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WO2015113200A1 - Injection de chlorhydrate de tapentadol et son procédé de préparation - Google Patents

Injection de chlorhydrate de tapentadol et son procédé de préparation Download PDF

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Publication number
WO2015113200A1
WO2015113200A1 PCT/CN2014/071658 CN2014071658W WO2015113200A1 WO 2015113200 A1 WO2015113200 A1 WO 2015113200A1 CN 2014071658 W CN2014071658 W CN 2014071658W WO 2015113200 A1 WO2015113200 A1 WO 2015113200A1
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WO
WIPO (PCT)
Prior art keywords
injection
sodium
tapentadol
tapentadol hydrochloride
hydrochloride
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2014/071658
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English (en)
Chinese (zh)
Inventor
吴仁荣
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
JIANGSU HUAZE PHARMACEUTICAL TECHNOLOGY Co Ltd
Original Assignee
JIANGSU HUAZE PHARMACEUTICAL TECHNOLOGY Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by JIANGSU HUAZE PHARMACEUTICAL TECHNOLOGY Co Ltd filed Critical JIANGSU HUAZE PHARMACEUTICAL TECHNOLOGY Co Ltd
Publication of WO2015113200A1 publication Critical patent/WO2015113200A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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

Definitions

  • the present invention relates to a new dosage form of tapentadol hydrochloride, in particular a small volume injection of tapentadol hydrochloride.
  • the invention also relates to a process for the preparation of a small volume injection of tapentadol hydrochloride.
  • Tacitabine hydrochloride is a synthetic central system analgesic with mechanisms of opioid and non-opioid effects. It first stimulates the opioid peptide receptors in the brain, spinal cord and gastrointestinal tract, thereby improving the brain and body's anti-pain ability. Then, tapentadol hydrochloride inhibits the re-uptake of the brain's analgesic norepinephrine, thereby passing The above two ways to achieve its analgesic effect.
  • the most common adverse reactions associated with tapentadol hydrochloride include: nausea, dizziness, vomiting, and lethargy. Labeling of tapentadol hydrochloride includes: There is a risk of respiratory depression; when drinking alcohol, taking other opioids or illicit drugs, it can cause addictive inhibition of the central nervous system.
  • Tagatamine is a pure enantiomer, a variety of animal models show that oral absorption is rapid
  • the main metabolic pathway of tapentadol is the second phase of glucuronidation.
  • the first phase has less biotransformation.
  • his sprayed polyglucosaminide metabolite has no affinity for MOR, NE transporters or any other target.
  • No activity was observed in the mouse appendix test injected intravenously or intracerebroventricularly. This is the obvious difference between his tapenta and other opioids, such as codeine or tilidine, and tramadol. All of these drugs require metabolic activation or morphine is converted to the more potent morphine-6-glucuronide.
  • the CYP2D6 enzyme does not require the conversion of active metabolites, thus reducing the likelihood of individual differences in the analgesic response to tapentadol.
  • In vitro studies have shown that there is no interaction between tapentadol and cytochrome P-450 enzyme, and no inhibition or induction of human hepatocytes.
  • Tmax The combined TAD peak concentration time (Tmax) was between 1.25 and 2.0 h, and the concentration of unconjugated tapentadol in all volunteers was very low (Cmax was 0.07 ⁇ 0.03 g-eq base I ml), overall
  • the area under the plasma concentration curve (AUC) O ⁇ 120 (unbound + combined) of heptadol is about 64% of the total radioactive carbon AUC 0 ⁇ 120, and the whole blood radiocarbon Tmax is 1.25 ⁇ 1.5 h. Similar to morphine (20 to 30), the clearance rate of 1531 ml / min after intravenous injection is equivalent to hepatic blood flow (1400 ml I min).
  • the existing oral preparations have the first-pass effect of the liver, and have the disadvantages of low bioavailability, slow absorption distribution, and slow onset of action.
  • the object of the present invention is to provide a small volume injection of tapentadol hydrochloride, which is directly intravenously injected, to overcome the above-mentioned deficiencies of the existing oral preparations, to expand the use of tapentadol hydrochloride, and to improve the dosage of tapentadol hydrochloride.
  • the level of clinical use makes it suitable for diseases such as moderate to severe pain.
  • the tapentadol hydrochloride injection of the present invention comprises a pharmaceutically acceptable carrier and an additive comprising an effective amount of the active ingredient capitata salt or tapentadol and a pharmaceutically acceptable preparation for injection.
  • the pharmaceutically acceptable carriers and additives of the present invention are antioxidants, P H value regulators, isotonicity adjusting agents and water for injection.
  • the pharmaceutically acceptable carrier and the additive may be selected from one or more of an antioxidant, a P H value regulator, an isotonicity adjusting agent and water for injection; preferably, the pharmaceutically acceptable carrier and the additive are selected from the group consisting of antioxidants, P H value regulator, isotonicity regulator and water for injection into the stomach.
  • the P H value adjusting agent may be selected from one or more selected from the group consisting of sodium acetate trihydrate, sodium citrate, sodium carbonate, and the like, preferably sodium acetate trihydrate.
  • the isotonicity adjusting agent may be selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium lactate, glucose, xylitol, mannitol, sorbitol or dextran, preferably sodium chloride.
  • the antioxidant may be selected from the group consisting of sodium sulfite, sodium hydrogen sulfite, sodium metabisulfite or sodium thiosulfate, preferably sodium hydrogen sulfite.
  • the amount of the pharmaceutically acceptable carrier to be used in the preparation is also not particularly limited and can be used within the range which does not affect the effect of the injection of the present invention.
  • the pH of the tapentadol hydrochloride injection provided by the present invention is 5.5 to 6.5. In this pH range, the tapentadol hydrochloride injection is the most stable.
  • the osmotic pressure ratio of the tapentadol hydrochloride injection provided by the present invention is 0.9 to 1.1.
  • the present invention provides a solution of tapentadol hydrochloride, which contains 10 mg to 100 mg of tapentadol hydrochloride per ml of the injection, preferably 50 mg of tapentadol hydrochloride per ml of the injection.
  • the object of the invention is achieved in that the preparation method comprises the following steps:
  • the preparation method of tapentadol hydrochloride injection comprises the following steps: Weigh the prescribed amount of tapentadol hydrochloride and a pharmaceutically acceptable carrier, add an appropriate amount of water for injection, and add 0.6% of the injection needle to the activated carbon, 50 ° C ⁇ Stirring at 60 °C for 30 min, decarbonization by filtration, cooling to room temperature, adjusting the pH value of 5.5 ⁇ 6.5 with 1 mol/L sodium acetate trihydrate, adding water for injection to the whole amount, determining the intermediate content and pH value, and passing the 0.22 ⁇ micro
  • the membrane was filtered, filled in an ampule, and sterilized by autoclaving at 121 °C for 20 min.
  • the tapasalazine hydrochloride injection of the invention has the advantages of high bioavailability, good drug absorption, rapid distribution, quick onset, etc., and expands the use of tapentadol hydrochloride to improve the dosage.
  • the clinical use level of tapentadol hydrochloride is the clinical use level of tapentadol hydrochloride.
  • the natastatin hydrochloride injection solution of the invention is reasonable, the process is simple, and the stability is good. After accelerated test at 40 °C for 6 months, the appearance traits, P H, active ingredient content and related substances did not change significantly.
  • the preparation method is the same as the embodiment except that the added auxiliary materials are different.
  • the preparation method is the same as in the same embodiment except that the added auxiliary materials are different.
  • the preparation method is the same as the same embodiment 1 except that the added auxiliary materials are different.
  • the preparation method is the same as in the same embodiment except that the added auxiliary materials are different.
  • the preparation method was the same as in Example 1 except that the excipients added were different.
  • the preparation method was the same as in Example 1 except that the excipients added were different.
  • Sample lot number, source of tapentadol hydrochloride (Example 1, specification: 2ml: lOOmg; batch number: 20130601 20130602, 20130603): The company made it; The inner package is 2ml ampoules, plus small box, 2 boxes per box support.
  • the present invention is an accelerated (40 ° C) test for 6 months in the simulated commercial packaging state of the present invention, and samples are detected at 1, 2, 3, and 6 months, respectively. There were no significant changes in the indicators.
  • the clinical route of the administration of tapentadol hydrochloride is intravenous drip.
  • the following indicators are specially designed: (1) The irritating effect of the injection of Taprofloxacin on the ear vein of rabbits (2) Systemic allergic test of chlorhexidine hydrochloride on guinea pigs; (3) Hydrolysis of catalyzed hemolytic test.
  • Test drug Hydrochlorhexidine hydrochloride injection (Example 1), Specifications: 2 mL per strain: 100 mg.
  • Positive control drugs Use fresh egg whites that can cause animal allergies.
  • Negative control drug 0.9% sodium chloride injection.
  • the administration route is the same as the clinical practice or the experimental method. Guinea pigs were sensitized by intraperitoneal injection and stimulated by intravenous administration; rabbits were administered by intravenous infusion of the ear.
  • 6.1 Rabbits divided into test group and negative control group. The test drug group was administered at a dose of 15 mg/kg, the administration volume was 10 m ⁇ J kg, and the negative control group was given an equal volume of 0.9% sodium chloride injection.
  • 6.2 Guinea pig divided into test group, positive control group and negative control group. The test group was given a solution of tapentadol hydrochloride, the positive control group was given 5% fresh egg white, the negative control group was given 0.9% sodium chloride injection, and the sensitization volume was 0.5 mL/only. The dosage volume at the time of challenge was 2 mIJ.
  • Rabbit blood cells 2% red blood cell suspension. When the test drug is used, it is diluted to a clinical use concentration according to the clinical use method (2 mL of tapentadol hydrochloride is added to 100 mL of sodium chloride injection, 2%), and is now ready for use. Five dose groups were set, and the dosing volumes were 0.5 mL, 0.4 mL, 0.3 mL, 0.2 mL, and 0.1 mL, respectively. The negative control group was 0.9% sodium chloride injection, the dosage volume was 2.5 mL, and the positive control group was distilled water. The volume of the addition solution was 2.5 mL.
  • Tapasotalt hydrochloride injection is not irritating to rabbit ear veins.
  • Tetrandre hydrochloride injection has no systemic allergic reaction to guinea pigs.
  • Tantastatin hydrochloride injection did not produce hemolysis and coagulation on rabbit red blood cells.
  • test group and the negative control group were given.
  • the left ear of the rabbit was instilled with 0.9% sodium chloride injection, and the right ear was instilled with tapentadol hydrochloride injection for self-control.
  • the test drug, tapentadol hydrochloride is administered at a dose of 15 mg/kg, which is equivalent to 15 times the clinical dose.
  • the negative control group was given an equal volume of 0.9% sodium chloride injection, and the administration volume was 10 mIJkg.
  • the instillation amount is lOm! Jkg, and the instillation speed is lm! Jmin (20 drops/min), 2 times a day for 5 consecutive days.
  • the injection site of the rabbit was visually observed and recorded after 72 hours before and after the last administration, and the blood vessels and surrounding tissues at the injection site were observed to have redness and stimuli.
  • the rabbit was sacrificed and the ear piece was cut, 10% Neutral formaldehyde fixation, paraffin-embedded sections, HE staining, histopathological examination.
  • the 0.9% sodium chloride injection control group and the tapentadol hydrochloride injection group had no wall injury in the ear vein, no thrombosis, no local tissue degeneration and necrosis, congestion and edema, and inflammatory cell infiltration around the blood vessels. There is focal or scattered inflammatory cell infiltration around only a few blood vessels.
  • Intravenous infusion of tapentadol hydrochloride has no stimulating effect on local blood vessels in rabbits.
  • test group The test group, the positive control group and the negative control group were set. 6 guinea pigs per group. The test group was given a spray solution of tapentadol hydrochloride, the positive control group was given 5% fresh egg white, and the negative control group was given 0.9% sodium chloride injection. The volume of the drug was 0.5 mIJ when sensitized. The dose was 2 mIJ only when challenged.
  • guinea pigs 20 guinea pigs, adapted for 3 days. Eighteen guinea pigs were randomly divided into 3 groups according to body weight, with 6 rats in each group. The remaining 2 guinea pigs are routinely used for the purpose of self-injection of a dose of the test drug after an injection of an allergic reaction to observe the presence or absence of similar allergic reactions caused by the test drug for judgment. Reference.
  • the test drug group was intraperitoneally injected with tapentadol hydrochloride, the positive control group was given 5% fresh egg white, and the negative control group was given 0.9% sodium chloride injection.
  • the sensitized drug volume was 0.5 mIJ, every other day. Times, a total of 3 times.
  • the state of each guinea pig was observed daily, and the body weight of the guinea pig was weighed on the first and last sensitization and on the day of the challenge, and the change in body weight was observed.
  • 3 guinea pigs in each group were injected with the corresponding drugs intravenously, and the dose was 2 mL/only.
  • each guinea pig in the 5% fresh egg white positive control group showed a certain degree of agitation. Irritating, sneezing, sneezing, coughing, convulsions, gait instability, jumping, wheezing, convulsions, tidal breathing, shock to death, etc., and most of them die in about 3 minutes, the incidence of allergies is 100%, strong to Very strong positive allergic reaction. All of the guinea pigs in the 0.9% sodium chloride injection group and the tapentadol hydrochloride group had allergic symptoms and allergic reactions were negative. It indicated that the tantastatin hydrochloride injection had no systemic allergic reaction to guinea pigs (see Table 5).
  • Tubes 1 to 5 are for the test tube, tube No. 6 is the negative control tube, and tube No. 7 is the positive control tube.
  • hemolysis and red blood cell agglutination were carried out according to the criteria of "Technical Guidelines for Chemical Drug Irritant, Allergic and Hemolytic Research" to determine the effect of the test drug on hemolysis in vitro.

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Emergency Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Dermatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention a pour objet une injection de chlorhydrate de tapentadol et son procédé de préparation. L'injection comprend une quantité efficace de principe actif d'un sel de chlorhydrate de tapentadol ou une base de tapentadol ainsi qu'un support pharmaceutiquement acceptable et un additif.
PCT/CN2014/071658 2014-01-28 2014-03-03 Injection de chlorhydrate de tapentadol et son procédé de préparation Ceased WO2015113200A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410042768.5A CN103735500B (zh) 2014-01-28 2014-01-28 盐酸他喷他多注射液及其制备方法
CN201410042768.5 2014-01-28

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190388364A1 (en) * 2017-02-23 2019-12-26 Grünenthal GmbH Tapentadol as a local anesthetic
US10898452B2 (en) 2016-09-23 2021-01-26 Gruenenthal Gmbh Stable formulation for parenteral administration of Tapentadol
US11013701B2 (en) 2015-03-27 2021-05-25 Grünenthal GmbH Stable formulation for parenteral administration of tapentadol
US11547678B2 (en) 2011-03-04 2023-01-10 Gruenenthal Gmbh Aqueous pharmaceutical formulation of tapentadol for oral administration

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105037180B (zh) * 2015-04-19 2017-10-10 安徽省逸欣铭医药科技有限公司 一种双重作用的中枢性镇痛新化合物、制备方法及用途
ES2968153T3 (es) * 2017-01-11 2024-05-08 Torrent Pharmaceuticals Ltd Composición nasal de tapentadol
CN108066820A (zh) * 2017-12-28 2018-05-25 江苏艾尔康生物医药科技有限公司 一种自体真皮成纤维细胞注射液

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103501775A (zh) * 2011-03-04 2014-01-08 格吕伦塔尔有限公司 他喷他多的胃肠外给药

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103501775A (zh) * 2011-03-04 2014-01-08 格吕伦塔尔有限公司 他喷他多的胃肠外给药

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11547678B2 (en) 2011-03-04 2023-01-10 Gruenenthal Gmbh Aqueous pharmaceutical formulation of tapentadol for oral administration
US11013701B2 (en) 2015-03-27 2021-05-25 Grünenthal GmbH Stable formulation for parenteral administration of tapentadol
US10898452B2 (en) 2016-09-23 2021-01-26 Gruenenthal Gmbh Stable formulation for parenteral administration of Tapentadol
US20190388364A1 (en) * 2017-02-23 2019-12-26 Grünenthal GmbH Tapentadol as a local anesthetic

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CN103735500A (zh) 2014-04-23
CN103735500B (zh) 2016-01-20

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