CN113164469A

CN113164469A - Pharmaceutical formulations of dinabulin adipate and acetamidophenol and methods of treating pain

Info

Publication number: CN113164469A
Application number: CN201880096947.3A
Authority: CN
Inventors: 胡幼圃; 陈衍纶
Original assignee: Yage Biological Tech Co ltd
Current assignee: Yage Biological Tech Co ltd
Priority date: 2018-09-03
Filing date: 2018-09-03
Publication date: 2021-07-23
Also published as: CA3111271A1; JP2023078480A; IL280822A; ZA202102209B; JP2021535216A; WO2020047703A1; AU2018440280B2; JP7318987B2; AU2018440280A1; CL2021000309A1; KR20210054560A; EP3846815A4; SG11202101974WA; EP3846815A1

Abstract

The present invention relates to pharmaceutical compositions/conjugates/kits and methods for the treatment of pain that provide synergistic analgesic effects with fewer side effects.

Description

Pharmaceutical formulations of dinabulin adipate and acetamidophenol and methods of treating pain

Technical Field

The present invention relates to novel drug combinations wherein the compounds have synergistic (synergistic) analgesic activity. The invention also relates to a pharmaceutical formulation and method for treating pain, in particular providing enhanced analgesia.

Background

Many drugs have been developed today for the treatment of pain. However, the problem of side effects must be solved. Recent reports published in the Proceeds of the National Academy of Sciences of the United States of America (PNAS) indicate that persons taking non-aspirin non-steroidal anti-inflammatory drugs (non-aspirin non-inflammatory drugs; NSAIDs) ibuprofen (ibuprofen) not only increase the incidence of heart attack and stroke (FDA warnings) each time and last for months, but also threaten fertility. Acetaminophen is not a non-aspirin non-steroidal anti-inflammatory drug (NSAIDs), but has hepatotoxic or nephrotoxic side effects.

In addition, overuse of highly addictive opiates (opioids) poses a health crisis worldwide, particularly in the united states, with over 6 million deaths due to overdosing in 2016 only. In the united states, tens of thousands of people die each year from overdosing with opioids; over 5 million people die in the last year. This is the same number of deaths in the United states in the world of war.

Novel opiates, such as nabufrine (nalbuphine), buprenorphine (buprenorphine), and metofenol (butorphol), so-called narcotic agonist-antagonist analgesics, have been developed. It shows dual action of agonist and antagonist to opioid receptors as reported by Schmidt, W.K. et al (Drug Alcohol depend.14,339, 1985; British Journal of pain.6,11-16,2012), wherein the dual action of those drugs is indicated to have not only high affinity to opioid receptors but also to act as antagonists. For example, nabufrine is an antagonist of the Mu receptor (Mu receptor) and an agonist of the Kappa receptor (Kappa receptor). These agonist/antagonist drugs ameliorate the adverse effects of opiates, such as addiction and respiratory depression. Nabufrine is the most widely used drug and has excellent therapeutic efficacy. After 6 months of continuous use of nabufrine, no obvious addiction or addition effect (addition) was observed. They exhibit only a slight respiratory depression with the narcotic agonist-antagonist analgesics. In clinical use, nabufrine is safer than conventional narcotic analgesics and is classified as narcotic slurry (Drug Alcohol depend.14,339, 1985; Anaesthesist.63,135-143,2014).

Nabufrine is a synthetic agonist-antagonist that is chemically associated with naloxone (a narcotic antagonist) and oxymorphone (an oxymorphone; a potent narcotic analgesic). The effects of nabufrine on kappa receptors, which alternate between the perception of pain and the emotional response to pain, may be obtained by altering the release of neurotransmitters when afferent nerves are sensitive to pain stimuli. Oral administration of nabufrine has been shown to have only one-fourth to one-fifth the efficacy of intramuscular administration of nabufrine (as a post-operative analgesic). The conventional form of nabufrine is not practical for oral administration due to the bioavailability (bioavailability) of less than 5% by oral administration, as described in Br J Clin Pharmacol 1988; 25:264-8.

In this double-blind, randomized, parallel, placebo-controlled study, the analgesic effect of a single oral dose of nabufrine, acetaminophen, and the efficacy contribution of their combination to post-operative pain in 128 hospitalized patients was evaluated. Patients were assessed hourly and reported individually at 6-hour intervals as an indicator of analgesic response. For most total analgesia and spike analgesia assays, nabufrine alone and acetamidophenol alone, both were significantly superior to placebo. However, the efficacy of the conjugate of nabufrine and acetamidophenol was not significant for either analgesic assay, indicating that the conjugate had only additive effects of the components (additive effect), as described in CLIN PHARMACOL THER 1986; 39:295-9.

Oil of dicabuthyl dinalbuphine (SDE) is a pharmaceutically acceptable long-acting dosage form that is administered once a day, or once a few days. Even if administered in large amounts, the occurrence of side effects can be minimized. SDE has the advantages of long duration, side effects, and safety, and can improve treatment quality. For postoperative patients, the dosing interval may be set to 7 days, rather than 3-5 hours. The dosage form of the present invention is administered to patients for the final stage of cancer, rather than hospitalization, giving the same therapeutic efficacy.

An ideal analgesic should exhibit a short onset time (onset time), long-acting, high-potency, no addiction, no or minimal respiratory depression, and should have few side effects. In view of the present global opioid crisis, there is a clear need to provide novel pharmaceutical formulations and methods for treating pain, particularly moderate to severe pain, without addiction, respiratory depression, with short onset, long duration, and few side effects, and with new findings, including combined better results, such as synergy.

Disclosure of Invention

The present invention provides a novel pharmaceutical formulation and method for treating pain. In particular, the pharmaceutical formulation comprises dinabulin adipate (sebacryl dinalbuphine) or a metabolite or derivative thereof and/or acetaminophen (AAP) or a derivative thereof, together with one or more pharmaceutically acceptable excipients. The pharmaceutical formulations of the present invention provide a combined/synergistic (synergistic) effect of pain relief with improved onset time (shorter), duration of action, oral bioavailability (AUC), and peak maxima.

In some embodiments, the pharmaceutical formulations of the invention comprise a therapeutically effective amount of a first analgesic agent which is dicarbamphinium adipate (sebamorphine) or a metabolite or derivative thereof, and/or a therapeutically effective amount of a second analgesic agent which is acetaminophen (AAP) or a derivative thereof, together with one or more pharmaceutically acceptable excipients.

In some embodiments, the pharmaceutical formulations of the present invention comprise:

a first analgesic composition comprising a therapeutically effective amount of a first analgesic agent which is a bisnobufalin adipate (sebamoyl dinalbuphine) or a metabolite or derivative thereof; and

a second analgesic composition comprising a therapeutically effective amount of a second analgesic that is acetamidophenol or a derivative thereof.

In some embodiments, the first analgesic agent is a free base form of bis-nabufrine adipate (rebanyl dinalbuphine) or a pharmaceutically acceptable salt.

In some embodiments, the first analgesic agent is dinabulin adipate (SDE), e.g., as described in U.S. patent No. 6,225,321.

In some embodiments, the first analgesic agent is an agent that acts in an amount effective to enhance the bioavailability of the first analgesic agent.

In some embodiments, the second analgesic agent is acetaminophen (AAP), for example, as described in U.S. patent application No. 14/441,317(US20170172950a 1).

In some embodiments, the excipient used herein is selected from the group consisting of any one of Eudragit S100(Eudragit S100), dicalcium phosphate dehydrate (calcium phosphate dehydrate), Pluronic F68(Pluronic F68), hexitol (hexitol), Crospovidone (Crospovidone), Sodium starch glycolate (Sodium starch glycolate), Aerosil 200, sucralose (sucralose), menthol (menthol), Saccharin (saccharan), Sodium benzoate (Sodium benzoate), Glyceryl behenate (Glyceryl benzoate), Sodium lauryl sulfate (Sodium lauryl sulfate), povidone K30(Providone K30), and combinations thereof.

In some embodiments, the first analgesic composition is formulated in an extended 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 a subject in need thereof, comprising administering to the subject an analgesic drug formulation, or in particular an analgesic drug conjugate as described herein. Also provided is the use of such an analgesic drug preparation or analgesic drug conjugate as described herein for the manufacture of a medicament for the treatment of pain in a subject in need thereof.

The details of one or more embodiments of the invention are set forth in the description below. Other features and advantages of the invention will be apparent from the following detailed description of several specific embodiments, and from the claims.

Drawings

The specific examples shown below are intended to illustrate the invention. It should be understood, however, that the intention is not to limit the invention to the particular embodiments described. In the drawings:

FIG. 1 shows the analgesic effect on SD rats after oral administration of SDE 75mg/kg, AAP 100mg/kg, and a combination thereof (SDE + AAP) using the standard palm pressure test (paw pressure test).

FIG. 2 shows the analgesic effect on SD rats after oral administration of NAL 60mg/kg, AAP 100mg/kg, and combinations thereof using paw pressure test (paw pressure test) in SD rats.

Detailed Description

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.

The articles "a" and "an" as used herein mean one or more (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 terms "comprises," "comprising," or the like, are generally used in an inclusive/sense, meaning that one or more features, ingredients, or components are allowed to be present. The terms "comprising" or "containing" and the like encompass the terms "consisting of or" consisting of.

The present invention provides a novel pharmaceutical formulation and method for treating pain. In particular, the pharmaceutical formulations of the present invention comprise nabufrine or a derivative thereof and/or acetamidophenol or a derivative thereof, together with one or more pharmaceutically acceptable excipients. The pharmaceutical formulations of the present invention can provide a comprehensive and/or synergistic effect of pain relief, improved oral bioavailability, and fewer side effects.

The term "pharmaceutical formulation" as used herein may refer to any form of medicament, e.g., a composition, combination, or kit. A composition may refer to a homogeneous mixture, for example, in a form such as a tablet, capsule, pill, powder, granule, solution, suspension, and emulsion, and any pharmaceutically acceptable form. A combination may refer to a product taken from the combination of two or more active ingredients, which are physically present separately in one or more packaging units for sequential administration according to time. Kits may refer to a collection or combination of the above pharmaceutical preparations, preferably supplied in separate forms within a single container. Preferably, the container also contains instructions for using such pharmaceutical formulations or for carrying out the methods of the invention.

The term "Nalbuphine (NAL)" as used herein is intended to encompass the nalbuphine itself and chemical derivatives of the nalbuphine structure having equivalent pharmaceutical utility, including nalbuphine in free base form or pharmaceutically acceptable salts (except for nalbuphine hydrochloride) or esters of nalbuphine, including mono-or polyesters, such as bisnalbuphine adipate (SDE), as described, for example, in U.S. patent No. 6,225,321, the entire contents of which are incorporated herein by reference.

The term "acetaminophen (AAP)" as used herein is intended to encompass acetaminophen itself as well as chemical derivatives of acetaminopher structures having equivalent pharmaceutical utility, as described, for example, in U.S. patent application No. 14/441,317(US20170172950a1), the entire contents of which are incorporated herein by reference.

According to the present invention, the analgesic pharmaceutical formulation described herein may comprise a therapeutically effective amount of a first analgesic agent which is nabufrine or a derivative thereof, and/or a therapeutically effective amount of a second analgesic agent 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 formulated with one or more pharmaceutically acceptable excipients.

In some embodiments, the excipient used herein is selected from the group consisting of any one of eucalyptus S100, dicalcium phosphate dehydrate, pluronic F68, hexitol (hexitol), crospovidone, Sodium starch glycolate (Sodium starch glycolate), Aerosil 200, sucralose (sucralose), menthol (menthol), Saccharin (saccharan), Sodium benzoate (Sodium benzoate), Glyceryl behenate (Glyceryl benzene sulfonate), Sodium lauryl sulfate (Sodium lauryl sulfate), povidone K30, and combinations thereof.

In some embodiments, the pharmaceutical formulations of the invention comprise a combination of a first analgesic (NAL or derivative thereof) and a second analgesic (AAP or derivative thereof) as described herein. In some embodiments, the amount of the first analgesic agent is 1mg or more, 5mg or more, 10mg or more, 20mg or more, 30mg or more, 50mg or more, 75mg or more per dose. In particular embodiments, the amount of the second analgesic agent is 100mg or more, 200mg or more, 300mg or more, 500mg or more, 750mg or more, 900mg or more, 1000mg or more per dose. In some embodiments, the second analgesic agent and the first analgesic agent (AAP or derivative thereof: NAL or derivative thereof) 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)

Are present.

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

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

In some embodiments, a pharmaceutical formulation comprising a first analgesic agent and a second analgesic agent as described herein provides a faster onset of analgesia and/or a longer duration of analgesia when compared to the first analgesic agent or the second analgesic agent alone. In some embodiments, a more rapid onset of analgesia may refer to analgesia achieved within 30 minutes, such as less than 25 minutes, 20 minutes, or 15 minutes, of administration. In some embodiments, a longer period of analgesia may refer to analgesia lasting more than 30min, such as more than 40min, more than 50min, more than 60min, more than 70min, more than 80min, more than 90min, or more than 100 min.

In some embodiments, a pharmaceutical formulation comprising a first analgesic agent and a second analgesic agent as described herein results in one or more pharmacokinetic parameters (e.g., AUC, T) of the first analgesic agent and the second analgesic agent of the pharmaceutical formulation when compared to the respective value of the first analgesic agent in the first analgesic composition or the second analgesic agent in the second analgesic composition_max) The amount of (c) increases. For example, the values of the particular pharmacokinetic parameter for a pharmaceutical formulation containing a first analgesic agent and a second analgesic agent as described herein can be at least 20% greater (e.g., 30% greater, 50% greater, 1-fold greater, 2-fold greater, or higher) than the value for the first analgesic agent of the first analgesic composition or the second analgesic agent of the second analgesic composition.

In some embodiments, the side effects comprise renal toxicity and/or hepatic toxicity caused by the first analgesic and/or the second analgesic. In some embodiments, the side effect comprises respiratory depression or risk of addiction.

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

Toxicity (e.g., renal toxicity and/or hepatic toxicity) as used herein may be caused by an excess of AAP. Overdose can refer to a dose administered that 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 prescribed by a physician for the treatment or prevention of a disease condition or alleviation of its symptoms. For example, acetamidophenol (paracetamol) tablets are currently marketed as an oral AAP drug, and are administered to adults at standard doses of 500mg to 1g acetamidophenol every 4-6 hours, up to 4g per day, as needed. An excess of AAP refers to a dose that can be greater than a useful or standard dose of AAP, e.g., 5%, 10%, 20%, 30%, 50%, 75%, 100% or more.

The term "treatment" as used herein means a therapeutic measure of a disease or a symptom or condition of a disease, including, but not limited to, the application or administration of one or more active agents to an individual suffering from a disease or disease symptom or condition or exacerbation of a disease. The therapeutic measures are aimed at treating, curing, alleviating, relieving, altering, remedying, ameliorating, improving, or affecting the disease, a symptom or condition of the disease, a disability caused by the disease, or an exacerbation of the disease. In particular, the present invention provides a drug conjugate and a method for treating pain.

As used herein, the terms "individual" or "subject" and the like include a human or non-human animal, particularly a mammal, such as a companion animal (e.g., dogs, cats and the like), farm animal (e.g., cows, sheep, pigs, horses, and the like), or laboratory animal (e.g., rats, mice, guinea pigs, and the like).

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

For delivery and ingestion purposes, an effective amount of the active ingredients of the present invention may be formulated with pharmaceutically acceptable excipients to form a pharmaceutical formulation in a suitable form. Depending on the route of administration, the pharmaceutical compositions of the present invention preferably comprise from 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 ingredients of the composition (and does not interfere with the action of the active ingredients), and preferably, the carrier stabilizes the active ingredients and renders the subject to be treated safe. Such carriers may be diluents, carriers, excipients, or matrices for the active ingredient. Some examples of suitable excipients include lactose, glucose, starch, acacia, gelatin, calcium silicate, microcrystalline cellulose, sterile water, syrup, and methyl cellulose. The composition may additionally comprise lubricating agents, such as talc, magnesium stearate, and mineral oil; a wetting agent; emulsifying and suspending agents; preservatives, such as methyl and propyl hydroxybenzoate; a sweetener; and a flavoring agent. The compositions of the present invention provide rapid, sustained, or delayed release of the active ingredient after administration to a patient. According to the present invention, the composition may be in the form of tablets, pills, powders, buccal tablets, sachets, troches, elixirs, suspensions, emulsions, solutions, syrups, soft and hard gelatin capsules, suppositories, sterile injections, and packaged powders.

The pharmaceutical formulations of the present invention may be delivered via any physiologically acceptable route, such as oral, parenteral (e.g., intramuscular, intravenous, subcutaneous, and intraperitoneal), transdermal, suppository, and intranasal routes. 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 render the solution isotonic with respect to blood. The preparation of suitable parenteral compositions under sterile conditions can be accomplished by standard pharmacological techniques well known to those skilled in the art without the need for additional creative work.

In some embodiments, the pharmaceutical formulation is, for example, a composition in a form 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 a gel, spray, emulsion, lozenge, dispersible tablet, enteric coating, capsule, soft capsule, granule, suspension, microsphere, oral implant, intramuscular injection, intravenous injection, implantable injection, modified release formulation, and other pharmaceutically acceptable forms.

In some embodiments, it is preferred to provide an extended release portion of the first analgesic and an immediate release portion of the second analgesic, which provides a rapid onset of analgesia and an extended duration of analgesia.

The invention also provides a method for treating pain in a subject in need thereof comprising administering to the subject an analgesic pharmaceutical formulation as described herein. In particular, the methods of the invention provide a synergistic effect for pain relief, improved oral bioavailability, and fewer side effects.

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

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

The invention is further illustrated by the following examples, which are provided for purposes of illustration and not limitation.

Examples

1. Materials and methods

1.1 animals

Male Sprague-Dawley rats weighing between 260 and 330 g were purchased from BioLASCO (Taipei, Taiwan, China). Rats were housed under controlled conditions (free access to food and water); comprising a 12 hour light-dark cycle, a temperature of 22 ℃ and a humidity of 60%. All experiments were performed according to the IACUC Protocol for animal Care and Use of Animals, and Animals were treated in a moral and humane manner in compliance with legal regulations.

1.2 drugs and reagents

Nabufrine is supplied by Yung-Shin Pharmaceutical ind, co., Ltd. (taizhou, taiwan, tai). SDE is supplied by Yung-Shin Pharmaceutical ind, co., Ltd. (taizhou, taiwan, china). AAP product (a Pharmaceutical preparation) is supplied by China Chemical & Pharmaceutical co., Ltd. (new bamboo county, taiwan). Acetamidophenol powder was purchased from Sigma-aldrich (St. Louis, Mo., USA). Isoamyl alcohol was purchased from Mallinckrodt baker. 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 on a liquid chromatography-mass spectrometry (LC-MS) scale.

1.3 pharmacodynamic Studies

The analgesic effect was studied using Randall and Selitto's paw pressure test. Pain threshold (nociceptive threshold) is expressed in grams and measured with a pain gauge (algesimeter) (IITC inc. life Science, CA) applied to the left hind paw of the rat. All animals were tested 15, 30, and 45 minutes prior to drug treatment to obtain an average baseline. The results are expressed as percentage of maximum possible effect (% MPE) according to the formula% MPA ═ X100 (test value-baseline value)/(cut-off value-baseline value), cut-off value: 750 g. AUC (area under the curve) is independent of each individual, and the value measured at each time point is subtracted from its baseline value and integrated, and then the average value is calculated. Negative values (% MPA and AUC) were taken as 0. The% MPA for each individual was independent of the Tmax maximum kurtosis, and then the mean was calculated. 20% MPA was used as a baseline value for effective analgesia, and the onset time of action up to 20% MPA and the duration of action of 20% MPA were analyzed. Pharmacodynamic studies were conducted comparing the analgesic effect of orally administered SDE 75mg/kg alone, AAP product alone (100mg/kg), and a combination of SDE 75mg/kg and AAP product (100mg/kg), or NAL 60mg/kg alone, AAP product alone (100mg/kg), and a combination of NAL 60mg/kg and AAP product (100mg/kg) on rats. Anti-nociceptive thresholds (anti-nociceptive thresholds) were determined after 30, 60, 90, 120, 150, 180, 210, 240, 270, and 300 minutes of drug administration.

1.4 pharmacokinetic Studies

Rats received 75mg/kg SDE alone, AAP product alone (100mg/kg), and a combination of 75mg/kg SDE and AAP product (100mg/kg) orally, after which blood samples were collected at various time points. The samples were placed in a microfuge tube containing 20 μ L of 20IU heparin, centrifuged at 13300rpm for 10min at 4 ℃ to separate plasma, and stored at-80 ℃ until testing.

Each NAL concentration in the plasma samples was extracted using liquid-liquid extraction. 0.1mL aliquots of rat plasma samples were removed and 50. mu.L of 1N Na was added₂CO₃Previously, 50. mu.L of IS (naloxone): 2. mu.g/mL) was added. The extraction solvent (2mL of n-hexane: isoamyl alcohol ═ 9:1) was added, and the sample was shaken for 5min and placed at-80 ℃ for 30 min. The upper organic phase was poured into a fresh glass tube and under a gentle stream of nitrogen at 40 ℃: (

MA, USA), the solvent was evaporated to dryness. The residue was reconstituted in 100 μ L mobile phase and shaken for 30 seconds. Subsequently, the samples were transferred to an autosampler vial and analyzed using ultra high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).

NAL was analyzed by UPLC (Waters acquisition, Milford, MA, USA) coupling an electrospray ionization (ESI) interface to a Biosystems-Sciex API 3000 series triple-quadrupole mass spectrometer (Foster City, CA, USA). The chromatographic separation was performed using a Waters Acquity UPLC BEH HILIC, 2.1X 100mm, 1.7 μm column. Mobile phase solvent a was an aqueous solution containing 2mM ammonium formate and 0.1% formic acid, and solvent B was an acetonitrile solution containing 2mM ammonium formate and 0.1% formic acid. The total run time was 5min and the column temperature was maintained at 35 ℃. The moving phase composition is as follows: 13% A and 87% B. The residence times of NAL were 2.89 and 2.65min, respectively. Q1 and Q3 of NAL are 358.1 → 340.1 and 328.3 → 310.3. MS/MS data were collected and processed using Analyst1.4.2 software (Applied Biosystems-Sciex; Foster City, Calif.). NAL plasma concentrations were analyzed using WinNonlin 5.3 software (Pharsight, Mountain View, CA). Statistical significance of data from pharmacokinetic and pharmacodynamic studies was determined using single-factor analysis of variance (One-way ANOVA) from PRISM software.

2. Results

2.1 analgesic action of the pharmaceutical preparations (test 1)

Figure 1 shows the quantitative results of the anti-pain effect of oral administration of AAP alone, SDE alone, and a combination of AAP and SDE, with a threshold of 100% of the maximum possible analgesic effect (MPA). The anti-pain response was assessed using the calculated AUC (% MPA vs. time) and the duration of greater than 20% MPA for each group (table 1). Statistical analysis of the data showed that the combination of AAP and SDE exhibited synergistic analgesic effects compared to AAP or SDE alone, and that the combination of AAP and SDE exhibited synergistic analgesic effects (p <0.005) compared to AAP or SDE alone, with the combination of AAP and SDE exhibiting the relatively longest duration of action and the highest AUC values, representing superior bioavailability (p < 0.005). Importantly, the combination of AAP and SDE had a significantly better synergy (p <0.005) than SDE alone and AAP, respectively. The combination of AAP and SDE did have a synergistic effect in pain relief without the need to adjust the drug formulation.

TABLE 1 parameters of the analgesic effect of AAP alone, SDE alone, and a combination of AAP and SDE on SD rats.

AUC: the area under the curve is the baseline and integral of the detection value at each time point.

% MPA: percentage of analgesia possible at maximum.

Data are expressed as mean ± SE.

Counting: single factor variance analysis.

^ap<0.005, relative to AAP alone;^bp<0.005, relative to SDE alone;^ep<0.01, relative to AAP alone;^dp<0.01, relative to SDE alone;^ep<0.05, relative to AAP alone;^fp<0.05, relative to SDE alone.

2.2 analgesic Effect of multiple pharmaceutical preparations (test 2)

Fig. 2 shows the quantification of the anti-pain effect of oral administration of NAL, AAP, and NAL + AAP (with a threshold of 100% of Maximum Possible Analgesia (MPA)). The anti-pain response was assessed using the calculated AUC (% MPA vs. time) and the duration of greater than 50% MPA for each group (table 2). Statistical analysis of the data showed that NAL in combination with AAP exhibited synergistic analgesic effects (p <0.0001) compared to NAL or AAP alone.

TABLE 2

Data are expressed as mean ± SE.

% MPA: percentage of analgesia possible at maximum.

Counting: single factor variability analysis, # p <0.01, # p <0.005, # p <0.0001, compared to AAP and NAL, respectively.

Claims

1. An analgesic pharmaceutical formulation comprising a therapeutically effective amount of a first analgesic agent which is dinabulin adipate or a metabolite or derivative thereof and/or a therapeutically effective amount of a second analgesic agent which is acetamidophenol, AAP, or a derivative thereof, together with one or more pharmaceutically acceptable excipients.

2. The pharmaceutical formulation of claim 1, wherein the one or more pharmaceutically acceptable excipients are selected from the group consisting of any one of ewing S100, dicalcium phosphate dehydrate, pluronic F68, hexitol, cross-linked polyvinylpyrrolidone, sodium starch glycolate, Aerosil 200, sucralose, menthol, saccharin, sodium benzoate, glyceryl behenate, sodium lauryl sulfate, povidone K30, and combinations thereof.

3. The pharmaceutical formulation of claim 1, comprising a combination of the first analgesic agent and the second analgesic agent.

4. The pharmaceutical formulation of claim 1, wherein the first analgesic agent is a free base form of bis-nabufrine adipate or a pharmaceutically acceptable salt.

5. An analgesic pharmaceutical formulation comprising:

a first analgesic composition comprising a therapeutically effective amount of a first analgesic agent which is dinabulin adipate or a metabolite or derivative thereof; and

a second analgesic composition comprising a therapeutically effective amount of a second analgesic that is acetamidophenol, AAP, or a derivative thereof.

6. The pharmaceutical formulation of claim 5, comprising one or more pharmaceutically acceptable excipients selected from the group consisting of any one of Ewing S100, dicalcium phosphate dehydrate, pluronic F68, hexitol, cross-linked polyvinylpyrrolidone, sodium starch glycolate, Aerosil 200, sucralose, menthol, saccharin, sodium benzoate, glyceryl behenate, sodium lauryl sulfate, Povidone K30, and combinations thereof.

7. The pharmaceutical formulation of claim 6, further comprising one or more additional excipients as carriers and as a balance.

8. The pharmaceutical preparation of claim 5, wherein the first and second analgesic agents are present in an amount of 0-1000 mg.

9. The pharmaceutical formulation of claim 5, which provides combined (summation)/synergistic analgesic effects.

10. The pharmaceutical preparation of claim 9, wherein the combined/synergistic analgesic effect comprises higher efficacy, faster onset of analgesic effect, and/or longer duration of analgesic effect when compared to the first analgesic composition or the second analgesic composition alone.

11. The pharmaceutical preparation of claim 9, wherein the combined/synergistic analgesic effect comprises an increase in the amount of one or more pharmacodynamic parameters of the first analgesic agent and the second analgesic agent in the drug conjugate when compared to the respective value of the first analgesic agent in the first analgesic agent composition or the second analgesic agent in the second analgesic agent composition.

12. The pharmaceutical formulation of claim 5, wherein the first analgesic agent is the free base form of bis-nabufrine adipate or a pharmaceutically acceptable salt.

13. The pharmaceutical formulation of any one of claims 1 to 12, wherein the analgesic composition is administered in the form of a gel, spray, emulsion, lozenge, dispersible tablet, enteric coating, capsule, soft capsule, granule, suspension, microsphere, buccal implant, intramuscular injection, intravenous injection, implantable injection, modified release formulation and other pharmaceutically acceptable forms.

14. A method for treating pain in a subject in need thereof, comprising administering to the subject an analgesic pharmaceutical formulation of any one of claims 1 to 13.

15. Use of an analgesic pharmaceutical preparation according to any one of claims 1 to 13 for the manufacture of a medicament for the treatment of pain in a subject in need thereof.