the anesthetic pharmaceutical composition allows its visualization, and thereby allows localisation of the anesthetic and monitoring of its dispersion inside the subject. The visualisation can be performed using any medical imaging technology that is suitable for visualization of the particular contrast agent(s). Examples of such medical imaging technologies include, but are not limited to, computed tomography (CT) scans, magnetic resonance imaging (MRI) scans, an X-rays, and ultrasound.

[0068] Injection within the subject may be carried out using any suitable device or technique. In one particular example, to proceed with an injection of intraosseous lidocaine within the vertebral body, an introducer (i.e., a needle) is positioned within the bone. This can be done with imaging guidance (X-ray, fluoroscopy, CT-scan, ultrasound). Once the target is successfully reached, the anesthetic composition can be injected.

[0069] In one particular embodiment, the injection is performed with a system comprising a trocar and at least one stylet, as described and claimed in WO 2025 / 032530.

[0070] In embodiments, the anesthetic pharmaceutical composition of the invention provides a slow release of the anesthetic agent at a site of injection. Preferably the properties of the composition (e.g., viscosity) is such that the composition stays in place (i.e., at or around the location of the injection), instead of diffusing away. In one embodiment the composition of the invention is injected in a vertebra (e.g., a lumbar vertebra) using a syringe in a parapedicular approach and the anesthetic agent stays inside the vertebra instead of leaving the vertebral body to flow into the inferior vena cava, as does existing prior art compounds or anesthetic compositions.

[0071] The anesthetic pharmaceutical composition of the invention may find numerous applications in many different body structures or bones. Particularly, the following uses are foreseen for injection within the vertebral body. (1) Diagnostic utilization: proceeding with the diagnostic assessment and / or confirmation of a painful pain generator within the vertebral body. This may include among other: vertebrogenic back pain (confirming that the Modic Changes type 1 and type 2 are painful), a painful tumor, a fracture, etc. (2) Anesthetic utilization: the anesthetic pharmaceutical composition can be injected prior to performing a painful procedure (i.e., ablation, embolization, vertebral augmentation, etc.). (3) Therapeutic utilization: the anesthetic pharmaceutical composition could be coupled with therapeutic agents, such as alcohol, phenol, chemotherapy, etc.

[0072] Particular uses of the anesthetic pharmaceutical composition according to the invention include, but are not limited to the following: (a) diagnostic test for vertebrogenic back pain, e.g., to determine if a patient is a candidate for basivertebral nerve (BVN) ablation; (b) various types of intraosseous procedures performed under imaging guidance (including BVN ablation) and intraosseous procedure leaving hardware in place (i.e., sacroiliac joint fusion procedure, hip screw positioning, lumbar fusion surgery, etc.); (c) cancer therapy and / or tumor ablation for tumors that requires imaging guided treatment (e.g., soft tissue tumors or bone tumors) using ablation, microwave therapy, cryoablation, radiation therapy, etc.); (d) bone anesthesia before a bone biopsy (any bone in the body); (e) as an anesthetic for any surgical procedure of the vertebral body (e.g., kyphoplasty, vertebroplasty, mechanical vertebral augmentation (SpineJack™ (Stryker)) or others; (f) for injection within soft tissue wherein the anesthetic pharmaceutical composition isinjected within soft tissue or adjacent to peripheral neural structures for a longer and more precise diagnostic block (i.e., thanks to the contrast added and slow release) or for soft tissue surgeries / minimally invasive procedures; (g) image guided medical procedures that requires contrast and anesthetic (e.g., ultrasound, X-ray, fluoroscopy, CT-scan, MRI guidance, etc.); (h) hardware positioning (e.g., pedicle screws, implants, interbody spacer, etc.).

[0073] Using the anesthetic pharmaceutical composition of the invention may provide numerous benefits. For instance, the viscous gel permits the injection of the anesthetic locally in a controlled way. The contrast agent allows for the visualization in real time of the spatial distribution of the medication is distributed within the subject (e.g., vertebral body). The slow-release properties of the composition allow the anesthetic to “act” locally, the composition providing an environment favorable for radiofrequency ablation and for decreasing duration of the ablation. In addition, if the composition is very electrically conductive, it will act as an extension of the ablation probe when used in combination with a radiofrequency ablation. Controlling the localization of the deposition of the composition could allow to visualize, and thus control, the spatial distribution of the ablation to be performed and the resulting ablation lesion.

[0074] For instance, diagnostic block is a very frequent practice in interventional pain medicine. However, BVN ablation is one of the few procedures that is performed without a trial procedure or test procedure due to the highly vascularised vertebra. Using the anesthetic pharmaceutical composition in the course of a diagnostic block prior to a BVN ablation could thus be very beneficial. For instance, about 30% of patients (or 1 / 3) do not respond to a BVN ablation because it is very difficult to differentiate clinically between vertebrogenic or discogenic back pain. As such, 1 / 3 of patients get a costly and painful BVN treatment for which they do not get any therapeutic benefit. Using the anesthetic pharmaceutical composition of the invention in the course of a diagnostic block prior to a BVN ablation could thus increase effectiveness of BVN treatments from 70% to 100%.

[0075] Furthermore, BVN ablation clinical protocols currently suggest an ablation time of 15 minutes. This duration can be difficult to tolerate for patients with mild or moderate sedation. On the other hand proceeding with deep sedation or general anesthesia isundesirable because it increases the risks of morbidity / mortality as well as the risks of complications due to anesthesiology. The anesthetic pharmaceutical composition of the invention may allow to: (1) perform such procedure under local anesthetic; and (2) decrease the time of ablation due to the composition of the gel.

[0076] Using the anesthetic pharmaceutical composition of the invention may thus increase the comfort of the patient by providing a simpler local anesthesia, instead of sedation (moderate or deep sedation) or a general anesthesia. Having a local anesthesia may allow to reduce patient sedation, thereby improving patient comfort, improving recovery time, reducing cost, reducing need for anesthesiologist, reducing room time, reducing or eliminating overnight stay, etc.

[0077] In accordance with one particular embodiment, the anesthetic pharmaceutical composition of the invention, which has been packaged as defined hereinabove, may be used by following these steps:

[0078] i) Unpacking the hydrogel: Unpack the combined hydrogel components and the instruments necessary for its use, including, but not limited to, a mixer, syringe, needle, introducer, catheter, etc.

[0079] ii) Preparing the patient: Begin the medical intervention up to the point of hydrogel injection.

[0080] iii) Gelation / crosslinking: Initiate the gelation or crosslinking of the hydrogel precursor solution to lead to the formation of the hydrogel network (e.g., an injectable hydrogel). Depending on the chosen hydrogel material, this can be achieved through methods such as temperature-induced gelation, chemical crosslinking, or photopolymerization. Follow the recommended protocols and conditions to achieve the desired gelation characteristics.

[0081] iv) Administration of the hydrogel: Inject the desired quantity of mixed hydrogel, either before or after the completion of gelation / crossliking, to the site of intervention using the selected instruments.

[0082] v) Completion of the medical intervention: Continue with the medical intervention and dispose of the instruments and leftover material according to instructions.

[0083] System

[0084] Another related aspect of the invention concerns a system for concurrent anaesthesia and medical imaging of distribution of an anesthetic agent in a subject. In one particular embodiment the system comprises: (i) an anesthetic pharmaceutical composition and / or a kit as defined hereinbefore; and (ii) a medical imaging device allowing for visualization of the contrast agent. In embodiments the medical imaging device is selected from a computed tomography (CT) scan, a magnetic resonance imaging (MRI) scan, an X-ray machine, and an ultrasound scanner.

[0085] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of this invention and covered by the claims appended hereto. The invention is further illustrated by the following examples which should not be construed as further or specifically limiting. EXAMPLES

[0086] Example of a basivertebral nerve block (BVNB) diagnostic test

[0087] A patient presents with vertebrogenic back pain related to Modic type I and / or Modic type II endplate degenerative changes of a lumbar vertebral segment. The lumbar skin has been sterilely prepped above this segment and the subcutaneous tissues have been anesthetized with local anesthetic. To confirm this diagnosis, a curved bone introducer such as the one described in WO 2025 / 032530 is positioned along the vertebral body via a left parapedicular approach under fluoroscopic and / or CT scan guidance. An intraosseous stylet is advanced along center of the posterior third of one vertebral body. An hydrogel containing an anesthetic and a contrast agent in accordance with the present invention is injected under live X-ray guidance. The hydrogel stays contained in the posterior portion of the vertebral body slowly releasing the anesthetic locally andinterfering with excitation and conduction by action potentials of the nervous system (and basivertebral nerve) by blockade of the voltage-gate Na channels. The curved bone introducer placement and injection of the intraosseous hydrogel anesthetic are repeated for the adjacent affected vertebral body. The curved introducers are then removed from the skin and safely disposed.

[0088] The patient is brought back to the recovery room for monitoring. Over the next few hours, the patient is discharged from the facility and asked to answer a pain journal providing information on the pain decrease experienced in the lower lumbar region. If the pain relief is judged sufficient (more than 50-70% pain relief) the patient becomes a candidate for basivertebral nerve ablation.

[0089] Example of a basivertebral nerve ablation (BVNA)

[0090] A patient presents with vertebrogenic back pain related to Modic type I and / or Modic type II endplate degenerative changes of a lumbar vertebral segment. The lumbar skin has been sterilely prepped above this segment and the subcutaneous tissues have been anesthetized with local anesthetic. A trocar, having a curved distal tip as described in international PCT publication WO 2025 / 032530, is positioned along the vertebral body via a left parapedicular approach under fluoroscopic and / or CT scan guidance. An intraosseous stylet is advanced along center of the posterior third of one vertebral body. An hydrogel containing an anesthetic and a contrast agent in accordance with the present invention is injected under live X-ray guidance. The gel stays contained in the posterior portion of the vertebral body slowly releasing the anesthetic locally and interfering with excitation and conduction by action potentials of the nervous system (and basivertebral nerve) by blockade of the voltage-gate Na channels. The curved bone introducer placement and the intraosseous hydrogel anesthetic injections are repeated for the adjacent affected vertebral body.

[0091] A radiofrequency ablation probe is then positioned within the center of the posterior third of the vertebral body. Radiofrequency ablation treatment (between 50°C and 100°C for a period of time between 1 minute and 15 minutes) is performed simultaneously for all vertebrae affected. The curved bone introducer trocars andradiofrequency probes are removed and disposed of safely, and the patient is returned to recovery prior to being discharged. On clinical follow-up, 1.5 months to 3 months after the procedure, complete low back pain relief is achieved.

[0092] Example of use in vertebral augmentation

[0093] The patient presents with either a painful vertebral compression fracture or other criteria indicative of treatment. The lumbar skin is sterilely prepped at the level to be treated and the subcutaneous tissues have been anesthetized with local anesthetic. A bone introducer trocar is advanced within the vertebral body either with a pedicular or extrapedicular approach under CT-scan or fluoroscopic guidance. A bilateral bone introducer approach is also utilized, as necessary. An injection of the anesthetic pharmaceutical composition / hydrogel containing the anesthetic agent and the contrast agent is performed under live fluoroscopic guidance. The gel stays contained within the central portion of the vertebral body slowly releasing the anesthetic locally interfering with excitation and conduction by action potentials of the nervous system by blockade of the voltage-gate Na channel (targeting the basivertebral nerve and other branches).

[0094] The vertebral body is augmented through one or multiple trocars, directly with PMMA cement injection (i.e., vertebroplasty), or the vertebral body is augmented with a single or multiple inflated balloons followed by PMMA cement injection (i.e., kyphoplasty), or a single or multiple mechanical devices can be deployed in the vertebral body prior to PMMA cement injection (i.e., mechanical vertebral augmentation).The trocars are removed and safely disposed. The patient is returned to recovery prior to be discharged.

[0095] Example of use in tumor ablation

[0096] The skin above the area of interest (either soft tissue or bone) is sterilely prepped and the subcutaneous tissues are anesthetized with a local anesthetic. An introducer is advanced up to the site of interest, under ultrasound, CT-scan or fluoroscopic guidance. An hydrogel composition in accordance with the present invention containing an anesthetic and a contrast agent is injected under live imaging guidance around the site of interest. The gel stays contained within the area of interest releasing slowly the anesthetic interfering with excitation and conduction by action potentials of the nervous system byblockade of the voltage-gate Na channel of the nerves. The area of interest with pathology and / or tumor is then treated. Treatment within bones may require adding PMMA cement after the procedure, at the ablation site. The introducer trocar is disposed safely, and the patient returned to recovery prior to be discharged. * * *

[0097] Headings are included herein for reference and to aid in locating certain sections. These headings are not intended to limit the scope of the concepts described therein, and these concepts may have applicability in other sections throughout the entire specification. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

[0098] The singular forms “a”, “an” and “the” include corresponding plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an anesthetic agent" includes one or more of such agents and reference to "the method" includes reference to equivalent steps and methods known to those of ordinary skill in the art that could be modified or substituted for the methods described herein.

[0099] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, concentrations, properties, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about”. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the present specification and attached claims are approximations that may vary depending upon the properties sought to be obtained. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the embodiments are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors resulting from variations in experiments, testing measurements, statistical analyses, and such.[000100] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the present invention and scope of the appended claims.

Claims

CLAIMS:

1. An anesthetic pharmaceutical composition comprising an anesthetic agent and a contrast agent, both embedded in a gel.

2. The composition of claim 1, wherein said composition has a viscosity providing for slow release of the anesthetic agent in osseous tissues.

3. The composition of claim 1 or 2, wherein said composition has viscosity sufficient for the composition to remain at a deposition site for an extended duration and not be washed out by blood perfusion.

4. The composition of any one of claims 1 to 3, wherein the anesthetic agent is selected from the group consisting of lidocaine, benzocaine, tetracaine, bupivacaine, ropivacaine, mepivacaine, procaine, chloroprocaine, articaine prilocaine, dexamethasone and mixtures thereof.

5. The composition of any one of claims 1 to 4, wherein the anesthetic agent comprises lidocaine.

6. The composition of any one of claims 1 to 5, wherein the anesthetic agent comprises lidocaine and at least one of epinephrine and tetracaine.

7. The composition of any one of claims 1 to 6, wherein the contrast agent is selected from the group consisting of iodinated contrast agents, gadolinium-based contrast agents, barium sulfate, iron oxide nanoparticles, silver nanoparticles, nanomaterials, metal-based nanoparticles, microbubbles, gold nanoparticles, bismuth-containing compounds, zirconium compounds, and phosphocalcic apatite.

8. The composition of any one of claims 1 to 7, wherein the contrast agent is iohexol.

9. The composition of any one of claims 1 to 8, wherein said gel consists of a hydrogel.

10. The composition of any one of claims 1 to 9, wherein the gel is composed of a hyaluronic acid matrix.

11. The composition of any one of claims 1 to 9, wherein the gel comprises a polyethylene glycol (PEG) matrix.

12. The composition of any one of claims 1 to 11, wherein said composition provides for concurrent anaesthesia and medical imaging inside a subject’s body.

13. The composition of any one of claims 1 to 12, wherein said composition is formulated to provide a release of the anesthetic agent at about 100 mg / h to about 1500 mg / h.

14. The composition of any one of claims 1 to 13, wherein said composition comprises a viscosity of about 1 to about 500 poise.

15. The composition of any one of claims 1 to 14, wherein said composition further comprises compound(s) that affect electrical and / or thermal conductivity, an ablation medication, and / or a chemotherapeutic agent.

16. The composition of any one of claims 1 to 15, wherein said composition is a sterile composition.

17. The composition of any one of claims 1 to 16, wherein said composition is formulated for one or more of diagnostic testing, for an intraosseous procedure, for cancer therapy and / or tumor ablation, for bone biopsy, for a surgical procedure of the vertebral body, for an injection within soft tissue, and / or for an image guided medical procedure.

18. An anesthetic pharmaceutical composition, comprising: - an anesthetic agent; and - a contrast agent; - an hydrogel embedding the anesthetic agent and the contrast agent; wherein said hydrogel has a viscosity providing for a slow-release of the anesthetic agent in osseous tissues; wherein the anesthetic agent is selected from the group consisting of lidocaine, benzocaine, tetracaine, bupivacaine, ropivacaine, mepivacaine, procaine, chloroprocaine, articaine prilocaine, dexamethasone, corticosteroids and mixtures thereof; andwherein the contrast agent is selected from the group consisting of iodinated contrast agents, gadolinium-based contrast agents, barium sulfate, iron oxide nanoparticles, silver nanoparticles, nanomaterials, metal-based nanoparticles, microbubbles, gold nanoparticles, bismuth-containing compounds, zirconium compounds and phosphocalcic apatite.

19. An anesthetic pharmaceutical composition, comprising: - an anesthetic agent; and - a contrast agent; - an hydrogel embedding the anesthetic agent and the contrast agent; wherein said composition has viscosity sufficient for the composition to remain at a deposition site for an extended duration and not be washed out by blood perfusion; wherein the anesthetic agent is selected from the group consisting of lidocaine, benzocaine, tetracaine, bupivacaine, ropivacaine, mepivacaine, procaine, chloroprocaine, articaine prilocaine, dexamethasone, corticosteroids and mixtures thereof; and wherein the contrast agent is selected from the group consisting of iodinated contrast agents, gadolinium-based contrast agents, barium sulfate, iron oxide nanoparticles, silver nanoparticles, nanomaterials, metal-based nanoparticles, microbubbles, gold nanoparticles, bismuth-containing compounds, zirconium compounds and phosphocalcic apatite.

20. A kit for concurrent anaesthesia and medical imaging of distribution of an anesthetic agent in a subject, comprising: (i) an anesthetic pharmaceutical composition as defined in any one of claims 1 to 19; and (ii) a trocar and at least one stylet.

21. A kit for concurrent anaesthesia and medical imaging of distribution of an anesthetic agent in a subject, comprising: (i) a hydrogel precursor solution comprising an hydrogel matrix, an anesthetic agent and a contrast agent; and (ii) a crosslinking agent, said leading crosslinking agent to formation of a hydrogel network when mixed with the hydrogel precursor solution.

22. A method for concurrent anaesthesia and medical imaging of distribution of an anesthetic agent in a subject, comprising: - providing an anesthetic pharmaceutical composition as defined in any one of claims 1 to 19, and / or a kit as defined in claim 20 or 21; - injecting said anesthetic pharmaceutical composition into said subject; - visualizing injection of the anesthetic pharmaceutical composition using a medical imaging technology allowing for visualization of the contrast agent.

23. The method of claim 22, wherein said injection is selected from intraosseous injection, injection within soft tissue, tumor injection, injection adjacent to peripheral neural structures.

24. The method of claim 22 or 23, wherein said subject is a human patient.

25. The method of claim 24, wherein said human patient requires pain mitigation.

26. The method of claim 24 or 25, wherein said human patient is in need of one or more of diagnostic testing, an intraosseous procedure, cancer therapy, tumor ablation, bone biopsy, a surgical procedure of the vertebral body, and an image guided medical procedure.

27. The method of claim 24 or 25, wherein said human patient is in need of treatment or ablation of the basivertebral nerve (BVN).

28. The method of any one of claims 22 to 27, wherein said medical imaging technology is selected from the group consisting of a computed tomography (CT) scan, a magnetic resonance imaging (MRI) scan, an X-ray, and ultrasound.

29. Use of an anesthetic pharmaceutical composition as defined in any one of claims 1 to 19, for concurrent anaesthesia and medical imaging of distribution of the anesthetic agent in a subject in need of a painful medical procedure.

30. A system for concurrent anaesthesia and medical imaging of distribution of an anesthetic agent in a subject, comprising: (i) an anesthetic pharmaceutical composition asdefined in any one of claims 1 to 19; and (ii) a medical imaging device allowing for visualization of the contrast agent.

31. The system of claim 30, wherein said medical imaging device is selected from the group consisting of a computed tomography (CT) scan, a magnetic resonance imaging (MRI) scan, an X-ray machine, and an ultrasound scanner.

32. A method for the manufacture of an anesthetic pharmaceutical composition as defined in any one of claims 1 to 19, comprising: - providing at least one anesthetic agent, at least one contrast agent and a biocompatible hydrogel matrix material; - preparing a hydrogel precursor solution by dissolving or dispersing the hydrogel matrix material in a biocompatible solvent or buffer; - incorporating the at least one anesthetic agent and the at least one contrast agent into the hydrogel precursor solution; - initiating gelation or crosslinking of the hydrogel precursor solution to lead to the formation of a hydrogel network incorporating the at least one anesthetic agent and the at least one contrast agent.