Caffeine composition

Abstract

Compositions comprising one or more of, for example, lactic acid, acetic acid, aspartic acid, and glutamic acid, caffeine, and sodium benzoate, processes for making the compositions, and methods of using the compositions. Methods include accelerating emergence from anesthesia and / or countering the effects of anesthesia, including reversing the effects of anesthesia. The methods also include treating opioid intoxication or overdose.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 107,026, filed October 29, 2020, and U.S. Provisional Patent Application No. 63 / 178,815, filed April 23, 2021, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure relates to the field of caffeine compositions. Background Technology

[0004] Caffeine has the potential for various commercial applications, including pharmaceutical applications. For example, in rat studies, intravenous administration of caffeine has effectively accelerated recovery from anesthesia. The same has been observed in humans. Anesthetics are known to inhibit the release of neurotransmitters from neurons and secretory cells. Caffeine has been shown to increase intracellular cAMP levels, which is known to promote neurotransmitter release. In a single-center, double-blind, two-way crossover trial, participants received two general anesthesias at least 2 weeks apart. Administration of 15 mg / kg caffeine citrate infusion (equivalent to 7.5 mg / kg caffeine base) resulted in a significantly reduced mean time to recovery from anesthesia (16.5 ± 3.9 (SD) minutes with saline versus 9.6 ± 5.1 (SD) minutes with caffeine (P = 0.002)). Fong, R. et al., “Caffeine Accelerates Emergence from Isoflurane Anesthesia in Humans”, Anesthesiology, 129(5), pp. 912-920 (2018).

[0005] American Regent, Inc. has previously produced single-dose vials of caffeine and sodium benzoate, for example, for recovery from anesthesia, as reported by Warner et al., “Effects of Caffeine Administration on Sedation and Respiratory Parameters in Patients Recovering from Anesthesia,” Bosnian Journal of Basic Medical Sciences, 18(1), pp. 101–104 (2018). The standard dose was reported to be 125 mg caffeine and 125 mg sodium benzoate per milliliter. For the caffeine and sodium benzoate combination, the median dose given to patients was 150 mg caffeine benzoate, and the maximum dose was 250 mg caffeine benzoate. The results of this study are inconclusive, but this may be due to the limited dosage provided.

[0006] According to this disclosure, caffeine can also be effective in treating opioid overdose. Approximately 500,000 people worldwide die from drug abuse. More than 70% of these deaths are related to opioids, and more than 30% of these deaths are due to overdose. Naloxone, which is helpful in treating overdose, is listed in the World Health Organization's list of essential medicines. The rise in opioid use in the United States in recent decades has led to an epidemic known as the "opioid crisis." The United States is the largest consumer of opioids, accounting for approximately 80% of global consumption. In 2019, an estimated 10.1 million people aged 12 or older in the United States abused opioids. Specifically, 9.7 million abused prescription painkillers and 745,000 abused heroin (2019 National Survey of Drug Use and Health (NSDUH)). During the opioid crisis, an average of 128 people died every day in the United States as a result (CDC Opioid Basics 2020). Overdosing on opioids can have serious adverse health consequences, even if not fatal.

[0007] In 2016, the national opioid-related hospitalization rate was 297 per 100,000 people. In 2017, US emergency departments treated 967,615 non-fatal overdose cases. Between 2012 and 2017, the overall incidence of naloxone dosing events (multiple doses counted as one event) increased by 75.1%, from 573.6 per 100,000 emergency medical events to 1004.4 per 100,000 events.

[0008] Naloxone's duration of action is 30-60 minutes. Naloxone is a non-selective and competitive opioid receptor antagonist. In cases of opioid overdose, multiple doses of naloxone may be required because most opioids have a longer duration of action than naloxone, and residual opioids may remain in the body if the patient's physiological ability to metabolize and / or eliminate opioids is impaired before, during, and after the overdose.

[0009] Naloxone presents several challenges in its use for treating opioid overdoses due to its limited duration of action. For example, multiple doses are often required, which can be inconvenient, especially in mobile transport or emergency room settings. Furthermore, naloxone often poses respiratory challenges that must be monitored and / or managed.

[0010] However, caffeine's poor solubility is well-known. For example, to effectively act as a facilitator of recovery from anesthesia, sufficient caffeine should be delivered via an appropriate drug delivery route. Caffeine has a solubility of 16 mg / mL at room temperature, and given that a 100 kg person requires 754 mg of caffeine to wake up, for indications related to anesthesia recovery (such as those used in clinical trials), this translates to a dose exceeding 47 mL. This volume is too large and inconvenient for clinicians to administer via bolus intravenous injection before, during, and / or after surgery. In a typical operating room, many medications are packaged in 6 mL vials containing up to 5.25 mL of fluid for intravenous delivery. Therefore, a 47 mL dose would require at least nine vials, which is impractical for hospital use.

[0011] For caffeine citrate, the solubility of caffeine is approximately 56 mg / mL. At a dosage of 15 mg caffeine citrate per kilogram of body weight, this would provide a 100 kg person with 1500 mg caffeine citrate, or approximately 754 mg of caffeine. Therefore, approximately 27 mL of solution (1500 mg / 56 mg / mL) would be needed to deliver such a dose, which is still an impractically large amount.

[0012] Therefore, there is a need for compositions with improved caffeine solubility to enable more practical use of caffeine in commercial applications. Summary of the Invention

[0013] In this disclosure, a composition comprising caffeine and sodium benzoate is provided, which has increased caffeine solubility, thereby enabling the use of caffeine to accelerate recovery from anesthesia or otherwise reverse its effects. When administered alone or in combination with naloxone, the composition also enables the use of caffeine to treat opioid addiction or overdose.

[0014] In several aspects of this disclosure, compositions comprising one or more of lactic acid, acetic acid, aspartic acid, and glutamic acid, caffeine, and sodium benzoate are provided. In other aspects, compositions comprising an aqueous solution of caffeine and sodium benzoate are provided, along with means for increasing the solubility of caffeine in an aqueous solution. Other compositions are provided in aqueous solution form and comprising caffeine with a solubility in solution greater than about 235 mg / mL.

[0015] In other aspects of this disclosure, compositions comprising one or more of lactic acid, acetic acid, aspartic acid and glutamic acid, caffeine and sodium benzoate are provided, which are prepared by a process of combining one or more of lactic acid, acetic acid, aspartic acid and glutamic acid, caffeine and sodium benzoate in an aqueous solution.

[0016] In another aspect of this disclosure, methods are provided for accelerating recovery from anesthesia or resisting the effects of anesthesia (including reversing the effects of anesthesia), including administering a pharmaceutically effective amount of the composition of this disclosure to a patient undergoing a medical procedure using an anesthetic.

[0017] In a further aspect of this disclosure, a composition comprising one or more of lactic acid, acetic acid, aspartic acid and glutamic acid, caffeine and sodium benzoate in a pharmaceutically effective amount is provided for use in treating host mammals undergoing anesthetic medical procedures.

[0018] In another aspect of this disclosure, a composition comprising one or more of lactic acid, acetic acid, aspartic acid and glutamic acid, caffeine and sodium benzoate in a pharmaceutically effective amount is used for accelerating recovery from anesthesia or antagonizing the effects of anesthesia, including reversing the effects of anesthesia in a host mammal.

[0019] In a further aspect of this disclosure, a kit is provided comprising one or more of lactic acid, acetic acid, aspartic acid and glutamic acid, caffeine, sodium benzoate and optionally water.

[0020] In another aspect of this disclosure, a stable composition is provided.

[0021] In other aspects of this disclosure, methods for treating patients suffering from opioid addiction or overdose are provided, including treating patients in need with a pharmaceutically effective amount of the compositions of this disclosure.

[0022] In a further aspect of this disclosure, a pharmaceutical composition comprising one or more of lactic acid, acetic acid, aspartic acid and glutamic acid, caffeine and sodium benzoate is provided for use in treating host mammals undergoing opioid exposure or overdose treatment.

[0023] Further implementation methods are described in detail below. Detailed Implementation

[0024] Various additional embodiments of this disclosure will now be explained in more detail. The foregoing general description and the following detailed description are exemplary and illustrative only, and not intended to limit this disclosure or the claims. Any discussion of certain embodiments or features, including those described in the examples, is used to illustrate certain exemplary aspects of this disclosure. This disclosure and the claims are not limited to the embodiments specifically discussed herein.

[0025] This disclosure includes compositions comprising one or more of lactic acid, acetic acid, aspartic acid, and glutamic acid, caffeine, and sodium benzoate. The compositions may also contain water and may be in the form of a solution (e.g., an aqueous solution).

[0026] The composition also includes an aqueous solution of caffeine and sodium benzoate, and means for increasing the solubility of caffeine in the aqueous solution. The composition itself may also be an aqueous composition. An exemplary method for increasing the solubility of caffeine in an aqueous solution containing caffeine and sodium benzoate is lactic acid. Other exemplary means for increasing the solubility of caffeine in an aqueous solution containing caffeine and sodium benzoate are acetic acid, aspartic acid, and glutamic acid.

[0027] The compositions also include compositions in aqueous solution form, and contain caffeine with a solubility in solution greater than about 235 mg / mL. Such compositions may also contain sodium benzoate. The compositions may also contain one or more of, for example, lactic acid, acetic acid, aspartic acid, and glutamic acid.

[0028] The compositions disclosed herein also include those comprising caffeine, sodium benzoate, and one or more C2 to C5 carboxylic acids (e.g., lactic acid, aspartic acid, acetic acid, or glutamic acid). Other compositions comprise caffeine, sodium benzoate, and one or more C4 to C5 amino acids (e.g., aspartic acid and glutamic acid). Another composition comprises caffeine, sodium benzoate, and one or more C2 to C5 carboxylic alcohols (e.g., lactic acid). Further compositions comprise one or more C2 to C5 dicarboxylic acids (e.g., aspartic acid and glutamic acid). Any such compositions may also contain water and may be in solution form.

[0029] The compositions disclosed herein have improved caffeine solubility and can be stable compositions. In many embodiments, caffeine is added to a sodium benzoate solution and water is added during dissolution, followed by one or more of, for example, lactic acid, acetic acid, aspartic acid, and glutamic acid. Due to the improved solubility, the compositions disclosed herein can be used for commercial applications, such as delivering caffeine to accelerate recovery from anesthesia, or otherwise overcoming the effects of anesthesia, including reversing the effects of anesthesia. The compositions can also be used alone or in combination with naloxone to treat opioid overdose or drug addiction.

[0030] When measuring the solubility of caffeine in the compositions disclosed herein, the solid is typically added to the solution, and water is added in increasing amounts until all the solid becomes a solution. In several examples (e.g., RP1-49-2; RP1-49-3; RP1-49-4; RP1-49-5; and RP1-57-5), the concentration of caffeine in the solution is not a solubility measurement, but simply indicates the amount of caffeine in the solution with the specific amount of material added. The caffeine in such solutions is unsaturated. In other examples (e.g., RP1-60-1; RP1-60-2; and RP1-62-4), a slurry is prepared, and water is added until the solid dissolves. Therefore, these concentrations more accurately reflect the solubility of caffeine.

[0031] For example, by combining lactic acid with caffeine and sodium benzoate in various combinations, higher caffeine solubility than previously reported can be obtained, such as a solubility of 396 mg / mL measured in RP1-62-4. Therefore, in these and other embodiments, the solubility of caffeine in the compositions of this disclosure (including those comprising one or more of lactic acid, acetic acid, aspartic acid, and glutamic acid, caffeine, sodium benzoate, and water) can be greater than about 235 mg / mL, or 236 mg / mL or more, or 237 mg / mL or more, or 238 mg / mL or more, or 240 mg / mL or more, or 250 mg / mL or more, or greater than 250 mg / mL. Examples include about 240 mg / mL to about 500 mg / mL, about 300 mg / mL to about 450 mg / mL, about 300 mg / mL to about 400 mg / mL, about 340 mg / mL to about 420 mg / mL, about 360 mg / mL to about 400 mg / mL, about 250 mg / mL to about 400 mg / mL, about 350 mg / mL to about 400 mg / mL, about 260 mg / mL to about 500 mg / mL, and about 260 mg / mL to about 400 mg / mL.

[0032] This document also describes the stability of the caffeine compositions. At least some of the compositions disclosed herein are stable against the formation of precipitates. For example, at least some compositions do not exhibit precipitation after a duration of at least one week, such as at ambient temperatures (e.g., from 20°C to 22°C) or at operating room temperatures (e.g., from 12°C to 18°C). In some embodiments, no precipitation occurs for more than eight weeks at these temperatures or even under refrigeration conditions (e.g., such as 3°C to 5°C or -2°C). In some embodiments, no precipitation occurs for more than three months, regardless of whether the composition is refrigerated.

[0033] In an additional embodiment, at least some of the compositions of this disclosure are thermally stable when exposed to a temperature of 135°C for 45 minutes. Thermal stability can be assessed, for example, by HPLC chemical stability evaluation. After exposure to these conditions, no additional extraneous peaks were observed in the compositions, indicating that the components of the compositions did not decompose into other chemical substances. The thermal stability under these conditions indicates that these compositions should be capable of terminal sterilization.

[0034] In this disclosure, solubility and concentration measurements are used with the word "about" to describe the measurements. For example, with regard to solubility, the term indicates the variability introduced by the measurement technique, in this case about 0 to 2%. When the value or range of solubility, concentration, or other indicative parameter mentioned is modified by the term "about," the exact value or range also constitutes an embodiment of this disclosure.

[0035] Tables 1A, 1B, and 1C provide certain data parameters for eight examples containing caffeine, sodium benzoate, and water. For seven materials, lactic acid is also included. Methods for preparing the compositions are given in Examples 2 and 3. In each composition, the mass or volume of the materials used, the molecular weight of each component, the concentration of lactic acid used, and the lactic acid density are provided. The relative compositional composition by mass and equivalent is also calculated, and the pH value is reported.

[0036] Formulation RPI-57-5 is a composition of equivalent mass consisting of caffeine and sodium benzoate, without added lactic acid. As mentioned above, a solubility of 235 mg caffeine per milliliter was found. For RP1-49-2;-3;-4; and-5;, a caffeine concentration of 250 mg / mL was found, but no attempt was made to determine the limit of caffeine in these compositions. Therefore, these compositions are unsaturated. In contrast, saturation conditions were attempted and approached in RP1-60-1;-2; and RP1-62-4, with a maximum concentration of approximately 396 mg / mL caffeine achieved. At such concentrations, only 1.9 mL of solution is required to administer 7.5 mg / kg (754 mg caffeine / 396 mg / mL) to a 100 kg person. This minimizes not only the total volume required but also the mass of the inactive ingredient delivered, making such concentrations suitable for commercial medical and food applications.

[0037] Table 1A

[0038]

[0039]

[0040] Table 1B

[0041]

[0042] Table 1C

[0043]

[0044] • Caffeine molar mass: 194.19 g / mol

[0045] • Molar mass of sodium benzoate: 144.11 g / mol

[0046] • Molar mass of lactic acid: 90.08 g / mol

[0047] The density of the lactic acid solution used was measured to be 1.103 g / mL.

[0048] The concentration of lactic acid solution in water is 88.47%.

[0049] The compositions disclosed herein may include, for example, a caffeine to sodium benzoate molar ratio of about 1:1.0 to about 1:1.5, such as about 1:1.0 to about 1:1.45, or about 1:1:1.3 to about 1:1.5, or about 1:1.3 to about 1:1.45, including 1:1.1, 1:1.15, 1:1.2, 1:1.25, 1:1.3, 1:1.35, 1:1.4, 1:1.45, and 1:1.5. In these and other embodiments, the molar ratio of caffeine to the total moles of lactic acid, acetic acid, aspartic acid, and glutamic acid can be from about 1:0.1 to about 1:0.3, including 1:0.11, 1:0.12, 1:0.13, 1:0.14, 1:0.15, 1:0.16, 1:0.17, 1:0.18, 1:0.19, 1:0.2, 1:0.21, 1:0.22, 1:0.23, 1:0.24, 1:0.25, 1:0.26, 1:0.27, 1:0.28, 1:0.29, and 1:0.3. The composition may also contain a molar ratio of sodium benzoate to the total moles of lactic acid, acetic acid, aspartic acid, and glutamic acid from about 1:0.15 to about 1:0.18.

[0050] The pH values ​​of the compositions of the present invention are typically from about 5 to about 6, such as from about 5.80 to about 5.92, or from about 5.70 to about 5.90, including about 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, and about 5.9. Other examples of pH values ​​include about 5.80, 5.81, 5.82, 5.83, 5.84, 5.85, 5.86, 5.87, 5.88, 5.89, 5.90, 5.91, and about 5.92.

[0051] At least some of the disclosed compositions may contain about 15% to about 25% by weight of caffeine, about 15% to about 25% by weight of sodium benzoate, about 1% to about 3% by weight of lactic acid, and about 50% to about 70% by weight of water. Such ranges may further include about 15% to about 22% by weight of caffeine, about 16% to about 24% by weight of sodium benzoate, about 1.4% to about 1.8% by weight of lactic acid, and about 50% to about 66% by weight of water.

[0052] In many embodiments, the weight percentage of sodium benzoate is greater than the weight percentage of caffeine. In many embodiments, the difference between the weight percentage of sodium benzoate and the weight percentage of caffeine is from about 1% to about 2%. For example, in a composition containing 2690.5 mg of sodium benzoate, 2500.2 mg of caffeine, 302.505 mg of lactic acid, and water in a total volume of 6.3 mL, the weight percentage of sodium benzoate is 23.3%, and the weight percentage of caffeine is 21.7%, with a difference of about 1.6%.

[0053] In some embodiments, the compositions disclosed herein comprise less than 14% by weight of lactic acid (or an alternative weight percentage of lactic acid, acetic acid, aspartic acid, and glutamic acid), for example, about 1% to about 3% by weight of lactic acid. These and other compositions may comprise more than 30% by weight of water, for example, more than 50% by weight of water. The composition may also comprise a higher weight percentage of caffeine than lactic acid (or a combined weight percentage of lactic acid, acetic acid, aspartic acid, and glutamic acid).

[0054] Other embodiments of the compositions of the present invention include caffeine, sodium benzoate, lactic acid, and water;

[0055] The composition is in the form of an aqueous solution;

[0056] The molar ratio of caffeine to sodium benzoate is approximately 1:1.3 to approximately 1:1.45.

[0057] The molar ratio of sodium benzoate to lactic acid is approximately 1:0.15 to approximately 1:0.18; and

[0058] The caffeine described therein has a solubility of 250 mg / mL or greater in an aqueous solution.

[0059] In preparation, the compositions of the present invention can be in a solid, dry state and then optionally reconstituted with water. The solid, dry compositions can, on their own, be administered to a patient according to the methods of this disclosure. For example, they can be formed into a film and administered to the patient in this form.

[0060] In some embodiments, the compositions disclosed herein are pharmaceutical compositions that optionally include one or more pharmaceutically acceptable excipients. Classical excipients include preservatives, antioxidants, and buffers, including any combination of two or more of these. Exemplary preservatives include parabens and parabens. Exemplary antioxidants include ascorbic acid salts, bisulfites, and thioglycerol. Exemplary buffers include bicarbonates, phosphates, and tromethamine.

[0061] The dosage of caffeine may be related to the individual's weight. This can include doses ranging from about 2.5 mg caffeine / kg body weight to about 15 mg caffeine / kg body weight, such as 7.5 mg / kg, 10 mg / kg, or 12.5 mg / kg. Therefore, the dosage range could be, for example, from about 250 mg of caffeine to about 1200 mg of caffeine. One such dose is about 750 mg of caffeine.

[0062] This disclosure includes methods for delivering the compositions of this disclosure (typically aqueous and in solution form) to a patient to accelerate recovery from anesthesia or otherwise resist the effects of anesthesia, such as by reversing the anesthetic effect. Early development of caffeine for such effects has been hampered by poor solubility. The compositions of this disclosure include those with improved caffeine solubility. Caffeine compositions (e.g., pharmaceutical compositions) may be administered before, during, or after anesthesia delivery.

[0063] Classic anesthetics are those that can be used for surgery or other medical procedures. Anesthetics can be delivered by inhalation or intravenously. Inhaled anesthetic gases include halothane, isoflurane, enflurane, desflurane, and sevoflurane. Other anesthetics besides inhalation can also be used. NMDA receptor agonists, such as ketamine, or alpha-2 agonists (e.g., dexmedetomidine) can be used. Other examples include etomidate, lidocaine, magnesium, fentanyl, theophylline, methylphenidate, redantane, or various combinations thereof, such as redantane and fentanyl. Another example is propofol. Opioids, such as fentanyl, remifentanil, morphine, and hydromorphone, can also be used.

[0064] For example, when delivered intravenously, the dose can be given as a bolus, as an infusion, or via a drip or through a small intravenous bag such as a 50 mL bag. For example, when the dose is provided as an intravenous infusion, it can be given at any appropriate time interval, such as over a 10-minute interval. Administration can occur simultaneously with, before, or after the administration of anesthetics, such as 10 minutes before the end of surgery. For example, the composition can be given at any appropriate point during the surgical procedure, or postoperatively in the recovery room, after induction or intubation at the start of surgery, or at any time during the entire surgical procedure to mitigate adverse events such as cardiac depression and hemodynamic instability caused by general anesthesia.

[0065] Awakening from anesthesia typically occurs faster than without the use of the caffeine composition of this disclosure. In many embodiments, administration of the composition of this disclosure will not expedite the patient's awakening from anesthesia unless the patient has stopped receiving the anesthetic. Awakening can be rapid and includes, for example, 30 minutes or faster, 15 minutes or faster, or 15 minutes or faster. In these and other embodiments, one or more pharmaceutically acceptable excipients may be added to the composition. For example, excipients suitable for parenteral compositions (e.g., intravenous compositions) may be added.

[0066] In many embodiments, the compositions of this disclosure do not contain alcohols. Such alcohols include polyols such as ethylene glycol. Polyethylene glycol is an example of such a diol.

[0067] The methods disclosed herein can be used to accelerate recovery from anesthesia or otherwise counteract the effects of anesthesia, such as reversing the effects of anesthesia on human or non-human vertebrate mammals. Examples of non-human animals include companion animals (e.g., dogs and cats) and agricultural animals (e.g., horses, cattle, and pigs).

[0068] Considering the increased solubility of caffeine in the compositions of this disclosure, various routes of caffeine delivery in the methods of this disclosure can be used to deliver the compositions. These include parenteral, intravenous, intramuscular, subcutaneous, and oral routes (e.g., oral or oral mucosal routes). In some embodiments, the compositions of this disclosure, including the pharmaceutical compositions of this disclosure, are not oral dosage forms. In some embodiments, the compositions of this disclosure are not contained in capsules. For example, in some embodiments, the compositions of this disclosure are not in the form of an aqueous solution within a capsule.

[0069] Therefore, other embodiments include parenteral pharmaceutical compositions comprising the compositions disclosed herein. The parenteral composition may have any suitable dose volume (e.g., about 2 to about 8 mL). The composition may be formulated for intravenous administration, or for intramuscular or subcutaneous administration.

[0070] Embodiments also include the use of the pharmaceutical compositions of this disclosure for treating a host mammal undergoing a medical procedure involving anesthetics. The pharmaceutical compositions may comprise one or more pharmaceutically acceptable excipients. Such compositions may optionally be in a non-oral dosage form. The pharmaceutical compositions may be, for example, an intravenous dosage form and the host mammal may be human. Alternatively, the host mammal may be a non-human mammal.

[0071] This disclosure also includes the use of the pharmaceutical compositions of this disclosure for accelerating or counteracting the effects of anesthesia in a host mammal (e.g., a human). Counteracting the effects of anesthesia may be, for example, reversing the effects of anesthesia. The pharmaceutical composition may comprise one or more pharmaceutically acceptable excipients. The composition may optionally be a non-oral dosage form. The pharmaceutical composition may be, for example, an intravenous dosage form and the host mammal may be a human. Alternatively, the host mammal may be a non-human mammal.

[0072] The compositions disclosed herein can also be provided to patients receiving naloxone to help overcome the limitations of naloxone due to its ability to stimulate respiratory responses, and the duration of action after administration can be extended by up to 4-6 hours with the addition of caffeine. Not limited to theory, caffeine, as a bronchodilator, CNS stimulant, myocardial stimulant, and diuretic, is believed to counteract the harmful effects of opioid overdose, either alone or in combination with naloxone.

[0073] Opioid overdose typically results in acute and / or recurrent respiratory depression, requiring repeated administration of naloxone. Respiratory depression (i.e., respiratory rate <12 breaths / min or apnea without physiological sleep) and room air oxygen saturation <90% indicate opioid overdose, especially when accompanied by coma and / or miosis. Naloxone administered under current standards of care can cause competitive antagonism of opioid receptors, leading to respiratory depression, decreased respiratory rate, and / or apnea. Recurrent respiratory depression frequently occurs when caring for patients with opioid overdose or those who have taken long-acting or sustained-release opioids. Initial management of opioid overdose includes maintaining adequate oxygenation (respiratory rate >12 breaths / min, oxygen saturation >90%) through ventilation. Failure to support the patient's airway, respiration, and circulation can lead to negative consequences, morbidity, and mortality.

[0074] Administration of caffeine, including caffeine in the compositions of this disclosure, can be used to control opioid overdose or drug use and to alleviate respiratory depression, decreased respiratory rate, and / or apnea. Therefore, another embodiment of this disclosure includes a method of treating a patient suffering from opioid overdose or drug use, comprising administering to the patient an effective amount of the compositions of this disclosure (e.g., pharmaceutical compositions), including parenteral administration. Such administration may include doses from about 2.5 mg caffeine / kg body weight to about 15 mg caffeine / kg body weight, including the doses previously mentioned for administering the compositions of this disclosure. Such administration may be performed in lieu of or in addition to naloxone administration, and in some embodiments, this reduces the amount of naloxone required for clinical benefit.

[0075] Opioid overdose is usually associated with or directly attributable to an incorrect dosage of the approved drug. If a patient increases the appropriate dose or duration of an opioid beyond acceptable limits, the resulting opioid toxicity can lead to complications and adverse events. Overdose is typically associated with illicit drug use and consumption. Overdose can impair life-sustaining systems (such as a normally functioning heartbeat and respiration) and can have potentially life-threatening consequences (such as respiratory arrest). Exemplary opioids include oxycodone, hydrocodone, morphine, methadone, fentanyl, and heroin.

[0076] The compositions of this disclosure can be administered before, after, or simultaneously with naloxone. In some embodiments, administering the caffeine compositions of this disclosure to patients suffering from opioid exposure or overdose reduces pulmonary edema, including, for example, by increasing diuresis. In many embodiments, when administered to patients suffering from opioid exposure or overdose, the caffeine compositions of this disclosure stimulate the myocardium and increase heart rate, cardiac output, and pulse rate, and / or mean arterial blood pressure. Routes of administration may include, for example, intravenous, intramuscular, or subcutaneous administration. The compositions can be administered by bolus injection or by infusion or drip.

[0077] Opioid withdrawal may be partly attributed to naloxone administration. In many embodiments of this disclosure, administering the caffeine composition of this disclosure to patients suffering from opioid addiction or overdose and who have already received naloxone limits the accumulation of physiological symptoms of opioid withdrawal. Management of such symptoms is possible because caffeine has the opposite physiological effects on opioids, such as reducing norepinephrine stimulation of the brain and reducing hypotension by stimulating the central nervous system.

[0078] Opioid addiction or overdose can also be caused by polymers (such as benzodiazepines). (Those of the same class) opioid addiction. The caffeine composition disclosed herein can also be formulated with compounds other than naloxone to treat opioid addiction or overdose. Such compounds include opioid agonist de-remitting agents or α2-adrenergic agonists.

[0079] This disclosure also includes the use of the pharmaceutical compositions of this disclosure for the treatment of host mammals suffering from opioid exposure or overdose. The pharmaceutical compositions may comprise water and / or one or more pharmaceutically acceptable excipients. Such compositions may optionally be in non-oral dosage forms. The pharmaceutical compositions may be, for example, intravenous dosage forms and the host mammal may be human. Alternatively, the host mammal may be a non-human mammal.

[0080] This disclosure also includes a process for preparing a caffeine pharmaceutical composition. Such a process may include mixing water with sodium benzoate to form a solution; treating the sodium benzoate solution with caffeine; and then adding one or more of lactic acid, acetic acid, aspartic acid, and glutamic acid to form the caffeine pharmaceutical composition. The added lactic acid, acetic acid, aspartic acid, and glutamic acid may optionally be in an aqueous solution. In some embodiments, the pharmaceutical composition is an intravenous dosage form.

[0081] The caffeine pharmaceutical compositions prepared by this process form additional embodiments of this disclosure. The compositions may contain one or more pharmaceutically acceptable excipients. The compositions are also configured for any suitable route of administration, such as intravenous, intramuscular, subcutaneous, oral, or oral mucosal delivery.

[0082] Other applications of the compositions disclosed herein include the use of caffeine in beverages, foods, and confectionery (including desserts). Because caffeine is bitter, reducing the caffeine content in a product can increase the content of sweeteners or other non-bitter components, thereby improving the overall flavor of the product.

[0083] Therefore, other embodiments of this disclosure include beverages, foods, or confectionery, such as beverages, foods, or confectionery intended for oral consumption by mammals, which contain the compositions of this disclosure. These foods include baked goods made from flour, such as cakes, pastries, donuts, or cookies. This includes such foods having one or more toppings or coatings containing the compositions of this disclosure. Foods also include chocolate, and confectionery includes chewing gum and breath fresheners. Exemplary beverages include carbonated drinks, tea, coffee, and energy drinks.

[0084] The compositions disclosed herein can be included in intermediate products during the preparation of beverages, foods, or confectionery as flavor-enhancing additives to suppress bitterness or odor, or otherwise to make intermediate or final products more palatable. The compositions can also be added after the beverage, food, or confectionery has been prepared.

[0085] Exemplary Implementation

[0086] Other exemplary embodiments of this disclosure include those provided in the following non-limiting terms.

[0087] Clause 1. A composition comprising one or more of lactic acid, acetic acid, aspartic acid and glutamic acid, caffeine and sodium benzoate.

[0088] Clause 2. The composition according to Clause 1 further comprises water.

[0089] Clause 3. The composition according to Clause 2, wherein the composition is in solution form.

[0090] Clause 4. A composition comprising:

[0091] An aqueous solution of caffeine and sodium benzoate, and

[0092] A means to increase the solubility of caffeine in this aqueous solution.

[0093] Clause 5. A composition in the form of an aqueous solution comprising caffeine with a solubility greater than about 235 mg / mL in the solution.

[0094] Clause 6. The composition according to Clause 5 comprises sodium benzoate.

[0095] Clause 7. The composition according to any one of Clauses 1-6, comprising lactic acid.

[0096] Clause 8. The composition according to any one of Clauses 1-7 comprises acetic acid.

[0097] Clause 9. The composition according to any one of Clauses 1-8, comprising glutamic acid.

[0098] Clause 10. The composition according to any one of Clauses 1-9, comprising aspartic acid.

[0099] Clause 11. The composition according to any one of Clauses 1-6, comprising two or more of lactic acid, acetic acid, aspartic acid and glutamic acid.

[0100] Clause 12. The composition according to any one of Clauses 1-11, comprising sodium benzoate, wherein the molar ratio of caffeine to sodium benzoate is from about 1:1.0 to about 1:1.5.

[0101] Clause 13. The composition according to Clause 12, wherein the molar ratio of caffeine to sodium benzoate is from about 1:1.0 to about 1:1.45.

[0102] Clause 14. The composition according to Clause 12, wherein the molar ratio of caffeine to sodium benzoate is from about 1:1.3 to about 1:1.50.

[0103] Clause 15. The composition according to Clause 12, wherein the molar ratio of caffeine to sodium benzoate is from about 1:1.3 to about 1:1.45.

[0104] Clause 16. The composition according to Clause 12, wherein the molar ratio of caffeine to sodium benzoate is approximately 1:1.4.

[0105] Clause 17. The composition according to Clause 12, wherein the molar ratio of caffeine to sodium benzoate is approximately 1:1.45.

[0106] Clause 18. The composition according to any one of Clauses 1-17, comprising one or more of lactic acid, acetic acid, aspartic acid and glutamic acid, wherein the molar ratio of caffeine to the total moles of lactic acid, acetic acid, aspartic acid and glutamic acid is from about 1:0.1 to about 1:0.3.

[0107] Clause 19. The composition according to Clause 18, wherein the molar ratio of the total moles of caffeine to lactic acid, acetic acid, aspartic acid and glutamic acid is approximately 1:0.2.

[0108] Clause 20. The composition according to Clause 18, wherein the molar ratio of the total moles of caffeine to lactic acid, acetic acid, aspartic acid and glutamic acid is approximately 1:0.21.

[0109] Clause 21. The composition according to Clause 18, wherein the molar ratio of the total moles of caffeine to lactic acid, acetic acid, aspartic acid and glutamic acid is approximately 1:0.22.

[0110] Clause 22. The composition according to Clause 18, wherein the molar ratio of the total moles of caffeine to lactic acid, acetic acid, aspartic acid and glutamic acid is approximately 1:0.26.

[0111] Clause 23. The composition according to any one of Clauses 1-22, comprising one or more of lactic acid, acetic acid, aspartic acid and glutamic acid and sodium benzoate, wherein the molar ratio of the sodium benzoate to the total moles of lactic acid, acetic acid, aspartic acid and glutamic acid is from about 1:0.15 to about 1:0.18.

[0112] Clause 24. The composition according to any one of Clauses 3-23, wherein the pH of the composition is about 5 to about 6.

[0113] Clause 25. The composition according to Clause 24, wherein the pH is from about 5.80 to about 5.92.

[0114] Clause 26. The composition according to Clause 24, wherein the pH is from about 5.70 to about 5.90.

[0115] Clause 27. The composition according to any one of Clauses 2-4 and 6-26, wherein the caffeine has a solubility greater than about 235 mg / mL.

[0116] Clause 28. The composition according to any one of Clauses 2-27, wherein the caffeine has a solubility of 236 mg / ml or greater.

[0117] Clause 29. The composition according to any one of Clauses 2-28, wherein the caffeine has a solubility of 238 mg / ml or greater.

[0118] Clause 30. The composition according to Clause 29, wherein the caffeine has a solubility of 240 mg / ml or greater.

[0119] Clause 31. The composition according to Clause 29, wherein the caffeine has a solubility of 250 mg / mL or greater.

[0120] Clause 32. The composition according to Clause 29, wherein the solubility of said caffeine is from about 240 mg / mL to about 500 mg / mL.

[0121] Clause 33. The composition according to Clause 29, wherein the caffeine has a solubility of about 300 mg / mL to about 400 mg / mL.

[0122] Clause 34. The composition according to Clause 29, wherein the solubility of said caffeine is from about 300 mg / mL to about 450 mg / mL.

[0123] Clause 35. The composition according to Clause 29, wherein the solubility of said caffeine is from about 340 mg / mL to about 420 mg / mL.

[0124] Clause 36. The composition according to Clause 29, wherein the solubility of said caffeine is from about 360 mg / mL to about 400 mg / mL.

[0125] Clause 37. The composition according to any one of Clauses 2-3, wherein the caffeine is in the weight percentage of about 15% to about 25%, the sodium benzoate is in the weight percentage of about 15% to about 25%, the lactic acid is in the weight percentage of about 1% to about 3%, and the water is in the weight percentage of about 50% to about 70%.

[0126] Clause 38. The composition according to Clause 37, wherein the caffeine is in the weight percentage of about 15% to about 22%, the sodium benzoate is in the weight percentage of about 16% to about 24%, the lactic acid is in the weight percentage of about 1.4% to about 1.8%, and the water is in the weight percentage of about 50% to about 66%.

[0127] Clause 39. The composition according to any one of Clauses 1-36, comprising less than 14% by weight of lactic acid.

[0128] Clause 40. The composition according to Clause 39 comprises about 1% by weight to about 3% by weight of lactic acid.

[0129] Clause 41. The composition according to any one of Clauses 1-36 and 39-40 contains more than 30% by weight of water.

[0130] Clause 42. The composition according to Clause 41 contains 50% by weight or more water.

[0131] Clause 43. The composition according to any one of Clauses 1-36 and 39-42, comprising caffeine in a higher percentage by weight than lactic acid.

[0132] Clause 44. The composition according to any one of Clauses 1-43, comprising sodium benzoate, wherein the difference in weight percentage between said sodium benzoate and caffeine is 1 to 2 by weight.

[0133] Clause 45. A composition comprising caffeine, sodium benzoate, lactic acid, and water;

[0134] The composition is in the form of an aqueous solution;

[0135] The molar ratio of caffeine to sodium benzoate is approximately 1:1.3 to approximately 1:1.45.

[0136] The molar ratio of sodium benzoate to lactic acid is approximately 1:0.15 to approximately 1:0.18; and

[0137] The caffeine in the aqueous solution has a solubility of 250 mg / mL or greater.

[0138] Clause 46. The composition according to any one of Clauses 2-45, wherein the composition is stable against the formation of precipitates.

[0139] Clause 47. The composition according to Clause 46 is in the form of an aqueous solution and does not exhibit precipitation after a duration of at least one week.

[0140] Clause 48. The composition according to Clause 47, which does not show precipitation after a duration of at least eight weeks.

[0141] Clause 49. The composition according to Clause 48, which does not show precipitation after a duration of at least three months.

[0142] Clause 50. The composition according to any one of Clauses 2-49, wherein the composition is thermally stable when subjected to a temperature of 135°C for 45 minutes.

[0143] Clause 51. The composition according to any one of Clauses 1, 6-23, 39-40 and 43-44, wherein the composition is in a solid, dry state.

[0144] Clause 52. A composition comprising caffeine, sodium benzoate and lactic acid.

[0145] Clause 53. The composition according to Clause 52 further comprises water.

[0146] Clause 54. The composition according to Clause 53, wherein the composition is in the form of an aqueous solution.

[0147] Clause 55. The composition according to any one of Clauses 53-54, wherein the composition is stable against the formation of precipitates, wherein the composition is thermally stable when subjected to a temperature of 135°C for 45 minutes, or both.

[0148] Clause 56. A pharmaceutical composition comprising a compound as described in any one of Clauses 1-55 and optionally one or more pharmaceutically acceptable excipients.

[0149] Clause 57. The pharmaceutical composition according to Clause 56, wherein the amount of caffeine is from about 250 mg to about 1200 mg.

[0150] Clause 58. The pharmaceutical composition according to Clause 57, wherein the amount of caffeine is about 750 mg.

[0151] Clause 59. A pharmaceutical composition according to any one of Clauses 56-58, wherein the one or more pharmaceutically acceptable excipients comprise one or more preservatives, one or more antioxidants, one or more buffers, or any combination of two or more of these substances.

[0152] Clause 60. A kit comprising one or more of lactic acid, acetic acid, aspartic acid and glutamic acid, caffeine and sodium benzoate.

[0153] Clause 61. The kit described in Clause 60 contains lactic acid.

[0154] Clause 62. The kit according to any one of Clauses 60-61 further comprises water.

[0155] Clause 63. A method for accelerating recovery from anesthesia or counteracting the effects of anesthesia, comprising administering to a subject undergoing a medical procedure with an anesthetic a pharmaceutically effective amount of any one of Clauses 1-59.

[0156] Clause 64. The method described in Clause 63, wherein the administration is parenteral.

[0157] Clause 65. The method of Clause 63, wherein the administration is intravenous, intramuscular, subcutaneous, oral, or oral mucosal administration.

[0158] Clause 66. The method according to any one of Clauses 63-65, wherein the administration is performed by bolus injection.

[0159] Clause 67. The method according to any one of Clauses 63-65, wherein the administration is performed by infusion or drip.

[0160] Clause 68. The method according to any one of Clauses 63-67, wherein the administration of the drug occurs simultaneously with the administration of an anesthetic to the patient.

[0161] Clause 69. The method according to any one of Clauses 63-67, wherein the administration occurs after delivery of the anesthetic to the patient.

[0162] Clause 70. The method according to any one of Clauses 63-67, wherein the administration occurs before the delivery of the anesthetic to the patient.

[0163] Clause 71. The method according to any one of Clauses 63-70, wherein the anesthetic is one or more of halothane, isoflurane, enflurane, desflurane, sevoflurane, etomidate, lidocaine, magnesium, fentanyl, theophylline, methylphenidate, preladenant, fentanyl, remifentanil, morphine, hydromorphone, and propofol.

[0164] Clause 72. The method according to any one of Clauses 63-70, wherein the anesthetic agent is propofol.

[0165] Clause 73. The method according to any one of Clauses 63-72, comprising accelerating recovery from anesthesia, wherein the recovery from anesthesia is at least 15 minutes faster than in the case where the composition of any one of Clauses 1-59 is not administered.

[0166] Clause 74. The method according to any one of Clauses 63-72, comprising accelerating recovery from anesthesia, wherein the recovery from anesthesia is at least 30 minutes faster than in the case where the composition of any one of Clauses 1-59 is not administered.

[0167] Clause 75. The method according to any one of Clauses 63-74, comprising counteracting anesthetic effects, wherein the method of counteracting anesthetic effects is to reverse the anesthetic effects.

[0168] Clause 76. A parenteral pharmaceutical composition comprising any one of the compositions described in Clauses 1-59.

[0169] Clause 77. The parenteral drug composition according to Clause 76, wherein the dose volume is about 2 to about 8 mL.

[0170] Clause 78. The parenteral pharmaceutical composition according to any one of Clauses 76-77, which is configured for intravenous administration.

[0171] Clause 79. The parenteral drug composition according to any one of Clauses 76-77, which is configured for use via intramuscular or subcutaneous route.

[0172] Clause 80. A pharmaceutical composition comprising one or more of lactic acid, acetic acid, aspartic acid and glutamic acid, caffeine and sodium benzoate in an aqueous solution, for use in treating host mammals undergoing medical procedures employing anesthetics.

[0173] Clause 81. The use as described in Clause 80, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0174] Clause 82. Use according to any one of Clauses 80-81, wherein the pharmaceutical composition is not an oral dosage form.

[0175] Clause 83. Use according to any one of Clauses 80-82, wherein the pharmaceutical composition is an intravenous dosage form and the host mammal is a human.

[0176] Clause 84. A pharmaceutical composition comprising one or more of lactic acid, acetic acid, aspartic acid and glutamic acid, caffeine and sodium benzoate in an aqueous solution, for use in accelerating the recovery of a host mammal from anesthesia or in antagonizing the effects of anesthesia.

[0177] Clause 85. The use described in Clause 84, wherein the mammal is a human.

[0178] Clause 86. Use according to any one of Clauses 84-85, wherein the pharmaceutical composition is not an oral dosage form.

[0179] Clause 87. Use according to any one of Clauses 84-86, wherein the pharmaceutical composition is an intravenous dosage form and the host mammal is a human.

[0180] Clause 88. For the purposes of any of Clauses 84-87, the method of counteracting anesthetic effects is to reverse the anesthetic effects.

[0181] Clause 89. The method according to any one of Clauses 80-82, 84, 86 and 88, wherein the host mammal is a non-human mammal.

[0182] Clause 90. A process for preparing a caffeine pharmaceutical composition, comprising mixing water with sodium benzoate to form a solution; treating the sodium benzoate solution with caffeine; and then adding one or more of lactic acid, acetic acid, aspartic acid, and glutamic acid to form a caffeine pharmaceutical composition.

[0183] Clause 91. The process according to Clause 90, wherein one or more of the lactic acid, acetic acid, aspartic acid and glutamic acid are in an aqueous solution.

[0184] Clause 92. A caffeine pharmaceutical composition prepared according to any one of Clauses 90-91.

[0185] Clause 93. The caffeine pharmaceutical composition according to Clause 92 further comprises one or more pharmaceutically acceptable excipients.

[0186] Clause 94. The pharmaceutical composition according to any one of Clauses 92-93, wherein the pharmaceutical composition is an intravenous dosage form.

[0187] Clause 95. The caffeine pharmaceutical composition according to any one of Clauses 92-93, which is configured for intravenous, intramuscular, subcutaneous, oral, or oral mucosal delivery.

[0188] Clause 96. A method of treating a patient suffering from opioid addiction or overdose, comprising administering to the patient a pharmaceutically effective amount of any one of Clauses 1-59.

[0189] Clause 97. The method described in Clause 96, wherein the administration is parenteral.

[0190] Clause 98. The method of Clause 96, wherein the administration is intravenous, intramuscular, or subcutaneous.

[0191] Clause 99. The method according to any one of Clauses 96-98, wherein the administration is performed by bolus injection.

[0192] Clause 100. The method according to any one of Clauses 96-98, wherein the administration is performed by infusion or drip.

[0193] Clause 101. The method according to any one of Clauses 96-100, wherein the patient is co-administered with naloxone.

[0194] Clause 102. The method according to Clause 101, wherein the naloxone is co-administered before administering the composition as described in any one of Clauses 1-59.

[0195] Clause 103. The method according to Clause 101, wherein the naloxone is co-administered in the composition as described in any one of Clauses 1-59.

[0196] Clause 104. The method according to Clause 101, wherein the naloxone is co-administered after administration of the composition as described in any one of Clauses 1-59.

[0197] Clause 105. The method according to any one of Clauses 96-104, wherein the opioid is oxycodone, hydrocodone, morphine, methadone, fentanyl, or heroin.

[0198] Clause 106. A pharmaceutical composition comprising one or more of lactic acid, acetic acid, aspartic acid and glutamic acid, caffeine and sodium benzoate, for use in treating host mammals suffering from opioid exposure or overdose.

[0199] Clause 107. The use as described in Clause 106, wherein the pharmaceutical composition further comprises water.

[0200] Clause 108. Use according to any one of Clauses 106-107, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0201] Clause 109. Use according to any one of Clauses 106-108, wherein the pharmaceutical composition is not an oral dosage form.

[0202] Clause 110. Use according to any one of Clauses 106-109, wherein the pharmaceutical composition is an intravenous dosage form and the host mammal is a human.

[0203] Clause 111. A beverage, food, or confectionery comprising any one of the compositions described in Clauses 1-55.

[0204] Clause 112. The beverage, food or confectionery described in Clause 111 is a baked good made from flour.

[0205] Clause 113. The beverage, food, or confectionery referred to in Clause 112 is a cake, pastry, donut, or biscuit.

[0206] Clause 114. The beverage, food or confectionery referred to in Clause 111 is chocolate.

[0207] Clause 115. The beverage, food or confectionery described in Clause 111 is chewing gum or breath freshener.

[0208] Clause 116. A beverage, food, or confectionery as described in Clause 111 is a beverage, wherein the beverage is a carbonated beverage, tea, coffee, or energy drink.

[0209] Clause 117. A composition comprising caffeine, sodium benzoate and one or more C2 to C5 carboxylic acids.

[0210] Clause 118. A composition comprising caffeine, sodium benzoate and one or more C4 to C5 amino acids.

[0211] Clause 119. A composition comprising caffeine, sodium benzoate and one or more C2 to C5 carboxylic alcohols.

[0212] Clause 120. A composition comprising caffeine, sodium benzoate, and one or more C2 to C5 dicarboxylic acids.

[0213] Clause 121. The composition according to any one of Clauses 117-120 further comprises water.

[0214] Clause 122. The composition according to Clause 121, wherein the composition is in solution form.

[0215] Example

[0216] Example 1 – Materials, Equipment, and Software

[0217] The following materials, equipment and software were used in embodiments 2-3 of this disclosure.

[0218] Material:

[0219] • Distilled water (Meijer, batch number 39-222, expiry date 10 / 31 / 2020), (also known as water)

[0220] • Lactic acid in aqueous solution ≥85% ACS reagent (EMD Millipore Corp., lot number 56169630), (also known as lactic acid)

[0221] • Caffeine (Acros, batch number A0405347), 98.5%

[0222] Sodium benzoate (TCI, batch number FAPHB-JF), >98%

[0223] equipment:

[0224] Denver Instruments A-250 balance

[0225] Eppendorf Research 1000 pipette, range 0.100–5.000 mL

[0226] • Ultrasonic cleaning machine (Model O Conx. Jewelry cleaning machine)

[0227] Escali model PRS00S scale

[0228] Mettler Toledo AG104 balance

[0229] • VWR Scientific Symphony SB21 pH meter, equipped with a Cole-Parmer glass electrode, BNC (05991-61)

[0230] VELP Scientifica mixing plates

[0231] Example 2 – Preparation of a composition of caffeine, sodium benzoate and lactic acid

[0232] Hundreds of experiments were conducted in the experimental model design to confirm the enhanced solubility of caffeine in sodium benzoate. Most did not produce caffeine that remained soluble in solution for the desired time period. Several positive results are reported in this paper. The composition was prepared by the following process, with the amounts of materials used listed in Tables 2 and 3. A magnetic stir bar was placed in a 20 mL flashing vial, and the vial was placed on a stirring plate; all additions were made while stirring. Approximately half of the water was added to the vial, followed by the sodium benzoate, and the mixture was stirred until dissolved. The appropriate weight of caffeine was added to the vial, and the remaining water was added to the vial. Lactic acid was then added to the vial, and the vial was capped.

[0233] Table 2

[0234]

[0235] Table 3

[0236]

[0237] Samples of each composition were refrigerated at -2°C and kept clear for more than 8 weeks.

[0238] Example 3 – Other formulations of a combination of caffeine, sodium benzoate, and lactic acid

[0239] Sample: RP1-57-5 (235mg: 235mg, caffeine: sodium benzoate)

[0240] Accurately weigh 2,350.2 mg of sodium benzoate and add it to a 20 mL scintillation vial containing a stir bar. Accurately weigh 2,350.1 mg of caffeine and add it to the same vial. Then transfer 10 mL of distilled water into the vial and cap it. Place the vial on a magnetic stir plate and allow stirring at 300 rpm until all solids are completely dissolved, yielding a solution containing 235 mg / mL caffeine. The pH was measured to be 8.01.

[0241] Sample: RP1-60-1

[0242] Place a magnetic stir bar in a 20 mL scintillation vial and place the vial on a stirring plate. While stirring at 300 rpm, transfer 5 mL of distilled water into the vial. Accurately weigh 2597.5 mg of sodium benzoate and add it to the vial; stir until the sodium benzoate is completely dissolved. Accurately weigh 2500.3 mg of caffeine and add it to the same vial. Add 1.25 mL of distilled water to the vial, then immediately add 249 μL of an 88.47 wt% lactic acid solution and cap the vial. Add 1.0 mL of distilled water the next day, and 0.5 mL the following day. Stir the vial at 300 rpm until all solids are completely dissolved, yielding a solution containing 313 mg of caffeine per mL. The pH was measured to be 5.87.

[0243] Sample: RP1-60-2

[0244] Place a magnetic stir bar in a 20 mL scintillation vial and place the vial on a stirring plate. While stirring at 300 rpm, transfer 5 mL of distilled water into the vial. Accurately weigh 2,690.2 mg of sodium benzoate and add it to the vial; stir until the sodium benzoate is completely dissolved. Accurately weigh 2,500.1 mg of caffeine and add it to the same vial. Add 1.25 mL of distilled water to the vial, then immediately add 258 μL of an 88.47% by weight lactic acid solution and cap the vial. Add 1.0 mL of distilled water the next day, and 0.25 mL the following day. Stir the vial at 300 rpm until all solids are completely dissolved, yielding a solution containing 322 mg of caffeine per mL. The pH was measured to be 5.94.

[0245] Sample: RP1-62-4 (396 mg / mL caffeine, 18% sodium terebenzoate lactate).

[0246] Place a magnetic stir bar in a 20 mL scintillation vial and place the vial on a stirring plate. While stirring at 300 rpm, transfer 5 mL of distilled water into the vial. Accurately weigh 2,690.5 mg of sodium benzoate and add it to the vial; stir until the sodium benzoate is completely dissolved. Accurately weigh 2,500.2 mg of caffeine and add it to the same vial. Add 1 mL of distilled water to the vial, then immediately add 310 μL of an 88.47 wt% lactic acid solution and cap the vial. Stir the vial at 300 rpm until all solids are completely dissolved, yielding a solution containing 396 mg of caffeine per mL. The pH was measured to be 5.91.

[0247] The solids in all samples remained dissolved for at least three weeks.

[0248] Example 4 – Samples RP1-65-1, RP1-65-2 and RP1-68-1

[0249] Reconstruct sample RP1-62-4 at 10 ml and 100 ml scales (two samples). The order of addition is half water, sodium benzoate, stir to dissolve, caffeine, remaining water, and lactic acid. A second addition of water is used to rinse any residual solids from the glassware. Prepare larger-scale samples in 250 ml Pyrex glass culture flasks with large stir bar. Remove the samples from the stir plate and store them on a lab bench under ambient conditions.

[0250] Table 4 provides detailed formulations of the prepared compositions.

[0251] Table 4

[0252] Composition Caffeine (mg) Sodium benzoate (mg) Lactic acid (mL) Water (mL) RP1-65-1 2500.0 2690.4 0.310 9.690 RP1-65-2 25003.0 269050 3.100 96.900 RP1-68-1 25001.4 269044 3.100 96.900

[0253] Approximately two weeks later, the pH values ​​of compositions RP1-65-1, RP1-65-2, and RP1-68-1 were measured to be 5.78, 5.77, and 5.77, respectively. The caffeine solubility of the compositions was 250 mg / ml. All compositions remained clear for three months.

[0254] Example 5 – Compositions containing acetic acid, aspartic acid, or glutamic acid

[0255] Several compositions that achieve 250 mg / ml of caffeine and exhibit long-term stability are summarized in Table 5 below.

[0256] Table 5

[0257]

[0258] These formulations were reconstructed, replacing lactic acid with acetic acid (glacial acetic acid, VWR Chemicals), aspartic acid (D-aspartic acid (99+%)), or glutamic acid (L-glutamic acid 99%, Aldrich Chemicals Co., Inc.). All samples were prepared in 20 ml scintillation vials, first adding approximately half water, then sodium benzoate (stirring until dissolved), followed by caffeine, the remaining water, and the acid. If the acid to be added was solid, a second addition of water was made last, not after the caffeine.

[0259] The acetic acid sample (Table 6) dissolved rapidly within 15 minutes, had a pH value that was essentially the same as that of the lactic acid sample, and remained dissolved for more than three months.

[0260] Table 6

[0261]

[0262] The aspartic acid samples (Table 7) dissolved relatively quickly. After about one month, all solutions were pale yellow. After three months, the first two samples had formed precipitates, while the latter three samples remained clear.

[0263] Table 7

[0264]

[0265] The glutamate samples (Table 8) dissolved relatively quickly on the same or the following day. After three months, the first sample had formed a precipitate, while all other samples remained clear.

[0266] Table 8

[0267]

[0268] Example 6 – Mass Production Method

[0269] The following materials and equipment are used for a batch production method of an exemplary composition comprising caffeine, sodium benzoate, and water.

[0270] Material:

[0271] ·caffeine

[0272] ·% sodium benzoate

[0273] ·water

[0274] • Aqueous lactic acid solution (~88.5%)

[0275] equipment:

[0276] Glass culture medium bottles

[0277] ·scraper

[0278] Weighing container

[0279] Magnetic stirring rod

[0280] Glass funnel

[0281] · Balance

[0282] • Pipettes, 5000μL

[0283] · Mixing plate

[0284] Mass production methods include the processes described in the following steps.

[0285] Place the clean magnetic stir bar into a clean 250mL glass culture medium bottle, place the bottle on a stirring plate (300rpm) and accurately measure 30mL of water (one-third of the total water volume), record the volume and add it to the bottle.

[0286] Place the clean glass funnel at the top of the bottle opening.

[0287] Accurately weigh sodium benzoate (26.9044g) into a suitable container, record the weight, and slowly add it into the funnel using a clean scraper, ensuring that no powdery solid spills out.

[0288] The funnel, scraper, and weighing container are rinsed into the bottle with 5 mL of water, precisely measured as an aliquot of the sample. A total of 30 mL of water is required for a thorough rinse.

[0289] After removing the funnel, cap the bottle and stir until the sodium benzoate is completely dissolved. Once a clear solution has formed in the bottle, remove the cap and place a clean glass funnel over the top of the bottle opening.

[0290] Accurately weigh 25.0014 g of caffeine into a suitable container, record the weight, and slowly add it to the funnel using a clean spatula, ensuring no powdery solid spills out. Rinse the funnel, spatula, and weighing container with a precisely measured 5 mL aliquot of water into the bottle. A total of 30 mL of water is needed for a thorough rinse. After removing the funnel, accurately measure the remaining water (6.9 mL), record the volume, and add it to the bottle.

[0291] Accurately measure the lactic acid (3.1 mL), immediately add it to the bottle, cap it again, and stir (300 rpm) until all solids are completely dissolved.

[0292] Example 7 – Stability of the composition after treatment at 135°C for 45 minutes

[0293] A 10,000-fold dilution of a 250 mg / mL caffeine and 18% lactic acid:sodium benzoate mixture was added to an amber-colored HPLC vial, tightly sealed, and placed in an oven at 135°C. After 45 minutes, the vial was removed and analyzed by HPLC.

[0294] The HPLC chromatogram of the unheated sample showed appropriate peak shapes with no overlapping peaks. The peak with a retention time of 4.209 min corresponds to caffeine, while the peak with a retention time of 7.545 min corresponds to sodium benzoate. HPLC results used for chemical stability assessment of the composition showed no other extraneous peaks after exposure to 135 °C for 45 min.

[0295] Example 8 – Predictive

[0296] A 200-pound male was treated with an opioid overdose using a publicly available caffeine composition ranging from 2.5 mg caffeine / kg body weight to 15 mg caffeine / kg body weight, administered intravenously in combination with naloxone. This combination reversed general acute respiratory depression and / or recurrent respiratory depression associated with opioid overdose and reduced the dose and frequency of naloxone.

Claims

1. A pharmaceutical composition suitable for parenteral administration to patients, comprising one or more of lactic acid, acetic acid, aspartic acid and glutamic acid, caffeine, sodium benzoate and water, wherein the pharmaceutical composition is in solution form, and wherein the molar ratio of the caffeine to the total molar ratio of lactic acid, acetic acid, aspartic acid and glutamic acid is 1:0.1 to 1:0.

3.

2. The pharmaceutical composition according to claim 1, wherein it comprises lactic acid.

3. The pharmaceutical composition according to claim 1, wherein it comprises acetic acid.

4. The pharmaceutical composition according to claim 1, wherein it comprises glutamic acid.

5. The pharmaceutical composition according to claim 1, wherein it comprises aspartic acid.

6. The pharmaceutical composition according to claim 1, comprising two or more of lactic acid, acetic acid, aspartic acid and glutamic acid.

7. The pharmaceutical composition according to claim 1, wherein the molar ratio of caffeine to sodium benzoate is 1:1.0 to 1:1.

5.

8. The pharmaceutical composition according to claim 7, wherein the molar ratio of caffeine to sodium benzoate is from 1:1.0 to 1:1.

45.

9. The pharmaceutical composition according to claim 7, wherein the molar ratio of caffeine to sodium benzoate is from 1:1.3 to 1:1.

50.

10. The pharmaceutical composition according to claim 7, wherein the molar ratio of caffeine to sodium benzoate is from 1:1.3 to 1:1.

45.

11. The pharmaceutical composition according to claim 7, wherein the molar ratio of caffeine to sodium benzoate is 1:1.

4.

12. The pharmaceutical composition according to claim 7, wherein the molar ratio of caffeine to sodium benzoate is 1:1.

45.

13. The pharmaceutical composition according to claim 1, wherein the molar ratio of caffeine to the total molar ratio of lactic acid, acetic acid, aspartic acid and glutamic acid is 1:0.

2.

14. The pharmaceutical composition according to claim 1, wherein the molar ratio of caffeine to the total molar ratio of lactic acid, acetic acid, aspartic acid and glutamic acid is 1:0.

21.

15. The pharmaceutical composition according to claim 1, wherein the molar ratio of caffeine to the total molar ratio of lactic acid, acetic acid, aspartic acid and glutamic acid is 1:0.

22.

16. The pharmaceutical composition according to claim 1, wherein the molar ratio of caffeine to the total molar ratio of lactic acid, acetic acid, aspartic acid and glutamic acid is 1:0.

26.

17. The pharmaceutical composition according to claim 1, wherein the molar ratio of sodium benzoate to the total molar ratio of lactic acid, acetic acid, aspartic acid and glutamic acid is 1:0.15 to 1:0.

18.

18. The pharmaceutical composition according to claim 1, wherein the pH of the pharmaceutical composition is 5 to 6.

19. The pharmaceutical composition according to claim 18, wherein the pH is from 5.80 to 5.

92.

20. The pharmaceutical composition according to claim 18, wherein the pH is 5.70 to 5.

90.

21. The pharmaceutical composition according to claim 1, wherein the solubility of caffeine is greater than 235 mg / mL.

22. The pharmaceutical composition of claim 1, wherein the solubility of caffeine is 236 mg / ml or greater.

23. The pharmaceutical composition of claim 1, wherein the solubility of caffeine is 238 mg / ml or greater.

24. The pharmaceutical composition of claim 23, wherein the caffeine has a solubility of 240 mg / ml or greater.

25. The pharmaceutical composition of claim 23, wherein the caffeine has a solubility of 250 mg / mL or greater.

26. The pharmaceutical composition of claim 23, wherein the solubility of caffeine is from 240 mg / mL to 500 mg / mL.

27. The pharmaceutical composition of claim 23, wherein the solubility of caffeine is from 300 mg / mL to 400 mg / mL.

28. The pharmaceutical composition of claim 23, wherein the solubility of caffeine is from 300 mg / mL to 450 mg / mL.

29. The pharmaceutical composition of claim 23, wherein the solubility of caffeine is from 340 mg / mL to 420 mg / mL.

30. The pharmaceutical composition of claim 23, wherein the solubility of caffeine is from 360 mg / mL to 400 mg / mL.

31. The pharmaceutical composition according to claim 1, wherein the caffeine is present in a weight percentage of 15% to 25%, the sodium benzoate in a weight percentage of 15% to 25%, the lactic acid in a weight percentage of 1% to 3%, and the water in a weight percentage of 50% to 70%; wherein, The total weight percentage of all components in the pharmaceutical composition does not exceed 100%.

32. The pharmaceutical composition of claim 31, wherein the caffeine comprises 15% to 22% by weight, the sodium benzoate comprises 16% to 24% by weight, the lactic acid comprises 1.4% to 1.8% by weight, and the water comprises 50% to 66% by weight; wherein, The total weight percentage of all components in the pharmaceutical composition is 100%.

33. The pharmaceutical composition according to claim 1, wherein it contains less than 14% by weight of lactic acid.

34. The pharmaceutical composition according to claim 33, comprising 1% to 3% by weight of lactic acid.

35. The pharmaceutical composition according to claim 1, comprising more than 30% by weight of water.

36. The pharmaceutical composition of claim 35, comprising 50% by weight or more water.

37. The pharmaceutical composition of claim 1, wherein the difference in weight percentage between sodium benzoate and caffeine is 1 to 2 by weight.

38. The pharmaceutical composition according to claim 1, comprising caffeine, sodium benzoate, lactic acid, and water; The pharmaceutical composition is in the form of an aqueous solution; The molar ratio of caffeine to lactic acid is 1:0.1 to 1:0.

3. The molar ratio of caffeine to sodium benzoate is 1:1.3 to 1:1.

45. The molar ratio of sodium benzoate to lactic acid is 1:0.15 to 1:0.18; and The caffeine in the aqueous solution has a solubility of 250 mg / mL or greater.

39. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is stable against the formation of precipitates.

40. The pharmaceutical composition of claim 39, wherein no precipitation occurs after a duration of at least one week.

41. The pharmaceutical composition of claim 40, wherein no precipitation occurs after a duration of at least eight weeks.

42. The pharmaceutical composition according to claim 41, wherein no precipitation occurs after a duration of at least three months.

43. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is subjected to 135 o The temperature at C is thermally stable for 45 minutes.

44. A pharmaceutical composition comprising the pharmaceutical composition of claim 1 and optionally one or more pharmaceutically acceptable excipients.

45. The pharmaceutical composition of claim 44, wherein the amount of caffeine is from 250 mg to 1200 mg.

46. ​​The pharmaceutical composition according to claim 45, wherein the amount of caffeine is 750 mg.

47. The pharmaceutical composition of claim 46, wherein the one or more pharmaceutically acceptable excipients comprise one or more preservatives, one or more antioxidants, one or more buffers, or any combination of two or more of these substances.

48. Use of the pharmaceutical composition of claim 1 in the preparation of a medicament for accelerating or counteracting the effects of anesthesia in a patient undergoing a medical procedure using an anesthetic, wherein the medicament is used in a method comprising administering a pharmaceutically effective amount of the pharmaceutical composition to the patient.

49. The use according to claim 48, wherein the administration is intravenous, intramuscular, or subcutaneous.

50. The use according to claim 48, wherein the administration is performed by bolus injection.

51. The use according to claim 48, wherein the administration is performed by infusion or drip.

52. The use according to claim 48, wherein the anesthetic is one or more of halothane, isoflurane, enflurane, desflurane, sevoflurane, etomidate, lidocaine, magnesium, fentanyl, theophylline, methylphenidate, remdesivir, fentanyl, remifentanil, morphine, hydromorphone, and propofol.

53. The use according to claim 48, wherein the anesthetic is propofol.

54. Use of the pharmaceutical composition according to claim 1 in the preparation of a medicament for treating a host mammal undergoing a medical procedure employing an anesthetic.

55. The use according to claim 54, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

56. The use according to claim 54 or 55, wherein the pharmaceutical composition is an intravenous dosage form and the host mammal is a human.

57. A process for preparing the caffeine pharmaceutical composition of claim 1, comprising mixing water with sodium benzoate to form a solution; treating the sodium benzoate solution with caffeine; and then adding one or more of lactic acid, acetic acid, aspartic acid, and glutamic acid to form the caffeine pharmaceutical composition.

58. Use of the pharmaceutical composition of claim 1 in the preparation of a medicament for treating patients suffering from opioid addiction or overdose, wherein the medicament is used in a method comprising administering a pharmaceutically effective amount of the pharmaceutical composition to the patient.

59. The use according to claim 58, wherein the administration is intravenous, intramuscular, or subcutaneous.

60. The use according to claim 58, wherein the administration is performed by bolus injection.

61. The use according to claim 58, wherein the administration is performed by infusion or drip.

62. The use according to claim 58, wherein the opioid is oxycodone, hydrocodone, morphine, methadone, fentanyl, or heroin.

63. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition does not contain polyethylene glycol.

64. The pharmaceutical composition according to claim 1, further comprising one or more parabens.

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