Long-acting anesthetic formulations

Abstract

The invention belongs to the technical field of pain relief, and relates to a pharmaceutical composition which comprises at least one anesthetic. The anesthetic is selected from the group consisting of ropivacaine, bupivacaine, eticaine, levobupivacaine, lidocaine, linocaine, mepivacaine, articaine, dibuvacaine, levobupivacaine, prilocaine, benzocaine, cloprocaine, cocaine, procaine, promecaine, tetracaine, and any pharmaceutically acceptable salts, hydrates thereof, as well as pharmaceutically acceptable salts, hydrates thereof. A solvate or a prodrug; at least one alkanolamine selected from the group consisting of: triethanolamine, tripropanolamine, and trimethylamine; water; and optionally a pharmaceutically acceptable diluent, carrier and / or excipient. The disclosure also relates to the use of the composition for providing pain relief, methods of treatment, methods of producing the pharmaceutical composition, and carbon quantum dots formed from the components of the pharmaceutical composition.

Description

Technical Field

[0001] The inventive concepts described herein generally relate to pharmaceutical compositions comprising anesthetics. Specifically, the inventive concepts relate to a pharmaceutical composition having a long-lasting anesthetic effect, and the production of such a composition. Background Art

[0002] Local anesthetics cause sensory or motor blockade by reversibly inhibiting nerve impulses, thereby not producing pain in a specific part of the body without losing consciousness. When a doctor is about to perform surgery or pain examination, local anesthetics are used to anesthetize body parts, or provide pain relief when needed. These agents can be grouped based on type. The ester group of local anesthetics includes benzocaine, chloroprocaine, cocaine, procaine, proparacaine and tetracaine. The amide group of local anesthetics includes articaine, bupivacaine, cinchocaine, etidocaine, levobupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine and trimecaine. These drugs have a similar mechanism of action, in which they produce a reversible inhibitory effect on the influx of sodium ions, thereby blocking the impulse conduction of nerve fibers.

[0003] The drugs ropivacaine and bupivacaine are highly similar, differing only in the presence or absence of a methyl group. However, ropivacaine benefits from greater efficacy, which may be partly because ropivacaine is sold as an optionally pure S-enantiomer. Ropivacaine is a well-tolerated anesthetic drug that is effective for surgical anesthesia and for relieving postoperative pain and labor pain (Kuthiala and Chaudhary, 2011).

[0004] Carbon quantum dots are a class of nanomaterials that have attracted much attention due to their low toxicity, water solubility, and fluorescence. Therefore, it is thought that carbon quantum dots could prove useful in the fields of imaging and drug delivery. Qu et al. describe the synthesis of ibuprofen-based carbon quantum dots and show that these dots are stable, non-toxic, and have good biocompatibility in water. In addition, the anti-inflammatory properties of ibuprofen are retained.

[0005] Although local anesthetics are effective for surgical anesthesia and pain relief, there is still room for improvement, such as pharmacokinetic (PK) properties or pharmacodynamic (PD) properties in mammals. Despite the efforts made in the field of anesthetic products, there is still a need for improved products. It is desirable to provide improved products, and if such products are long-acting, it will bring greater benefits to mankind. Summary of the invention

[0006] The object of the present invention is to at least partially reduce or overcome the challenges in the prior art, and to provide means for treating, alleviating and / or preventing pain. These and other purposes are achieved in whole or in part by aspects of the inventive concept as disclosed herein. The inventors have unexpectedly found that the following pharmaceutical composition is effective in providing a long-acting anesthetic effect, and the pharmaceutical composition comprises at least one anesthetic selected from the group consisting of: ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, benzocaine, chloroprocaine, cocaine, procaine, proparacaine, tetracaine and any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof; at least one alkanolamine selected from the group consisting of: triethanolamine, tripropanolamine and trimethanolamine; water; and optionally a pharmaceutically acceptable diluent, carrier and / or excipient. Therefore, in a first aspect of the present invention, a pharmaceutical composition is provided which benefits from prolonged duration of pain relief when compared to a similar compound not formulated according to the composition of the present invention. The inventors have shown that the composition according to the present invention prolongs the duration of pain relief in vivo. It is envisaged that prolonged pain relief in vivo at least partially replaces the need for opioid therapy, which is commonly used as a postoperative rescue drug in clinical practice. Therefore, the use of the composition according to the present invention can reduce the risk of complications caused by opioid therapy.

[0007] In one embodiment, the at least one anesthetic is selected from the group consisting of: ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, and any pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof. In one embodiment, the at least one anesthetic is selected from the group consisting of: ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, and any pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof. In one embodiment, the pharmaceutical composition further comprises polyethylene glycol (PEG).

[0008] Preferably, the composition comprises carbon quantum dots. Without being bound by theory, it is envisioned that the carbon quantum dots increase the therapeutic effect of the anesthetic in the composition of the present invention or improve the pharmacokinetic and / or pharmacodynamic properties. Without being bound by theory, such an increase may be the result of increased water solubility; or the result of increased cellular internalization of the anesthetic; or, the anesthetic binds to the carbon quantum dots for a period of time, thereby providing a sustained release effect of the anesthetic. In one embodiment, the carbon quantum dots comprise at least one of the at least one anesthetic. In one embodiment, the carbon quantum dots comprise at least one of the alkanolamines, the alkanolamine being selected from the group consisting of triethanolamine, tripropanolamine and trimethanolamine. In one embodiment, the carbon quantum dots comprise triethanolamine.

[0009] In one embodiment, the carbon quantum dots further comprise PEG. In one embodiment, the PEG is located on the surface of the carbon quantum dots.

[0010] Several routes of administration are contemplated. In one embodiment, the composition is formulated for administration by injection or by external administration.

[0011] In one embodiment, the composition is formulated for administration as a nerve block to the lower and upper extremities, various joints, intra-articularly, subcutaneously, intrathecally. Preferably, administration is not intravenous.

[0012] In one embodiment, the administration is by external application, such as by patch, cream, gel or by spray. Such administration may be beneficial because the use of external composition may not require a licensed physician to apply the pharmaceutical composition. Therefore, the subject who needs anesthesia can voluntarily administer the composition to himself. Self-administration has the advantage of allowing the patient to adjust the dosage or frequency of drug therapy according to a subjective evaluation of his / her symptom or according to a schedule prescribed by the attending physician. The term "schedule prescribed by the attending physician" includes such alternatives, wherein the patient conducts a subjective evaluation of his / her symptom (whether unassisted or assisted by a questionnaire or range or scale, or using an algorithm or computer program), thereby indicating the appropriate next dosage.

[0013] Transdermal administration using a composition according to the present invention formulated as a cream, gel and ointment or in the form of an adherent medical patch is another possible form of administration, which is similarly suitable for self-administration. The advantages of self-administration listed above are also applicable to transdermal administration, and its additional advantage is that, if desired or necessary, administration can be easily interrupted, for example, by removing a medical patch. When the external composition is in the form of a patch, gel or spray, the composition may include other ingredients. The technician understands which other ingredients are suitable for specific external use. For example, a spray may need to add a propellant. Suitable propellants are obvious to the technician. Lotions, skin creams or ointments may need to add an emollient. Suitable emollients are obvious to the technician.

[0014] The gel may require the addition of a gelling agent such as a gelling polymer. Suitable polymers are apparent to the skilled person. For example, cellulose, such as a nonionic water-soluble cellulose ether. In addition, the gel may contain an alcohol, such as a C1-C4 alcohol, such as a C1-C3 alcohol or a C2-C4 alcohol, such as ethanol. In addition, the gel may contain benzyl alcohol. In some embodiments, the gel contains ropivacaine and lidocaine. In some embodiments, the gel contains ropivacaine and lidocaine, benzyl alcohol, ethanol, and Klucel MFX. In addition, the gel may contain sodium borate (Borax). An example of a gel containing ropivacaine and lidocaine is described in Example 5.

[0015] The patch may contain additional agents and may contain more than one local anesthetic. In one embodiment, when the external composition is in the form of a patch, the composition comprises at least one of bupivacaine and ropivacaine, and also lidocaine, such as the composition comprises ropivacaine and lidocaine.

[0016] It is also possible to administer the composition via a reservoir formulation that releases an effective amount of an anesthetic as disclosed herein over a period of time. The skilled person will appreciate that a reservoir formulation can be adapted to deliver a desired effective dose as prescribed by the attending physician. The reservoir formulation can be a subcutaneous reservoir formulation. Thus, in one embodiment, the administration is performed via a reservoir formulation, such as a subcutaneous reservoir formulation.

[0017] In one embodiment, the administration is by injection, such as by parenteral injection or by subcutaneous injection. In one embodiment, the administration is as a single injection. Since the composition of the present invention has a long-acting effect, a single injection may be appropriate when administering the composition of the present invention, which may be time-efficient.

[0018] Conventionally used excipients for intravenous administration are, for example, sterile water for injection (WFI), sterile buffers (e.g., buffering the solution to pH 7.4), albumin solutions, lipid solutions, cyclodextrins and variants thereof, etc. Conventionally used excipients for subcutaneous administration are, for example, sterile water for injection (WFI), sterile buffers (e.g., buffering the solution to pH 7.4), lipid solutions, cyclodextrins, etc. Conventionally used excipients for subcutaneous administration via a subcutaneous delivery system (such as a subcutaneous stick) are, for example, sterile water for injection (WFI), sterile buffers (e.g., buffering the solution to pH 7.4), lipid solutions, cyclodextrins, etc.

[0019] Conventionally used excipients for transdermal and / or subcutaneous administration are, for example, vaseline, liquid paraffin, glycerin, water, MCT oil, sesame oil and the like.

[0020] The skilled person will appreciate that the appropriate dosage will naturally vary depending on the mode of administration, the specific condition to be treated or the desired effect, the patient's sex, age, weight and health status, and other possible factors assessed by the attending physician. In one embodiment, the dosage of the anesthetic is a single dose (unit dose) of from 5 to 600 mg, such as from 10 to 500 mg, such as from 20 to 450 mg, such as from 50 to 400 mg, such as from 100 to 400 mg, such as from 200 to 350 mg, such as from 200 to 300 mg.

[0021] In one embodiment, the concentration of the anesthetic is 1-20 mg / ml of the composition, such as 2-15 mg / ml, such as 5-10 mg / ml, such as 5 mg / ml. Commonly used doses are 2.5 mg / ml; 5 mg / ml; 7.5 mg / ml, 10 mg / ml; 20 mg / ml; 30 mg / ml; and depend on the specific anesthetic used and the specific conditions.

[0022] In one embodiment, in the composition, the concentration of the alkanolamine is 0.1-20 M (mol / dm 3 ), such as in the range of 0.2-18M, such as in the range of 0.2-18M, such as in the range of 0.5-15M, such as in the range of 1-12M, such as in the range of 2-10M, such as in the range of 3-8M, such as in the range of 4-6M, such as about 5M.

[0023] In one embodiment, in the composition, the concentration of the anesthetic is between 0.1-500 mM (mol / dm 3), such as in the range of 1-400 mM, such as in the range of 100-300 mM, such as in the range of 220-260 mM, such as in the range of 240-250 mM, such as about 245 mM.

[0024] In one embodiment, the concentration of PEG is about 0.1-100 μM, such as about 1-50 μM, such as about 5-15 μM, such as about 8 μM.

[0025] The composition of the present invention can be prepared with different proportions of the components thereof. For example, in one embodiment, in the composition, the molar ratio of the alkanolamine to the anesthetic is at least 2:1, such as at least 3:1, such as at least 4:1, such as at least 5:1, such as at least 6:1, such as at least 7:1, such as at least 8:1, such as at least 9:1, such as at least 10:1, such as at least 11:1, such as at least 12:1, such as at least 13:1, such as at least 14:1, such as at least 15:1, such as at least 16:1, such as at least 17:1, such as at least 18:1, such as at least 19:1, such as at least 20:1, such as at least 21:1, such as at least 22:1, such as at least 23:1, such as at least 24:1, such as at least 25:1.

[0026] Compositions of the invention having different pH values ​​can be prepared. For example, in one embodiment, the pH of the composition is from pH 5 to pH 8, such as about pH 5, or such as about pH 5.5, or such as about pH 6, or such as about pH 6.5, or such as about pH 7, or such as about pH 7.5.

[0027] As discussed above, the present invention provides a formulation comprising at least one anesthetic selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, benzocaine, chloroprocaine, cocaine, procaine, proparacaine, tetracaine, and any pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

[0028] In one embodiment, the at least one anesthetic agent is selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, benzocaine, chloroprocaine, procaine, proparacaine, tetracaine, and any pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

[0029] In one embodiment, the at least one anesthetic agent is selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, benzocaine, chloroprocaine, cocaine, procaine, proparacaine, tetracaine, and any pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

[0030] In one embodiment, the at least one anesthetic agent is selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, chloroprocaine, cocaine, procaine, proparacaine, and tetracaine.

[0031] In one embodiment, the at least one anesthetic is selected from the group consisting of: ropivacaine, bupivacaine, etidocaine, levobupivacaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, chloroprocaine, cocaine, procaine, proparacaine, and tetracaine. In one embodiment, the at least one anesthetic is selected from the group consisting of: ropivacaine, bupivacaine, etidocaine, levobupivacaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, chloroprocaine, procaine, proparacaine, and tetracaine. In one embodiment, the at least one anesthetic is selected from the group consisting of: ropivacaine, bupivacaine, etidocaine, levobupivacaine, lignocaine, mepivacaine, and prilocaine. In one embodiment, the at least one anesthetic is selected from the group consisting of: ropivacaine, bupivacaine, etidocaine, mepivacaine, and prilocaine. In one embodiment, the at least one anesthetic is selected from the group consisting of: ropivacaine, bupivacaine, mepivacaine, and prilocaine. In one embodiment, the at least one anesthetic is selected from the group consisting of: ropivacaine, bupivacaine, and prilocaine. In one embodiment, the at least one anesthetic is selected from the group consisting of: ropivacaine, bupivacaine, and mepivacaine. In one embodiment, the at least one anesthetic is selected from the group consisting of: ropivacaine, bupivacaine, and etidocaine. In one embodiment, the anesthetic is selected from the group consisting of: ropivacaine, bupivacaine, and lidocaine. In one embodiment, the at least one anesthetic is a combination of ropivacaine and lidocaine. In one embodiment, the at least one anesthetic is a combination of bupivacaine and lidocaine. In one embodiment, the anesthetic is selected from the group consisting of: ropivacaine and bupivacaine. In one embodiment, the anesthetic is bupivacaine. For clarity, the chemical formula of bupivacaine is represented by Formula I below:

[0032]

[0033] In one embodiment, the anesthetic is lidocaine. For clarity, the chemical formula of lidocaine is represented by the following formula II:

[0034]

[0035] In one embodiment, the anesthetic is ropivacaine. For clarity, the chemical formula of ropivacaine is represented by Formula III below:

[0036]

[0037] In one embodiment, when the anesthetic is ropivacaine, the ropivacaine is in basic form. In one embodiment, the ropivacaine is present as a hydrochloride salt. Other pharmaceutically acceptable salts are also contemplated as being suitable for the composition.

[0038] The skilled person understands that pharmaceutically acceptable salts of the anesthetic according to this aspect of the present disclosure are suitable for use in the composition. Salts suitable for use in medicine are those in which the counterion is pharmaceutically acceptable. Examples of such pharmaceutically acceptable salts according to the present invention include those formed with organic or inorganic acids or bases. In particular, suitable salts formed with acids according to the present invention include those formed with: inorganic acids; strong organic carboxylic acids, such as unsubstituted or, for example, halogen-substituted alkanecarboxylic acids of 1 to 4 carbon atoms, such as saturated or unsaturated dicarboxylic acids, such as hydroxycarboxylic acids, such as amino acids; or organic sulfonic acids, such as unsubstituted or, for example, halogen-substituted (C1-C4) alkyl or aryl sulfonic acids. Pharmaceutically acceptable acid addition salts include those formed with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, citric acid, tartaric acid, acetic acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, succinic acid, perchloric acid, fumaric acid, maleic acid, glycolic acid, lactic acid, salicylic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, isethionic acid, ascorbic acid, malic acid, phthalic acid, aspartic acid, and glutamic acid, lysine and arginine.

[0039] In one embodiment, ropivacaine is present in its S-enantiomer form. Preferably, S-ropivacaine may be present in an enantiomeric excess. Such an excess still allows the presence of R-ropivacaine, however, the amount of R-ropivacaine is smaller than that of the S-form.

[0040] The composition may comprise PEG. In one embodiment, the PEG is selected from the group consisting of PEG-3350, PEG-4000, PEG-6000, PEG-8000 and PEG-10000. In one embodiment, the PEG is PEG-3350 or PEG-4000. In a preferred embodiment, the PEG is PEG-4000.

[0041] The composition according to the present invention comprises water. The water can be purified water suitable for pharmaceutical applications. The water can be sterile water for injection (WFI). The water can be deionized water (diH2O). The water can be distilled water (dH2O). In one embodiment, the water is distilled water. The distilled water can be MilliQ water. In one embodiment, the water is deionized water.

[0042] In one embodiment, the composition consists of:

[0043] Ropivacaine;

[0044] Triethanolamine;

[0045] water; and optionally

[0046] Pharmaceutically acceptable diluents, carriers and / or excipients.

[0047] In one embodiment, the composition consists of:

[0048] Ropivacaine;

[0049] Triethanolamine;

[0050] water;

[0051] PEG-4000; and optionally

[0052] Pharmaceutically acceptable diluents, carriers and / or excipients.

[0053] In one embodiment, in the composition, the molar ratio of triethanolamine to ropivacaine is at least 2:1, such as at least 3:1, such as at least 4:1, such as at least 5:1, such as at least 6:1, such as at least 7:1, such as at least 8:1, such as at least 9:1, such as at least 10:1, such as at least 11:1, such as at least 12:1, such as at least 13:1, such as at least 14:1, such as at least 15:1, such as at least 16:1, such as at least 17:1, such as at least 18:1, such as at least 19:1, such as at least 20:1, such as at least 21:1, such as at least 22:1, such as at least 23:1, such as at least 24:1, such as at least 25:1.

[0054] In one embodiment, in the composition, the concentration of triethanolamine is between 0.1 and 20 M (mol / dm 3 ), such as in the range of 0.2-18M, such as in the range of 0.2-18M, such as in the range of 0.5-15M, such as in the range of 1-12M, such as in the range of 2-10M, such as in the range of 3-8M, such as in the range of 4-6M, such as about 5M.

[0055] In one embodiment, the concentration of ropivacaine in the composition is between 0.1 and 500 mM (mol / dm 3 ), such as in the range of 1-400 mM, such as in the range of 100-300 mM, such as in the range of 220-260 mM, such as in the range of 240-250 mM, such as about 245 mM.

[0056] The composition can be suitable for storage, such as long-term storage. The composition can benefit from stability maintained over time. In one embodiment, the composition is stored for at least 1 day, such as at least 1 week, such as at least 2 weeks, such as at least 3 weeks, such as at least 4 weeks, such as at least 5 weeks, such as at least 6 weeks, such as at least 7 weeks, such as at least 8 weeks, such as at least 9 weeks, such as at least 10 weeks, such as at least 3 months, such as at least 6 months, such as at least 1 year, such as at least 2 years. For example, the compositions 1 and 2 of Example 1 are subsequently used in Example 3. Example 3 shows that the composition is stable over a longer period of time and at different temperatures.

[0057] In one embodiment, the composition benefits from thermal stability. Thus, the composition may remain thermally stable after storage at a temperature of at least 4°C, such as at least 7°C, such as at least 10°C, such as at least 15°C, such as at least 20°C, such as at least 25°C, such as at least 30°C, such as at least 35°C, such as at least 40°C.

[0058] Although stability can be determined in several ways, it is obvious to those skilled in the art, but in one embodiment of maintaining stability, stability is determined by the coefficient of variation. As used herein, the term stability is intended to mean that unwanted phenomena, such as degradation of composition components, will not occur. As used herein, the components of the phrase composition are intended to include both the original components added to the composition and any components formed during the preparation of the composition. Preferably, stability is determined by the coefficient of variation ("CV"). Technicians recognize that the lower sample-to-sample variation measurement value (e.g., in a series of measurements over time or at different temperatures) indicates a higher degree of stability maintained. In one embodiment, "maintained stability" means that the CV shown after comparing different samples is at most about 20%, such as at most 15%, such as at most 10%, such as at most 5%, such as at most 2.5%. As known to those skilled in the art, other methods of measuring and representing the stability maintained or maintained are also possible.

[0059] Compositions intended for long-term storage may suitably be in the form of freeze-dried compositions. Therefore, in one embodiment, the composition is freeze-dried. After freeze-drying the composition of the present invention, water will be removed from the composition. However, it is conceivable that a small portion of water is still present in the freeze-dried composition.

[0060] It should be understood that the compositions according to the present disclosure can be used as therapeutic compositions. Immediate therapeutic effects, such as long-lasting anesthetic effects, can be achieved, for example, by administering the compositions.

[0061] On the other hand, a pharmaceutical composition according to a first aspect is provided, for use in treating, alleviating or preventing pain by applying the composition to a patient in need. In one embodiment, the treatment, alleviating or preventing pain provides long-acting anesthesia, and the anesthesia lasts at least 0.5 hours, such as lasting at least 1 hour, such as lasting at least 2 hours, such as lasting at least 3 hours, such as lasting at least 4 hours, such as lasting at least 5 hours, such as lasting at least 6 hours, such as lasting at least 7 hours, such as lasting at least 8 hours, such as lasting at least 9 hours, such as lasting at least 10 hours, such as lasting at least 11 hours, such as lasting at least 12 hours, such as lasting at least 1 day, such as lasting at least two days, such as lasting at least 3 days, such as lasting at least 4 days, such as lasting at least 5 days. The example of long-acting pain relief using the composition of the present invention is described in Example 2 and 3. Another example of long-acting pain relief using the composition of the present invention is described in Example 6. Anesthesia can be measured in several ways. Technicians understand that anesthesia can be measured subjectively and objectively. For example, for subjective measurement, the patient can be asked whether the stimulation is hurting or producing another uncomfortable feeling. Such a stimulus may be, for example, a pinprick test, a squeeze test, or the stimulus may result from a surgical procedure or pain test.

[0062] For example, for objective measurements, vital parameters such as pulse, blood pressure and / or respiratory rate can be measured. This is common during surgical procedures. For objective measurements, muscle activity can also be measured by measuring the blockade of sensory or motor nerves through neurophysiological tests with surface electrodes on the skin, such as EMG (electromyography) for muscle activity (for example, you ask the patient to lift his leg, flex his foot, etc.).

[0063] It will be appreciated by the skilled artisan that the compositions according to the invention can be used to treat all types of pain. In one embodiment, the pain is nociceptive pain or neuropathic pain. In one embodiment, the pain is caused by surgery, injury or trauma. In one embodiment, the pain is postoperative pain, traumatic pain or chronic pain.

[0064] In one embodiment, the use is combined with an additional therapeutic agent. Suitable candidates for combination therapy are obvious to those skilled in the art and include, for example, a non-limiting list of antibacterial agents; antifungal agents, antiviral agents, antiseptics, anti-inflammatory agents, anti-inflammatory agents / analgesics (NSAIDs) and antipruritic agents. For example, the additional therapeutically active agent can be selected from the following: antibacterial agents such as oxytetracycline, fusidic acid, gentamicin, mupirocin, retapamulin (and pharmaceutically acceptable salts and derivatives thereof); antifungal agents such as nystatin, clotrimazole, miconazole, econazole, ketoconazole, bifonazole, and combinations of imidazole and triazole derivatives, ciclopirox olamine, terbinafine, fluconazole, and amorolfine (and pharmaceutically acceptable salts and derivatives thereof); antiviral agents such as acyclovir, valacyclovir, penciclovir, famciclovir, foscarnet sodium (trisodium phosphate formate hexahydrate) and docosanol (and pharmaceutically acceptable salts and derivatives thereof); and pharmaceutically acceptable salts and derivatives thereof); preservatives such as chlorhexidine, benzalkonium chloride and hydrogen peroxide; anti-inflammatory agents (glucocorticoids) such as hydrocortisone, clobetasone, triamcinolone acetonide, betamethasone, mometasone, desonide, prednisolone and clobetasol (and pharmaceutically acceptable salts and derivatives thereof); anti-inflammatory / analgesic agents (NSAIDs) such as acetylsalicylic acid, diclofenac, ketoprofen, ibuprofen, naproxen, capsaicin and nicotinate (and pharmaceutically acceptable salts and derivatives thereof); and antipruritic agents such as glucocorticoids, for example, hydrocortisone, clobetasone, clobetasol, desonide, mometasone and betamethasone.

[0065] In one embodiment, the administered dose is from about 0.1 to about 100 ml per kg body weight, such as from about 0.2 to about 50 ml per kg body weight, such as from about 0.3 to about 30 ml of the composition per kg body weight, such as from about 0.4 to about 20 ml of the composition per kg body weight, such as from about 0.5 to about 10 ml of the composition per kg body weight, such as from about 1 to about 5 ml of the composition per kg body weight.

[0066] In one embodiment, the administered dose is about 0.1 mg of the anesthetic per kg body weight, such as about 0.2 mg of the anesthetic per kg body weight, such as about 0.3 mg of the anesthetic per kg body weight, such as about 0.4 mg of the anesthetic per kg body weight, such as about 0.5 mg of the anesthetic per kg body weight, such as about 0.6 mg of the anesthetic per kg body weight, such as about 0.7 mg of the anesthetic per kg body weight, such as about 0.75 mg of the anesthetic per kg body weight, such as about 0.8 mg of the anesthetic per kg body weight, such as about 0.9 mg of the anesthetic per kg body weight, such as about 10 mg of the anesthetic per kg body weight.

[0067] On the other hand, a method for treating, alleviating or preventing pain is provided, the method comprising administering a therapeutically effective amount of a composition according to the first aspect to a patient in need thereof. In one embodiment, the pain is caused by surgery, injury or trauma. In one embodiment, the method further comprises administering an additional therapeutic agent.

[0068] Suitable additional therapeutic agents for combination therapy will be apparent to those skilled in the art and include, for example, a non-limiting list of opioids and other opioid analogs, irritants, antibacterial agents; antifungal agents, antiviral agents, antiseptics, anti-inflammatory agents, anti-inflammatory / analgesics (NSAIDs), and antipruritic agents. For example, the therapeutically active agent of the present invention can be selected from stimulants such as ephedrine; antibacterial agents such as oxytetracycline, fusidic acid, gentamicin, mupirocin, retapamulin (and pharmaceutically acceptable salts and derivatives thereof); antifungal agents such as nystatin, clotrimazole, miconazole, econazole, ketoconazole, bifonazole, and combinations of imidazole and triazole derivatives, ciclopirox olamine, terbinafine, fluconazole, and amorolfine (and pharmaceutically acceptable salts and derivatives thereof); antiviral agents such as acyclovir, valacyclovir, penciclovir, famciclovir, foscarnet (trisodium phosphate formate hexahydrate) and docosanol (and pharmaceutically acceptable salts and derivatives thereof); and pharmaceutically acceptable salts and derivatives thereof); preservatives such as chlorhexidine, benzalkonium chloride and hydrogen peroxide; anti-inflammatory agents (glucocorticoids) such as hydrocortisone, clobetasone, triamcinolone acetonide, betamethasone, mometasone, desonide, prednisolone and clobetasol (and pharmaceutically acceptable salts and derivatives thereof); anti-inflammatory / analgesic agents (NSAIDs) such as acetylsalicylic acid, diclofenac, ketoprofen, ibuprofen, naproxen, capsaicin and nicotinate (and pharmaceutically acceptable salts and derivatives thereof); and antipruritic agents such as glucocorticoids, for example, hydrocortisone, clobetasone, clobetasol, desonide, mometasone and betamethasone.

[0069] In another aspect, a method for producing a composition is provided, the composition comprising carbon quantum dots and at least one anesthetic selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, benzocaine, chloroprocaine, cocaine, procaine, proparacaine, tetracaine, and any pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof; the method comprising:

[0070] a) contacting an alkanolamine selected from the group consisting of triethanolamine, tripropanolamine and trimethanolamine with water to obtain a mixture;

[0071] b) heating the mixture to obtain carbon quantum dots;

[0072] c) adding to the mixture at least one anesthetic selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, and any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof; wherein steps b) and c) can be performed in any order;

[0073] d) optionally adding PEG to the mixture;

[0074] Thereby, a composition comprising carbon quantum dots and the anesthetic is obtained.

[0075] In one embodiment, the at least one anesthetic is selected from the list consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, and any pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof. In one embodiment, the at least one anesthetic is selected from the list consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, and any pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

[0076] In one embodiment, step c) precedes step b), which means that the mixture being heated is a mixture comprising alkanolamine, water and at least one anesthetic. In this embodiment, the mixture comprising alkanolamine, water and at least one anesthetic forms carbon quantum dots.

[0077] In one embodiment, step b) precedes step c), which means that the mixture being heated is a mixture comprising alkanolamine and water. In this embodiment, the mixture comprising alkanolamine and water forms carbon quantum dots.

[0078] As shown in the attached examples, the pharmaceutical compositions according to the present disclosure can be prepared by different routes. In one embodiment, the anesthetic, alkanolamine and water are heated to form carbon quantum dots, followed by the addition of PEG. This route is similar to the composition 1 described in Example 1.

[0079] In one embodiment, the alkanolamine and water are heated to form carbon quantum dots, followed by the addition of an anesthetic and then PEG. This approach is similar to composition 2 described in Example 1. Example 2 of the present application shows that both compositions 1 and 2 of the present invention provide a longer duration of pain relief compared to the compositions of the prior art.

[0080] In one embodiment, the heating is at a temperature between 100°C and 200°C, such as between 120°C and 170°C, such as between 130°C and 150°C, such as at 140°C. In one embodiment, the heating is performed by microwaves. The heating may also be performed by a hot plate or any other conventional heating means, as will be apparent to those skilled in the art. In a preferred embodiment, the heating is performed by a microwave oven.

[0081] Centrifugation can be used to separate different components within the composition based on weight or based on size (such as based on particle weight or based on particle size). Therefore, in one embodiment, the method further comprises the step of centrifuging the composition comprising carbon quantum dots and the anesthetic. In one embodiment, the centrifugal speed is 2000-5000rpm, such as 4000rpm. In one embodiment, the centrifugation lasts for at least 5 minutes, such as at least 10 minutes. The technician will understand the appropriate conditions for centrifugation.

[0082] On the other hand, according to the above aspects, there is provided a carbon quantum dot containing an anesthetic, which can be obtained by a method for producing a composition containing carbon quantum dots and at least one anesthetic, the anesthetic being selected from the group consisting of: ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, and any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

[0083] In one embodiment, the at least one anesthetic is selected from the list consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, and any pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof. In one embodiment, the at least one anesthetic is selected from the list consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, and any pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

[0084] In one embodiment, the anesthetic is selected from the group consisting of ropivacaine, bupivacaine and lidocaine. In one embodiment, the anesthetic is ropivacaine. In one embodiment, the alkanolamine is triethanolamine. In one embodiment, the carbon quantum dots further comprise PEG, optionally wherein the PEG is selected from the group consisting of PEG-3350, PEG-4000, PEG-6000, PEG-8000 and PEG-10000. In one embodiment, the PEG is PEG-4000.

[0085] In one embodiment, the dots are fluorescent. The dots may emit light having a wavelength of from 400 to 600 nm, such as from 415 to 430 nm, such as about 425 nm. In one embodiment, the dots have an average diameter between 1 and 20 nm, such as from 2 to 18 nm, such as from 3 to 15 nm, such as from 4 to 12 nm, such as from 5 to 10 nm. Under UV light, by visual inspection, the carbon quantum dots may appear blue.

[0086] In yet another aspect, there is provided a carbon quantum dot formed from a composition comprising:

[0087] - at least one anesthetic selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, benzocaine, chloroprocaine, cocaine, procaine, proparacaine, tetracaine, and any pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof;

[0088] - at least one alkanolamine selected from the group consisting of triethanolamine, tripropanolamine and trimethanolamine; and

[0089] -water.

[0090] In one embodiment, the at least one anesthetic is selected from the list consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, and any pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof. In one embodiment, the at least one anesthetic is selected from the list consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, and any pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

[0091] In one embodiment, the dots are fluorescent. The dots may emit light having a wavelength of from 400 to 600 nm, such as from 415 to 430 nm, such as about 425 nm. In one embodiment, the dots have an average diameter of from 1 to 20 nm, such as from 2 to 18 nm, such as from 3 to 15 nm, such as from 4 to 12 nm, such as from 5 to 10 nm. Under UV light, by visual inspection, the carbon quantum dots may appear blue.

[0092] In a related aspect, there is provided the use of a composition according to the above aspects for the manufacture of a medicament for use in the treatment of pain.

[0093] definition

[0094] Unless otherwise explained, all technical terms and scientific terms used herein have the same meanings as those generally understood by those of ordinary skill in the art to which this disclosure belongs. Unless the context clearly indicates otherwise, the singular terms "a / an" and "the" include plural references. Similarly, unless the context clearly indicates otherwise, the word "or" is intended to include "and". Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The term "comprising" means "including". In the event of a conflict, the present specification (including the explanation of the term) shall prevail compared to the definition of any other source. In addition, all materials, methods and embodiments are illustrative and are not intended to be restrictive.

[0095] The term "pharmaceutical composition" is used in its broadest sense and covers all pharmaceutically suitable compositions containing at least one active substance and optional carriers, adjuvants, diluents, components, etc. The term "pharmaceutical composition" also covers compositions comprising the active substance in the form of derivatives or prodrugs such as pharmaceutically acceptable salts, sulfates and esters. The manufacture of pharmaceutical compositions for different routes of administration falls within the capabilities of the skilled galenical chemist.

[0096] The term "prodrug" is used herein to describe a compound that participates in a chemical reaction to form an anesthetic according to the present invention.

[0097] The terms "administration" and "mode of administration" and "route of administration" are also used in their broadest sense. The pharmaceutical compositions of the present invention can be administered in a variety of ways, depending largely on whether the topical or external mode of administration is best suited for the particular pain to be treated. These different modes of administration are, for example, external (e.g., on the skin), topical (including ophthalmic and to various mucous membranes, such as vaginal and rectal delivery), oral or parenteral. The preparation of such compositions and formulations is well known to those skilled in the art of formulation and can be adapted to formulate the compositions of the present invention.

[0098] Typical single-dose compositions (or unit-dose compositions) are those containing an effective dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

[0099] It should be understood that in addition to the ingredients particularly mentioned above, the compositions of this invention may include other agents conventional in the art having regard to the type of formulation in question.

[0100] The terms "composition" and "formulation" are used interchangeably throughout the application and are intended to have the same meaning, as will be apparent to one skilled in the art.

[0101] The terms "subject" and "patient" are used interchangeably throughout the application and are intended to have the same meaning, as will be apparent to one skilled in the art.

[0102] As used herein, when the term "about" or "approximately" is used with respect to a numerical value, it should be interpreted as a range of ±10%, such as ±9%, such as ±8%, such as ±7%, such as ±6%, such as ±5%, such as ±4%, such as ±3%, such as ±2%, such as ±1%. For example, when a value is described as about 10, this means that the value is actually in the range of from 9 to 11, such as in the range of from 9.9 to 10.9, such as in the range of from 9.8 to 10.8, such as in the range of from 9.7 to 10.7, such as in the range of from 9.6 to 10.6, such as in the range of from 9.5 to 10.5, such as in the range of from 9.4 to 10.4, such as in the range of from 9.3 to 10.3, such as in the range of from 9.2 to 10.2, such as in the range of from 9.1 to 10.1.

[0103] The skilled person knows that numerical values ​​related to measurements are subject to measurement errors, which limit their accuracy. For this reason, the general convention in scientific and technical literature applies: the last decimal place of a numerical value indicates its accuracy. In the absence of other error tolerances, the maximum tolerance is determined by applying the rounding convention to the last decimal place, e.g., for a measurement of 3.5 cm, the error tolerance is 3.45-3.54. When interpreting numerical ranges in patent specifications, the skilled person proceeds on the same basis.

[0104] As will be apparent to one skilled in the art, the term tripropanolamine encompasses triisopropanolamine.

[0105] Although the present invention has been described with reference to various exemplary aspects and embodiments, it will be appreciated by those skilled in the art that various changes may be made and elements thereof may be replaced with equivalents without departing from the scope of the present invention. Therefore, it is intended that the present invention is not limited to any particular embodiment contemplated, but that the present invention will include all embodiments falling within the scope of the appended claims. The present invention is further illustrated by the following non-limiting examples. BRIEF DESCRIPTION OF THE DRAWINGS

[0106] Figure 1 Fluorescence spectra are shown. Samples were prepared according to Example 1 (compositions 1-3; which are denoted as Tests 1-3).

[0107] Figure 2 Fluorescence spectra are shown (average of 3 readings). Samples were prepared according to Example 4, Sample 3 and Sample 4 (see Table 10).

[0108] Figure 3Fluorescence spectra are shown (average of 3 readings). Samples were prepared according to Example 4, Sample 5 (see Table 10).

[0109] References

[0110] Kuthiala and Chaudhary.Ropivacaine:A review of its pharmacology and clinical use.Indian J Anesth 2011;55:104-10.

[0111] Qu et al.Synthesis of bifunctional carbon quantum dots for bioimagingand anti-inflammation.Nanotechnology 2020;31.175102 Example

[0112] Example 1: Characterization of Quantum Dots

[0113] Materials and methods

[0114] Ropivacaine was purchased from AK Scientific (purity 98%). Triethanolamine was purchased from Chemtronica. PEG4000 was purchased from Chemtronica. The microwave oven used was a Milestone MLS1200 Pyro high temperature muffle furnace with temperature control function.

[0115] Preparation of Compositions 1-3

[0116] Composition 1 - Composition consisting of ropivacaine, triethanolamine, water and PEG400

[0117] 1. Mix ropivacaine free base (0.4 g) with purified water (2 mL) and triethanolamine (4 mL).

[0118] 2. Heat treat the mixture from step 1 at 140°C for 20 minutes in a microwave oven.

[0119] 3. Take 0.5 mL of sample for fluorescence and particle size measurement.

[0120] 4. Add PEG4000 (0.2 mg).

[0121] 5. Take 0.5 mL of sample for fluorescence and particle size measurement.

[0122] observe:

[0123] The solution was not clear at any step.

[0124] Composition 2 - Composition consisting of ropivacaine, triethanolamine, water and PEG400

[0125] 1. Combine purified water (2 mL) and triethanolamine (4 mL).

[0126] 2. Heat treat the mixture from step 1 at 140°C for 20 minutes in a microwave oven.

[0127] 3. Take 0.5 mL of sample for fluorescence and particle size measurement.

[0128] 4. To the mixture from step 2 was added ropivacaine free base (0.4 g).

[0129] 5. Add PEG4000 (0.2 mg).

[0130] 6. Take 0.5 mL of sample for fluorescence and particle size measurement.

[0131] observe:

[0132] Not a clear solution in step 4

[0133] Composition 3 - Composition consisting of ropivacaine, water and PEG400

[0134] 1. Mix ropivacaine free base (0.4 g) with purified water (2 mL).

[0135] 2. Heat treat the mixture from step 1 at 140°C for 20 minutes in a microwave oven.

[0136] 3. Take 0.5 mL of sample for fluorescence and particle size measurement.

[0137] 4. Add PEG4000 (0.2 mg).

[0138] 5. Take 0.5 mL of sample for fluorescence and particle size measurement.

[0139] observe:

[0140] The solution was not clear at any step.

[0141] Solubility

[0142] A visual inspection of the solubility was performed. The results are shown in Table 1.

[0143] Table 1.

[0144] Test No. Before microwave After microwave After adding PEG 1 turbid turbid Turbid / partially clear 2 clarify Clear (beige) Partially turbid (beige) 3 Phase 2 Phase 2 Stage 2 / Partially turbid

[0145] Fluorescence measurement

[0146] Fluorescence was measured on a microplate reader (Thermo Scientific Varioscan LUX SN 3020-836, REF VLBL001D1, Model 3020). According to the method described for compositions 1, 2 and 3, 0.5 mL of sample was taken for measurement. Samples were prepared by centrifugal filtration through a 0.45 μm filter. Measurements were taken in duplicate. The emission wavelength used was 400-700 nm, and the excitation wavelength used was 350 nm. Absorbance (AU) was measured.

[0147] Table 2.

[0148] entry Maximum strength A Maximum strength B A Composition 1 before adding PEG 4.022 3.868 B Composition 1 after adding PEG 3.863 3.4008 C Composition 2 before adding ropivacaine and PEG 21.66 20.47 D Composition 2 after adding ropivacaine and PEG 15.55 8.850 E Composition 3 before adding PEG 0.8577 0.8725 F Composition 3 after adding PEG 1.251 1.035

[0149] result

[0150] The fluorescence was essentially blue. The highest fluorescence intensity was found for composition 2 and was highest before the addition of PEG. PEG appeared to reduce the fluorescence. Samples of composition 1 showed significant fluorescence both before and after the addition of PEG. Essentially no fluorescence was observed in composition 3. The fluorescence spectrum is shown in Figure 1 .

[0151] Note the following relationship to items AF:

[0152] A and B, which correspond to the composition in which ropivacaine, water and triethanolamine were heated in a microwave, followed by the addition of PEG for entry B; show high fluorescence, with a slight decrease in fluorescence intensity after the addition of PEG.

[0153] C and D, which correspond to compositions in which water and triethanolamine were heated in a microwave, ropivacaine was added after heat treatment, followed by PEG for entry D; significant fluorescence was shown, with a slight decrease in fluorescence intensity after the addition of PEG.

[0154] E and F, which correspond to compositions in which only ropivacaine was heated in a microwave, followed by the addition of PEG, show low fluorescence.

[0155] Particle size measurement

[0156] The average particle size distribution by intensity (Z-ave) was measured with dynamic light scattering on a Zetasizer Nano ZS from Malvern Instruments. According to compositions 1, 2 and 3, 0.5 mL of sample was taken for measurement. The samples were prepared by centrifugal filtration through a 0.45 μm filter. The measurements were taken in duplicate.

[0157] PDI: dimensionless value of the width of the distribution (polydistribution index). If < 0.3, the distribution is generally considered to be monodisperse (unimodal). As can be seen in Table 3, all samples except entry E are considered to be unimodal.

[0158] Table 3.

[0159] entry Z-Ave[nm] PDI A Composition 1 before adding PEG 5.382 0.234 B Composition 1 after adding PEG 5.838 0.247 C Composition before adding API and PEG 2 9.276 0.244 D Composition after adding API and PEG 2 7.399 0.237 E Composition 3 before adding PEG 132.9 0.345 F Composition 3 after adding PEG 3.77 0.16

[0160] The result is the average of the repeated measurements

[0161] The particle size (Z-Ave) is consistent with that expected for blue fluorescent carbon quantum dots.

[0162] in conclusion

[0163] Composition 1 does contain carbon quantum dots, which suggests that such dots can be formed from triethanolamine, ropivacaine, and water when heated. It appears that ropivacaine can be turned into any anesthetic according to the present invention and will produce the same similar results.

[0164] Composition 2 did contain carbon quantum dots, suggesting that such dots can be formed from triethanolamine and water when heated. According to the present invention, it appears that ropivacaine can be turned into any anesthetic and will produce the same similar results.

[0165] Composition 3 contained no carbon quantum dots, indicating that such dots could not be formed from ropivacaine and water.

[0166] Without being bound by any theory, it is believed that the fluorescence and small particle size are due to the formation of carbon quantum dots, which are formed during the microwave thermal treatment of triethanolamine. The improved formulations were also tested in vivo in animal models to evaluate the duration of local anesthesia, see Examples 2 and 3.

[0167] Example 2: In vivo studies

[0168] To evaluate the administration of local anesthesia in sensitivity testing in female rats, a pilot study and an efficacy study were conducted.

[0169] The experiments were performed at Redoxis AB, Lund (Sweden). The animals were housed in a modern, approved animal facility to ensure the welfare of the animals. All experiments performed at Redoxis received ethical approval and followed Swedish national law.

[0170] Sprauge Dawley rats (female, 10 weeks) were obtained from Janvier Europe. Rats were housed in the animal facility of Medicon Village in Lund, Sweden. Rats were housed in polystyrene cages (Type III cages, 2-3 rats per cage) containing sawdust with a 12 h light / dark cycle. Rats were fed a standard rodent diet and water ad libitum. Rats were acclimated for approximately one week before the start of the experiment. On day 1, rats were identified by marking the tail with a permanent marker.

[0171] Local anesthetic composition - pilot study

[0172] Table 4.

[0173]

[0174] Group composition

[0175] Rats were weighed on day -1 (one day before the start of the experiment) to determine the average weight of the animals included in the experiment.

[0176] Compounds and administration

[0177] The formulation of reference anesthesia ropivacaine was prepared so that the pH of the composition and the concentration and dosage of ropivacaine were substantially the same as the composition of the present invention. The concentration of ropivacaine in the formulation was 5 mg / ml and was administered at a dosage of 1 mg / kg body weight in 2 animals and at a dosage of 0.25 mg / kg body weight in 2 animals; and a placebo PBS (phosphate buffered saline) was administered in 2 animals. Vehicle and reference anesthesia were administered sc (subcutaneously) in a single injection form at time 0.

[0178] Sensitivity testing and assessment

[0179] Before testing, the rats were shaved on their backs and allowed to acclimate to the experimental environment for 30 minutes. Sensitivity testing was performed by touching each rat with a needle at 5 different time points (30 min, 1 h, 2 h, 3 h, 4 h, 5 h) within 5 hours after the test item was applied. The rats' reactions were evaluated by visual inspection in the form of skin wrinkling.

[0180] Health Assessment

[0181] Macroscopic Assessment: The health assessment of the rats was monitored throughout the study. Any adverse effects were observed according to the health assessment protocol. If the health of the rats was not good (e.g., the rats were dehydrated or had problems with kyphotic posture), such rats were removed from the experiment. However, all the rats used in this experiment remained healthy.

[0182] result

[0183] The results show that the design of the study is suitable for testing the efficacy of ropivacaine. The results (data not shown) show that the group receiving the ropivacaine at a dosage of 0.25 mg / kg body weight has a duration of anesthetic effect of 2 h, and the group receiving the ropivacaine at a dosage of 1 mg / kg body weight has a duration of anesthetic effect of 5 h. The placebo group has no anesthetic effect.

[0184] Local Anesthesia Testing - Efficacy Testing

[0185] Table 5.

[0186]

[0187] Group composition

[0188] Rats were weighed on day -1 (one day before the start of the experiment) to determine the average weight of the animals included in the experiment.

[0189] Compounds and administration

[0190] The formulation of reference anesthesia ropivacaine was prepared in the same manner as used for the pilot study. The concentration of ropivacaine in the formulation (reference and both Composition 1 and Composition 2) was 0.5 mg / ml, and the dose administered was 0.25 mg / kg body weight. At time 0, vehicle, reference anesthesia, Composition 1 anesthesia, and Composition 2 anesthesia were administered subcutaneously in a single injection.

[0191] Sensitivity testing and assessment

[0192] Before the test, the rats were shaved on the back and adapted to the experimental environment for 30 minutes. At 6 different time points (30min, 1h, 2h, 3h, 4h, 5h) within 6 hours after the test item was applied, the sensitivity test was performed by touching each rat with a needle. The rats' reactions were evaluated by visual inspection in the form of skin wrinkling, and the value of each monitored response was 0 (no response) or 1 (response). No response proved that the rats had experienced anesthesia.

[0193] Health Assessment

[0194] Macroscopic Assessment: The health assessment of the rats was monitored throughout the study. Any adverse effects were observed according to the health assessment protocol. If the health of the rats was not good (e.g., the rats were dehydrated or had problems with kyphotic posture), such rats were removed from the experiment. However, all the rats used in this experiment remained healthy.

[0195] result

[0196] Table 6. Results from the pinprick test. Group 1 received placebo, Group 2 received ropivacaine, Group 3 received a composition according to the invention (Composition 1) and Group 4 received a composition according to the invention (Composition 2).

[0197] Group ID 0,5h 1h 2h 3h 4h 5h 1 B2 0 1 0 1 1 1 1 C3 1 1 0 1 1 1 1 D3 0 0 0 0 0 1 2 C2 0 0 1 1 1 1 2 B3 1 1 1 1 1 1 2 A1 0 0 0 1 0 1 3 A3 0 0 0 0 1 1 3 C1 0 0 0 0 1 1 3 D1 0 0 0 0 0 1 4 A2 0 0 0 0 1 1 4 B1 0 0 0 0 1 1 4 D2 1 1 1 1 1 1

[0198] The results can be expressed as the mean of the first response. It is apparent from Table 6 that the composition according to the invention benefits from an extended duration of anesthesia. Compared to the prior art (Group 2), the duration of Group 3 was about 2.4 times (2.4 times the duration of anesthesia), and the duration of Group 4 was about 1.6 times (1.6 times the duration of anesthesia).

[0199] Table 7. Mean values ​​of first responses.

[0200] Group Average value of first response (h) 2 1.8 3 4.3 4 2.8

[0201] in conclusion

[0202] Composition 1 (used in Group 3) did contain carbon quantum dots, suggesting that such dots produced increased duration of pain relief in vivo. According to the present invention, it appears that ropivacaine could be turned into any anesthetic and would produce the same similar in vivo effects.

[0203] Composition 2 (used in Group 4) did contain carbon quantum dots, suggesting that such dots produced increased duration of pain relief in vivo. According to the present invention, it appears that ropivacaine could be turned into any anesthetic and would produce the same similar in vivo effects.

[0204] Experiment 3: In vivo test 3

[0205] Table 8.

[0206]

[0207] animal

[0208] Male Wistar albino rats weighing 200-250 g obtained from the Experimental Animals Laboratory of SYLAB were used in the experiments. The animals were placed under 12 hours of light and 12 hours of darkness under standard conditions and fed with standard pellet water (ad libitum). All studies were conducted in accordance with international ethical rules and no animal laws were violated.

[0209] Compounds and administration

[0210] The formulations used were the same as in Example 2, and were stored separately. These formulations were stored at different temperatures for 7 months. First, these formulations were stored in a cold store for 6 months. Thereafter, the temperature storage was changed; before use, these formulations were repeatedly stored at room temperature and in a refrigerator.

[0211] The compositions were administered subcutaneously as a single injection at time 0. The compositions were administered in close proximity to the sciatic nerve.

[0212] Group 1: Ropivacaine 7.5 mg / ml, 1.1-1.2 ml. Total = at least 8.25 mg ropivacaine. The composition is commercial ropivacaine (Ropivacaina Inibsa, injectable solution).

[0213] Group 2: Ropivacaine 4 mg / ml, 2 ml, pH 5 (Test 1). Total = 8 mg ropivacaine. The composition is Composition 1 in Example 1.

[0214] Group 3: Ropivacaine 4 mg / ml, 2 ml, pH 5 (Test 2). The composition is Composition 2 in Example 1.

[0215] Sensitivity testing and assessment

[0216] Sensitivity testing was performed by touching each rat with tweezers at 9 different time points (1 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h and 9 h) within 9 hours after the test item was applied. The rat's response was evaluated by visual inspection in the form of skin wrinkling, and the value of each monitored response was 0 (no response), 0.5 (low response) or 1 (response). No response proved that the rat experienced anesthesia. Low response proved that the rat partially experienced anesthesia.

[0217] result

[0218] Table 8a-c Results of the susceptibility test. Group 1 received a commercially available ropivacaine formulation, Group 2 received a composition according to the invention (Composition 1) and Group 3 received a composition according to the invention (Composition 2).

[0219] Table 8a.

[0220]

[0221] Table 8b.

[0222]

[0223] Table 8c.

[0224]

[0225]

[0226] discuss

[0227] For two of the rats in the experiment, the syringe injected into the wrong location, either into the nerve itself (rat 1) or not close to the sciatic nerve (rat 2). This was due to human error and sudden movements of the rats.

[0228] Rat 1 experienced convulsions, which are believed to be due to paralysis caused by the composition being mistakenly injected into the sciatic nerve. Administration of the composition may result in an increase in the effect of anesthesia, which is evidence of a side effect based on misapplication to a nerve. As shown in Table 8a, Rat 1 had an increased effect, which was not due to the prior art composition itself, but rather to the side effect.

[0229] During the administration of the local anesthetic composition, rat 10 unexpectedly jumped up. This resulted in the injection being administered in the wrong part of the rat, away from the sciatic nerve. As shown in Table 8c, rat 10 did not feel any anesthetic effect at all. It is believed that the reason for not experiencing any anesthetic effect was that the injection was administered in the wrong part of the rat.

[0230] in conclusion

[0231] Composition 1 (used in Group 2) did contain carbon quantum dots, indicating that such dots produced increased duration of pain relief in vivo. According to the present invention, it appears that ropivacaine could be turned into any anesthetic and would produce the same similar in vivo effects.

[0232] Composition 2 (used in Group 3) did contain carbon quantum dots, suggesting that such dots produced increased duration of pain relief in vivo. According to the present invention, it appears that ropivacaine could become any anesthetic and would produce the same similar in vivo effects.

[0233] When comparing Tables 8a, 8b and 8c, it is evident that the compositions according to the invention (Tables 8b and 8c) produce a more prolonged anesthetic effect than the composition of the prior art (Table 8a).

[0234] Example 4: Further characterization of formulations

[0235] The aim of this work was to evaluate whether and to what extent triethanolamine is converted into other substances during microwave thermal treatment and whether this treatment produces any substances that could affect the stability of ropivacaine.

[0236] Material

[0237] Table 9. Materials used

[0238]

[0239] method

[0240] Thermal Treatment of Triethanolamine

[0241] Triethanolamine (TEA) was mixed with water in a volume ratio of 2 parts triethanolamine to 1 part water. The mixture was then heat treated in a microwave oven at 140°C / 500W for 20 minutes (m high temperature muffle furnace mls 1200pyro). The microwave oven was preheated to 140°C before the sample was placed in the microwave oven. The temperature was allowed to drop to 100°C before the sample was removed from the microwave oven, which took about another 10 minutes.

[0242] Preparation of final formulation

[0243] To 3 mL of the heat treated triethanolamine / water mixture was added 200 mg of ropivacaine free base and 100 mL of PEG 4000. The mixture was diluted with water to about 90% of its final volume and the pH was adjusted to about 5.0 to give a clear solution.

[0244] Furthermore, a form without PEG 4000 was used in the evaluation.

[0245] Fluorescence measurement

[0246] Fluorescence was measured using a fluorometer VARIOSKAN LUX from Thermo Scientific equipped with a plate reader. For the measurement, 100 or 300 μL of sample according to 3.1.2 were added to a black 96-well plate. The excitation wavelength was selected to be 350 nm. Samples were analyzed in duplicate or triplicate.

[0247] Chromatographic analysis

[0248] Gas chromatography (GC)

[0249] Agilent Technologies 6890 series GC system with flame ionization detector (FID) was used for qualitative and quantitative analysis of samples at the early stage of the formulation process and relative to triethanolamine and derivatives. The GC-FID was equipped with an Rxi-35sil MS column with dimensions of 30m*0.25mm ID and a film thickness of 0.5um (Restek). According to the method of European Pharmacopoeia 11.0, monograph 01 / 2017:1577 "Triethanolamine". According to this method, the mobile phase is phosphate buffer at pH 8: acetonitrile = 1:1 (v / v%).

[0250] For quantification, a single point calibration was performed using heptane as an internal standard.

[0251] Qualitative analysis was also performed using a 6890N GC system connected to a 5973N mass selective detector (Agilent technologies) and electron impact (EI) at 70 eV for mass ionization. The column used was a Rxi-5Sil MS (Rui Si Tai Kang Company) with dimensions of 30m*0.25mm ID, 0.25um DF.

[0252] For identification purposes, the obtained spectral mass spectrometry data were compared with reference data from the Wiley / NIST spectral library (SBN: 978-1-119-75033-8).

[0253] Liquid chromatography (LC)

[0254] Qualitative LC analysis was performed on samples from the formulation process stage after the addition of ropivacaine. LC analysis with ultraviolet (UV) detection was performed on a Thermo Fisher Scientific Vanquish UPLC instrument using a Waters BEH C18 1.7um 2.1*150mm column at a flow rate of 0.3mL / min. Other methods refer to the European Pharmacopoeia 11.1, Monograph 01 / 2017:2335 "Ropivacaine hydrochloride monohydrate".

[0255] LC analysis with UV and MS detection was performed on a Waters Acquity UPLC Quattro Micro MS instrument using electrospray ionization (ESI) in positive and negative switching mode. The method used was based on monograph 01 / 2017:2335 as described above, however, the mobile phase was changed to an MS-compatible phase; instead of using 0.1% NH3 / MeCN phosphate buffer with gradient elution.

[0256] Impurity Analysis: 2,6-Dimethylaniline

[0257] One of the impurities of ropivacaine, designated as impurity H (carcinogenic 2,6-dimethylaniline) in the pharmacopoeial monograph Eu Pharm 11.1, 01 / 2017:2335, was analyzed in the prepared formulations by LC-UV and LC-UV-MS against a 2,6-dimethylaniline reference material.

[0258] result

[0259] Prepared samples

[0260] Table 10. Samples of Example 4

[0261]

[0262] According to the above-mentioned heat treatment with triethanolamine, samples No. 2 and No. 4 were treated in a microwave oven.

[0263] In sample number 5, 23E0492-03, ropivacaine was added after the microwave treatment of sample 2.

[0264] All samples were clear liquids at room temperature (20°C-22°C).

[0265] Fluorescence measurement

[0266] Figure 2 Fluorescence graphs of compositions containing triethanolamine and water are shown. The graph shows the fluorescence measurements (in triplicate) of Formulation 2 before and after microwave treatment (Table 10, Sample 4). The circles show the fluorescence after microwave treatment, and the small triangles show the fluorescence before microwave treatment (Table 10, Sample 3). As can be seen in the graph, fluorescence is present in formulations that have been microwaved.

[0267] Figure 3 A fluorescence graph is shown for a composition containing triethanolamine and water that was microwaved prior to the subsequent addition of ropivacaine. The graph shows the fluorescence measurements (in triplicate) for Sample 5 of Table 10; i.e., formulation 23E0492-03. As can be seen in the graph, fluorescence is present in the formulation that has been microwaved prior to the addition of ropivacaine.

[0268] Chromatographic analysis

[0269] Qualitative GC-Analysis

[0270] In the analysis of the sample of the triethanolamine + water formulation treated with microwaves (Table 11, 23E0492-02, sample number 2), in addition to triethanolamine, six peaks were detected at>0.05 area % by GC-FID. See Table 11. By GC-MS (with reference to the Wiley / NIST spectral reference library), one of the impurities was identified as diethanolamine (peak number 3 in Table 11), which is one of the three specific impurities of triethanolamine in the EU Pharmacopoeia monograph (impurity B). Diethanolamine is also present in the triethanolamine reference sample, but its content is at a lower level of 0.01 area%. Peak number 1 represents impurity A specified by EU Pharmacopoeia monograph 01 / 2017:1577, which may be monoethanolamine. A level of 0.08 area % was also detected in the triethanolamine reference sample. The remaining four peaks (peak numbers 2, 5, 6, 7) cannot be identified.

[0271] Table 11. Peaks detected by GC-FID analysis for sample 23E0492-02 (microwave treated triethanolamine + water formulation).

[0272]

[0273] LC analysis

[0274] In the analysis of the microwaved triethanolamine + water sample with added ropivacaine formulation (23E0492-03), in addition to the triethanolamine and ropivacaine peaks, only one peak was detected by LC-UV at the >0.05 area % level. This is peak number 2 in Table 12 at 0.2 area % (UV 240nm). The impurity could not be identified by LC-MS. It is likely related to ropivacaine as it is also present in the ropivacaine reference sample (at 0.5 area %).

[0275] Table 12. Peaks detected by LC-UV analysis of sample 23E0492-03 (entry 5; microwaved triethanolamine + water / ropivacaine added).

[0276]

[0277] 4.4.3. Quantitative GC determination of triethanolamine

[0278] GC-FID analysis was performed using an adapted pharmacopeia method (01 / 2017:1577, Ph. Eur. 11.0) and a single-point calibration with an internal standard (heptane). The method was adapted in that the method was slightly modified, such as the injection volume was changed from 2 μL to 1 μL, the GC column was changed from 5% phenyl to 35% phenyl, and the concentration of the injected standard triethanolamine and sample was reduced from 100 mg / mL to one-tenth, i.e., 10 mg / mL, due to the overload of the analyte with the original concentration. The analysis showed that the triethanolamine content did not change significantly before and after the heat treatment of the formulation procedure (i.e., microwave heating or autoclaving) (see Table 13).

[0279] Table 13. Results of quantification of triethanolamine in selected samples by GC-FID analysis.

[0280]

[0281] 4.5. Impurity analysis: 2,6-dimethylaniline

[0282] As analyzed by UPLC-UV (240 nm) and UPLC-UV-MS (full scan m / z 50-800), the specific impurity H of European Pharmacopoeia 11.1, 01 / 2017:2335-2,6-dimethylaniline was not detected in the ropivacaine reference standard and the ropivacaine formulation sample heated by microwave triethanolamine (<0.05 area %). Therefore, it is concluded that 2,6-dimethylaniline is not generated in the processing of the formulation of the present disclosure.

[0283] Table 14. UPLC-UV analysis of 2,6-dimethylaniline impurities in selected samples

[0284]

[0285]

[0286] Table 15. UPLC-UV-MS analysis of 2,6-dimethylaniline impurities in selected samples

[0287]

[0288] Example 5: In vivo testing

[0289] A formulation according to the present disclosure (such as a formulation according to Example 2, Composition 1 or 2) is formulated as a gel. The composition comprises ropivacaine and lidocaine. The concentration of ropivacaine in the formulation is 25 mg / ml. The concentration of lidocaine in the formulation is 25 mg / ml.

[0290] (25 mg / ml lidocaine and 25 mg / ml prilocaine, formulated as a gel) was used as a positive control. Administration of the formulation according to the present disclosure is equivalent to administration, i.e. The administration of prilocaine in the formulation of the present disclosure is equivalent to the administration of ropivacaine in the formulation of the present disclosure.

[0291] The formulation was tested in 25-40 healthy medical student volunteers after appropriate ethical approval. The formulation was tested by applying the formulation to the skin between the base of fingers 2 and 3 (near the MCP joint - Meta carpo phalangeal joint) on the dorsal (upper) side of the hand of the test subject.

[0292] At several time points, such as after 10 minutes, 20 minutes, and 60 minutes, the skin and the entire finger were tested for numbness by a pin prick test on the fingertip.

[0293] Expected Results

[0294] It is expected that numbness of all fingers will be achieved within a period of time from the application of the composition of the present invention to the skin, such as within 10 minutes or within 20 minutes. Numbness of the entire finger will not be achieved within a period of time after application to the skin.

[0295] The compounds of the formulation will produce numbness in all the fingers of the hand to which the composition is applied, i.e. the subject may not feel anything in said fingers, or at least the sensation in said fingers is reduced. During the time when the formulation of the invention is effective, the subject may partially or fully extend and flex the fingers.

[0296] The results are expected to show that the formulation at least partially penetrates the skin of the human subject.

[0297] Numbness of the fingertips is evidence of penetration of the composition through the skin, since the composition was applied to the skin between fingers 2 and 3 (approximately 5 cm away), but numbness was produced at the fingertips, i.e., the effect was produced at another location some distance from the application site.

[0298] The expected results show that compared with standard treatment In comparison, the formulations according to the present disclosure are more effective, ie, numbness is produced more quickly and the numbness lasts longer.

[0299] Example 6: In vivo testing in humans; knee surgery

[0300] The purpose of this trial was to test the composition of the invention as a pain relief for use in knee surgery.

[0301] The formulation according to the present disclosure (such as the formulation according to Example 2, Composition 1 or 2) is formulated for injection. The concentration of ropivacaine is 5 mg / ml. The volume to be injected is proportional to the subject's body weight, so that each patient receives 30-130 ml of formulation, depending on the body weight. Commercially available ropivacaine (5 mg / ml) formulated for injection is used as a positive control. The administration of the formulation according to the present disclosure is equivalent to that of the positive control. The compositions tested have approximately the same injection volume and have the same pH.

[0302] The formulation is injected as a sciatic / femoral nerve block, which is standard for this procedure and will be apparent to one skilled in the art.

[0303] The subjects were otherwise healthy middle-aged men and women with osteoarthritis (OA) of the knee and undergoing knee surgery. Prior to the surgery, the formulation was injected into the subjects under sterile conditions and ultrasound guidance.

[0304] The surgery begins 15-20 minutes after the injection (when anesthesia takes effect). The surgery lasts 60 to 90 minutes.

[0305] The study was performed according to a standard protocol and with appropriate ethical approval.

[0306] Ideally, the anesthetic effect should last long enough but not interfere with the patient's mobility. The following outcome measures were monitored in the study from 0 to 72 hours after injection:

[0307] Duration of pain relief

[0308] Time to rebound effect (ie, when the effects of anesthesia have worn off)

[0309] The effect of the composition on the patient's motor function (i.e., interference with the patient's movement)

[0310] Time before rescue medication is required (ie, time before the patient requires additional pain relief, such as opiates)

[0311] Expected Results

[0312] An initial partial paralysis of the legs was expected, and a complete loss of sensation in the legs was observed for each composition tested in the experiment (both for the composition of the invention and for the composition according to the prior art). This is due to the large volume injected and the well-known effects of anesthetic drugs.

[0313] It is expected that complete loss of sensation in the legs may last for 4-5 hours after application of the prior art composition.

[0314] It is expected that complete loss of sensation in the legs may be achieved for more than 4-5 hours, such as 10-12 hours, following application of the composition of the invention.

[0315] The results are expected to show that the formulations according to the present disclosure are more effective, i.e. produce a longer duration of loss of sensation in the legs, compared to standard treatment. The formulations according to the present disclosure are expected to provide loss of sensation for more than 6 hours, such as for at least 10 hours.

Claims

1. A pharmaceutical composition comprising: - at least one anesthetic selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, benzocaine, chloroprocaine, cocaine, procaine, proparacaine, tetracaine, and any pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof; - at least one alkanolamine selected from the group consisting of triethanolamine, tripropanolamine and trimethanolamine; - water; and optionally - Pharmaceutically acceptable diluents, carriers and / or excipients.

2. The pharmaceutical composition of claim 1, wherein the at least one anesthetic agent is selected from the list consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, and any pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

3. The pharmaceutical composition according to any one of claims 1 to 2, wherein the at least one anesthetic is selected from the list consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine and any pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

4. The pharmaceutical composition according to any one of claims 1 to 3, further comprising polyethylene glycol (PEG).

5. A pharmaceutical composition according to any one of the preceding claims, wherein the composition comprises carbon quantum dots.

6. The pharmaceutical composition of claim 5, wherein the carbon quantum dots comprise the at least one alkanolamine.

7. The pharmaceutical composition according to any one of claims 5 to 6, wherein the carbon quantum dots comprise the at least one anesthetic.

8. The pharmaceutical composition according to any one of claims 5 to 7, wherein the carbon quantum dots further comprise PEG.

9. The pharmaceutical composition of claim 8, wherein the PEG is located on the surface of the carbon quantum dots.

10. The pharmaceutical composition according to any one of the preceding claims, wherein the composition is formulated for administration by injection or by external application.

11. The pharmaceutical composition according to claim 10, wherein the administration is performed by injection, such as by parenteral injection or by subcutaneous injection.

12. The pharmaceutical composition according to any one of claims 10 to 11, wherein the administration is as a single injection.

13. The pharmaceutical composition according to claim 10, wherein the administration is by external administration, such as by a patch, a cream, a gel or by a spray.

14. A pharmaceutical composition according to any one of claims 10 to 13, wherein the dose of the anesthetic is a single dose of from 5 to 600 mg, such as from 10 to 500 mg, such as from 20 to 450 mg, such as from 50 to 400 mg, such as from 100 to 400 mg, such as from 200 to 350 mg, such as from 200 to 300 mg.

15. The pharmaceutical composition according to any one of claims 10 to 14, wherein the concentration of the anesthetic is 2-15 mg / ml of the composition, such as 5-10 mg / ml of the composition, such as 5 mg / ml of the composition.

16. The pharmaceutical composition according to any one of the preceding claims, wherein the anesthetic is selected from the group consisting of ropivacaine, bupivacaine and lidocaine.

17. The pharmaceutical composition according to any one of the preceding claims, wherein the anesthetic is bupivacaine.

18. The pharmaceutical composition according to any one of claims 1 to 16, wherein the anesthetic is lidocaine.

19. The pharmaceutical composition according to any one of claims 1 to 16, wherein the anesthetic is ropivacaine.

20. The pharmaceutical composition according to any one of claims 1 to 16 and 19, wherein the ropivacaine is in basic form.

21. The pharmaceutical composition according to any one of claims 19 to 20, wherein the ropivacaine is present as the hydrochloride salt.

22. The pharmaceutical composition according to any one of claims 19 to 21, wherein the ropivacaine is present in the form of its S-enantiomer.

23. The pharmaceutical composition according to any one of claims 4 to 22, wherein the PEG is selected from the group consisting of PEG-3350, PEG-4000, PEG-6000, PEG-8000 and PEG-10000.

24. The pharmaceutical composition according to any one of claims 4 to 23, wherein the PEG is PEG-3350 or PEG-4000, preferably PEG-4000.

25. A pharmaceutical composition according to any one of the preceding claims, wherein the water is distilled water.

26. A pharmaceutical composition according to any one of the preceding claims, wherein the composition consists of: Ropivacaine; Triethanolamine; water; PEG-4000; and optionally Pharmaceutically acceptable diluents, carriers and / or excipients.

27. The pharmaceutical composition of claim 26, wherein the molar ratio of triethanolamine to ropivacaine in the composition is at least 2:1, such as at least 3:1, such as at least 4:1, such as at least 5:1, such as at least 6:1, such as at least 7:1, such as at least 8:1, such as at least 9:1, such as at least 10:1, such as at least 11:1, such as at least 12:1, such as at least 13:1, such as at least 14:1, such as at least 15:1, such as at least 16:1, such as at least 17:1, such as at least 18:1, such as at least 19:1, such as at least 20:1, such as at least 21:1, such as at least 22:1, such as at least 23:1, such as at least 24:1, such as at least 25:

1.

28. A pharmaceutical composition according to any one of the preceding claims, wherein the composition is stable after storage for at least 1 day, such as at least 1 week, such as at least 2 weeks, such as at least 3 weeks, such as at least 4 weeks, such as at least 5 weeks, such as at least 6 weeks, such as at least 7 weeks, such as at least 8 weeks, such as at least 9 weeks, such as at least 10 weeks, such as at least 3 months, such as at least 6 months, such as at least 1 year, such as at least 2 years.

29. A pharmaceutical composition according to any one of the preceding claims, wherein the composition remains thermally stable after storage at a temperature of at least 4°C, such as at least 7°C, such as at least 10°C, such as at least 15°C, such as at least 20°C, such as at least 25°C, such as at least 30°C, such as at least 35°C, such as at least 40°C.

30. A pharmaceutical composition according to any one of the preceding claims, wherein the stability is determined by the coefficient of variation.

31. A pharmaceutical composition according to any one of the preceding claims, wherein the composition is freeze-dried.

32. A pharmaceutical composition according to any one of the preceding claims for use in the treatment, alleviation or prevention of pain by administering the composition to a patient in need thereof.

33. A pharmaceutical composition for use according to claim 32, wherein the treatment, relief or prevention of pain provides long-acting anesthesia, the anesthesia lasting at least 0.5 hour, such as lasting at least 1 hour, such as lasting at least 2 hours, such as lasting at least 3 hours, such as lasting at least 4 hours, such as lasting at least 5 hours, such as lasting at least 6 hours, such as lasting at least 7 hours, such as lasting at least 8 hours, such as lasting at least 9 hours, such as lasting at least 10 hours, such as lasting at least 11 hours, such as lasting at least 12 hours, such as lasting at least 1 day, such as lasting at least 2 days, such as lasting at least 3 days, such as lasting at least 4 days, such as lasting at least 5 days.

34. The pharmaceutical composition for use according to claim 33, wherein the pain is nociceptive pain or neuropathic pain.

35. The pharmaceutical composition for use according to claim 31, wherein the pain is caused by surgery, injury or trauma.

36. The pharmaceutical composition for use according to claim 35, wherein the pain is postoperative pain, traumatic pain or chronic pain.

37. A pharmaceutical composition for use according to any one of claims 32 to 36, wherein the use is in combination with an additional therapeutic agent.

38. A pharmaceutical composition for use according to any one of claims 32 to 37, wherein the composition is to be administered at a dose of from about 0.1 to about 100 ml of the composition per kg body weight, such as from about 0.2 to about 50 ml of the composition per kg body weight, such as from about 0.3 to about 30 ml of the composition per kg body weight, such as from about 0.4 to about 20 ml of the composition per kg body weight, such as from about 0.5 to about 10 ml of the composition per kg body weight.

39. A pharmaceutical composition for use according to any one of claims 32 to 38, wherein the composition is to be administered in a dose of about 0.1 mg of the anesthetic per kg body weight, such as about 0.2 mg of the anesthetic per kg body weight, such as a dose of about 0.3 mg of the anesthetic per kg body weight, such as a dose of about 0.4 mg of the anesthetic per kg body weight, such as a dose of about 0.5 mg of the anesthetic per kg body weight, such as a dose of about 0.6 mg of the anesthetic per kg body weight, such as a dose of about 0.7 mg of the anesthetic per kg body weight, such as a dose of about 0.75 mg of the anesthetic per kg body weight, such as a dose of about 0.8 mg of the anesthetic per kg body weight, such as a dose of about 0.9 mg of the anesthetic per kg body weight, such as a dose of about 10 mg of the anesthetic per kg body weight.

40. A method of treating, alleviating or preventing pain, comprising administering to a patient in need thereof a therapeutically effective amount of a composition according to any one of claims 1 to 39.

41. The method of claim 40, wherein the pain is caused by surgery, injury or trauma.

42. A method for producing a composition comprising carbon quantum dots and at least one anesthetic selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, and any pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof; the method comprising: a) contacting an alkanolamine selected from the group consisting of triethanolamine, tripropanolamine and trimethanolamine with water to obtain a mixture; b) heating the mixture to obtain carbon quantum dots; c) adding to the mixture at least one anesthetic selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, benzocaine, chloroprocaine, cocaine, procaine, proparacaine, tetracaine, and any pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof; Wherein steps b) and c) can be performed in any order; d) optionally adding PEG to the mixture; Thereby, a composition comprising carbon quantum dots and the anesthetic is obtained.

43. The method of claim 42, wherein the at least one anesthetic agent is selected from the list consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, and any pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

44. The method of claim 42, wherein the at least one anesthetic agent is selected from the list consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, and any pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

45. The method according to any one of claims 42 to 44, wherein step b) precedes step c).

46. ​​The method of any one of claims 42 to 44, wherein step c) precedes step b).

47. The method of any one of claims 42 to 46, wherein the heating is to a temperature between 100°C and 200°C, such as between 120°C and 170°C, such as between 130°C and 150°C, such as at about 140°C.

48. The method of any one of claims 42 to 47, wherein the heating is performed by microwaves.

49. The method of any one of claims 42 to 48, further comprising the step of centrifuging the composition comprising carbon quantum dots and the anesthetic agent.

50. The method of claim 49, wherein the centrifugation is performed at a speed of 2000-5000 rpm, such as 4000 rpm.

51. The method according to any one of claims 42 to 50, wherein the centrifugation is continued for at least 5 minutes, such as for at least 10 minutes.

52. A composition comprising carbon quantum dots and an anesthetic, the composition being obtainable by the method according to any one of claims 42 to 49, the anesthetic being selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, benzocaine, chloroprocaine, cocaine, procaine, proparacaine, tetracaine, and any pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

53. The composition of claim 52, wherein the at least one anesthetic is selected from the list consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, and any pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

54. The composition of claim 52, wherein the at least one anesthetic is selected from the list consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, and any pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

55. A carbon quantum dot formed from a composition comprising: - at least one anesthetic selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, benzocaine, chloroprocaine, cocaine, procaine, proparacaine, tetracaine, and any pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof; - at least one alkanolamine selected from the group consisting of triethanolamine, tripropanolamine and trimethanolamine; and -water.

56. The carbon quantum dots of claim 55, wherein the at least one anesthetic is selected from the list consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, and any pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

57. The carbon quantum dots of claim 56, wherein the at least one anesthetic is selected from the list consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, and any pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

58. The carbon quantum dot according to any one of claims 55 to 57, further comprising PEG, optionally wherein the PEG is selected from the group consisting of: PEG-3350, PEG-4000, PEG-6000, PEG-8000 and PEG-10000.

59. The carbon quantum dot according to any one of claims 55 to 58, wherein the anesthetic is selected from the group consisting of: ropivacaine, bupivacaine and lidocaine.

60. The carbon quantum dot according to any one of claims 55 to 59, wherein the anesthetic is ropivacaine.

61. The carbon quantum dot according to any one of claims 55 to 60, wherein the alkanolamine is triethanolamine.

62. The carbon quantum dot of any one of claims 55 to 61, wherein the PEG is PEG-4000.

63. Carbon quantum dots according to any one of claims 55 to 62, wherein the dots are fluorescent, optionally wherein the dots emit light at a wavelength from 400 to 600 nm, such as from 415 to 430 nm, such as about 425 nm.

64. Carbon quantum dots according to any one of claims 55 to 63, wherein the dots have an average diameter from 1 to 20 nm, such as from 2 to 18 nm, such as from 3 to 15 nm, such as from 4 to 12 nm, such as from 5 to 10 nm.

65. Use of a composition according to any one of claims 1 to 39 and 52 to 54 or a carbon quantum dot according to any one of claims 55 to 64 for the manufacture of a medicament for use in treating pain.

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