TW202010496A - 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

Medicinal preparation of dinabufurin adipate and acetaminophen and method for treating pain

The present invention relates to a novel drug conjugate in which the compound has synergistic analgesic activity. The invention also relates to a pharmaceutical preparation and method for treating pain, in particular to provide an enhanced analgesic effect.

Many medicines have been developed for the treatment of pain. However, the problem of side effects must be resolved. A recent report published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) stated that taking non-aspirin nonsteroidal anti-inflammatory drugs (non-aspirin nonsteroidal anti-inflammatory drugs ; NSAIDs) Ibuprofen (ibuprofen) people, not only will increase the rate of heart attacks and strokes (FDA warning) for several months, but also make their fertility threatened. Acetaminophen is not a non-aspirin non-steroidal anti-inflammatory drug (NSAIDs), but has side effects of hepatotoxicity or nephrotoxicity.

In addition, the excessive use of highly addictive opioids has caused a health crisis worldwide, especially in the United States, where more than 60,000 people died from overdose in 2016 alone. In the United States, tens of thousands of people die from opioid overdose each year; more than 50,000 people died last year. This is the same as the number of Americans who died in the Vietnam War.

New opioids have been developed, such as nalbuphine, buprenorphine, butorphanol, also known as anesthesia agonist-antagonist analgesics. It exhibits dual effects on agonists and antagonists of opioid receptors, as reported by Schmidt, WK et al. (Drug Alcohol Depend. 14, 339, 1985; British Journal of Pain. 6, 11-16, 2012) , Which states that the dual action of their drugs not only has a high affinity for opioid receptors, but also acts as an antagonist. For example, Nabufurin is an antagonist of µ receptor (Mu receptor) and an agonist of Kappa receptor (Kappa receptor). Their agonist/antagonist drugs improve the adverse effects of opioids, such as addiction and respiratory depression. Nabufurin is the most widely used drug with excellent therapeutic efficacy. After 6 months of continuous use of Nabufurin, no obvious addiction and addition were found. Their anesthesia agonist-antagonist analgesics showed only slight respiratory depression. In clinical use, nabufurin is safer than conventional anesthetic analgesics and is classified as narcotics slush (Drug Alcohol Depend. 14, 339, 1985; Anaesthesist. 63, 135-143, 2014) .

Nabufurin is a synthetic agonist-antagonist, which is chemically related to naloxone (naxloxone; anesthetic antagonist) and oxymorphone (oxymorphone; a powerful anesthetic analgesic). The effect of nabufurin on κ receptors occurs alternately in the perception of pain and the emotional response to pain, possibly by changing the release of neurotransmitters when the afferent nerves are sensitive to pain stimuli. It has been confirmed that oral administration of nabufurin has only one-fourth to one-fifth of the effect of intramuscular injection of nabufurin (as an analgesic after surgery). Nabufulin in its conventional form is not practical when administered orally, because the bioavailability of 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 a single oral dose of nabufurin and acetaminophen and their combination on postoperative pain in 128 hospitalized patients were evaluated Contribution of efficacy. The patient is evaluated every hour and a 6-hour individual report can be used as an indicator of analgesic response. For the determination of most total analgesia and peak analgesia, nabfuline alone and acetaminophen alone are significantly better than placebo. However, for any analgesic assay, the efficacy of the combination of nabufurin and acetaminophen is not significant, indicating that the combination has only an additive effect of the components, as described in CLIN PHARMACOL THER 1986; 39:295 -9.

Sinabufulin adipate (SDE) oil is a pharmaceutically acceptable long-acting dosage form, which is administered once a day or once every 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 the quality of treatment. For postoperative patients, the dosing interval can be set to 7 days instead of 3-5 hours. For the final cancer stage, the dosage form of the present invention administered to the patient, rather than hospitalization, can give the same therapeutic effect.

An ideal analgesic should exhibit short onset time, long-acting, high efficiency, no addiction, no or minimal respiratory depression, and should have few side effects. Due to the current global crisis of opioids, there is clearly a need to provide novel pharmaceutical preparations and methods for the treatment of pain, especially moderate to severe pain without addiction, respiratory depression, and with short onset and long duration, and There are fewer side effects, and there are new discoveries, including better results, such as synergy.

The present invention provides a novel pharmaceutical preparation and method for treating pain. In particular, the pharmaceutical preparation comprises bisnabufurine adipate or its metabolite or derivative and/or acetaminophen (AAP) or its derivative, together with one or more pharmaceutically acceptable excipients. 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 embodiments, the pharmaceutical preparation of the present invention comprises a therapeutically effective amount of one of the first analgesics, which is dinabufurine adipate or its metabolite or derivative, and/or a therapeutically effective amount of the second An analgesic, which is acetaminophen (AAP) or its derivatives, in combination 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 the first analgesic agent, which is bisnabufurine adipate or its metabolite or Derivatives; and (ii) a second analgesic composition comprising a therapeutically effective amount of a second analgesic, which is acetaminophen or a derivative thereof.

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

In some specific embodiments, the first analgesic agent is bisnabufurine adipate (SDE), for example, as described in US Patent No. 6,225,321.

In some 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 agent is acetaminophen (AAP), for example, as described in US Patent Application No. 14/441,317 (US20170172950A1).

In some specific embodiments, the excipients used herein are selected from Eudragit S100 (Eudragit S100), dehydrated dicalcium phosphate, Pluronic F68 (Pluronic F68), hexitol, cross-linked polyvinylpyrrolidone ( Crospovidone), sodium starch glycolate, Aerosil 200, sucralose, menthol, saccharin, sodium benzoate, glyceryl behenate, sodium lauryl sulfate, Providone K30 (Providone K30), and any combination thereof Formed into groups.

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 an individual in need thereof, comprising administering to the individual an analgesic pharmaceutical formulation, or specifically an analgesic pharmaceutical conjugate described herein. Also provided is the use of such analgesic pharmaceutical preparations or analgesic drug conjugates described herein for the manufacture of a medicament for the treatment of pain in an individual in need.

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

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

The articles "a" and "one" used in this article mean one or more than one grammatical object in the text (ie, at least one). For example, "a component" means one component or more than one component.

The words "comprising" or "containing" are generally used in the meaning of including/covering, meaning that one or more features, ingredients, or components are allowed. The words "contains" or "contains" cover the terms "consisting of" or "consisting of ~".

The invention provides a novel pharmaceutical preparation and a method for treating pain. In particular, the pharmaceutical preparation of the present invention comprises nabufurin or its derivatives and/or acetaminophen or its derivatives, together with one or more pharmaceutically acceptable excipients. 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 medicine, for example, a composition, combination, or kit. The composition may refer to a homogeneous mixture, for example, in the form of, for example, tablets, capsules, pills, powders, granules, solutions, suspensions, and emulsions, and any pharmaceutically acceptable form. Combination may refer to a product taken from combining two or more active ingredients, which are physically separated in one or more packaging units to be administered in chronological order. The kit may refer to a collection or combination of the above-mentioned pharmaceutical preparations, preferably, supplied in a separate form within a single container. Preferably, the container also contains instructions for using such pharmaceutical preparations or implementing the method of the invention.

The term "Nabufurin (NAL)" used in this article is intended to cover the chemical derivatives of Nabufurin itself and the structure of Nabufurin with the same drug effect, including Nabufurin or the free base form Pharmaceutically acceptable salts (except Nabufurin hydrochloride) or Nabufurin esters (including monoesters or polyesters, such as dinabufurin adipate (SDE), for example, Described in US Patent No. 6,225,321, the entire contents of which are hereby incorporated into this case as a reference).

The term "acetaminophen (AAP)" as used herein is intended to cover acetaminophen itself and chemical derivatives of acetaminophen structures with equivalent pharmaceutical utility, for example, described in US Patent Application No. 14/441,317 (US20170172950A1), the entire contents of which are here Incorporated into this case for reference.

According to the present invention, the analgesic pharmaceutical formulation described herein may include a therapeutically effective amount of the first analgesic, which is nabfuline or its derivatives, and/or a therapeutically effective amount of the second analgesic, which is acetaminophen (AAP) or its derivatives.

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

In some specific embodiments, the excipients used herein are selected from the group consisting of Utech S100, dehydrated dicalcium phosphate, pluronic F68, hexitol, cross-linked polyvinylpyrrolidone, sodium starch glycolate, Aerosil 200 , Sucralose, menthol, saccharin, sodium benzoate, glyceryl behenate, sodium lauryl sulfate, povidone K30, and any combination thereof.

In some specific embodiments, the pharmaceutical formulation of the present invention comprises a combination of a first analgesic (NAL or its derivative) and a second analgesic (AAP or its derivative) described herein. In some specific 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 specific embodiments, 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, and 1000 mg or more per dose. In some specific embodiments, the second analgesic agent and the first analgesic agent (AAP or its derivative: NAL or its derivative) are in a weight ratio of 1-1,000: 1 or more (eg, 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) exist.

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

The synergistic effect used herein means, for example, the simultaneous action of individual factors or active agents, the sum of all effects of which is greater than the effect of individual factors.

In some embodiments, when compared to the first analgesic agent or the second analgesic agent alone, the pharmaceutical formulation containing the first analgesic agent and the second analgesic agent described herein provides a faster-acting analgesic effect and /Or longer duration of analgesic effects. In some specific embodiments, the faster-acting analgesic effect may refer to the analgesic effect within 30 minutes of administration, such as less than 25 minutes, 20 minutes, or 15 minutes. In some embodiments, a longer period of analgesic effect may refer to an analgesic effect lasting more than 30 min, such as more than 40 min, more than 50 min, more than 60 min, more than 70 min, more than 80 min, more than 90 min, or 100 min the above.

In some embodiments, when compared to the individual values of the first analgesic agent in the first analgesic composition or the second analgesic agent in the second analgesic composition, the first analgesic agent described herein contains The pharmaceutical preparation of the second analgesic increases the amount of one or more pharmacokinetic parameters (eg, AUC, T _max ) of the first analgesic and the second analgesic of the pharmaceutical preparation. For example, the specific pharmacokinetic parameter values of the pharmaceutical formulation containing the first analgesic and second analgesic described herein may be comparable to the first analgesic of the first analgesic composition or the second analgesic of the second analgesic composition The height of the agent is at least 20% or more (eg, 30% or more, 50% or more, more than 1 times, more than 2 times, or higher).

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

Compared with the amount of the control group (or normal group), the increase of the toxicity index or condition can be regarded as an indicator of the induction or occurrence of toxicity (toxic state). The terms "normal amount" or "control amount" as used herein mean that the described value is within an acceptable range of values, where a person of ordinary skill in the art and/or medical professional (eg, doctor) expects a healthy individual Or groups with similar physical characteristics and medical history have this value. When compared with the corresponding toxicity status, the amount of toxicity index or condition is "reduced", which can be regarded as an index of toxicity reduction or elimination. In particular, when the reduction in toxicity index or condition is close to or even lower than the normal amount or the control amount, the toxicity can be regarded as "eradication".

The toxicity (such as nephrotoxicity and/or hepatotoxicity) used in this article can be caused by excessive AAP. An overdose may refer to a dose greater than a useful or standard dose, which is an effective dose approved by a drug regulatory agency (such as the Food and Drug Administration) or prescribed by a physician to treat or prevent a disease state or alleviate its symptoms. For example, acetaminophen (paracetamol) tablets are currently approved on the market for oral administration of AAP drugs. For adults, the standard dose is 500 mg to 1 g of acetaminophen every 4-6 hours as needed. , Up to 4 g per day. AAP overdose refers to a dose that can be greater than the useful or standard dose of AAP, for example, 5%, 10%, 20%, 30%, 50%, 75%, 100% or more.

The term "treatment" as used herein means a treatment for a disease or a symptom or condition of a disease, including but not limited to, the application or administration of one or more activities of an individual suffering from a disease or a disease symptom or condition or aggravation of the disease Agent. The purpose of treatment is to treat, cure, alleviate, alleviate, change, remedy, improve, improve, or affect the disease, the symptoms or conditions of the disease, the disability caused by the disease, or the deterioration of the disease. In particular, the present invention provides a drug conjugate and method for treating pain.

The terms "individual" or "subject" as used herein 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.).

The term "effective amount" as used herein means that the amount of an active ingredient achieves the desired biological effect or therapeutic effect on the individual who is to be treated (such as pain relief).

For the purpose of delivery and ingestion, 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 from about 0.1 to about 100% by weight of 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 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, carriers, excipients, or bases of the active ingredients. 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 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. After the composition of the present invention is administered to a patient, it can provide the effect of rapid, sustained, or delayed release of the active ingredient. According to the invention, the composition can 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 packaging powder.

The pharmaceutical preparations of the present invention can be delivered via any physiologically acceptable route, such as oral, parenteral (such as muscle, vein, subcutaneous, and abdominal cavity), 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 non-oral compositions under sterile conditions can be accomplished using standard pharmacological techniques known to those skilled in the art, without the need for additional creative work.

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 Oral administration.

In some specific embodiments, the composition is a gel, spray, emulsion, lozenge, dispersible tablet, tablet, enteral coating agent, capsule, soft capsule, granule, suspension, microsphere , Oral implants, intramuscular injections, intravenous injections, implantable injections, modified release agents and other pharmaceutically acceptable forms.

In some embodiments, it is preferred to provide a first analgesic with an extended-release portion and a second analgesic with an immediate-release portion, which can provide a fast-acting analgesic effect and a prolonged analgesic effect.

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

In particular, the method of the present invention is suitable for the treatment of 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 present invention can be further illustrated by the following examples, which are provided for illustration rather than limitation.

Examples

1. Materials and Methods

1.1 animal

Male Sprague-Dawley rats weighing between 260 and 330 grams were purchased from BioLASCO (Taipei, Taiwan). The rats were kept under controlled conditions (free access to food and water); including a 12-hour light-dark cycle, a temperature of 22°C, and a humidity of 60%. All experiments are conducted in accordance with IACUC's Protocol for the Care and Use of Animals, and animals are treated in a ethical and humane manner consistent with the law.

1.2 Drugs and reagents

Nabfulin is supplied by Yung-Shin Pharmaceutical Ind. Co., Ltd. (Taichung County, Taiwan). SDE is supplied by Yung-Shin Pharmaceutical Ind. Co., Ltd. (Taichung County, Taiwan). AAP products (a pharmaceutical preparation) are 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, Inc. (Center Valley, PA, USA). Acetonitrile and methanol were purchased from Merck (Darmstadt, Germany). The liquid chromatography-mass spectrometry (LC-MS) grade was used for analysis.

1.3 Pharmacodynamic study

The analgesic effect study uses the claw pressure test of Randall and Selitto. The nociceptive threshold is expressed in grams and measured with an analgesimeter (IITC Inc. Life Science, CA), which is applied to the left hind paw of rats. All animals were tested at 15, 30, and 45 minutes before drug treatment to obtain an average baseline. The result is expressed as a percentage of maximum possible effect (% MPE), based on the formula% MPA = (test value – baseline value) / (cutoff value – baseline value) X 100, cutoff value: 750 g. AUC (area under the curve) has nothing to do with each individual body. The measured value at each time point is subtracted from its baseline value and integrated, then the average value is calculated. Negative values (%MPA and AUC) are regarded as 0. The %MPA of each body has nothing to do with the maximum peak value of Tmax, and then the average value is calculated. Taking 20% MPA as the baseline value of effective analgesic effect, the effect onset time of reaching 20% MPA and the duration of action of 20% MPA were analyzed. Conduct pharmacodynamic studies to compare oral administration of SDE 75 mg/kg alone, AAP product alone (100 mg/kg), and a combination of SDE 75 mg/kg and AAP product (100 mg/kg), or The analgesic effect of NAL 60 mg/kg alone, AAP product alone (100 mg/kg), and the combination of NAL 60 mg/kg and AAP product (100 mg/kg) on rats. After 30, 60, 90, 120, 150, 180, 210, 240, 270, and 300 minutes of drug administration, anti-nociceptive thresholds were determined.

1.4 Pharmacokinetic studies

Rats received SDE 75 mg/kg alone, AAP product alone (100 mg/kg), and a combination of SDE 75 mg/kg and AAP product (100 mg/kg), and then collected at different time points Blood samples. Place the sample in a microcentrifuge tube containing 20 μL of 20 IU heparin, centrifuge at 13300 rpm for 10 minutes at 4°C to separate the plasma, and store at −80°C until the experiment.

The liquid-liquid extraction method was used to extract the concentration of each NAL in plasma samples. Take a 0.1 mL aliquot of rat plasma sample and add 50 μL of IS (naloxone: 2 μg/mL) before adding 50 μL of 1N Na ₂ CO ₃ . The extraction solvent (2 mL of n-hexane: isoamyl alcohol = 9:1) was added, and 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 (Zymark® MA, USA) at 40°C. The residue was reconstituted in 100 μL of mobile phase and shaken for 30 seconds. Subsequently, the sample was transferred to an autosampler vial and analyzed by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).

Use UPLC (Waters AcquityTM Milford, MA, USA) to couple an ESI interface to Biosystems-Sciex API 3000 series triple-quadrupole mass spectrometer (Foster City, CA, USA) Way to analyze NAL. For chromatography separation, Waters Acquity UPLC BEH HILIC, 2.1×100 mm, 1.7 μm columns were used. 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. The total running time is 5 min, and the column temperature is maintained at 35°C. The mobile phase composition is as follows: 13% A and 87% B. The retention time of NAL was 2.89 and 2.65 min, respectively. The Q1 and Q3 of NAL are 358.1→340.1 and 328.3→310.3. Use Analyst 1.4.2 software (Applied Biosystems-Sciex; Foster City, CA) to collect and process MS/MS data. The NAL plasma concentration was analyzed using WinNonlin 5.3 software (Pharsight, Mountain View, CA). One-way ANOVA of PRISM software was used to determine the statistical significance of the data obtained from the pharmacokinetic and pharmacodynamic studies.

2. result

2.1 Analgesic effect of pharmaceutical preparations (test 1 )

Figure 1 shows the quantitative results of the anti-pain effect of oral administration of AAP alone, SDE alone, and the combination of AAP and SDE (the threshold of the maximum possible analgesic effect (MPA)% is 100%). The anti-pain response was evaluated by calculating the AUC (%MPA vs. time) and the duration of each group’s MPA greater than 20% (Table 1). Statistical analysis of the data shows that the combination of AAP and SDE exhibits a synergistic analgesic effect compared to AAP or SDE alone, and the combination of AAP and SDE exhibits a synergistic analgesic effect compared to AAP or SDE alone ( p <0.005 ), where the combination of AAP and SDE exhibits the relatively longest duration of action and the highest AUC value, representing superior bioavailability ( p <0.005). Importantly, the combination of AAP and SDE has significantly better synergy than SDE and AAP alone ( p <0.005). The combination of AAP and SDE does have a synergistic effect on pain relief without the need to adjust the drug formulation.

AUC：曲線下面積為各時間點的檢測值基線與積分。 %MPA：最大可能鎮痛百分比。 數據以平均值 ± SE表示。 統計：單因子變異數分析。^a p ＜ 0.005，相對於單獨的AAP；^b p ＜ 0.005，相對於單獨的SDE；^e p ＜ 0.01，相對於單獨的AAP；^d p ＜ 0.01，相對於單獨的SDE；^e p ＜ 0.05，相對於單獨的AAP；^f p ＜ 0.05，相對於單獨的SDE。Table 1. Parameters of the analgesic effect of AAP alone, SDE alone, and the combination of AAP and SDE on SD rats.

AUC: The area under the curve is the baseline and integral of the detected value at each time point. %MPA: The maximum possible percentage of analgesia. The data are expressed as mean ± SE. Statistics: Analysis of single factor variance. ^a p <0.005, relative to AAP alone; ^b p <0.005, relative to SDE alone; ^e p <0.01, relative to AAP alone; ^d p <0.01, relative to SDE alone; ^e p <0.05, relative For AAP alone; ^f p <0.05, relative to SDE alone.

2.2 Analgesic effects of multiple pharmaceutical preparations (test 2 )

Figure 2 shows the quantitative results of the anti-pain effect of oral administration of NAL, AAP, and NAL+AAP (the threshold of maximum possible analgesia (MPA)% is 100%). The anti-pain response was evaluated by calculating the AUC (%MPA vs. time) and the duration of each group’s MPA greater than 50% (Table 2). Statistical analysis of the data shows that the combination of NAL and AAP exhibits a synergistic analgesic effect compared to NAL or AAP alone (p <0.0001).

數據以平均值 ± SE表示。 AUC：曲線下面積為各時間點的檢測值基線與積分。 %MPA：最大可能鎮痛百分比。 統計：單因子變異數分析，**p ＜ 0.01，***p ＜ 0.005，****p ＜ 0.0001，分別相較於AAP與NAL。Table 2

The data are expressed as mean ± SE. AUC: The area under the curve is the baseline and integral of the detected value at each time point. %MPA: The maximum percentage of possible analgesia. Statistics: Single factor analysis of variance, ** p <0.01, *** p <0.005, **** p <0.0001, respectively, compared with AAP and NAL.

The specific examples shown below are intended to illustrate the present invention. However, it should be understood that the invention is not limited to the preferred embodiments shown. In the diagram:

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

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

Claims (15)

An analgesic pharmaceutical preparation, comprising a therapeutically effective amount of a first analgesic, which is bisnabufurine adipate or its metabolite or derivative, 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. The pharmaceutical preparation according to claim 1, wherein the one or more pharmaceutically acceptable excipients are selected from Eudragit S100 (Eudragit S100), dehydrated dicalcium phosphate, Pluronic F68 (Pluronic F68), hexose Alcohol, cross-linked polyvinylpyrrolidone (Crospovidone), sodium starch glycolate, Aerosil 200, sucralose, menthol, saccharin, sodium benzoate, glyceryl behenate, sodium lauryl sulfate, povidone K30 (Providone K30) , Or any combination of them. The pharmaceutical preparation according to claim 1, comprising a combination of the first analgesic agent and the second analgesic agent. The pharmaceutical preparation according to claim 1, wherein the first analgesic agent is bisnabufurine adipate or a pharmaceutically acceptable salt 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 dinabufurine adipate or its metabolite or derivative; and (ii) A second analgesic composition comprising a therapeutically effective amount of a second analgesic, which is acetaminophen or a derivative thereof. The pharmaceutical preparation according to claim 5, which comprises one or more pharmaceutically acceptable excipients selected from the group consisting of Utech S100, dehydrated dicalcium phosphate, pluronic F68, hexitol, cross-linked polyvinylpyrrolidone, A group consisting of any of sodium starch glycolate, Aerosil 200, sucralose, menthol, saccharin, sodium benzoate, glyceryl behenate, sodium lauryl sulfate, povidone K30, and combinations thereof. The pharmaceutical preparation according to claim 6, further comprising one or more additional excipients as a carrier and as a balance. The pharmaceutical preparation according to claim 5, wherein the amounts of the first and second analgesics are 0-1000 mg. If the pharmaceutical preparation of claim 5, it provides a summation/synergistic analgesic effect. The pharmaceutical preparation according to claim 9, wherein when compared with the first analgesic composition or the second analgesic composition alone, the combined/synergistic analgesic effect includes higher efficacy and faster analgesic effect occurs , And/or longer periods of analgesia. The pharmaceutical formulation of claim 9, wherein when compared to the individual values of the first analgesic agent or the second analgesic agent in the first analgesic composition in the first analgesic composition, the combined/synergistic analgesic effect includes The amount of one or more pharmacokinetic parameters of the first analgesic and the second analgesic in the drug conjugate increases. The pharmaceutical preparation according to claim 5, wherein the first analgesic is bisnabufurine adipate or a pharmaceutically acceptable salt in free base form. The pharmaceutical preparation according to any one of claims 1 to 12, wherein the analgesic composition is in the form of gel, spray, emulsion, lozenge, dispersible tablet, tablet, enteral coating agent, capsule, soft capsule Agents, granules, suspensions, microspheres, oral implants, intramuscular injections, intravenous injections, implantable injections, modified release agents and other pharmaceutically acceptable forms. A method for treating pain in an individual in need thereof, comprising administering to the individual an analgesic pharmaceutical preparation according to any one of claims 1 to 13. The use of an analgesic pharmaceutical preparation according to any one of claims 1 to 13 for the manufacture of a medicament to treat pain in an individual in need.

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