TWI854959B - Pharmaceutical preparations of sebacoyl dinalbuphine and acetaminophen and methods for treating pain - Google Patents

Abstract

The present invention relates to pharmaceutical compositions/combination/kit and methods for treating pain, which provide synergistic analgesic effects and less side effects.

Description

Pharmaceutical preparation of bisnabufulin sebacate and acetaminophen and method for treating pain

The present invention relates to a novel drug conjugate wherein the compounds have synergistic analgesic activity. The present invention also relates to a pharmaceutical formulation and method for treating pain, specifically providing enhanced analgesic effect.

Many drugs have been developed to treat pain. However, the problem of side effects must be addressed. A recent report published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) found that people who take ibuprofen, a non-aspirin nonsteroidal anti-inflammatory drug (NSAID), not only have an increased risk of heart attack and stroke (FDA warning) for several months each time, but also threaten their fertility. Acetaminophen is not a non-aspirin nonsteroidal anti-inflammatory drug (NSAID), but has hepatotoxic or nephrotoxic side effects.

In addition, the overuse of highly addictive opioids has caused a health crisis around the world, 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 from opioid overdoses every year; more than 50,000 died last year. This is the same number of deaths in the United States during the Vietnam War.

New opium drugs have been developed, such as nalbuphine, buprenorphine, and butorphanol, which are so-called anesthetic agonist-antagonist analgesics. They exhibit dual effects of agonists and antagonists on opium receptors, as reported by Schmidt, W.K. et al. (Drug Alcohol Depend. 14, 339, 1985; British Journal of Pain. 6, 11-16, 2012), which point out that these drugs have dual effects, not only have high affinity for opium receptors, but also can act as antagonists. For example, nabuvolin is a mu receptor antagonist and a kappa receptor agonist. These agonist/antagonist drugs improve the adverse reactions of opium drugs, such as addiction and respiratory depression. Nabuvolin is the most widely used drug with excellent therapeutic efficacy. After 6 months of continuous use of nabuvolin, no obvious addiction and additive effects were found. These anesthetic agonist-antagonist analgesics only show mild respiratory depression. In clinical use, narcotic analgesics are safer than conventional narcotic analgesics and are classified as narcotics slush (Drug Alcohol Depend.14,339,1985; Anaesthesist.63,135-143,2014).

Nabufulin is a synthetic agonist-antagonist chemically related to naloxone (a narcotic antagonist) and oxymorphone (a potent narcotic analgesic). Nabufulin's actions on kappa receptors play a role in both the perception of pain and the emotional response to pain, possibly by altering the release of neurotransmitters from afferent nerves that are sensitive to painful stimuli. Oral nabufulin has been shown to be only one-fourth to one-fifth as effective as intramuscular nabufulin as a postoperative analgesic. Nabufulin in its conventional form is not practical for oral administration because its bioavailability by oral administration is less than 5%, as described in Br J Clin Pharmacol 1988;25:264-8.

In this double-blind, randomized, parallel, placebo-controlled study, the analgesic effects of single oral doses of nabufulin, acetaminophen, and their combination on postoperative pain in 128 hospitalized patients were evaluated. Patients assessed individual reports hourly for 6 hours as an index of analgesic response. Nabufulin alone and acetaminophen alone were significantly superior to placebo for most measures of total and peak analgesia. However, the efficacy of the combination of nabufulin and acetaminophen was not significant for any of the analgesic measures, indicating that the combination had only an additive effect of the components as described in CLIN PHARMACOL THER 1986;39:295-9.

SDE oil is a pharmaceutically acceptable long-acting formulation that is administered once a day or once every few days. Even with large doses, side effects can be minimized. SDE has the advantages of long duration, side effects, and safety, 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 the terminal stage of cancer, the same therapeutic effect can be given to patients by administering the formulation of the present invention instead of hospitalization.

An ideal analgesic should exhibit a short onset time, long-acting, high efficacy, no addiction, no or minimal respiratory depression, and should have few side effects. Due to the current global opioid crisis, there is a clear need to provide novel pharmaceutical formulations and methods for treating pain, especially moderate to severe pain, without addiction, respiratory depression, and with a short onset time, long duration, and few side effects, and with new discoveries, including combining better results, such as synergy.

The present invention provides a novel pharmaceutical preparation and method for treating pain. In particular, the pharmaceutical preparation comprises dinabufulin sebacate or its metabolites or derivatives and/or acetaminophen (AAP) or its derivatives, together with one or more pharmaceutically acceptable formulations. The pharmaceutical preparation of the present invention can provide a summation/synergistic effect of pain relief, as well as improved onset time (shorter), duration of action, oral bioavailability (AUC), and maximum peak.

In some specific embodiments, the pharmaceutical preparation of the present invention comprises a therapeutically effective amount of a first analgesic, which is bisnabufulin sebacate or its metabolites or derivatives, and/or a therapeutically effective amount of a second analgesic, which is acetaminophen (AAP) or its derivatives, together with one or more pharmaceutically acceptable excipients.

In some specific embodiments, the pharmaceutical preparation of the present invention comprises: (i) a first analgesic composition comprising a therapeutically effective amount of a first analgesic, which is bisnabufulin sebacate or a metabolite or derivative thereof; and (ii) a second analgesic composition comprising a therapeutically effective amount of a second analgesic, which is acetaminophen or a derivative thereof.

In some embodiments, the first analgesic is dinabufulin sebacate in free base form or a pharmaceutically acceptable salt thereof.

In some embodiments, the first analgesic is bisnabufulin sebacate (SDE), for example, as described in U.S. Patent No. 6,225,321.

In some embodiments, the first analgesic is administered in an effective amount to act as a bioavailability enhancer of the first analgesic.

In some embodiments, the second analgesic is acetaminophen (AAP), for example, as described in U.S. Patent Application No. 14/441,317 (US20170172950A1).

In some specific embodiments, the excipient used herein is selected from the group consisting of any one of Eudragit S100, dehydrated dicalcium phosphate, Pluronic F68, hexyl alcohol, cross-linked polyvinyl pyrrolidone (Crospovidone), sodium starch glycolate, Aerosil 200, sucralose, menthol, saccharin, sodium benzoate, glyceryl behenate, sodium lauryl sulfate, Providone K30, and combinations thereof.

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

In another aspect, the present invention provides a method for treating pain in an individual in need thereof, comprising administering to the individual an analgesic drug formulation, or in particular an analgesic drug conjugate as described herein. Also provided is the use of such analgesic drug formulation or analgesic drug conjugate as described herein for the manufacture of a medicament for treating pain in an individual in need thereof.

The following description describes the details of one or more specific embodiments of the present invention. Other features or advantages of the present invention will be apparent from the detailed description of the following specific embodiments and the attached patent application scope.

The specific embodiments shown below are intended to illustrate the present invention. However, it should be understood that the present invention is not limited to the preferred specific embodiments shown. In the drawings: Figure 1 shows the analgesic effect of SDE 75mg/kg, AAP 100mg/kg, and their combination (SDE+AAP) on SD rats after oral administration using a standard paw pressure test.

Figure 2 shows the analgesic effect of oral administration of 60mg/kg NAL, 100mg/kg AAP, and their combination on SD rats using the paw pressure test.

Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art in the field of the invention.

As used herein, the articles "a" and "an" refer to one or more than one (i.e., at least one) of the grammatical object of the text. For example, "an element" means one element or more than one element.

The words "include" or "contain" are usually used in the sense of including/covering, meaning that one or more features, ingredients, or components are allowed to be present. The words "include" or "contain" cover the terms "consisting of" or "consisting of".

The present invention provides a novel pharmaceutical preparation and a method for treating pain. Specifically, the pharmaceutical preparation of the present invention comprises nabufulin or its derivatives and/or acetaminophen or its derivatives, together with one or more pharmaceutically acceptable formulations. The pharmaceutical preparation of the present invention can provide a comprehensive/synergistic effect of pain relief, improved oral bioavailability, and fewer side effects.

The term "pharmaceutical preparation" as used herein may refer to any form of drug, for example, a composition, combination, or kit. A composition may refer to a homogeneous mixture, for example, in the form of tablets, capsules, pills, powders, granules, solutions, suspensions, and emulsions and any pharmaceutically acceptable form. A combination may refer to a product obtained by combining two or more active ingredients, which are physically separated in one or more packaging units for administration in a time sequence. A kit may refer to a collection or combination of the above-mentioned pharmaceutical preparations, preferably, supplied in a separate form in a single container. Preferably, the container also contains instructions for using such pharmaceutical preparations or practicing the method of the invention.

The term "Nal" as used herein is intended to cover Nal itself and chemical derivatives of the Nal structure having equivalent pharmaceutical efficacy, including Nal in free base form or pharmaceutically acceptable salts (except Nal hydrochloride) or esters of Nal (including monoesters or polyesters, such as bis-Nal sebacate (SDE), for example, described in U.S. Patent No. 6,225,321, the entire contents of which are hereby incorporated by reference).

The term "acetaminophen (AAP)" as used herein is intended to cover acetaminophen itself and chemical derivatives of the acetaminophen structure with equivalent pharmaceutical efficacy, such as those described in U.S. Patent Application No. 14/441,317 (US20170172950A1), the entire contents of which are hereby incorporated by reference.

According to the present invention, the analgesic drug preparation described herein may include a therapeutically effective amount of a first analgesic, which is nabufulin or a derivative thereof, and/or a therapeutically effective amount of a second analgesic, which is acetaminophen (AAP) or a derivative thereof.

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

In some specific embodiments, the excipient used herein is selected from the group consisting of any one of Eudragit S100, dehydrated dicalcium phosphate, Pluronic F68, hexyl alcohol, cross-linked polyvinyl pyrrolidone, sodium starch glycolate, Aerosil 200, sucralose, menthol, saccharin, sodium benzoate, glyceryl behenate, sodium lauryl sulfate, povidone K30, and combinations thereof.

In some embodiments, the pharmaceutical preparation of the present invention comprises a combination of a first analgesic (NAL or its derivative) and a second analgesic (AAP or its derivative) as described herein. In some embodiments, the amount of the first analgesic is 1 mg or more, 5 mg or more, 10 mg or more, 20 mg or more, 30 mg or more, 50 mg or more, or 75 mg or more per dose. In a specific embodiment, the amount of the 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, or 1000 mg or more per dose. In some specific embodiments, the second analgesic and the first analgesic (AAP or its derivative: NAL or its derivative) are present in a weight ratio of 1-1,000:1 or more (e.g., about 1.5:1, 5:1, 10:1, 25:1, 50:1, 75:1; 100:1, 200:1, 300:1, 500:1, or 1,000:1).

According to the present invention, the pharmaceutical preparation provides a synergistic analgesic effect for pain relief.

Synergy as used herein, for example, means the simultaneous action of individual factors or agents, the sum of their effects being greater than the effect of each individual factor.

In some embodiments, the pharmaceutical preparation containing the first analgesic and the second analgesic described herein provides a faster onset of analgesia and/or a longer analgesic duration when compared to the first analgesic or the second analgesic alone. In some embodiments, a faster onset of analgesia may mean that the analgesia is achieved within 30 minutes of administration, such as less than 25 minutes, 20 minutes, or 15 minutes. In some embodiments, a longer analgesic duration may mean that the analgesic effect lasts for more than 30 minutes, such as more than 40 minutes, more than 50 minutes, more than 60 minutes, more than 70 minutes, more than 80 minutes, more than 90 minutes, or more than 100 minutes.

In some embodiments, a pharmaceutical formulation comprising the first analgesic and the second analgesic described herein provides for an increase in the amount of one or more pharmacokinetic parameters (e.g., AUC, _Tmax) of the first analgesic and the second analgesic in the pharmaceutical formulation when compared to the individual values of the first analgesic in the first analgesic composition or the second analgesic in the second analgesic composition. For example, the specific pharmacokinetic parameter value of the pharmaceutical formulation containing the first analgesic and the second analgesic described herein may be at least 20% higher (e.g., 30% higher, 50% higher, 1-fold higher, 2-fold higher, or higher) than that of the first analgesic of the first analgesic composition or the second analgesic of the second analgesic composition.

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

An increase in the amount of a toxicity index or condition compared to the amount of a control group (or normal group) can be considered an indicator of the induction or occurrence of toxicity (toxic state). As used herein, the terms "normal amount" or "control group amount" mean that the described value is within the acceptable range of values, where a person of ordinary skill in the art and/or a medical professional (e.g., a physician) would expect a healthy individual or a group with similar physical characteristics and medical history to have that value. A "reduction" in the amount of a toxicity index or condition, when compared to the corresponding toxic state, can be considered an indicator of reduced or eliminated toxicity. In particular, when the amount of the reduction in the toxicity index or condition is close to or even lower than the normal amount or control group amount, the toxicity can be considered "eradicated".

As used herein, toxicity (e.g., renal toxicity and/or hepatotoxicity) may result from an overdose of AAP. An overdose may refer to an amount administered that is greater than the useful or standard dose, which is an effective dose approved by a drug regulatory agency (e.g., the Food and Drug Administration) or prescribed by a physician for the treatment or prevention of a disease condition or the relief of its symptoms. For example, paracetamol tablets are currently marketed as an approved oral AAP medication, with a standard dose of 500 mg to 1 g of paracetamol taken every 4-6 hours, up to a maximum of 4 g per day, for adults, as needed. An overdose of AAP refers to a dose that is greater than the useful or standard dose of AAP by, for example, 5%, 10%, 20%, 30%, 50%, 75%, 100%, or more.

As used herein, the term "treatment" means a treatment for a disease or a symptom or condition of a disease, including, but not limited to, applying or administering one or more active agents to an individual suffering from a disease or a symptom or condition of a disease or a deterioration of a disease. The purpose of the treatment is to cure, treat, alleviate, relieve, alter, remedy, improve, improve, or affect a disease, a symptom or condition of a disease, a disability caused by a disease, or a deterioration of a disease. In particular, the present invention provides a drug conjugate and a method for treating pain.

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

As used herein, the term "effective amount" means the amount of an active ingredient that achieves the desired biological efficacy or therapeutic effect in the subject to be treated (e.g., pain relief).

For the purpose of delivery and uptake, an effective amount of the active ingredient of the present invention can be formulated with a pharmaceutically acceptable excipient to form a suitable form of pharmaceutical preparation. Depending on the route of administration, the pharmaceutical composition of the present invention preferably contains about 0.1 to about 100% by weight of the active ingredient, based on the total weight of the composition. The term "pharmaceutically acceptable" as used herein means that the carrier is compatible with the active ingredient of the composition (and does not affect the action of the active ingredient), and preferably, the carrier can stabilize the active ingredient and make the individual to be treated safe. Such carriers can be diluents, vehicles, excipients, or substrates for the active ingredient. Some examples of suitable excipients include lactose, glucose, starch, gum arabic, gelatin, calcium silicate, microcrystalline cellulose, sterile water, syrup, and methylcellulose. The composition may additionally contain lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate; sweeteners; and flavoring agents. The composition of the present invention can provide a rapid, sustained, or delayed release of the active ingredient after administration to a patient. According to the present invention, the composition can be in the form of tablets, pills, powders, buccal tablets, packets, troches, elixirs, suspensions, emulsions, solutions, syrups, soft and hard gelatin capsules, suppositories, sterile injections, and packaged powders.

The pharmaceutical preparation of the present invention can be delivered by any physiologically acceptable route, such as oral, parenteral (such as intramuscular, intravenous, subcutaneous, and intraperitoneal), transdermal, suppository, and intranasal methods. For parenteral administration, it is preferably used in the form of a sterile aqueous solution, which may contain other substances, such as salts or glucose, sufficient to make the solution isotonic to the blood. The preparation of suitable parenteral compositions under sterile conditions can be accomplished by standard pharmacological techniques known to those skilled in the art without the need for additional creative labor.

In some embodiments, the pharmaceutical preparation is, for example, a composition selected from the group consisting of tablets, capsules, pills, powders, granules, solutions, suspensions, and emulsions, preferably for oral administration.

In some embodiments, the composition is administered in the form of gel, spray, emulsion, tablet, dispersible tablet, tablet, enteral coating, capsule, soft capsule, granule, suspension, microsphere, oral implant, intramuscular injection, intravenous injection, implantable injection, modified release form and other pharmaceutically acceptable forms.

In some embodiments, it is preferred to provide a first analgesic with a delayed release portion and a second analgesic with an immediate release portion, which can provide a rapid onset of analgesia and a prolonged analgesia.

The present invention also provides a method for treating pain in an individual in need thereof, comprising administering to the individual an analgesic drug formulation described herein. Specifically, the method of the present invention provides synergistic effects in relieving pain, improved oral bioavailability, and fewer side effects.

In particular, the methods of the invention are useful for treating moderate to severe/deep pain, such as pain associated with cancer, renal or biliary colic, migraine or vascular headaches, surgical pain, and burns.

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

The present invention may be further illustrated by the following examples, which are provided for the purpose of illustration and not limitation.

Embodiment

1. Materials and methods

1.1 Animals

Male Sprague-Dawley rats weighing between 260 and 330 g were purchased from BioLASCO (Taipei, Taiwan). Rats were housed under controlled conditions (free access to food and water); including a 12-h light-dark cycle, a temperature of 22°C, and a humidity of 60%. All experiments were conducted in accordance with the IACUC Protocol for the Care and Use of Animals, and animals were treated ethically and humanely in accordance with legal regulations.

1.2 Drugs and reagents

Nabufulin was supplied by Yung-Shin Pharmaceutical Ind. Co., Ltd. (Taichung County, Taiwan). SDE was supplied by Yung-Shin Pharmaceutical Ind. Co., Ltd. (Taichung County, Taiwan). AAP product (a drug preparation) was supplied by China Chemical & Pharmaceutical Co., Ltd. (Hsinchu County, Taiwan). Acetaminophen powder was purchased from Sigma-aldrich (St. Louis, MO, USA). Isoamyl alcohol was purchased from Mallinckrodt baker.lnc. (Phillipsburg, NJ, USA). Hexane was purchased from Avantor performance materials, lnc. (Center Valley, PA, USA). Acetonitrile and methanol were purchased from Merck (Darmstadt, Germany). The analysis was performed by liquid chromatography-mass spectrometry (LC-MS).

1.3 Pharmacodynamic studies

The analgesic effect was studied using the Randall and Selitto paw pressure test. The nociceptive threshold was expressed in grams and was measured with an analgesimeter (IITC Inc. Life Science, CA) applied to the left hind paw of the rat. All animals were tested 15, 30, and 45 minutes before drug treatment to obtain a mean baseline. The results were expressed as the maximum possible effect percentage (% MPE) according to the formula % MPA = (test value - baseline value) / (cutoff value - baseline value) X 100, cutoff value: 750 g. The AUC (area under the curve) was independent of each individual, and the test value at each time point was subtracted from its own baseline value and integrated, and then the mean value was calculated. Negative values (% MPA and AUC) were considered to be 0. The %MPA of each individual was not related to the maximum peak value of Tmax, and the average value was then calculated. Taking 20% MPA as the baseline value of effective analgesia, the onset time to reach 20% MPA and the duration of action of 20% MPA were analyzed. Pharmacodynamic studies were conducted to compare the analgesic effects of oral administration of SDE 75mg/kg alone, AAP product alone (100mg/kg), and the combination of SDE 75mg/kg and AAP product (100mg/kg), or NAL 60mg/kg alone, AAP product alone (100mg/kg), and the combination of NAL 60mg/kg and AAP product (100mg/kg) in rats. Anti-nociceptive thresholds were measured 30, 60, 90, 120, 150, 180, 210, 240, 270, and 300 minutes after drug administration.

1.4 Pharmacokinetic studies

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

The concentration of each NAL in plasma samples was extracted by liquid-liquid extraction. A 0.1 mL aliquot of rat plasma sample was taken and 50 μL of IS (naloxone: 2 μg/mL) was added before adding 50 μL of 1N Na ₂ CO _3. The extraction solvent (2 mL of n-hexane: isoamyl alcohol = 9:1) was added, the sample was shaken for 5 min and placed at -80°C for 30 min. The upper organic phase was poured into a new glass tube and the solvent was evaporated to dryness under a gentle nitrogen flow at 40°C (Zymark® MA, USA). The residue was reconstituted in 100 μL of mobile phase and shaken for 30 seconds. The samples were then transferred to autosampler vials and analyzed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).

NAL was analyzed by UPLC (Waters AcquityTM Milford, MA, USA) coupled to an electrospray ionization (ESI) interface on a Biosystems-Sciex API 3000 series triple-quadrupole mass spectrometer (Foster City, CA, USA). The separation was performed using a Waters Acquity UPLC BEH HILIC, 2.1×100 mm, 1.7 μm column. The mobile phase solvent A was an aqueous solution containing 2 mM ammonium formate and 0.1% formic acid, and solvent B was an acetonitrile solution containing 2 mM ammonium formate and 0.1% formic acid. The total run time was 5 min, and the column temperature was maintained at 35°C. The mobile phase composition was as follows: 13% A and 87% B. The retention times of NAL were 2.89 and 2.65 mm, respectively. The Q1 and Q3 of NAL were 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, CA). NAL plasma concentrations were analyzed using WinNonlin 5.3 software (Pharsight, Mountain View, CA). One-way ANOVA using PRISM software was used to determine the statistical significance of the data obtained from the pharmacokinetic and pharmacodynamic studies.

2. Results

2.1 Analgesic effect of pharmaceutical preparations (Test 1)

Figure 1 shows the quantitative results of the antinociceptive effects of oral administration of AAP alone, SDE alone, and the combination of AAP and SDE (where the threshold of maximal possible analgesia (MPA) % is 100%). The antinociceptive response was evaluated by calculating AUC (%MPA over time) and the duration of MPA greater than 20% in each group (Table 1). Statistical analysis of the data showed that the combination of AAP and SDE exhibited synergistic analgesia compared with AAP or SDE alone, and the combination of AAP and SDE exhibited synergistic analgesia compared with AAP or SDE alone ( p <0.005), among which the combination of AAP and SDE exhibited the longest relative duration of action and the highest AUC value, representing superior bioavailability ( p <0.005). Importantly, the combination of AAP and SDE had a significantly superior synergistic effect than SDE and AAP alone ( p < 0.005). The combination of AAP and SDE does have a synergistic effect in relieving pain, without the need to adjust the drug formulation.

2.2 Analgesic effects of multiple pharmaceutical preparations (Test 2)

Figure 2 shows the quantitative results of the antinociceptive effects of oral administration of NAL, AAP, and NAL+AAP (where the threshold of maximum possible analgesia (MPA)% is 100%). The antinociceptive response was evaluated by calculating AUC (%MPA over time) and the duration of MPA greater than 50% in each group (Table 2). Statistical analysis of the data showed that the combination of NAL and AAP exhibited a synergistic analgesic effect compared with NAL or AAP alone (p<0.0001).

Claims (12)

An analgesic pharmaceutical preparation comprising a therapeutically effective amount of a first analgesic, which is dinabufulin sebacate, and a therapeutically effective amount of a second analgesic, which is acetaminophen (AAP), together with one or more pharmaceutically acceptable excipients. The pharmaceutical preparation of claim 1, wherein the one or more pharmaceutically acceptable excipients are selected from the group consisting of Eudragit S100, dehydrated dicalcium phosphate, Pluronic F68, hexyl alcohol, cross-linked polyvinyl pyrrolidone (Crospovidone), sodium starch glycolate, Aerosil 200, sucralose, menthol, saccharin, sodium benzoate, glyceryl behenate, sodium lauryl sulfate, Providone K30, and any combination thereof. The pharmaceutical preparation of claim 1, wherein the first analgesic is bisnabufulin sebacate in free base form. An analgesic pharmaceutical preparation comprising: (i) a first analgesic composition comprising a therapeutically effective amount of a first analgesic, which is dinabufulin sebacate; and (ii) a second analgesic composition comprising a therapeutically effective amount of a second analgesic, which is acetaminophen. The pharmaceutical preparation of claim 4 comprises one or more pharmaceutically acceptable excipients selected from the group consisting of any one of Eudragit S100, dehydrated dicalcium phosphate, Pluronic F68, hexyl alcohol, cross-linked polyvinyl pyrrolidone, sodium starch glycolate, Aerosil 200, sucralose, menthol, saccharin, sodium benzoate, glyceryl behenate, sodium lauryl sulfate, povidone K30, and combinations thereof. The pharmaceutical preparation of claim 5 further comprises one or more additional excipients to serve as carriers and balance. The pharmaceutical preparation of claim 4 provides a synergistic analgesic effect. The pharmaceutical preparation of claim 7, wherein the synergistic analgesic effect comprises higher efficacy, faster onset of analgesia, and/or longer duration of analgesia when compared to the first analgesic composition or the second analgesic composition alone. The pharmaceutical preparation of claim 7, wherein the synergistic analgesic effect comprises an increase in the amount of one or more pharmacodynamic parameters of the first analgesic and the second analgesic in the drug combination when compared to the individual values of the first analgesic in the first analgesic composition or the second analgesic in the second analgesic composition. The pharmaceutical preparation of claim 4, wherein the first analgesic is bisnabufulin sebacate in free base form. A pharmaceutical preparation as claimed in any one of claims 1 to 10, wherein the analgesic composition is administered in the form of gel, spray, emulsion, tablet, dispersible tablet, tablet, enteral coating, capsule, soft capsule, granule, suspension, microsphere, oral implant, intramuscular injection, intravenous injection, implantable injection, modified release dosage form and other pharmaceutically acceptable forms. A use of an analgesic pharmaceutical preparation as claimed in any one of claims 1 to 11 for the manufacture of a medicament for treating pain in an individual in need thereof.