JP2023078480A - Pharmaceutical preparations of sebacoyl dinalbuphine and acetaminophen and methods for treating pain - Google Patents

Abstract

To provide pharmaceutical compositions, combinations, kits and methods for treating pain, which provide synergistic analgesic effects and less side effects.SOLUTION: A pharmaceutical preparation comprises sebacoyl dinalbuphine or its metabolites or derivatives and/or acetaminophen (AAP) or its derivatives, together with one or more pharmaceutically acceptable excipients.SELECTED DRAWING: Figure 1

Description

The present invention relates to novel drug conjugates in which the compounds have synergistic analgesic action. The present invention also relates to pharmaceutical formulations and methods for treating pain, specifically those that provide enhanced analgesic efficacy.

Many pharmaceuticals have now been developed to treat pain. However, the problem of side effects needs to be resolved. Recently, in a paper published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS), non-aspirin nonsteroidal anti-inflammatory drugs ugs; NSAIDs) There is an increased risk of heart attack and stroke every few months after taking ibuprofen (an FDA warning), and it can affect fertility. Also, acetaminophen, although not a non-steroidal anti-inflammatory drug (NSAIDs), has hepatotoxic or nephrotoxic side effects.

It should be noted that overdose of highly addictive opioids has become a global health crisis, especially in the United States, where more than 60,000 people died from overdoses in 2016 alone. In the United States, tens of thousands of people die each year from opioid overdoses, with more than 50,000 deaths last year. This is the same number of Americans who died in the Vietnam War.

Currently, new opioid pharmaceuticals have been developed, such as nalbuphine, buprenorphine, butorphanol, the so-called narcotic agonist-antagonist analgesics. It exhibits dual effects of opioid receptor agonist and antagonist, see, for example, Schmidt, W.; K. A paper by Mr. et al. . As an example, nalbuphine is a Mu receptor antagonist and a Kappa receptor agonist. These agonist-antagonist drugs ameliorated adverse reactions of opioid drugs, such as dependence and respiratory depression. Nalbuphine is the most used drug and has excellent therapeutic efficacy. After continuous administration of nalbuphine for 6 months, no obvious dependence or addition was observed. These narcotic agonist-antagonist analgesics produced only mild respiratory depression. In clinical use, nalbuphine is safer than traditional narcotic analgesics and is classified as a narcotics slush (Non-Patent Document 2).

Nalbuphine is a synthetic agonist-antagonist, chemically related to naloxone (anesthetic antagonist) and oxymorphone (potent anesthetic analgesic). Nalbuphine's effects on kappa receptors may alternate in pain perception and emotional responses to pain, possibly by altering neurotransmitter release when afferent nerves are sensitive to painful stimuli. Oral administration of nalbuphine has been shown to be 4- to 5-fold less effective than intramuscular nalbuphine (as a postoperative analgesic). Conventional nalbuphine has been found to be impractical due to its oral bioavailability of 5% or less (eg, Non-Patent Document 3).

In this double-blind, randomized, parallel design, placebo-controlled study, the efficacy contribution of analgesic effects of single oral doses of nalbuphine, acetaminophen, and their combination on postoperative pain in 128 hospitalized patients evaluated. Patients are evaluated hourly and 6-hour individual reports are used as an index of analgesic response. For measures of total analgesia and peak analgesia, nalbuphine alone and acetaminophen alone are each significantly superior to placebo. However, the efficacy of the nalbuphine and acetaminophen conjugate was not significant in any analgesic assay. It shows that the complex has only an additive effect of the components, as described in Non-Patent Document 4.

Sebacoyl dinalbuphine (SDE) oil is a pharmaceutically acceptable long-acting dosage form that is administered once a day or once every few days. Side effects can be minimized even at high doses. SDEs have long-term, side-effect, and safety advantages, which can improve the quality of treatment. For postoperative patients, the dosing interval can be set to 7 days instead of 3-5 hours. For end-stage cancer, administration of the dosage forms of the present invention to patients rather than hospitalization can provide the same therapeutic benefit.

Drug Alcohol Depend. 14, 339, 1985; British Journal of Pain. 6, 11-16, 2012 Drug Alcohol Depend. 14, 339, 1985; 63, 135-143, 2014 Br J Clin Pharmacol 1988;25:264-8 CLIN PHARMACOL THER 1986;39:295-9

An ideal analgesic should have a short onset time, long action, high efficiency, no dependence, no or minimal respiratory depression, and few side effects. For the current global opioid crisis, new formulations that do not cause addiction or respiratory depression, include shorter onset, longer action, fewer side effects, and better outcomes (e.g. synergistic interactions) There is a need to provide new pharmaceutical formulations and methods for treating pain (especially moderate to severe pain) with

The present invention provides novel pharmaceutical formulations and methods for treating pain. Specifically, the pharmaceutical formulation comprises sebacoyl dinalbuphine, or a metabolite or derivative thereof, and/or acetaminophen (AAP), or a derivative thereof, and one or more pharmaceutical agents. and excipients acceptable to The pharmaceutical formulations of the present invention exhibit a summation/synergistic analgesic effect of pain relief and improved time of onset (shorter), duration of action, oral bioavailability (AUC), and maximum peak can be provided.

In some specific embodiments, the pharmaceutical formulations of the present invention comprise a therapeutically effective amount of a first analgesic that is sebacoyl dinalbuphine, or a metabolite or derivative thereof, and/or acetamino a therapeutically effective amount of a second analgesic that is acetaminophen (AAP) or a derivative thereof, and one or more pharmaceutically acceptable excipients.

In some specific embodiments, the pharmaceutical formulations of the present invention comprise: (i) a therapeutically effective amount of a first analgesic that is sebacoyl dinalbuphine or a metabolite or derivative thereof; and (ii) a second analgesic composition comprising a therapeutically effective amount of a second analgesic that is acetaminophen or a derivative thereof.

In some specific embodiments, the first analgesic is sebacoyl dinalbuphine in the free base form or a pharmaceutically acceptable salt.

In some specific embodiments, the first analgesic is sebacoyl dinalbuphine (SDE), eg, as described in US Pat. No. 6,225,321.

In some specific embodiments, the first analgesic agent acts in an effective amount as a bioavailability enhancer of the first analgesic agent.

In some specific embodiments, the second analgesic is acetaminophen (AAP), eg, as described in US Patent Application No. 14/441,317 (US20170172950A1).

In some specific embodiments, the excipients used herein are Eudragit S100, Dicalcium phosphate dehydrate, Pluronic F68, Hexitol, Crospovidone, Sodium starch glycolate, Aerosil 200, Trichlorosucrose, Menthol, Saccharin, Sodium benzoate, Glyceryl behenate, Laurel Sodium lysate lauryl sulfate), Providedone K30, and combinations thereof.

In some specific embodiments, the first analgesic composition is formulated in sustained release form and the second analgesic composition is formulated in immediate release form.

Meanwhile, the present invention provides a method of treating pain in an individual in need thereof comprising administering to the individual a pharmaceutical formulation of an analgesic, or specifically a drug conjugate of an analgesic as described herein. Also provided is the use of the analgesic pharmaceutical formulations or analgesic drug conjugates described herein to manufacture a medicament for treating pain in an individual in need thereof.

The following description sets forth the details of one or more specific embodiments of the invention. Other features or advantages of the present invention will become apparent from the following detailed description of some specific embodiments and the appended claims.

FIG. 2 shows analgesic effects on SD rats after oral administration of SDE 75 mg/kg, AAP 100 mg/kg, and their combination (SDE+AAP) using a paw pressure test. FIG. 2 shows analgesic effects on SD rats after oral administration of 60 mg/kg NAL, 100 mg/kg AAP, and the combination thereof using a paw pressure test of SD rats.

The specific embodiments given below are for the purpose of illustrating the invention. However, it should be understood that the invention is not limited to the preferred and specific embodiments shown.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

As used herein, the articles "a" and "one" mean that the object of context is "one or more." For example, "an element" means one element or multiple elements.

Terms such as "comprise" or "contain" are synonymous with "comprise", "include", "contain", "comprise" and mean including one or more features, ingredients or components. do. Terms such as "comprise" or "contain" include the terms "consisting of" or "consisting of".

The present invention provides novel pharmaceutical formulations and methods for treating pain. Specifically, the pharmaceutical formulations of the present invention contain sebacoyldinalbuphine or a derivative thereof, and/or acetaminophen or a derivative thereof, and one or more pharmaceutically acceptable excipients. including. Pharmaceutical formulations according to the present invention can provide an overall and synergistic effect of pain relief, as well as improved oral bioavailability and fewer side effects.

As used herein, the term "pharmaceutical formulation" means any form of pharmaceutical product, such as a composition, combination, or kit. Composition means homogeneous mixtures in the form of, for example, tablets, capsules, pills, powders, granules, solutions, suspensions, and emulsions, and any pharmaceutically acceptable form. Combination means the chronological administration of two or more active ingredient products physically present in one or more unit packages, respectively. A kit can refer to a collection or combination of the above pharmaceutical formulations, preferably supplied in separate form in a single container. Preferably, the container also contains instructions for using these pharmaceutical formulations or for practicing the methods of the invention.

As used herein, the term "nalbuphine (NAL)" includes both nalbuphine itself and nalbuphine in its free base form or a pharmaceutically acceptable salt (other than nalbuphine hydrochloride) or an ester (monoester) of nalbuphine. or a polyester, such as sebacoyl dinalbuphine (SDE), described, for example, in U.S. Pat. No. 6,225,321, which is incorporated herein by reference in its entirety. is meant to include chemical derivatives that are the structure of nalbuphine having

As used herein, the term "acetaminophen (AAP)" is meant to include acetaminophen itself as well as chemical derivatives that are structural acetaminophens that have the same pharmacological effects. For example, US Patent Application No. 14/441,317 (US20170172950A1), which is incorporated herein by reference in its entirety.

According to the present invention, the analgesic pharmaceutical formulations described herein comprise a therapeutically effective amount of a first analgesic that is nalbuphine or a derivative thereof, and/or acetaminophen (AAP) or Including a therapeutically effective amount of a second analgesic that is a derivative.

Preferably, the first analgesic agent or the second analgesic agent described herein is in the form of a composition formulated with one or more pharmaceutically acceptable excipients.

In some specific embodiments, the excipients used herein are Eudragit S100, Dicalcium phosphate dehydrate, Pluronic F68, Hexitol, Crospovidone, Sodium starch glycolate, Aerosil 200, Trichlorosucrose, Menthol, Saccharin, Sodium benzoate, Glyceryl behenate, Laurel Sodium lysate lauryl sulfate), Providedone K30, and complexes thereof.

In some specific embodiments, the pharmaceutical formulations of the present invention are a combination of a first analgesic agent (NAL or derivative thereof) and a second analgesic agent (AAP or derivative thereof) as described herein. Including complexes. In some specific embodiments, the amount of first analgesic is 1 mg or greater, 5 mg or greater, 10 mg or greater, 20 mg or greater, 30 mg or greater, 50 mg or greater, 75 mg or greater per dose. In certain specific embodiments, the amount of second analgesic is 100 mg or more, 200 mg or more, 300 mg or more, 500 mg or more, 750 mg or more, 900 mg or more, 1000 mg or more per dose. In some specific embodiments, the ratio of the second analgesic to the first analgesic (AAP or derivative thereof: NAL or derivative thereof) is 1-1000:1 or greater (eg, about 1.5:1 , 5:1, 10:1, 25:1, 50:1, 75:1, 100:1, 200:1, 300:1, 500:1, or 1000:1).

According to the invention, the pharmaceutical formulations provide synergistic analgesic effects for pain relief.

Synergistic interaction, as used herein, means, for example, the simultaneous action of individual factors or active agents, the sum of the effects of all of which is greater than the effects of the individual factors.

In some specific embodiments, the pharmaceutical formulations comprising the first analgesic agent and the second analgesic agent described herein are more rapid acting when compared to the first analgesic agent alone or the second analgesic agent alone. provide potent analgesic effect and/or longer lasting analgesic effect. In some specific embodiments, a more immediate analgesic effect means producing an analgesic effect within 30 minutes, e.g., within 25 minutes, 20 minutes, or 15 minutes after administration. be able to. In some specific embodiments, a longer duration analgesic effect is one in which the analgesic effect lasts 30 minutes or more, such as 40 minutes or more, 50 minutes or more, 60 minutes or more, 70 minutes or more, 80 minutes or more, 90 minutes or more. or longer, or lasting longer than 100 minutes.

In some specific embodiments, the value when comparing the first analgesic agent in the first analgesic composition or the second analgesic agent in the second analgesic composition, respectively, is the second A pharmaceutical formulation comprising one analgesic and a second analgesic increases the amount of one or more pharmacokinetic parameters (eg, AUC, Tmax) of the first analgesic and the second analgesic in the pharmaceutical formulation. For example, certain pharmacokinetic parameters of a pharmaceutical formulation comprising a first analgesic agent and a second analgesic agent described herein may be the first analgesic agent in the first analgesic composition or the second analgesic agent in the second analgesic composition. It can be at least 20% higher (eg, 30% or more, 50% or more, 1-fold or more, 2-fold or more, or more) than the specified pharmacokinetic parameter of the two analgesics.

In some specific embodiments, side effects include renal toxicity and/or liver toxicity caused by the first analgesic and/or the second analgesic. In some specific embodiments, side effects include respiratory depression or risk of addiction.

An increase in the amount of toxicity index or toxic condition compared to the amount of a control group (or normal group) can be taken as an indication of the induction or development of toxicity (toxic state). As used herein, the terms "normal amount" or "control amount" mean that the stated numerical value is within a range of acceptable values, in which persons skilled in the art and/or medical professionals (e.g., Physicians) would expect healthy subjects or a group with similar physical characteristics and medical history to have such values. A toxicity index or "reduction" in the amount of a toxicity condition when compared to a corresponding toxicity condition can be considered an indication of a reduction or elimination of toxicity. In particular, a toxicity can be considered "eradicated" if the amount of reduction in toxicity index or toxicity condition is close to or below the normal or control amount.

As used herein, toxicity (eg, renal toxicity and/or liver toxicity) can be caused by excess AAP. Overdose means that the dose is greater than a useful or standard dose, which is an effective dose approved by a drug regulatory agency (e.g., the Food and Drug Administration), or to treat or prevent a medical condition or symptom thereof. is an effective dose prescribed by a physician to relieve For example, paracetamol tablets are the currently marketed approved orally administered AAP drug. For adults, the standard dose is 500 mg to 1 g of paracetamol taken every 4 to 6 hours as needed, up to a maximum of 4 g per day. An overdose of AAP means that the dose of AAP is greater than a useful or standard dose (e.g., 5%, 10%, 20%, 30%, 50%, 75%, 100% or more). .

As used herein, the term "treatment" means to treat a disease or a symptom or condition of a disease, by administering one or more active agents to the disease or symptom or condition of the disease or pathogen exacerbation. Including, but not limited to, applying or administering to an individual. The purpose of treatment is to treat, cure, alleviate, alleviate, alter, correct, ameliorate, ameliorate, or affect a disease, a symptom or condition of a disease, a disorder caused by a disease, or an exacerbation of a disease. Specifically, the present invention provides pharmaceutical conjugates and methods for treating pain.

As used herein, terms such as "individual" or "subject" include human or non-human animals, specifically mammals, such as companion animals (e.g., dogs, cats, and the like), It means livestock (eg, cattle, sheep, pigs, horses, etc.) or experimental animals (eg, rats, mice, guinea pigs, etc.).

As used herein, the term "effective amount" means that amount of active ingredient that achieves the desired biological or therapeutic effect (eg, pain relief) in the individual being treated.

For purposes of delivery and uptake, an effective amount of the active ingredient of the present invention can be formulated with pharmaceutically acceptable excipients to form a pharmaceutical preparation in a suitable form. Depending on the route of administration, pharmaceutical compositions according to the invention preferably contain from about 0.1 to about 100% by weight of active ingredient, based on the total weight of the composition. As used herein, the term "pharmaceutically acceptable" means that the carrier is compatible with the active ingredient of the composition (and does not affect the action of the active ingredient); Preferably, the components can be stabilized to make the individual treated safer. The carrier can be a diluent, carrier, excipient, or base of the active ingredient. Some examples of suitable excipients include lactose, glucose, starch, acacia, gelatin, calcium silicate, microcrystalline cellulose, sterile water, syrup, and methylcellulose. The compositions further include lubricants such as talc, magnesium stearate and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate, sweeteners and flavor enhancers. It's okay. After the composition according to the invention is administered to the patient, it can provide rapid, sustained or delayed release of the active ingredient. According to the present invention, the compositions include tablets, pills, powders, buccal tablets, sachets, troches, elixirs, suspensions, emulsions, solutions, syrups, soft and hard gelatin capsules, suppositories, sterile injections, and It may be in the form of a packaged powder.

The pharmaceutical formulations of the present invention are delivered via any physiologically acceptable route, including oral, parenteral (eg, intramuscular, intravenous, subcutaneous, and intraperitoneal), transdermal, suppository, and intranasal methods. be able to. For parenteral administration it is preferably used in the form of a sterile aqueous solution which may contain other substances such as sufficient salts or glucose to make the solution isotonic with blood. For those skilled in the art, without further creative work, the formulation of suitable parenteral compositions can be accomplished under sterile conditions using standard pharmacological techniques which are state of the art. .

In some specific embodiments, the pharmaceutical formulation is selected from the group consisting of, for example, tablets, capsules, pills, powders, granules, solutions, suspensions, emulsions, and combinations thereof, preferably orally administered. is.

In some specific embodiments, the compositions are gels, sprays, emulsions, lozenges, dispersible tablets, tablets, enteric coatings, capsules, soft capsules, granules, suspensions, microspheres, oral implants. , intramuscular injections, intravenous injections, implantable injections, modified release agents, and other pharmaceutically acceptable forms.

In some specific embodiments, preferably a first analgesic agent having a sustained release portion and a second analgesic agent having an immediate release portion, which can preferably provide immediate analgesic and sustained analgesic effects. is to provide

The present invention also provides a method of treating pain in an individual in need thereof comprising administering to the individual a pharmaceutical formulation of an analgesic agent described herein. Specifically, the present invention provides a synergistic interaction of pain relief, as well as improved oral bioavailability and fewer side effects.

Specifically, the methods of the present invention are used to treat moderate to severe/deep pain, such as pain associated with cancer, renal or gallstone colic, migraine or vascular headache, postoperative pain, and burns. Suitable for

In some specific embodiments, the first analgesic and the second analgesic can be administered simultaneously or sequentially.

The invention can be further illustrated by the following examples. However, the following examples are provided for illustration and are not intended to limit the invention.

Example

1. Materials and methods

1.1 Animals

Male Sprague-Dawley rats weighing 260-330 g were purchased from BioLASCO (Taipei, Taiwan). Rats were housed under controlled conditions including a 12-hour light-dark cycle, a temperature of 22° C., and a humidity of 60% (with food and water available ad libitum). All experiments were conducted in accordance with the IACUC Protocol for the Care and Use of Animals, and animals were treated in a legally compliant, ethical and humane manner.

1.2 Medicines and Reagents

Nalbuphine is available from Yung-Shin Pharmaceutical Ind. Co. , Ltd. (Taichung County, Taiwan). SDE is available from Yung-Shin Pharmaceutical Ind. Co. , Ltd. (Taichung County, Taiwan). AAP products (pharmaceutical formulations) are manufactured by China Chemical & Pharmaceutical Co., Ltd. , Ltd. (Hsinchu County, Taiwan). Acetaminophen powder was purchased from Sigma-aldrich (St. Louis, MO, USA). Isoamyl alcohol was obtained from Mallinckrodt baker. lnc. (Phillipsburg, NJ, USA). Hexane was obtained from Avantor Performance Materials, Inc. (Center Valley, PA, USA). Acetonitrile and methanol were purchased from Merck (Darmstadt, Germany). Analysis was performed at liquid chromatography-mass spectrometry (LC-MS) grade.

1.3 Pharmacodynamic studies

For studies of analgesic effects, the claw pressure test of Randall and Selitto was employed. The nociceptive threshold is expressed in grams and was measured with an analgesimeter (IITC Inc. Life Science, Calif.) applied to the rat's left hindpaw nail. All animals were tested 15, 30, and 45 minutes prior to drug treatment to obtain a mean baseline. Results are expressed as percentage of maximum possible effect (%MPE) based on the formula %MPA = (test value - baseline value) / (cutoff value - baseline value) x 100, cutoff value: 750g. . The AUC (area under the curve) was calculated by subtracting the detected value at each time point from the baseline value and integrating it, regardless of each individual, and calculating the average value. Negative values (%MPA and AUC) are considered zero. The %MPA for each individual was independent of the maximum peak value of Tmax and was then averaged. 20% MPA was adopted as the baseline value for effective analgesic effect, and the onset time to reach 20% MPA and the duration of effect of 20% MPA were analyzed. Pharmacodynamic studies were performed with 75 mg/kg SDE alone, AAP product alone (100 mg/kg), and a complex of 75 mg/kg SDE and AAP product (100 mg/kg), or 60 mg/kg NAL alone, AAP Analgesic effects on rats were compared for oral administration of the product alone (100 mg/kg) and a complex of 60 mg/kg NAL and AAP product (100 mg/kg). Anti-nociceptive thresholds were measured after 30, 60, 90, 120, 150, 180, 210, 240, 270, and 300 minutes of drug administration.

1.4 Pharmacokinetic studies

Rats were orally administered 75 mg/kg SDE alone, AAP product (100 mg/kg) alone, and a complex of 75 mg/kg SDE and AAP product (100 mg/kg) and blood samples were collected at different time points. Samples were placed in microcentrifuge tubes containing 20 μL of 20 IU heparin and centrifuged at 13300 rpm for 10 min at 4° C. to separate plasma and stored at −80° C. until experimentation.

A liquid-liquid extraction method was used to extract the concentration of each NAL in the plasma samples. A 0.1 mL aliquot of rat plasma sample was taken and 50 μL of IS (naloxone: 2 μg/mL) was added followed by 50 μL of 1N Na.₂CO₃was added. An extraction solvent (2 mL of n-hexane:isoamyl alcohol=9:1) was added and the sample was shaken for 5 minutes and left at -80° C. for 30 minutes. Pour the upper organic phase into a new glass tube and remove the solvent at 40° C. with a gentle nitrogen flow (Zymark MA, USA) to dryness. The residue was reconstituted with 100 μL of mobile phase and shaken for 30 seconds. Samples were subsequently transferred to autosampler vials and analyzed by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).

The electrospray ionization (ESI) interface was connected to a Biosystems-Sciex API 3000 series triple-quadrupole mass spectrometer (Foster City, CA, USA) using UPLC (Waters Acquity™ Milford, MA, USA). NAL was analyzed by binding to A Waters Acquity UPLC BEH HILIC, 2.1×100 mm, 1.7 μm column was used for chromatographic separations. Mobile phase solvent A is an aqueous solution containing 2 mM ammonium formate and 0.1% formic acid and solvent B is an acetonitrile solution containing 2 mM ammonium formate and 0.1% formic acid. Total run time was 5 minutes and column temperature was maintained at 35°C. The composition of the mobile phase is 13% A and 87% B as follows. The retention times of NAL are 2.89 min and 2.65 min, respectively. NAL Q1 and Q3 are 358.1→340.1 and 328.3→310.3. MS/MS data were collected and processed using Analyst 1.4.2 software (Applied Biosystems-Sciex; Foster City, Calif.). Plasma concentrations of NAL were analyzed using WinNonlin 5.3 software (Pharsight, Mountain View, Calif.). Statistical significance of data obtained from pharmacokinetic and pharmacodynamic studies was determined using PRISM software's One-way ANOVA.

2. result

2.1 Analgesic effect of pharmaceutical formulation (Test 1)

FIG. 1 shows the quantitative results of the anti-pain effects of oral administration of AAP alone, SDE alone, and the complex of AAP and SDE (in which the maximum possible pain relief rate (MPA) % threshold is 100%). ). Anti-pain responses were assessed by calculating AUC (% MPA vs. time) and the duration of MPA greater than 20% in each group (Table 1). Statistical analysis of the data showed that the complex of AAP and SDE exhibited more synergistic analgesic effects than either AAP or SDE alone, and that the complex of AAP and SDE exhibited more synergistic analgesic effects than either AAP or SDE alone. showed a synergistic analgesic effect (p<0.005), among which the complex of AAP and SDE displayed the longest duration of action and the highest AUC value, showing superior It represents bioavailability (p<0.005). Importantly, the complex of AAP and SDE has significantly better synergy than SDE and AAP alone, respectively (p<0.005). The conjugate of AAP and SDE definitely has a synergistic effect on pain relief without the need to adjust the formulation.

2.2 Analgesic effects of multiple pharmaceutical preparations (Test 2)

FIG. 2 shows the quantitative results of the anti-pain effects of oral administration of NAL, AAP, and NAL+AAP (wherein the maximum possible pain relief rate (MPA) % threshold is 100%). Anti-pain responses were assessed by calculating AUC (% MPA versus time) and the duration of MPA greater than 50% in each group (Table 2). Statistical analysis of the data shows that the complex of NAL and AAP exhibits a synergistic analgesic effect over NAL alone or AAP alone (p<0.0001).

Claims (15)

A pharmaceutical formulation for analgesia, comprising:
The pharmaceutical formulation comprises
a therapeutically effective amount of a first analgesic that is sebacoyl dinalbuphine or a compound that causes sebacoyl dinalbuphine to be present in the body after administration; and
a therapeutically effective amount of a second analgesic that is acetaminophen (AAP) or a compound that causes acetaminophen to be present in the body after administration;
A pharmaceutical formulation comprising one or more pharmaceutically acceptable excipients. The one or more pharmaceutically acceptable excipients are poly(methacrylic acid-co-methyl methacrylate), dicalcium phosphate dehydrate, propylene glycol block polyether F68, Hexitol , Crospovidone, Sodium Starch Glycolate, Fumed Doshirica 200, Trichlorosucrose, Mentol, Menthol, Sakkarin. (SACCHARIN), Sodium Benzoate, and Guliceric (Sodium Benzoate) 2. The pharmaceutical formulation according to claim 1, characterized in that it is selected from the group consisting of Glyceryl behenate, Sodium lauryl sulfate, polyvinylpyrrolidone, and complexes thereof. 2. The pharmaceutical formulation of claim 1, comprising a combination of said first analgesic agent and said second analgesic agent. 2. The pharmaceutical formulation of claim 1, wherein the first analgesic is sebacoyl dinalbuphine in free base form or a pharmaceutically acceptable salt. A pharmaceutical formulation for analgesia, comprising:
The pharmaceutical formulation comprises
(i) a first analgesic composition comprising a therapeutically effective amount of a first analgesic that is sebacoyl dinalbuphine or a compound that causes sebacoyl dinalbuphine to be present in the body after administration;
(ii) a second analgesic composition comprising a therapeutically effective amount of a second analgesic that is acetaminophen (AAP) or a compound that causes acetaminophen to be present in the body after administration. pharmaceutical formulation. Poly(methacrylic acid-co-methyl methacrylate), Dicalcium phosphate dehydrate, Propylene glycol block polyether F68, Hexitol, Crospovidone, Sodium starch glycolate, Fumed Silica 200, Trichlorosucrose, Menthol, Saccharin, Sodium benzoate, Glyceryl behenate, Sodium lauryl sulfate, Polyvinyl pyrrolidone, and 6. A pharmaceutical formulation according to claim 5, comprising one or more pharmaceutically acceptable excipients selected from the group consisting of these combinations. 7. A pharmaceutical formulation according to claim 6, further comprising one or more additional excipients as carriers and balances. Pharmaceutical formulation according to claim 5, characterized in that the amount of said first analgesic and said second analgesic is 0-1000 mg. 6. Pharmaceutical formulation according to claim 5, characterized in that it provides a summation/synergistic analgesic effect. When comparing the first analgesic composition or the second analgesic composition, respectively, the overall and synergistic analgesic effects are characterized by higher efficacy, faster onset of analgesic effect, and/or longer analgesic effect. 10. Pharmaceutical formulation according to claim 9, characterized in that it comprises a period of The value when the first analgesic in the first analgesic composition or the second analgesic in the second analgesic composition is compared, respectively, is included in the comprehensive and synergistic analgesic effect of the first analgesic 10. The pharmaceutical formulation of claim 9, wherein the amount of one or more pharmacokinetic parameters of the first analgesic agent in the pharmaceutical composition and the second analgesic agent in the second analgesic composition is increased. . 6. The pharmaceutical formulation of claim 5, wherein the first analgesic is sebacoyl dinalbuphine in free base form or a pharmaceutically acceptable salt. Said pharmaceutical formulations include gels, sprays, emulsions, lozenges, dispersible tablets, tablets, enteric coatings, capsules, soft capsules, granules, suspensions, microspheres, oral implants, intramuscular injections, intravenous injections, implantables. Pharmaceutical formulations according to any of claims 1 to 12, characterized in that they are administered in injection, modified release and other pharmaceutically acceptable forms. Use of a pharmaceutical formulation according to any of claims 1-13 for the manufacture of a medicament for pain relief. A pharmaceutical formulation according to any of claims 1-13 for treating pain in an individual in need thereof.

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