WO2020047703A1 - Pharmaceutical preparations of sebacoyl dinalbuphine and acetaminophen and methods for treating pain - Google Patents
Pharmaceutical preparations of sebacoyl dinalbuphine and acetaminophen and methods for treating pain Download PDFInfo
- Publication number
- WO2020047703A1 WO2020047703A1 PCT/CN2018/103786 CN2018103786W WO2020047703A1 WO 2020047703 A1 WO2020047703 A1 WO 2020047703A1 CN 2018103786 W CN2018103786 W CN 2018103786W WO 2020047703 A1 WO2020047703 A1 WO 2020047703A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- analgesic
- pharmaceutical preparation
- analgesic agent
- agent
- composition
- Prior art date
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Definitions
- This invention is related to a novel pharmaceutical combination of compounds having synergistic analgesic activity.
- the present invention also relates to pharmaceutical preparations and methods for treating pain, particularly providing enhanced analgesic effects.
- opiods drugs such as nalbuphine, buprenorphine, butorphanol, so-called narcotic agonist-antagonist analgesics have been developed. They exhibit a dual action of agonist and antagonist on opiods-receptors as reported by Schmidt, W. K.et al (Drug Alcohol Depend. 14, 339, 1985; British Journal of Pain. 6, 11-16, 2012) , where pointed out that dual action of those drugs not only had high affinity to opium receptor but also served as anatagonist. For example, nalbuphine was the antagonist for Mu receptor and agonist for Kappa receptor. Those agonist/antagonist drugs have improvement on untoward effects of opiods drugs, such as addiction and respiratory suppression.
- Nalbuphine is the most widely used one and has excellent therapeutic efficacy. After continuous use of nalbuphine for 6 months, no significant addiction and addition was found. Those narcotic agonist-antagonist analgesics exhibits only slight respiratory inhibition. In clinical use, nalbuphine is safer than the traditional narcotic analgesics and classified as narcotics slush (Drug Alcohol Depend. 14, 339, 1985; Anaesthesist. 63, 135-143, 2014) .
- Nalbuphine is a synthetic agonist-antagonist that is chemically related to both naxloxone, a narcotic antagonist, and oxymorphone, a potent narcotic analgesic.
- Action of nalbuphine at the kappa-receptors produce alternations in the perception of pain as well as the emotional response to pain, possibly by altering the release of neurotransmitters from afferent nerves sensitive to painful stimuli.
- Oral nalbuphine has been shown to be only one quarter to one fifth as potent as intramuscular nalbuphine as a postoperative analgesic.
- the conventional form of nalbuphine is not practical for oral administration, because the bioavailability through oral administration is less than 5%, as described in Br J Clin Pharmacol 1988; 25: 264-8.
- This double-blind, randomized, parallel, placebo-controlled study evaluated the analgesic effects of single oral doses of nalbuphine, acetaminophen, and the contribution of each to the efficacy of their combination in 128 hospitalized patients with postoperative pain. Subjective reports of patients evaluated each hour for 6 hours were used as indices of analgesic response. Both nalbuphine alone and acetaminophen alone were significantly superior to placebo for most measures of total and peak analgesia. However, the combination of nalbuphine and acetaminophen was not significant for any analgesic measurements, indicated the combination just have the additive effect of the components, as described in CLIN PHARMACOL THER 1986; 39: 295-9.
- Sebacoyl dinalbuphine (SDE) oil solution is a pharmaceutically acceptable long acting dosage forms, is administered once a day, or once for several days. Even when large amounts are administered, the occurrence of untoward effects were minimized.
- the advantage of SDE are long duration, untoward effects, and safety that should improve therapeutic quality.
- the dosing interval can be set up to 7 days instead of 3-5 hours for post-operation patient. For last cancer stage patient's administration of the present invention dosage forms, instead of hospitalization can be given the same therapeutic efficacy.
- An ideal analgesic should exhibit short onset time, long acting, potent, no addiction, no or minimum respiratory inhibition and should have few adverse effects. Due to the current worldwide opioids crisis, there is an obvious need to provide novel pharmaceutical preparations and methods for treating pain, especially moderate to severe pain without addiction, respiratory depression, with short onset time, long duration and less side effects, through new discovery including combination with better results such as synergic effects.
- Fig. 1 shows the analgesic profile in SD rats following oral administration of SDE 75 mg/kg, AAP 100 mg/kg and combo (SDE+AAP) with by a standard paw pressure test.
- Fig. 2 Analgesic profile in SD rats following oral administration either NAL 60 mg/kg, AAP 100 mg/kg and combinations oral administration by paw pressure in SD rats.
- the present invention provides a novel pharmaceutical preparation and method for treating pain.
- the pharmaceutical preparation comprises sebacoyl dinalbuphine or its metabolites or derivatives and/or acetaminophen (AAP) or its derivatives, together with one or more pharmaceutically acceptable excipients.
- AAP acetaminophen
- the pharmaceutical preparation of the present invention can provide summation/synergic effects of pain relief, improved onset time (shorter) , duration of action, oral bioavailability (AUC) and peak of maximum.
- the pharmaceutical preparation of the present invention comprises a therapeutically effective amount of a first analgesic agent which is sebacoyl dinalbuphine or its metabolites or derivatives and/or a therapeutically effective amount of a second analgesic agent which is acetaminophen (AAP) or its derivatives, together with one or more pharmaceutically acceptable excipients.
- a first analgesic agent which is sebacoyl dinalbuphine or its metabolites or derivatives
- a second analgesic agent which is acetaminophen (AAP) or its derivatives
- the pharmaceutical preparation of the present invention comprises
- a first analgesic composition comprising a therapeutically effective amount of a first analgesic agent which is sebacoyl dinalbuphine or its metabolites or derivatives;
- a second analgesic composition comprising a therapeutically effective amount of a second analgesic agent which is acetaminophen or its derivatives.
- the first analgesic agent is sebacoyl dinalbuphine in the free base form or a pharmaceutically acceptable salt.
- the first analgesic agent is sebacoyl dinalbuphine ester (SDE) , for example, as described in US Patent 6,225,321.
- SDE sebacoyl dinalbuphine ester
- the first analgesic agent is in an amount effective to act as a bioavailability enhancer of the first analgesic agent.
- the second analgesic agent is acetaminophen (AAP) , for example, as described in U.S. Patent Application No. 14/441,317 (US20170172950A1) .
- the excipient as used herein is selected from the group consisting of Eudragit S100, dicalcium phosphate dehydrate, Pluronic F68, hexitol, Crospovidone, Sodium starch glycolate, Aerosil 200, trichlorosucrose, menthol, Saccharin, Sodium benzoate, Glyceryl behenate, Sodium lauryl sulfate, Providone K30, and any combination thereof.
- the first analgesic composition is formulated as an extended form and the second analgesic composition is formulated as an immediate release form.
- the present invention provides a method for treating pain in a subject in need comprising administering to the subject an analgesic pharmaceutical preparation or specifically an analgesic pharmaceutical combination as described herein. Also provided is use of such analgesic pharmaceutical preparation or analgesic pharmaceutical combination as described herein for manufacturing a medicament for treating pain in a subject in need.
- the articles “a” and “an” refer to one or more than one (i.e., at least one) of the grammatical object of the article.
- an element means one element or more than one element.
- the present invention provides a novel pharmaceutical preparation and method for treating pain.
- the pharmaceutical preparation of the present invention comprises nalbuphine or its derivatives and/or acetaminophen or its derivatives, together with one or more pharmaceutically acceptable excipient.
- the pharmaceutical preparation of the present invention can provide summation/synergic effects of pain relief, improved oral bioavailability and less side effects.
- the term "pharmaceutical preparation” can refer to pharmaceuticals in any forms, for example, a composition, a combination or a kit.
- a composition can refer to a homogenous mixture, for example, in a form e.g. tablets, capsules, pills, powders, granules, solutions, suspensions and emulsions and any pharmaceutical acceptable forms.
- a combination can refer to a product obtained from combining two or more active ingredients which are present physically separately in one or more packaging units for time-sequential administration.
- a kit can refer to a collection or set of the aforementioned pharmaceutical preparation, preferably, provided in separate form within a single container. The container, also preferably, comprises instructions for using such pharmaceutical preparation or carrying out the methods of the present invention.
- nalbuphine NAL
- NAL nalbuphine
- SDE sebacoly dinalbuphine ester
- acetaminophen is intended to include acetaminophen itself and the chemical derivatives of the acetaminophen structure having equivalent pharmaceutical effect, for example, as described in U.S. Patent Application No. 14/441,317 (US20170172950A1) , the entire content of which is incorporated herein by reference.
- an analgesic pharmaceutical preparation as described herein may comprise a therapeutically effective amount of a first analgesic agent which is nalbuphine or its derivatives and/or a therapeutically effective amount of a second analgesic agent which is acetaminophen (AAP) or its derivatives.
- a first analgesic agent which is nalbuphine or its derivatives
- a second analgesic agent which is acetaminophen (AAP) or its derivatives.
- the first analgesic agent or the second analgesic agent, as described herein, is present in a form of a composition formulated with one or more pharmaceutically acceptable excipients.
- the excipient as used herein is selected from the group consisting of Eudragit S100, dicalcium phosphate dehydrate, Pluronic F68, hexitol, Crospovidone, Sodium starch glycolate, Aerosil 200, trichlorosucrose, menthol, Saccharin, Sodium benzoate, Glyceryl behenate, Sodium lauryl sulfate, Providone K30, and any combination thereof.
- the pharmaceutical preparation of the present invention comprises a combination of a first analgesic agent (NAL or its derivatives) and a second analgesic agent (AAP or its derivatives) as described herein.
- the first analgesic agent is in an amount of 1 mg or more, 5 mg or more, 10 mg or more, 20 mg or more, 30 mg or more, 50 mg or more, 75 mg or more, per dose.
- the second analgesic agent is in an amount of 100 mg or more, 200 mg or more, 300 mg or more, 500 mg or more, 750 mg or more, 900 mg or more, 1000 mg or more, per dose.
- the second analgesic agent and the first analgesic agent 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) .
- the pharmaceutical preparation provides a synergic analgesic effect of pain relief.
- a synergistic effect for example refers to simultaneous actions of separate factors or active agents which have a greater total effect than the sum of the individual factor effects.
- the pharmaceutical preparation comprising a first analgesic agent and a second analgesic agent as described herein provides a faster onset of analgesic effect and/or a longer duration of analgesic effect, when compared to the first analgesic agent or the second analgesic agent alone.
- the faster onset of analgesic effect can be meant to achieve analgesic effects within 30 min after administration e.g. less than 25 min, 20 min or 15 min.
- the longer duration of analgesic effect can be meant to sustain analgesic effects for 30 min or longer, e.g. 40 min or longer, 50 min or longer, 60 min or longer, 70 min or longer, 80 min or longer, 90 min or longer, or 100 min or longer.
- the pharmaceutical preparation comprising a first analgesic agent and a second analgesic as described herein provides an increased level of one or more pharmacokinetic parameters (e.g. AUC, T max ) of the first analgesic agent and the second analgesic agent in said pharmaceutical preparation, when compared to a respective value of the first analgesic agent in the first analgesic composition or the second analgesic agent in the second analgesic composition.
- pharmacokinetic parameters e.g. AUC, T max
- the value of a certain pharmacokinetic parameter of the pharmaceutical preparation comprising a first analgesic agent and a second analgesic as described herein may be at least 20%higher (e.g., 30%higher, 50%higher, 1-fold higher, 2-fold higher, or above) than that of the first analgesic agent in the first analgesic composition or the second analgesic agent in the second analgesic composition.
- the side effect includes nephrotoxicity and/or hepatotoxicity caused by the first analgesic agent and/or the second analgesic agent. In some embodiments, the side effect includes respiratory depression or addiction risk.
- An increased level of an index or condition of toxicity may be used as an indicator of induction or occurrence of the toxicity (a toxic state) which is compared with reference to a control (or normal) level thereof.
- a "normal level” or “control level” is meant to describe a value within an acceptable range of values that one of ordinary skill in the art and/or a medical professional e.g. a doctor would expect a healthy individual or population of similar physical characteristics and medical history to have.
- a "decreased" level of an index or condition of toxicity can be used as an indicator of reduction or removal of toxicity when compared with that of a corresponding toxic state. Especially, when a decreased level of an index or condition of toxicity comes close to or even becomes lower than a normal level or control level, the toxicity can be considered “eradicated. "
- the toxicity such as nephrotoxicity and/or hepatotoxicity can be caused by overdose of AAP.
- Overdose can refer to administration of a dose greater than a useful or standard dose that is an effective dose approved by a drug regulatory authority such as Food &Drug Administration or prescribed by a physician for treatment or prevention of a diseases condition or relief of symptoms thereof.
- a drug regulatory authority such as Food &Drug Administration
- paracetamol tablets are the currently AAP drugs approved in the market for oral administration, the standard dose of which is 500 mg to 1g paracetamol taken every 4-6 hours as required, up to a maximum of 4 g daily, for a human adult.
- Overdose of AAP can mean a dose greater than a useful or standard dose of AAP, for example, by 5%, 10%, 20%, 30%, 50%, 75%, 100%or more.
- the term “treating” refers to the therapeutic measures to a disease or the symptoms or conditions of a disease, which include but are not limited to applying or administering one or more active agents to a subject suffering from the disease or the symptoms or conditions of the disease or exacerbation of the disease.
- the purpose of the therapeutic measures is to treat, cure, mitigate, relieve, alter, remedy, ameliorate, improve, or affect the disease, the symptoms or conditions of the disease, disability caused by the disease, or exacerbation of the disease.
- the present invention provides a pharmaceutical combination and method for treating pain.
- the term “individual” or “subject” includes human or non-human animals, in particular mammal, for example, companion animals (such as dogs, cats and the like) , farm animals (such as cattle, sheep, pigs, horses, etc. ) , or laboratory animals (such as rats, mice, guinea pigs, etc. ) .
- the term “effective amount” refers to the amount of an active ingredient achieving desired biological efficacy or therapeutic effects in a subject being treated, for example, pain relief.
- an effective amount of an active ingredient according to the present invention may be formulated with a pharmaceutically acceptable excipient to form a suitable form of a pharmaceutical preparation.
- the pharmaceutical composition 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.
- pharmaceutically acceptable means that the carrier is compatible with the active ingredient of the composition (and does not affect the effect of the active ingredient) , and, preferably, the carrier may stabilize the active ingredient and is safe for the subjects being treated.
- Such carrier may be a diluent, vehicle, excipient, or matrix to the active ingredient.
- excipients include lactose, dextrose, starch, Arabic gum, gelatin, calcium silicate, microcrystalline cellulose, sterilized water, syrup, and methylcellulose.
- the composition may additionally comprise lubricants, such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives, such as methyl and propyl hydroxybenzoates; sweeteners; and flavoring agents.
- lubricants such as talc, magnesium stearate, and mineral oil
- wetting agents such as talc, magnesium stearate, and mineral oil
- emulsifying and suspending agents preservatives, such as methyl and propyl hydroxybenzoates
- sweeteners and flavoring agents.
- the composition of the present invention can provide the effect of rapid, continued, or delayed release of the active ingredient after administration to the patient.
- the form of said composition may be tablets, pills, powder, lozenges, packets, troches, elixers, suspensions, lotions, solutions, syrups, soft and hard gelatin capsules, suppositories, sterilized injection fluid, and packaged powder.
- the pharmaceutical preparation of the present invention may be delivered via any physiologically acceptable route, such as oral, parenteral (such as intramuscular, intravenous, subcutaneous, and intraperitoneal) , transdermal, suppository, and intranasal methods.
- parenteral administration it is preferably used in the form of a sterile water solution, which may comprise other substances, such as salts or glucose sufficient to make the solution isotonic to blood.
- Preparation of an appropriate parenteral composition under sterile conditions may be accomplished with standard pharmacological techniques well known to persons skilled in the art, and no extra creative labor is required.
- the pharmaceutical preparation is a composition e.g. in a form selected from the group consisting of tablets, capsules, pills, powders, granules, solutions, suspensions and emulsions, preferably for oral administration.
- the composition is administered in the form of gel, spray, emulsion, pastilles, dispersible tablets, tablets, enteral coated, capsules, soft capsules, granules, suspensions, microspheres, oral implants, intramuscular injection, intravenous injection, implantable injections, modified release and other pharmaceutically acceptable forms.
- the present invention also provides a method for treating pain in a subject in need comprising administering to the subject an analgesic pharmaceutical preparation as described herein.
- the method of the invention provides synergic effects of pain relief, improved oral bioavailability and less side effects.
- the method of the present invention is applicable in treating moderate to severe/deep pains, for example, associated with cancer, renal or biliary colic, migraine or vascular headaches, surgical pain and burn injury.
- the first analgesic agent and the second analgesic agent can be administered simultaneously or subsequently.
- mice Male Sprague-Dawley rats weights between 260 and 330 g were purchased from BioLASCO (Taipei, Taiwan) . The rats were housed in a controlled condition (free access to food and water) ; 12-h light-dark cycle, temperature 22°C and humidity 60%. All experiments were conducted in accordance with the IACUC's Protocol for the Care and Use of Animals and to treat the animals in an ethical and humane manner consistent with the law.
- Nalbuphine was supplied by Yung-Shin Pharmaceutical Ind. Co., Ltd. (Taichung Hsien, Taiwan) .
- SDE was supplied by Yung-Shin Pharmaceutical Ind. Co., Ltd. (Taichung Hsien, Taiwan) .
- AAP product (a drug formulation) was supplied by China Chemical &Pharmaceutical Co., Ltd (Hsinchu Hsien, Taiwan) .
- Acetaminophen powder were obtained from the Sigma-alorich (St. Louis, MO, USA) .
- Isopentyl alcohol was obtained from the Mallinckrodt baker. lnc. (Phillipsburg, NJ, USA) .
- Hexanes was obtained from the Avantor performance materials, lnc. (Center Valley, PA, USA) .
- Acetonitrile and methanol were obtained from Merck (Darmstadt, Germany) . Analysis was used to liquid chromatography-mass spectrometry (LC–MS
- Negative values are considered as zero.
- the maximum peak of %MPA and Tmax are independent of each individual, then calculated the average.
- %MPA and AUC negative values
- the anti-nociceptive thresholds were measured at 30, 60, 90, 120, 150, 180, 210, 240, 270, and 300 min after drug administration.
- the rats received orally SDE 75 mg/kg alone, AAP product (100 mg/kg) alone and combinations of SDE 75 mg/kg plus AAP product (100 mg/kg) , and then blood samples were collected in different time point.
- the samples put into microcentrifuge tubes contain 20 ⁇ L of 20 IU heparin and isolated plasma by centrifuged in 4°C, 13300 rpm for 10 min, and stored at -80°C until assay.
- UPLC–MS/MS ultra-high-performance liquid chromatography-tandem mass spectrometry
- NAL were analyzed using UPLC (Waters AcquityTM Milford, MA, USA) coupled to a Biosystems-Sciex API 3000 series triple-quadrupole mass spectrometer (Foster City, CA, USA) with an electrospray ionization (ESI) interface. Chromatographic separation was using Waters Acquity UPLC BEH HILIC, 2.1 ⁇ 100 mm, 1.7 ⁇ m column.
- the mobile phase solvent A contain 2 mM ammonium formate and 0.1%formic acid in water and solvent B contain 2 mM ammonium formate and 0.1%formic acid in acetonitrile.
- 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.
- NAL retention times were 2.89 and 2.65min, respectively.
- the Q1 and Q3 of NAL were 358.1 ⁇ 340.1 and 328.3 ⁇ 310.3.
- Analyst 1.4.2 software (Applied Biosystems-Sciex; Foster City, CA) was used to collect and process the MS/MS data.
- NAL plasma concentration were analyzed by WinNonlin 5.3 software (Pharsight, Mountain View, CA) .
- the statistical significance of data obtained from the pharmacokinetic and pharmacodynamic studies was determined using One-way ANOVA using the PRISM software.
- Fig. 1 shows the quantification of the anti-nociceptive effects of oral administration of AAP alone, SDE alone and combination of AAP and SDE (with %maximum possible analgesic (MPA) effect threshold value of 100%) .
- the anti-nociceptive response was evaluated by calculating the AUC (%MPA versus time) and the duration for which the MPA was greater than 20%for each group (Table 1) .
- AUC area under curve is each time point detection value baseline and integral.
- Fig. 2 shows quantification of the anti-nociceptive effects of oral administration of NAL, AAP and NAL+ AAP (with %maximum possible analgesic effect (MPA) threshold value of 100%) .
- the anti-nociceptive response was evaluated by calculating the AUC (%MPA versus time) and the duration for which the MPA was greater than 50%for each group (Table 2) .
- Statistical analysis of the data indicated that a combination of NAL and AAP exhibits synergistic analgesic effects as compared with NAL or AAP alone (p ⁇ 0.0001) .
- AUC area under curve is each time point detection value baseline and integral.
Abstract
Description
Claims (15)
- An analgesic pharmaceutical preparation, comprising a therapeutically effective amount of a first analgesic agent which is sebacoyl dinalbuphine or its metabolites or derivatives and/or a therapeutically effective amount of a second analgesic agent which is acetaminophen (AAP) or its derivatives, 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, dicalcium phosphate dehydrate, Pluronic F68, hexitol, Crospovidone, Sodium starch glycolate, Aerosil 200, trichlorosucrose, menthol, Saccharin, Sodium benzoate, Glyceryl behenate, Sodium lauryl sulfate, Providone K30 and any combination thereof.
- The pharmaceutical preparation of claim 1, which comprises a combination of the first analgesic agent and the second analgesic agent.
- The pharmaceutical preparation of claim 1, wherein the first analgesic agent is sebacoyl dinalbuphine in the free base form or a pharmaceutically acceptable salt.
- An analgesic pharmaceutical preparation, comprising(i) a first analgesic composition comprising a therapeutically effective amount of a first analgesic agent which is sebacoyl dinalbuphine or its metabolites or derivatives; and(ii) a second analgesic composition comprising a therapeutically effective amount of a second analgesic agent which is acetaminophen or its derivatives.
- The pharmaceutical preparation of claim 5, which comprises one or more pharmaceutically acceptable excipients selected from the group consisting of Eudragit S100, dicalcium phosphate dehydrate, Pluronic F68, hexitol, Crospovidone, Sodium starch glycolate, Aerosil 200, trichlorosucrose, menthol, Saccharin, Sodium benzoate, Glyceryl behenate, Sodium lauryl sulfate, Providone K30 and any combination thereof.
- The pharmaceutical preparation of claim 6, further comprising one or more additional excipients as a carrier as the balance.
- The pharmaceutical preparation of claim 5, wherein the amount of first and second analgesic is 0~1000 mg.
- The pharmaceutical preparation of claim 5, which provides a summation /synergistic analgesic effect.
- The pharmaceutical preparation of claim 9, wherein the summation /synergistic analgesic effect includes a higher potency, faster onset of analgesic effect and/or a longer duration of analgesic effect, when compared to the first analgesic composition or the second analgesic composition alone.
- The pharmaceutical preparation of claim 9, wherein the summation /synergistic analgesic effect includes an increased level of one or more pharmacodynamic parameters of the first analgesic agent and the second analgesic agent in said pharmaceutical combination, when compared to a respective value of the first analgesic agent in the first analgesic composition or the second analgesic agent in the second analgesic composition.
- The pharmaceutical preparation of claim 5, wherein the first analgesic agent is sebacoyl dinalbuphine in the free base form or a pharmaceutically acceptable salt.
- The pharmaceutical preparation as recited in any of claims 1-12, wherein the analgesic composition is administered in the form of gel, spray, emulsion, pastilles, dispersible tablets, tablets, enteral coated, capsules, soft capsules, granules, suspensions, microspheres, oral implants, intramuscular injection, intravenous injection, implantable injections, modified release and other pharmaceutically acceptable forms.
- A method for treating pain in a subject in need comprising administering to the subject an analgesic pharmaceutical preparation of any of claim 1-13.
- Use of an analgesic pharmaceutical preparation of any of claim 1-13 for manufacturing a medicament for treating pain in a subject in need.
Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201880096947.3A CN113164469A (en) | 2018-09-03 | 2018-09-03 | Pharmaceutical formulations of dinabulin adipate and acetamidophenol and methods of treating pain |
CA3111271A CA3111271A1 (en) | 2018-09-03 | 2018-09-03 | Pharmaceutical preparations of sebacoyl dinalbuphine and acetaminophen and methods for treating pain |
EP18932827.1A EP3846815A4 (en) | 2018-09-03 | 2018-09-03 | Pharmaceutical preparations of sebacoyl dinalbuphine and acetaminophen and methods for treating pain |
JP2021536123A JP7318987B2 (en) | 2018-09-03 | 2018-09-03 | Pharmaceutical formulations of sebacoyldinalbuphine and acetaminophen and methods of treating pain |
PCT/CN2018/103786 WO2020047703A1 (en) | 2018-09-03 | 2018-09-03 | Pharmaceutical preparations of sebacoyl dinalbuphine and acetaminophen and methods for treating pain |
SG11202101974WA SG11202101974WA (en) | 2018-09-03 | 2018-09-03 | Pharmaceutical preparations of sebacoyl dinalbuphine and acetaminophen and methods for treating pain |
KR1020217009905A KR20210054560A (en) | 2018-09-03 | 2018-09-03 | Pharmaceutical preparations of sebacoyl denalbuphine and acetaminophen and methods of treating pain |
AU2018440280A AU2018440280B2 (en) | 2018-09-03 | 2018-09-03 | Pharmaceutical preparations of sebacoyl dinalbuphine and acetaminophen and methods for treating pain |
CL2021000309A CL2021000309A1 (en) | 2018-09-03 | 2021-02-05 | Pharmaceutical preparations of sebacoyl dinalbuphine and acetaminophen and methods for treating pain. |
IL280822A IL280822A (en) | 2018-09-03 | 2021-02-11 | Pharmaceutical preparations of sebacoyl dinalbuphine and acetaminophen and methods for treating pain |
ZA2021/02209A ZA202102209B (en) | 2018-09-03 | 2021-03-31 | Pharmaceutical preparations of sebacoyl dinalbuphine and acetaminophen and methods for treating pain |
JP2023060264A JP2023078480A (en) | 2018-09-03 | 2023-04-03 | Pharmaceutical preparations of sebacoyl dinalbuphine and acetaminophen and methods for treating pain |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/CN2018/103786 WO2020047703A1 (en) | 2018-09-03 | 2018-09-03 | Pharmaceutical preparations of sebacoyl dinalbuphine and acetaminophen and methods for treating pain |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2020047703A1 true WO2020047703A1 (en) | 2020-03-12 |
Family
ID=69721971
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2018/103786 WO2020047703A1 (en) | 2018-09-03 | 2018-09-03 | Pharmaceutical preparations of sebacoyl dinalbuphine and acetaminophen and methods for treating pain |
Country Status (11)
Country | Link |
---|---|
EP (1) | EP3846815A4 (en) |
JP (2) | JP7318987B2 (en) |
KR (1) | KR20210054560A (en) |
CN (1) | CN113164469A (en) |
AU (1) | AU2018440280B2 (en) |
CA (1) | CA3111271A1 (en) |
CL (1) | CL2021000309A1 (en) |
IL (1) | IL280822A (en) |
SG (1) | SG11202101974WA (en) |
WO (1) | WO2020047703A1 (en) |
ZA (1) | ZA202102209B (en) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4237140A (en) * | 1979-05-18 | 1980-12-02 | E. I. Du Pont De Nemours And Company | Analgesic mixture of nalbuphine and acetaminophen |
US6225321B1 (en) * | 1997-06-05 | 2001-05-01 | Oliver Yoa-Pu Hu | Long analgesic acting nalbuphine polyester derivative and method of use |
WO2004054511A2 (en) * | 2002-12-13 | 2004-07-01 | The Regents Of The University Of California | Analgesic combination comprising nalbuphine |
WO2008107410A1 (en) * | 2007-03-02 | 2008-09-12 | Flamek Corp Oü | Analgesic composition of topically applied nonsteroidal antiinflammatory drugs and opioids |
US20170172950A1 (en) * | 2013-11-13 | 2017-06-22 | National Defense Education And Research Foundation | New hepatotoxicity-free pharmaceutical composition containing acetaminophen drugs |
-
2018
- 2018-09-03 AU AU2018440280A patent/AU2018440280B2/en active Active
- 2018-09-03 CN CN201880096947.3A patent/CN113164469A/en active Pending
- 2018-09-03 EP EP18932827.1A patent/EP3846815A4/en active Pending
- 2018-09-03 JP JP2021536123A patent/JP7318987B2/en active Active
- 2018-09-03 KR KR1020217009905A patent/KR20210054560A/en not_active Application Discontinuation
- 2018-09-03 CA CA3111271A patent/CA3111271A1/en active Pending
- 2018-09-03 SG SG11202101974WA patent/SG11202101974WA/en unknown
- 2018-09-03 WO PCT/CN2018/103786 patent/WO2020047703A1/en unknown
-
2021
- 2021-02-05 CL CL2021000309A patent/CL2021000309A1/en unknown
- 2021-02-11 IL IL280822A patent/IL280822A/en unknown
- 2021-03-31 ZA ZA2021/02209A patent/ZA202102209B/en unknown
-
2023
- 2023-04-03 JP JP2023060264A patent/JP2023078480A/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4237140A (en) * | 1979-05-18 | 1980-12-02 | E. I. Du Pont De Nemours And Company | Analgesic mixture of nalbuphine and acetaminophen |
US6225321B1 (en) * | 1997-06-05 | 2001-05-01 | Oliver Yoa-Pu Hu | Long analgesic acting nalbuphine polyester derivative and method of use |
WO2004054511A2 (en) * | 2002-12-13 | 2004-07-01 | The Regents Of The University Of California | Analgesic combination comprising nalbuphine |
WO2008107410A1 (en) * | 2007-03-02 | 2008-09-12 | Flamek Corp Oü | Analgesic composition of topically applied nonsteroidal antiinflammatory drugs and opioids |
US20170172950A1 (en) * | 2013-11-13 | 2017-06-22 | National Defense Education And Research Foundation | New hepatotoxicity-free pharmaceutical composition containing acetaminophen drugs |
Also Published As
Publication number | Publication date |
---|---|
JP7318987B2 (en) | 2023-08-01 |
ZA202102209B (en) | 2022-03-30 |
IL280822A (en) | 2021-04-29 |
AU2018440280A1 (en) | 2021-03-18 |
CA3111271A1 (en) | 2020-03-12 |
EP3846815A4 (en) | 2022-05-04 |
KR20210054560A (en) | 2021-05-13 |
JP2021535216A (en) | 2021-12-16 |
CN113164469A (en) | 2021-07-23 |
SG11202101974WA (en) | 2021-03-30 |
JP2023078480A (en) | 2023-06-06 |
CL2021000309A1 (en) | 2021-07-19 |
EP3846815A1 (en) | 2021-07-14 |
AU2018440280B2 (en) | 2022-11-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20080096872A1 (en) | Composition for Treatment of Pain Specification | |
JP7021298B2 (en) | Dosage form and therapeutic use of L-4-chlorokynurenine | |
EA039629B1 (en) | Pharmaceutical combination comprising a selective s1p1 receptor agonist | |
WO2015121218A1 (en) | Combination of baclofen, acamprosate and medium chain triglycerides for the treatment of neurological disorders | |
EP3107555A1 (en) | Compositions containing extracts of curcuma longa and echinacea angustifolia which are useful to reduce peripheral inflammation and pain | |
US20230181583A1 (en) | Treating liver disorders with an ssao inhibitor | |
AU2023251499A1 (en) | Combinations of opioids and N-acylethanolamines | |
WO2005034936A1 (en) | Use of l-butylphthalide in the manufacture of medicaments for prevention and treatment of cerebral infarct | |
US20200069675A1 (en) | Pharmaceutical preparations of sebacoyl dinalbuphine and acetaminophen and methods for treating pain | |
AU2018440280B2 (en) | Pharmaceutical preparations of sebacoyl dinalbuphine and acetaminophen and methods for treating pain | |
WO2012137054A1 (en) | Pharmaceutical composition containing cyclobenzaprine suitable to intranasal administration | |
TW202010496A (en) | Pharmaceutical preparations of sebacoyl dinalbuphine and acetaminophen and methods for treating pain | |
JP7257091B2 (en) | Dementia treatment and preventive drug | |
AU2018230521B2 (en) | Pharmaceutical compositions and uses thereof | |
WO2024092269A1 (en) | Improved oral bioavailable formulation for mitragyna speciosa (kratom) | |
EA042299B1 (en) | PHARMACEUTICAL COMPOSITIONS AND THEIR APPLICATIONS |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 18932827 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 3111271 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2021536123 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2018440280 Country of ref document: AU Date of ref document: 20180903 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 20217009905 Country of ref document: KR Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2018932827 Country of ref document: EP Effective date: 20210406 |