Long-acting anesthetic preparation

Abstract

The present invention belongs to the technical field of analgesia, and relates to a pharmaceutical composition containing 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, propalacaine, tetracaine, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs 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. The disclosure also relates to the use of the composition for providing analgesia, a treatment method, a method for manufacturing the pharmaceutical composition, and carbon quantum dots formed from the components of the pharmaceutical composition.

Description

Technical Field

[0001] The inventive concept described in this specification generally relates to a pharmaceutical composition containing an anesthetic. Specifically, this inventive concept relates to a pharmaceutical composition having a long-lasting anesthetic effect and to the manufacture of said composition.

Background Art

[0002] Local anesthetics reversibly suppress nerve impulses and cause blockage of sensory or motor nerves, thereby eliminating pain at specific locations in the body without loss of consciousness. They are used to paralyze areas of the body during surgery or painful examinations by a doctor, or to provide analgesia when necessary. The drugs can be classified based on type. Ester-type local anesthetics include benzocaine, chloroprocaine, cocaine, procaine, propoxycaine, and tetracaine. Amide-type local anesthetics include articaine, bupivacaine, cinchocaine, etidocaine, levobupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine, and trimecaine. These drugs have the same mechanism of action of reversibly inhibiting sodium ion influx and blocking impulse conduction in nerve fibers.

[0003] The drugs ropivacaine and bupivacaine are very similar and differ by only one methyl group. However, ropivacaine has the advantage of high efficacy, which may be due in part to the fact that ropivacaine is sold as a pure S-enantiomer if required. Ropivacaine is a highly tolerated anesthetic and is effective not only for intraoperative anesthesia but also for reducing postoperative pain and pain during labor (Kuthiala and Chaudhary, 2011).

[0004] Carbon quantum dots are a type of nanomaterial that has attracted attention due to their low toxicity, water solubility, and fluorescence emission. Therefore, it has been suggested that they may prove useful in the fields of imaging and drug delivery. Qu et al. described the synthesis of ibuprofen-based carbon quantum dots and showed that the dots are stable, non-toxic, and have good biocompatibility in water. Moreover, the anti-inflammatory properties of ibuprofen were retained.

[0005] Local anesthetics are effective for anesthesia and pain relief during surgery, but there is room for improvement in, for example, the pharmacokinetic (PK) properties and pharmacodynamic (PD) properties in the body of mammals. Although efforts have been made in the field of anesthetic products, there is still a need for improved products. If improved products with long-lasting effects were provided, it would bring greater benefits to humanity.

Brief Description of the Drawings

[0006]

Figure 1

Figure 2

Figure 3

Summary of the Invention

[0007] The object of the present invention is to at least partially alleviate or overcome the problems in the prior art and to provide means for treating, alleviating and / or preventing pain. These and other objects are fully or at least partially achieved by aspects of the inventive concept disclosed in this specification. The inventors have surprisingly found that 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, propoxycaine, tetracaine, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs 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, is effective in providing a long-lasting anesthetic effect. Accordingly, in a first aspect of the present invention, there is provided a pharmaceutical composition having the advantage that the duration of analgesia is prolonged as compared to similar compounds not formulated according to the composition of the present invention. The inventors have shown that the composition of the present invention provides an increase in the analgesic time in vivo. The increase in analgesia in vivo is expected to at least partially replace the need for treatment with opioids, which are commonly used clinically as postoperative rescue medications. Therefore, the use of the composition of the present invention may reduce the risk of complications in opioid treatment.

[0008] In one aspect, the at least one anesthetic is selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof. In one aspect, the at least one anesthetic is selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof. In one aspect, the pharmaceutical composition further contains polyethylene glycol (PEG).

[0009] Preferably, the composition contains carbon quantum dots. Without being bound by theory, it is contemplated that the carbon quantum dots may increase the therapeutic effect or improve the pharmacokinetic and / or pharmacodynamic properties of the anesthetic in the composition of the present invention. Without being bound by theory, such an increase may be the result of increased water solubility or increased uptake of the anesthetic into cells, or alternatively, the anesthetic may associate with the carbon quantum dots for a period of time, thereby resulting in a sustained release effect of the anesthetic. In one aspect, the carbon quantum dots contain the at least one anesthetic. In one aspect, the carbon quantum dots contain at least one alkanolamine selected from the group consisting of triethanolamine, tripropanolamine and trimethanolamine. In one aspect, the carbon quantum dots contain triethanolamine.

[0010] In one aspect, the carbon quantum dots further contain PEG. In one aspect, the PEG is on the surface of the carbon quantum dots.

[0011] Several routes of administration are contemplated. In one aspect, the composition is formulated for injection or topical administration.

[0012] In one aspect, the composition is formulated for administration as a nerve block into the lower and upper extremities, intra-articularly, subcutaneously, and intrathecally. Preferably, the administration is not intravenous administration.

[0013] In one aspect, the administration is by topical administration, such as by patch, cream, gel, or spray. Such administration can be beneficial because the local composition may obviate the need for a physician to administer the pharmaceutical composition. Thus, a subject in need of anesthesia may self-administer the composition. Self-administration has the advantage that the patient can adjust the dosage or frequency of the medicament based on a subjective assessment of their own condition or according to a schedule indicated by the attending physician. The term "schedule indicated by the attending physician" includes the option for the patient to subjectively evaluate their condition without relying on, or using, a questionnaire, range, or scale, or using an algorithm or computer program, and indicate the appropriate next administration.

[0014] Transdermal administration using the compositions of the present invention formulated as creams, gels, and ointments, or in the form of an adhesive pharmaceutical patch, is another administration form suitable for self-administration. The advantages of self-administration enumerated above also apply to transdermal administration, but transdermal administration also has the additional advantage that administration can be easily interrupted as needed, for example, by removing the pharmaceutical patch. When the local composition is a patch, gel, or spray, the composition may contain additional components. One of ordinary skill in the art understands which additional components are suitable for a particular topical use. For example, a spray may require a propellant. Suitable propellants will be apparent to one of ordinary skill in the art. Lotions, skin creams, or ointments may require a skin softening agent. Suitable skin softening agents will be apparent to one of ordinary skill in the art.

[0015] For gels, a gelling agent such as a gelling polymer may be required. Suitable polymers will be apparent to those skilled in the art. For example, cellulose such as nonionic water-soluble cellulose ether. In addition, the gel may contain an alcohol such as a C1-C3 alcohol or a C2-C4 alcohol such as a C1-C4 alcohol (e.g., ethanol). Further, 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.

[0016] The patch may contain another drug and may contain two or more local anesthetics. In one embodiment, when the topical composition is a patch, the composition contains at least one of bupivacaine and ropivacaine and further contains lidocaine. For example, the composition contains ropivacaine and lidocaine.

[0017] The composition can also be administered as a depot formulation that releases an effective amount of the anesthetic disclosed in the specification for a certain period of time. Those skilled in the art will understand that the depot formulation can be adapted to deliver the desired effective amount according to the prescription of the attending physician. The depot can be a subcutaneous depot formulation. Thus, in one embodiment, the administration is effected by a depot formulation such as a subcutaneous depot formulation.

[0018] In one embodiment, the administration is by injection, for example, parenteral injection or subcutaneous injection. In one embodiment, the administration is effected as a single injection. Since the effect of the composition of the present invention persists for a long time, a single injection may be appropriate for the administration of the composition of the present invention and may be time-efficient.

[0019] Conventional excipients for intravenous administration are, for example, water for injection (WFI), sterile buffers (e.g., buffering the solution at pH 7.4), albumin solutions, lipid solutions, cyclodextrins and their variants, etc. Conventional excipients for subcutaneous administration are, for example, water for injection (WFI), sterile buffers (e.g., buffering the solution at pH 7.4), lipid solutions, cyclodextrin, etc. Conventional excipients for subcutaneous administration by a subcutaneous delivery system such as a subcutaneous rod are, for example, water for injection (WFI), sterile buffers (e.g., buffering the solution at pH 7.4), lipid solutions, cyclodextrin, etc.

[0020] Conventional excipients for transdermal and / or subcutaneous administration are, for example, petrolatum, liquid paraffin, glycerin, water, MCT oil, sesame oil, etc.

[0021] One of ordinary skill in the art will understand that the appropriate dosage will, of course, vary depending on the method of administration, the specific condition being treated or the desired effect, the gender, age, weight and health status of the patient, and other factors evaluated by the attending physician. In one aspect, the dosage of the anesthetic is a single administration (unit dose) of 5 to 600 mg, such as 10 to 500 mg, such as 20 to 450 mg, such as 50 to 400 mg, such as 100 to 400 mg, such as 200 to 350 mg, such as 200 to 300 mg.

[0022] In one aspect, the concentration of the anesthetic in the composition is 1 to 20 mg per 1 ml of the composition, such as 2 to 15 mg, such as 5 to 10 mg, such as 5 mg. Commonly used dosages are 2.5 mg / ml; 5 mg / ml; 7.5 mg / ml, 10 mg / ml; 20 mg / ml; 30 mg / ml, depending on the anesthetic used and the conditions.

[0023] In one aspect, the concentration of the alkanolamine in the composition is 0.1 to 20 M (mol / dm 3 ), such as 0.2 to 18 M, such as 0.2 to 18 M, such as 0.5 to 15 M, such as 1 to 12 M, such as 2 to 10 M, such as 3 to 8 M, such as 4 to 6 M, such as about 5 M.

[0024] In one aspect, the concentration of the anesthetic in the composition is 0.1 to 500 mM (mmol / dm 3 ), for example 1 to 400 mM, for example 100 to 300 mM, for example 220 to 260 mM, for example 240 to 250 mM, for example about 245 mM.

[0025] In one aspect, the concentration of PEG is about 0.1 to 100 μM, for example about 1 to 50 μM, for example about 5 to 15 μM, for example about 8 μM.

[0026] The composition of the present invention may be prepared with different ratios of its components. For example, in one aspect, the molar ratio of alkanolamine to anesthetic in the composition is at least 2:1, for example at least 3:1, for example at least 4:1, for example at least 5:1, for example at least 6:1, for example at least 7:1, for example at least 8:1, for example at least 9:1, for example at least 10:1, for example at least 11:1, for example at least 12:1, for example at least 13:1, for example at least 14:1, for example at least 15:1, for example at least 16:1, for example at least 17:1, for example at least 18:1, for example at least 19:1, for example at least 20:1, for example at least 21:1, for example at least 22:1, for example at least 23:1, for example at least 24:1, for example at least 25:1.

[0027] The composition of the present invention may be prepared at different pH values. For example, in one aspect, the pH of the composition is 5 to 8, for example about 5, for example about 5.5, for example about 6, for example about 6.5, for example about 7, or for example about 7.5.

[0028] As discussed previously, the present invention provides a formulation containing 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, propoxycaine, tetracaine, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof.

[0029] 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, benzocaine, chloroprocaine, procaine, propoxycaine, tetracaine, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof.

[0030] 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, benzocaine, chloroprocaine, cocaine, procaine, propoxycaine, tetracaine, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof.

[0031] 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, chloroprocaine, cocaine, procaine, propoxycaine and tetracaine.

[0032] In one aspect, 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, propoxycaine, and tetracaine. In one aspect, 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, propoxycaine, and tetracaine. In one aspect, the at least one anesthetic is selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lignocaine, mepivacaine, and prilocaine. In one aspect, the at least one anesthetic is selected from the group consisting of ropivacaine, bupivacaine, etidocaine, mepivacaine, and prilocaine. In one aspect, the at least one anesthetic is selected from the group consisting of ropivacaine, bupivacaine, mepivacaine, and prilocaine. In one aspect, the at least one anesthetic is selected from the group consisting of ropivacaine, bupivacaine, and prilocaine. In one aspect, the at least one anesthetic is selected from the group consisting of ropivacaine, bupivacaine, and mepivacaine. In one aspect, the at least one anesthetic is selected from the group consisting of ropivacaine, bupivacaine, and etidocaine. In one aspect, the anesthetic is selected from the group consisting of ropivacaine, bupivacaine, and lidocaine. In one aspect, the at least one anesthetic is a combination of ropivacaine and lidocaine. In one aspect, the at least one anesthetic is a combination of bupivacaine and lidocaine. In one aspect, the anesthetic is selected from the group consisting of ropivacaine and bupivacaine. In one aspect, the anesthetic is bupivacaine. For the sake of clarity, the chemical formula of bupivacaine is Formula I:

[0033] [Chemical formula]

[0034] is shown as

[0035] In one aspect, the anesthetic is lidocaine. For clarity, the chemical formula of lidocaine is shown in Formula II:

[0036] [Chemical formula]

[0037] is shown as

[0038] In one aspect, the anesthetic is ropivacaine. For clarity, the chemical formula of ropivacaine is shown in Formula III:

[0039] [Chemical formula]

[0040] is shown as

[0041] In one aspect, when the anesthetic is ropivacaine, the ropivacaine is in an alkaline form. In one aspect, the ropivacaine exists as a hydrochloride salt. Other pharmaceutically acceptable salts are also contemplated as being suitable in the composition.

[0042] One skilled in the art understands that the pharmaceutically acceptable salts of the anesthetic agent according to this aspect of the present disclosure are suitable for use in a composition. A salt suitable for medical use is one in which the counterion is a pharmaceutically acceptable salt. Examples of such pharmaceutically acceptable salts of the present invention include salts formed with organic or inorganic acids or bases. In particular, suitable salts formed with the acids of the present invention include salts formed with mineral acids, strong organic carboxylic acids (e.g., alkane carboxylic acids having 1 to 4 carbon atoms, saturated dicarboxylic acids or unsaturated dicarboxylic acids, hydroxycarboxylic acids, amino acids, which may be unsubstituted or substituted with, for example, halogen), or organic sulfonic acids (e.g., (C1-C4) alkyl or arylsulfonic acids which may be unsubstituted or substituted with, for example, halogen). Pharmaceutically acceptable acid addition salts include those formed from 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.

[0043] In one aspect, ropivacaine is present in the form of the S-enantiomer. Preferably, S-ropivacaine may be present in enantiomeric excess. Such an excess may also have R-ropivacaine present, but in an amount less than that of the S-form.

[0044] The composition may contain PEG. In one aspect, the PEG is selected from the group consisting of PEG-3350, PEG-4000, PEG-6000, PEG-8000 and PEG-10000. In one aspect, the PEG is PEG-3350 or PEG-4000. In a preferred aspect, the PEG is PEG-4000.

[0045] The composition of the present invention contains water. The water may be purified water suitable for pharmaceuticals. The water may be water for injection (WFI). The water may be deionized water (diH2O). The water may be distilled water (dH2O). In certain embodiments, the water is distilled water. The distilled water may be Milli-Q water. In certain embodiments, the water is deionized water.

[0046] In certain embodiments, the composition ropivacaine; triethanolamine; water; and, optionally, pharmaceutically acceptable diluents, carriers and / or excipients; consisting of.

[0047] In certain embodiments, the composition ropivacaine; triethanolamine; water; PEG-4000; and, optionally, pharmaceutically acceptable diluents, carriers and / or excipients; consisting of.

[0048] In certain embodiments, 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.

[0049] In certain embodiments, the concentration of triethanolamine in the composition is 0.1 - 20 M (mol / dm 3)、for example, 0.2 to 18 M, for example, 0.2 to 18 M, for example, 0.5 to 15 M, for example, 1 to 12 M, for example, 2 to 10 M, for example, 3 to 8 M, for example, 4 to 6 M, for example, about 5 M.

[0050] In one aspect, the concentration of ropivacaine in the composition is 0.1 to 500 mM (mmol / dm 3 ), for example, 1 to 400 mM, for example, 100 to 300 mM, for example, 220 to 260 mM, for example, 240 to 250 mM, for example, about 245 mM.

[0051] The composition may be suitable for storage such as long-term storage. The composition may benefit from maintaining stability over time. In one aspect, the composition is stable for storage for at least 1 day, for example, at least 1 week, for example, at least 2 weeks, for example, at least 3 weeks, for example, at least 4 weeks, for example, at least 5 weeks, for example, at least 6 weeks, for example, at least 7 weeks, for example, at least 8 weeks, for example, at least 9 weeks, for example, at least 10 weeks, for example, at least 3 months, for example, at least 6 months, for example, at least 1 year, for example, at least 2 years. For example, Compositions 1 and 2 of Example 1 were then used in Example 3. Example 3 shows that the composition was stable at various temperatures for a long period of time.

[0052] In one aspect, the composition benefits from thermal stability. Therefore, the composition may be thermally stable for storage at at least 4°C, for example, at least 7°C, for example, at least 10°C, for example, at least 15°C, for example, at least 20°C, for example, at least 25°C, for example, at least 30°C, for example, at least 35°C, for example, at least 40°C.

[0053] Stability can be determined in several ways, but as will be apparent to those skilled in the art, in embodiments where stability is maintained, the stability is determined by the coefficient of variation. In this specification, the term "stability" is meant to mean that no undesirable phenomena such as decomposition of the components of the composition occur. In this specification, the expression "components of the composition" is intended to include both the original components added to the composition and the components formed during the preparation of the composition. Stability is preferably determined by the coefficient of variation ("CV"). Those skilled in the art will understand that low variation between samples (e.g., in measurements over time or at different temperatures) means a high degree of stability retention. In one embodiment, "stability retention" means that the CV shown when comparing various samples is at most about 20%, e.g., at most 15%, e.g., at most 10%, e.g., at most 5%, e.g., at most 2.5%. As is known among those skilled in the art, other methods of measuring and expressing stability retention or maintenance are possible.

[0054] Compositions intended for long-term storage may suitably be in the form of lyophilized compositions. Thus, in one embodiment, the composition is lyophilized. When the composition of the present invention is lyophilized, water is removed from the composition. However, it is believed that a small amount of water still remains in the lyophilized composition.

[0055] It should be understood that the compositions according to the present disclosure may be useful as therapeutic compositions. Direct therapeutic effects such as a long-lasting anesthetic effect may be achieved, for example, by application of the composition.

[0056] In another aspect, a pharmaceutical composition is provided by the first aspect, and is used for the treatment, alleviation or prevention of pain by administration of the composition to a patient in need thereof. In certain aspects, the treatment, alleviation or prevention of the pain provides a long-lasting anesthesia, and the anesthesia lasts for at least 0.5 hour, such as at least 1 hour, such as at least 2 hours, such as at least 3 hours, such as at least 4 hours, such as at least 5 hours, such as at least 6 hours, such as at least 7 hours, such as at least 8 hours, such as at least 9 hours, such as at least 10 hours, such as at least 11 hours, such as at least 12 hours, such as at least 1 day, such as at least 2 days, such as at least 3 days, such as at least 4 days, such as at least 5 days. Examples of long-lasting analgesia using the composition of the present invention are described in Examples 2 and 3. Another example of long-lasting analgesia using the composition of the present invention is described in Example 6. Anesthesia can be measured in several ways. Those skilled in the art will understand that anesthesia can be measured subjectively or objectively. For example, in subjective measurement, the patient is asked whether pain or another unpleasant sensation is caused by a stimulus. Such a stimulus may be, for example, a prick test, a pinch test, or the stimulus may occur during surgery or an examination accompanied by pain.

[0057] For example, in objective measurement, vital parameters such as pulse, blood pressure and / or respiratory rate may be measured. This is often done during surgery. In objective measurement, by performing a neurophysiological examination using surface electrodes on the skin (for example, you ask the patient to raise the leg, bend the foot, etc.), such as EMG (electromyogram) of muscle activity, the blockade of sensory or motor nerves can also be measured, and thereby, the muscle activity can be measured.

[0058] Those skilled in the art will understand that the composition of the present invention is useful for the treatment of all types of pain. In certain aspects, the pain is nociceptive pain or neuropathic pain. In certain aspects, the pain is caused by surgery, injury or trauma. In certain aspects, the pain is postoperative pain, trauma pain or chronic pain.

[0059] In one aspect, the use is in combination with another therapeutic agent. Suitable candidates for combination therapy will be apparent to those skilled in the art and include, for example, without limitation, antibacterial agents; antifungal agents, antiviral agents, disinfectants, anti-inflammatory agents, non-steroidal anti-inflammatory drugs (NSAIDs), and antipruritics. For example, another active therapeutic agent may be an antibacterial agent such as oxytetracycline, fusidic acid, gentamicin, mupirocin, retapamulin (as well as pharmaceutically acceptable salts and derivatives thereof); an antifungal agent such as nystatin, clotrimazole, miconazole, econazole, ketoconazole, bifonazole, combinations of imidazole and triazole derivatives, ciclopirox, terbinafine, fluconazole, and amorolfine (as well as pharmaceutically acceptable salts and derivatives thereof); an antiviral agent such as acyclovir, valacyclovir, penciclovir, famciclovir, phosphonoformate (sodium phosphonoformate hexahydrate), and docosanol (as well as pharmaceutically acceptable salts and derivatives thereof); a disinfectant such as chlorhexidine, benzalkonium chloride, and hydrogen peroxide; an anti-inflammatory agent (glucocorticoid) such as hydrocortisone, clobetasone, triamcinolone, betamethasone, mometasone, desonide, prednisolone, and clobetasol (as well as pharmaceutically acceptable salts and derivatives thereof); a non-steroidal anti-inflammatory drug (NSAIDs) such as acetylsalicylic acid, diclofenac, ketoprofen, ibuprofen, naproxen, capsaicin, and nicotinic acid esters (as well as pharmaceutically acceptable salts and derivatives thereof); and an antipruritic such as a glucocorticoid (e.g., hydrocortisone, clobetasone, clobetasol, desonide, mometasone, and betamethasone).

[0060] In one aspect, the administration is at a dose of about 0.1 to about 100 ml per kg of body weight, such as about 0.2 to about 50 ml per kg of body weight, such as about 0.3 to about 30 ml per kg of body weight, such as about 0.4 to about 20 ml per kg of body weight, such as about 0.5 to about 10 ml per kg of body weight, such as about 1 to about 5 ml of the composition per kg of body weight.

[0061] In one aspect, the administration is carried out at a dose starting from about 0.1 mg per kg of body weight, for example starting from about 0.2 mg per kg of body weight, for example starting from about 0.3 mg per kg of body weight, for example starting from about 0.4 mg per kg of body weight, for example at a dose of about 0.5 mg of the anesthetic per kg of body weight, for example at a dose of about 0.6 mg of the anesthetic per kg of body weight, for example at a dose of about 0.7 mg of the anesthetic per kg of body weight, for example at a dose of about 0.75 mg of the anesthetic per kg of body weight, for example at a dose of about 0.8 mg of the anesthetic per kg of body weight, for example at a dose of about 0.9 mg of the anesthetic per kg of body weight, for example at a dose of about 10 mg of the anesthetic per kg of body weight.

[0062] In another aspect, there is provided a method for treating, alleviating or preventing pain, comprising administering to a patient in need thereof a therapeutically effective amount of a composition according to the first aspect. In one aspect, the pain is caused by surgery, injury or trauma. In one aspect, the method further comprises administering another therapeutic agent.

[0063] Other therapeutic agents suitable for combination therapy will be apparent to those skilled in the art and include, for example, opioids as well as other opioid analogs, stimulants, antibacterial agents; antifungal agents, antiviral agents, disinfectants, anti-inflammatory agents, non-steroidal anti-inflammatory drugs (NSAIDs) and antipruritics, to name but a few. For example, the active therapeutic agents of the present invention include stimulants such as ephedrine; antibacterial agents such as oxytetracycline, fusidic acid, gentamicin, mupirocin, retapamulin (as well as pharmaceutically acceptable salts and derivatives thereof); antifungal agents such as nystatin, clotrimazole, miconazole, econazole, ketoconazole, bifonazole, combinations of imidazole and triazole derivatives, ciclopirox, terbinafine, fluconazole and amorolfine (as well as pharmaceutically acceptable salts and derivatives thereof); antiviral agents such as acyclovir, valacyclovir, penciclovir, famciclovir, foscarnet (sodium phosphonoformate hexahydrate) and docosanol (as well as pharmaceutically acceptable salts and derivatives thereof); disinfectants such as chlorhexidine, benzalkonium chloride and hydrogen peroxide; anti-inflammatory agents (glucocorticoids) such as hydrocortisone, clobetasone, triamcinolone, betamethasone, mometasone, desonide, prednisolone and clobetasol (as well as pharmaceutically acceptable salts and derivatives thereof); non-steroidal anti-inflammatory drugs (NSAIDs) such as acetylsalicylic acid, diclofenac, ketoprofen, ibuprofen, naproxen, capsaicin and nicotinic acid esters (as well as pharmaceutically acceptable salts and derivatives thereof); and antipruritics such as glucocorticoids (e.g. hydrocortisone, clobetasone, clobetasol, desonide, mometasone and betamethasone) may be selected.

[0064] In another aspect, there is provided 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, articaine, dibucaine, levobupivacaine, prilocaine, benzocaine, chloroprocaine, cocaine, procaine, propoxycaine, tetracaine and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, said method comprising: a) contacting an alkanolamine selected from the group consisting of triethanolamine, tripropanolamine and trimethanolamine with water to obtain a mixture; b) heating said mixture to obtain carbon quantum dots; c) adding to said mixture at least one anesthetic selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof; wherein steps b) and c) can be carried out in any order; d) optionally, adding PEG to said mixture; comprising: thereby obtaining a composition containing carbon quantum dots and said anesthetic.

[0065] In one embodiment, said at least one anesthetic is selected from the list consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof. In one embodiment, said at least one anesthetic is selected from the list consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof.

[0066] In one aspect, step c) is carried out before step b), that is, it means that the mixture to be heated is a mixture containing an alkanolamine, water and at least one anesthetic. In this aspect, the mixture containing an alkanolamine, water and at least one anesthetic forms carbon quantum dots.

[0067] In one aspect, step b) is carried out before step c), that is, it means that the mixture to be heated is a mixture containing an alkanolamine and water. In this aspect, the mixture containing an alkanolamine and water forms carbon quantum dots.

[0068] As shown in the examples, the pharmaceutical composition according to the present disclosure can be prepared by various routes. In one aspect, an anesthetic, an alkanolamine and water are heated to form carbon quantum dots, and then PEG is added. This route is the same as Composition 1 of Example 1.

[0069] In one aspect, an alkanolamine and water are heated to form carbon quantum dots, then an anesthetic is added, and then PEG is added. This route is the same as Composition 2 of Example 1. Example 2 of the present application shows that both Compositions 1 and 2 of the present invention provide a longer analgesic time compared to the compositions of the prior art.

[0070] In one aspect, the heating temperature is 100°C to 200°C, for example 120°C to 170°C, for example 130°C to 150°C, for example 140°C. In one aspect, the heating is by microwave. As will be apparent to those skilled in the art, the heating may be carried out using a heating plate or other conventional heating means. In a preferred aspect, the heating is by a microwave oven.

[0071] Centrifugation can be useful for separating various components within a composition by weight or size, such as the weight of particles or particle size. Thus, in one aspect, the method further includes a step of centrifuging the composition containing the anesthetic and the carbon quantum dots. In one aspect, the speed of the centrifugation is 2000 - 5000 rpm, for example 4000 rpm. In one aspect, the time of the centrifugation is at least 5 minutes, for example at least 10 minutes. Those skilled in the art understand the conditions suitable for centrifugation.

[0072] In another aspect, in accordance with the aspects described heretofore, provided are carbon quantum dots comprising an anesthetic selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, obtained by a method for producing a composition comprising carbon quantum dots and at least one anesthetic.

[0073] In one aspect, the at least one anesthetic is selected from the list consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof. In one aspect, the at least one anesthetic is selected from the list consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof.

[0074] In one aspect, the anesthetic is selected from the group consisting of ropivacaine, bupivacaine, and lidocaine. In one aspect, the anesthetic is ropivacaine. In one aspect, the alkanolamine is triethanolamine. In one aspect, the carbon quantum dots further contain PEG, and optionally, the PEG is selected from the group consisting of PEG-3350, PEG-4000, PEG-6000, PEG-8000, and PEG-10000. In one aspect, the PEG is PEG-4000.

[0075] In one aspect, the dots are fluorescent. The dots can emit light with a wavelength of 400 to 600 nm, such as 415 to 430 nm, such as about 425 nm. In one aspect, the average diameter of the dots is 1 to 20 nm, such as 2 to 18 nm, such as 3 to 15 nm, such as 4 to 12 nm, such as 5 to 10 nm. Under ultraviolet light, the carbon quantum dots may appear blue by visual inspection.

[0076] In yet another aspect, - 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, propalacaine, tetracaine, and pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof; - at least one alkanolamine selected from the group consisting of triethanolamine, tripropanolamine, and trimethanolamine; and, - water; There is provided carbon quantum dots formed from a composition containing

[0077] In one aspect, the at least one anesthetic is selected from the list consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, articaine, dibucaine, levobupivacaine, prilocaine, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof. In one aspect, the at least one anesthetic is selected from the list consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof.

[0078] In one aspect, the dots are fluorescent. The dots can emit light with a wavelength of 400 to 600 nm, such as 415 to 430 nm, such as about 425 nm. In one aspect, the average diameter of the dots is 1 to 20 nm, such as 2 to 18 nm, such as 3 to 15 nm, such as 4 to 12 nm, such as 5 to 10 nm. Under ultraviolet light, the carbon quantum dots may appear blue in visual inspection.

[0079] In a related aspect, there is provided the use of a composition according to the aspects described hitherto in the manufacture of a medicament for use in the treatment of pain.

[0080] Definitions Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The singular forms "a", "an" include plural referents unless the context clearly dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly dictates otherwise. Methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, but the appropriate methods and materials are described below. The term "comprising" means "including". In case of conflict, this specification, including definitions of terms, will control over other sources of information. Further, all materials, methods, and examples are illustrative only and not intended to be limiting.

[0081] The term "pharmaceutical composition" is used in its broadest sense and encompasses all pharmaceutically applicable compositions containing at least one active substance and, optionally, carriers, adjuvants, diluents, ingredients, etc. The term "pharmaceutical composition" also encompasses compositions containing active substances in the form of pharmaceutically acceptable salts, sulfates, esters and other derivatives or prodrugs. The manufacture of pharmaceutical compositions for different routes of administration is within the capabilities of those skilled in the art of pharmaceutical formulation.

[0082] The term "prodrug" is used in this specification to describe a compound that forms the anesthetic agent of the present invention by a chemical reaction.

[0083] The terms "administration", "mode of administration" and "route of administration" are also used in their broadest sense. The pharmaceutical compositions of the present invention may be administered in various ways, depending solely on whether a topical mode of administration is most appropriate for the particular pain to be treated. These various modes of administration are, for example, topical (e.g. skin, eyes, and various mucosae such as the vagina and rectum), oral or parenteral. Methods for preparing such compositions and formulations are generally known to those skilled in the field of pharmacy and may be applied to the formulation of the compositions of the present invention.

[0084] A normal single-dose composition (or unit-dose composition) is a composition containing an effective amount of the active ingredient as described above or an appropriate fraction thereof.

[0085] It should be understood that, in addition to the components specifically described above, the compositions of the present invention may contain other drugs commonly used in the art, taking into account the dosage form.

[0086] The terms "composition" and "formulation" are used interchangeably throughout the application and are intended to have the same meaning, as will be apparent to those skilled in the art.

[0087] The terms "subject" and "patient" are used interchangeably throughout the application and are intended to have the same meaning, as will be apparent to those skilled in the art.

[0088] In this specification, when the term "about" or "approximately" is used in connection with a numerical value, it is construed to mean within ±10%, e.g., ±9%, e.g., ±8%, e.g., ±7%, e.g., ±6%, e.g., ±5%, e.g., ±4%, e.g., ±3%, e.g., ±2%, e.g., ±1%. For example, if a value is stated to be about 10, this means that the value is actually between 9 and 11, e.g., between 9.9 and 10.9, e.g., between 9.8 and 10.8, e.g., between 9.7 and 10.7, e.g., between 9.6 and 10.6, e.g., between 9.5 and 10.5, e.g., between 9.4 and 10.4, e.g., between 9.3 and 10.3, e.g., between 9.2 and 10.2, e.g., between 9.1 and 10.1.

[0089] Those skilled in the art are aware that numerical values regarding measurements are affected by measurement errors that limit their accuracy. For this reason, the general convention in scientific and technical literature applies: the last digit after the decimal point of a numerical value indicates the degree of its accuracy. If no other error range is specified, the maximum range is confirmed by rounding the last digit after the decimal point. For example, if a measured value is 3.5 cm, the error range is 3.45 - 3.54. In the interpretation of value ranges in the specification, those skilled in the art proceed on the same basis.

[0090] As will be apparent to those skilled in the art, the term tripropanolamine includes tri - iso - propanolamine.

[0091] Although this invention has been described with reference to various exemplary aspects and embodiments, it will be understood by those skilled in the art that various changes can be made and its elements can be replaced with equivalents without departing from the scope of the invention. Accordingly, the invention is not intended to be limited to the particular aspects envisioned, but is intended to include all aspects that fall within the scope of the claims. The invention is further illustrated by the following non - limiting examples.

[0092] References Kuthiala and Chaudhary. Ropivacaine: A review of its pharmacology and clinical use. Indian J Anesth 2011; 55: 104-10. Qu et al. Synthesis of bifunctional carbon quantum dots for bioimaging and anti-inflammation. Nanotechnology 2020; 31. 175102.

Example

[0093] Example 1 Characterization of Quantum Dots Materials and Methods Ropivacaine was purchased from AK Scientific (purity 98%). Triethanolamine was purchased from Chemtronica. PEG4000 was purchased from Chemtronica. A microwave oven used was a Milestone MLS 1200 Pyro high-temperature muffle furnace equipped with a temperature control function.

[0094] Preparation of Compositions 1-3 Composition 1 - A composition consisting of ropivacaine, triethanolamine, water and PEG400 1. Ropivacaine free base (0.4 g) was mixed with purified water (2 mL) and triethanolamine (4 mL). 2. The mixture in Step 1 was heated in a microwave oven at 140 °C for 20 minutes. 3. 0.5 mL of the sample was taken for fluorescence and particle size measurement. 4. PEG4000 (0.2 mg) was added. 5. 0.5 mL of the sample was taken for fluorescence and particle size measurement.

[0095] Observation: It is not a clear solution at any stage.

[0096] Composition 2 - A composition consisting of ropivacaine, triethanolamine, water, and PEG400 1. Purified water (2 mL) was mixed with triethanolamine (4 mL). 2. The mixture from Step 1 was heated in a microwave oven at 140 °C for 20 minutes. 3. 0.5 mL of the sample was taken for fluorescence and particle size measurement. 4. Ropivacaine free base (0.4 g) was added to the mixture from Step 2. 5. PEG4000 (0.2 mg) was added. 6. 0.5 mL of the sample was taken for fluorescence and particle size measurement.

[0097] Observation: The solution in Step 4 is not clear.

[0098] Composition 3 - A composition consisting of ropivacaine, water, and PEG400 1. Ropivacaine free base (0.4 g) was mixed with purified water (2 mL). 2. The mixture from Step 1 was heated in a microwave oven at 140 °C for 20 minutes. 3. 0.5 mL of the sample was taken for fluorescence and particle size measurement. 4. PEG4000 (0.2 mg) was added. 5. 0.5 mL of the sample was taken for fluorescence and particle size measurement.

[0099] Observation: The solution is not clear at any stage.

[0100] Solubility Visual inspection of solubility was performed. The results are shown in Table 1.

[0101]

Table 1

[0102] Fluorescence measurement Fluorescence was measured using a microplate reader (Thermo Scientific Varioscan LUX SN 3020-836, REF VLBL001D1, Type 3020). A 0.5 mL sample was taken for measurement according to the method described for Compositions 1, 2, and 3. The sample was prepared by centrifugal filtration through a 0.45 μm filter. The measurement was performed twice. An emission wavelength of 400 - 700 nm was used with an excitation wavelength of 350 nm. Absorbance (AU) was measured.

[0103]

Table 2

[0104] Results The fluorescence was essentially blue. The fluorescence intensity of Composition 2 was the highest, and it was the highest before adding PEG. PEG seemed to reduce the fluorescence. The samples of Composition 1 also showed significant fluorescence before and after adding PEG. In Composition 3, essentially no fluorescence was observed. The fluorescence spectrum is shown in Figure 1.

[0105] Regarding Entries A - F, the following points were observed. A and B correspond to compositions where ropivacaine, water, and triethanolamine were heated in a microwave oven, and in Entry B, PEG was subsequently added; they showed high fluorescence, and the fluorescence intensity decreased slightly after adding PEG. C and D correspond to compositions where water and triethanolamine were heated in a microwave oven, ropivacaine was added after heat treatment, and in Entry D, PEG was subsequently added; they showed significant fluorescence, and the fluorescence intensity decreased slightly after adding PEG. E and F correspond to compositions where only ropivacaine was heated in a microwave oven and PEG was subsequently added, and they showed low fluorescence.

[0106] Particle size measurement The average particle size distribution (Z-ave) by intensity was measured by dynamic light scattering using a Zetasizer Nano ZS from Malvern Instruments. According to Compositions 1, 2, and 3, 0.5 mL of the sample was taken for measurement. The sample was prepared by centrifugal filtration through a 0.45 μm filter. The measurement was performed twice.

[0107] PDI: A dimensionless value (polydispersity index) of the width of the distribution. When it is less than 0.3, the distribution is usually regarded as monodisperse (unimodal). As can be understood from Table 3, all samples except Entry E are considered to be unimodal.

[0108]

Table 3

[0109] The particle size (Z-Ave) is consistent with the value predicted by the blue fluorescent carbon quantum dots.

[0110] Conclusion Composition 1 contains carbon quantum dots, which indicates that such dots can be formed from triethanolamine, ropivacaine, and water when heated. It is reasonable to assume that ropivacaine can be changed to any anesthetic of the present invention and similar results can be obtained.

[0111] Composition 2 contains carbon quantum dots, which indicates that such dots can be formed from triethanolamine and water when heated. It is reasonable to assume that ropivacaine can be changed to any anesthetic of the present invention and similar results can be obtained.

[0112] Composition 3 does not contain carbon quantum dots, which indicates that such dots cannot be formed from ropivacaine and water.

[0113] Although not restricted by any theory, fluorescence and small particle size are thought to be due to the formation of carbon quantum dots formed during the microwave heat treatment of triethanolamine. Also, the modified formulation was tested in vivo in an animal model to evaluate the duration of local anesthesia (see Examples 2 and 3).

[0114] Example 2 In Vivo Experiment Pilot and efficacy tests were conducted to evaluate the administration of local anesthesia in a sensitivity test with female rats.

[0115] The experiments were conducted at Redoxis AB, Lund (Sweden). The animals were housed in a state-of-the-art approved animal facility to ensure the well-being of the animals. All experiments conducted at Redoxis were ethically approved and conducted in accordance with Swedish national law.

[0116] Sprauge Dawley rats (female, 10 weeks old) were obtained from Janvier Europe. The rats were housed in the animal facility at Medicon Village, Lund, Sweden. The rats were housed in polystyrene cages (Type III cages) lined with wood shavings, with 2 - 3 rats per cage, on a 12-hour light / dark cycle. The rats were given free access to standard rodent feed and water. The rats were acclimated for approximately 1 week before the start of the experiment. The rats were identified by marking their tails with an oil-based marker on day 1.

[0117] Composition of Local Anesthetic - Pilot Test

[0118] [Table 4]

[0119] Group Composition To determine the average body weight of the animals used in the experiment, the body weight of the rats was measured on day 1 (the day before the start of the experiment).

[0120] Compound and Administration The reference anesthetic ropivacaine formulation was prepared such that the pH of the composition, the concentration and dosage of ropivacaine were essentially the same as those of the composition of the present invention. The concentration of ropivacaine in the formulation was 5 mg / ml, and 1 mg / kg body weight was administered to 2 rats, 0.25 mg / kg body weight to 2 rats, and placebo PBS (phosphate buffered saline) to 2 rats. The carrier and the reference anesthetic were injected subcutaneously (s.c.) once at time 0.

[0121] Sensitivity test / evaluation The rats were shaved on the back and acclimated to the experimental environment for 30 minutes before the test. The sensitivity test was performed by contacting a needle to each rat at five time points (30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours) within 5 hours after administration of the test substance. The reaction of the rats regarding the form of skin wrinkles was evaluated by visual inspection.

[0122] Health evaluation Visual evaluation: During the experiment, the rats were monitored to evaluate their health status. All side effects were observed according to the health evaluation protocol. If the health status of the rats was poor (e.g., rats with dehydration symptoms or problems with kyphosis), such rats were excluded from the experiment. However, all the rats used in this experiment were healthy.

[0123] Results The results showed that the design of this experiment was appropriate for testing the effectiveness of ropivacaine. The results showed that the duration of the anesthetic effect in the group administered 0.25 mg / kg body weight of ropivacaine was 2 hours, and the duration of the anesthetic effect in the group administered 1 mg / kg body weight of ropivacaine was 5 hours (data not shown). The placebo group had an anesthetic effect.

[0124] Local anesthetic test - effectiveness test

[0125]

Table 5

[0126] Group composition To determine the average body weight of the animals used in the experiment, the body weight of the rats was measured on the first day (the day before the start of the experiment).

[0127] Compound and administration The formulation of the reference anesthetic ropivacaine was prepared in the same manner as in the pilot study. (For reference, as well as for both Composition 1 and Composition 2) The concentration of ropivacaine was 0.5 mg / ml in the formulation and was administered at 0.25 mg / kg body weight. The carrier, as well as the anesthetics for reference, Composition 1, and Composition 2, were injected subcutaneously once at time 0.

[0128] Sensitivity test / evaluation The rats were shaved on the back and acclimated to the experimental environment for 30 minutes before the test. The sensitivity test was performed by contacting a needle to each rat at 6 time points (30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours) within 6 hours after the administration of the test substance. The reaction of the rats regarding the form of skin wrinkles was evaluated by visual inspection, and a value of 0 (no response) or 1 (response) was assigned to each response. No response indicates that the rat was anesthetized.

[0129] Health evaluation Visual evaluation: During the experiment, the rats were monitored to evaluate their health status. All side effects were observed according to the health evaluation protocol. If the health status of a rat was poor (e.g., a rat with symptoms of dehydration or problems with kyphosis), such a rat was excluded from the experiment. However, all the rats used in this experiment were healthy.

[0130] Results

[0131]

Table 6

[0132] Results can be presented as the average value of the initial response. As is evident from Table 6, the compositions of the present invention have the advantage of increased anesthesia duration. Compared with the prior art (Group 2), Group 3 had an approximately 2.4-fold increase in duration (the duration of the anesthetic effect was 2.4 times longer), and Group 4 had an approximately 1.6-fold increase in duration (the duration of the anesthetic effect was 1.6 times longer).

[0133]

Table 7

[0134] Conclusion Composition 1 (used in Group 3) contains carbon quantum dots, and such dots show an increase in analgesic duration in vivo. It is reasonable that ropivacaine can be changed to any anesthetic of the present invention and similar in vivo effects can be obtained.

[0135] Composition 2 (used in Group 4) contains carbon quantum dots, and such dots show an increase in analgesic duration in vivo. It is reasonable that ropivacaine can be changed to any anesthetic of the present invention and similar in vivo effects can be obtained.

[0136] Experiment 3 In Vivo Test 3

[0137]

Table 8

[0138] Animals Male Wistar albino rats weighing 200 - 250 g obtained from SYLAB Experimental Animals Laboratory were used in the experiment. The animals were housed under standard conditions with a 12-hour light-dark cycle and given standard pellets and water (ad libitum). All experiments were conducted in accordance with international ethical regulations without infringing on the rights of the animals.

[0139] Compound and Administration The formulation used was the same as in Example 2, with an additional storage period. The formulation was stored for 7 months at various temperatures. First, the formulation was stored in the freezer for 6 months. Subsequently, there was a change in temperature; storage at room temperature and in the refrigerator was repeated before use.

[0140] The composition was injected s.c. once at time 0. The composition was administered at a position close to the sciatic nerve.

[0141] Group 1: Ropivacaine 7.5 mg / ml, 1.1 - 1.2 ml. Total = at least 8.25 mg of ropivacaine. This composition is a commercially available ropivacaine. (Ropivacaina Inibsa, injection solution). Group 2: Ropivacaine 4 mg / ml, 2 ml, pH 5 (Test 1). Total = 8 mg of ropivacaine. This composition is Composition 1 of Example 1. Group 3: Ropivacaine 4 mg / ml, 2 ml, pH 5 (Test 2). This composition is Composition 2 of Example 1.

[0142] Sensitivity test / evaluation The sensitivity test was performed by contacting forceps with each rat at 9 time points (1 hour, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, and 9 hours) within 9 hours after administration of the test substance. The reaction of the rat regarding the form of skin wrinkles was evaluated by visual inspection, and a value of 0 (no response), 0.5 (weak response), or 1 (response) was assigned to each response. No response indicates that the rat was anesthetized. A weak response indicates that the rat was partially anesthetized.

[0143] Results Tables 8a - c. Results of the sensitivity test. A commercially available ropivacaine formulation was administered to Group 1, the composition of the present invention (Composition 1) was administered to Group 2, and the composition of the present invention (Composition 2) was administered to Group 3.

[0144]

Table 8a

[0145]

Table 8b

[0146]

Table 8c

[0147] Investigation In two rats, injections were made at incorrect locations, i.e., into the nerve itself (rat 1) or at a location not close to the sciatic nerve (rat 2). This was due to human error and sudden movement of the rats.

[0148] Rat 1 had convulsions, which is thought to be because the composition was accidentally administered to the sciatic nerve, causing paralysis. Administration of this composition may have caused an increase in the anesthetic effect, which is a side effect based on the accidental administration to the nerve. As shown in Table 8a, the effect increased in rat 1, but this was not due to the prior art composition itself, but rather due to the above-mentioned side effect.

[0149] When the local anesthetic composition was administered, rat 10 jumped unexpectedly. Therefore, the injection was made at an incorrect site far from the sciatic nerve of the rat. As can be understood from Table 8c, rat 10 did not feel any anesthetic effect at all. The reason for the lack of anesthetic effect is thought to be due to the administration to the incorrect site of the rat.

[0150] Conclusion Composition 1 (used in group 2) contains carbon quantum dots, and such dots show an increase in analgesic time in vivo. It is reasonable that ropivacaine can be changed to any anesthetic of the present invention and a similar in vivo effect can be obtained.

[0151] Composition 2 (used in group 3) contains carbon quantum dots, and such dots show an increase in analgesic time in vivo. It is reasonable that ropivacaine can be changed to any anesthetic of the present invention and a similar in vivo effect can be obtained.

[0152] From the comparison of Tables 8a, 8b, and 8c, it is clear that the compositions of the present invention (Tables 8b and 8c) provide a longer anesthetic effect compared to the prior art composition (Table 8a).

[0153] Example 4 Further Characterization of the Formulation The purpose of this experiment was to evaluate whether triethanolamine is converted to other substances during microwave heating treatment, to what extent it is converted, and whether this treatment produces substances that may affect the stability of ropivacaine.

[0154] Materials

[0155] [Table 9]

[0156] Methods Heat Treatment of Triethanolamine Triethanolamine (TEA) and water were mixed at a volume ratio of 2 parts triethanolamine to 1 part water. Then, this mixture was heat-treated in a microwave oven at 140 °C / 500 W for 20 minutes (High temp muffle furnace mls 1200 pyro). Before putting the sample into the oven, the oven was preheated to 140 °C. Before taking the sample out of the oven, the temperature was lowered to 100 °C, but this process took an additional approximately 10 minutes.

[0157] Manufacture of the Final Formulation To 3 mL of the heat-treated triethanolamine / water mixture, 200 mg of ropivacaine free base and 100 mL of PEG4000 were added. The mixture was diluted with water to approximately 90% of its final volume, and the pH was adjusted to approximately 5.0 to obtain a clear solution.

[0158] Those without PEG4000 were also used for evaluation.

[0159] Fluorescence Measurement Fluorescence was measured using a fluorescence photometer VARIOSKAN LUX, Thermo Scientific equipped with a plate reader. For the measurement, 100 μL or 300 μL of the sample according to 3.1.2 was added to a black 96-well plate. 350 nm was selected as the excitation wavelength. Two or three samples were analyzed.

[0160] Chromatographic analysis Gas chromatography (GC) Qualitative and quantitative analysis of samples at the first stage of formulation for triethanolamine and derivatives were performed using an Agilent Technologies 6890 Series GC System equipped with a flame ionization detector (FID). The GC-FID was equipped with an Rxi-35sil MS column (Restek) with dimensions of 30 m × 0.25 mm ID and a film thickness of 0.5 μm. The method conformed to the European Pharmacopoeia 11.0, Monograph 01 / 2017:1577 “Trolamine”. The mobile phase of this method was phosphate buffer at pH 8: acetonitrile = 1:1 (v / v%).

[0161] For quantification, single-point calibration was performed using heptane as the internal standard.

[0162] For qualitative analysis, a 6890N GC System (Agilent technologies) equipped with a 5973N mass selective detector was used, and ionization was performed by 70 eV electron impact (EI). The column used was an Rxi-5Sil MS (Restek) with dimensions of 30 m × 0.25 mm ID and 0.25 um DF.

[0163] For identification, the obtained spectral mass data was compared with the reference data in the Wiley / NIST spectral library (SBN: 978-1-119-75033-8).

[0164] Liquid chromatography (LC) Samples at the formulation stage after adding ropivacaine were analyzed by qualitative LC. LC analysis with ultraviolet (UV) detection was performed at a flow rate of 0.3 mL / min using a Thermo Fischer Scientific Vanquish UPLC instrument equipped with a Waters BEH C18 1.7um 2.1×150mm chromatography column. Other methods conformed to the European Pharmacopoeia 11.1, Monograph 01 / 2017:2335 "Ropivacaine Hydrochloride Monohydrate".

[0165] LC analysis with UV and MS detection was performed on a Waters Acquity UPLC Quattro Micro MS instrument equipped with electrospray ionization (ESI) in positive-negative switching mode. The method used was based on the above Monograph 01 / 2017:2335, but the mobile phase was changed to be MS-compatible; instead of phosphate buffer, a gradient elution of 0.1% NH3 / MeCN was used.

[0166] Impurity analysis: 2,6-dimethylaniline The carcinogenic 2,6-dimethylaniline in the prepared formulation (which is identified as one of the impurities of ropivacaine as impurity H in the pharmacopoeia monograph Eu Pharm 11.1, 01 / 2017:2335) was analyzed by LC-UV and LC-UV-MS against a 2,6-dimethylaniline reference substance.

[0167] Results Prepared samples

[0168]

Table 10

[0169] Sample numbers 2 and 4 were processed in a microwave oven according to the above heat treatment of triethanolamine.

[0170] In sample numbers 5 and 23E0492-03, ropivacaine was added after the microwave treatment of sample 2.

[0171] All samples were transparent liquids at room temperature (20 - 22 °C).

[0172] Fluorescence measurement Figure 2 shows the fluorescence of the composition containing triethanolamine and water. This figure shows the fluorescence measurements (3 times) of Preparation 2 before and after microwave treatment. The circles represent the fluorescence after microwave treatment (Table 10, Sample 4), and the small triangles represent the fluorescence before microwave treatment (Table 10, Sample 3). As can be understood from the figure, fluorescence is present in the microwave-treated preparation.

[0173] Figure 3 shows the fluorescence of the composition containing triethanolamine and water that was microwave-treated before adding ropivacaine. This figure shows the fluorescence measurements (3 times) of Sample 5 in Table 10, i.e., Formulation 23E0492 - 03. As can be understood from the figure, fluorescence is present in the preparation that was microwave-treated before adding ropivacaine.

[0174] Chromatographic analysis Quantitative GC analysis In the analysis of the microwave-heated triethanolamine + water formulation (Table 11, 23E0492 - 02, sample number 2), 6 peaks exceeding 0.05 area% were detected by GC-FID, separate from triethanolamine. See Table 11. One of the impurities was identified as diethanolamine by GC-MS (referring to the Wiley / NIST spectral reference library) (peak number 3 in Table 11), which is one of the three impurities of triethanolamine specified in the European Pharmacopoeia monograph (Impurity B). Diethanolamine was also present in the triethanolamine reference sample, but at a low level of 0.01 area%. Peak number 1 may be monoethanolamine, which is specified as Impurity A in the European Pharmacopoeia monograph 01 / 2017:1577. This was also detected in the triethanolamine reference sample at a level of 0.08 area%. The remaining 4 peaks (peak numbers 2, 5, 6, 7) could not be identified.

[0175]

Table 11

[0176] 4.4.2. LC Analysis In the analysis of the formulation (23E0492-03) prepared by adding ropivacaine to microwave-treated triethanolamine + water, one peak was detected by LC-UV at a level exceeding 0.05 area %. This was peak number 2 in Table 12 and was 0.2 area % (UV 240 nm). This impurity could not be identified by LC-MS. Since this is also present (at 0.5 area %) in the ropivacaine reference sample, it is probably related to ropivacaine.

[0177] [Table 12]

[0178] 4.4.3. GC Quantitative Analysis of Triethanolamine GC-FID analysis was performed by single-point calibration using the adapted pharmacopoeial method (01 / 2017:1577, Ph. Eur. 11.0) and an internal standard (heptane). This method was adapted in terms of minor modifications such as changing the injection volume from 2 μL to 1 μL, changing the GC column from 5% phenyl to 35% phenyl, and reducing the concentration of the standard triethanolamine and the sample to be injected from 100 mg / mL to 10 mg / mL because the analyte was overloaded at the original concentration. In the analysis, no significant change in the triethanolamine content was observed before and after the heat treatment of the formulation, i.e., microwave heating or autoclave treatment (see Table 13).

[0179] [Table 13]

[0180] 4.5. Impurity Analysis: 2,6-Dimethylaniline In the analysis by UPLC-UV (240 nm) and UPLC-UV-MS (fully scanning m / z 50 - 800), 2,6-dimethylaniline, which was identified as impurity H of ropivacaine in Ph. Eur. 11.1, 01 / 2017:2335, was not detected (less than 0.05 area %) in the ropivacaine reference standard nor in the formulation of ropivacaine with microwave-heated triethanolamine. Therefore, it was concluded that 2,6-dimethylaniline is not generated in the treatment of the formulations of this disclosure.

[0181]

Table 14

[0182]

Table 15

[0183] Example 5 In Vivo Test in Humans The formulations according to this disclosure, for example, the formulations of Composition 1 or 2 in Example 2, are formulated as gels. The composition contains 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.

[0184] Emla (registered trademark, a gel formulated with 25 mg / ml of lidocaine and 25 mg / ml of prilocaine) is used as a positive control. The dosage of the formulation according to this disclosure is equivalent to the dosage of Emla (registered trademark), that is, the dosage of prilocaine in Emla (registered trademark) is equivalent to the dosage of ropivacaine in the formulation of this disclosure.

[0185] After appropriate ethical approval, this formulation is tested on 25 - 40 healthy volunteer medical students. The formulation is tested by applying it to the skin at the base (near the MCP joint (metacarpophalangeal joint of the middle finger)) between the index finger and the middle finger on the back (upper side) of the hand of the test subject.

[0186] At several time points such as 10 minutes, 20 minutes, and 60 minutes later, the numbness of the skin and the entire finger is tested with a prick test on the fingertip.

[0187] Predicted results It is predicted that the numbness of all fingers will be achieved within a certain time, such as within 10 minutes or within 20 minutes, from the application of the composition of the present invention to the skin. It is not predicted that the numbness of the entire finger will be achieved within a certain time from the application of Emla® to the skin.

[0188] The compound of this formulation brings numbness to all fingers of the hand to which the composition is administered, that is, the subject may not feel anything in these fingers or at least the sensation may be reduced. The subject may be able to extend or bend the finger partially or completely while the formulation of the present invention is taking effect.

[0189] Results indicating that the formulation penetrates at least partially into the skin of a human subject are predicted.

[0190] The composition is applied to the skin between the index finger and the middle finger, but brings numbness to the fingertip (about 5 cm away), that is, the effect is obtained at another position away from the application site. Therefore, the numbness of the fingertip is evidence that the composition has penetrated the skin.

[0191] Results indicating that the formulation according to the present disclosure is more effective, that is, it brings numbness faster and for a longer time, are predicted as compared to standard treatment (Emla®).

[0192] Example 6 In vivo test in humans; Knee surgery The purpose of this experiment is to test the composition of the present invention as an analgesic for use in knee surgery.

[0193] The formulations according to the present disclosure, for example, the formulations of Composition 1 or 2 in Example 2, are formulated as injections. The concentration of ropivacaine is 5 mg / ml. The injection volume is proportional to the weight of the subject, and each patient is administered 30 to 130 ml of the formulation according to their weight. Commercially available ropivacaine for injection (5 mg / ml) is used as a positive control. The dosage 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 the same pH.

[0194] The formulation is injected as a sciatic / femoral nerve block, which is standard for this type of procedure, as will be apparent to those skilled in the art.

[0195] The subjects are healthy middle-aged men and women who have knee osteoarthritis (OA) and are undergoing knee surgery. Before the surgery, the formulation is injected into the subjects under sterile conditions and under ultrasonic guidance.

[0196] The surgery is started 15 to 20 minutes after the injection (after the anesthetic effect is obtained). The surgery time is 60 to 90 minutes.

[0197] This study is conducted in accordance with a standard protocol and with appropriate ethical approval.

[0198] Ideally, the anesthetic effect needs to last for a long time without interfering with the patient's mobility. In the study, the following evaluation items are monitored at 0 to 72 hours after injection.

[0199] Analgesia time Time until the appearance of a rebound effect (i.e., strong pain accompanying the disappearance of the anesthetic effect) Effect of the composition on the patient's motor function (i.e., interference with the patient's mobility) Time until a rescue drug is required (i.e., time until the patient requires an additional analgesic such as an opioid derivative)

[0200] Predicted results In all of the compositions tested with the present invention and the prior art, partial paralysis of the legs is initially observed, and a complete loss of sensation in the legs is predicted to occur. This is due to the large amount injected and the well-known effects of the anesthetic.

[0201] The prior art compositions are predicted to result in a complete loss of sensation in the legs 4 to 5 hours after application.

[0202] The compositions of the present invention are predicted to result in a complete loss of sensation in the legs 4 to 5 hours or more after application, for example 10 to 12 hours.

[0203] Compared to standard treatments, the formulations according to the present disclosure are more effective, i.e., it is predicted that the duration of loss of sensation in the legs will be longer. The formulations according to the present disclosure are predicted to cause loss of sensation for 6 hours or more, for example at least 10 hours.

Claims

1. - 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 pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof; - At least one alkanolamine selected from the group consisting of triethanolamine, trippropanolamine, and trimethanolamine; - Water; and, as needed, - Pharmaceutically acceptable diluents, carriers and / or excipients; A pharmaceutical composition containing, The aforementioned composition is a pharmaceutical composition containing carbon quantum dots.

2. The pharmaceutical composition according to claim 1, wherein the at least one anesthetic agent is selected from the list consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, alticaine, dibucaine, levobupivacaine, prilocaine, and pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof.

3. The pharmaceutical composition according to claim 1, further comprising polyethylene glycol (PEG).

4. The pharmaceutical composition according to claim 1, wherein the carbon quantum dot contains at least one alkanolamine.

5. The pharmaceutical composition according to claim 1, wherein the carbon quantum dot contains the at least one anesthetic agent.

6. The pharmaceutical composition according to claim 1, wherein the composition is formulated to be administered by injection or topical administration.

7. The pharmaceutical composition according to claim 1, wherein the anesthetic agent is selected from the group consisting of ropivacaine, bupivacaine, and lidocaine.

8. The aforementioned composition, Ropivacaine; Triethanolamine; water; PEG-4000; Carbon quantum dots; and, if necessary, Pharmacopoeia-acceptable diluents, carriers and / or excipients A pharmaceutical composition according to claim 1, comprising the above.

9. The pharmaceutical composition according to claim 1, which, when administered to a patient in need of the composition, treats, reduces, or prevents pain.

10. The pharmaceutical composition according to claim 9, wherein the treatment, reduction, or prevention of the pain provides anesthesia that lasts for a long period of time, and the anesthesia lasts for at least 0.5 hours.

11. A method for producing a composition containing carbon quantum dots and at least one anesthetic selected from the group consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, and pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof, a) A step of contacting an alkanolamine selected from the group consisting of triethanolamine, trippropanolamine, and trimethanolamine with water to obtain a mixture; b) A step of heating the mixture to obtain carbon quantum dots; c) Adding to the mixture at least one anesthetic selected from the list consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, and pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof; Here, steps b) and c) can be carried out in any order; d) Adding PEG to the mixture as needed; Includes, A method for obtaining a composition containing carbon quantum dots and the anesthetic.

12. The method according to claim 11, wherein step c) is performed before step b).

13. The method according to claim 11, wherein the heating temperature is 100°C to 200°C, for example 120°C to 170°C, for example 130°C to 150°C, for example about 140°C.

14. A composition comprising carbon quantum dots obtained by the method described in any one of claims 11 to 13, and an anesthetic selected from the list consisting of ropivacaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, lignocaine, mepivacaine, and pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof.

15. - 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 pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof; - At least one alkanolamine selected from the group consisting of triethanolamine, trippropanolamine, and trimethanolamine; and, - water Carbon quantum dots formed from a composition containing [the specified ingredient].

16. Use of the pharmaceutical composition according to claim 1 in the manufacture of a pharmaceutical product used for the treatment of pain.

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