WO2024082917A1 - Forme cristalline d'un sel de bupivacaine-meloxicam, monocristal de celui-ci, procédé de préparation correspondant et utilisation associée - Google Patents

Forme cristalline d'un sel de bupivacaine-meloxicam, monocristal de celui-ci, procédé de préparation correspondant et utilisation associée Download PDF

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Publication number
WO2024082917A1
WO2024082917A1 PCT/CN2023/120714 CN2023120714W WO2024082917A1 WO 2024082917 A1 WO2024082917 A1 WO 2024082917A1 CN 2023120714 W CN2023120714 W CN 2023120714W WO 2024082917 A1 WO2024082917 A1 WO 2024082917A1
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WIPO (PCT)
Prior art keywords
bupivacaine
crystal form
meloxicam
meloxicam salt
salt according
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PCT/CN2023/120714
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English (en)
Chinese (zh)
Inventor
唐田
陈柏州
梁东丽
孙彦辉
林锐彬
蒋娟娟
刘淑芬
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加立(深圳)生物科技有限公司
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Publication of WO2024082917A1 publication Critical patent/WO2024082917A1/fr

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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present application relates to the field of medical technology, and in particular to a crystal form A of bupivacaine meloxicam salt and a single crystal thereof, a preparation method and an application thereof.
  • Bupivacaine is an amide local anesthetic. Its first product on the market is bupivacaine hydrochloride injection, which was developed and marketed by Hospira in 1972. It is used for surgical operations, oral operations, diagnostic and therapeutic operations, and obstetric operations. Its trade name is Marcaine, so bupivacaine was also called Marcaine. As a non-opioid drug, bupivacaine avoids the addictiveness of opioids, but the conventional dosage concentration of bupivacaine is 0.5%. Therefore, it is urgent to increase its dosage concentration in clinical practice, and pharmacology urgently needs to solve its solubility.
  • Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) and antipyretic currently used to relieve symptoms of arthritis, fever, and as an analgesic for inflammatory conditions.
  • NSAID nonsteroidal anti-inflammatory drug
  • Meloxicam was originally developed by Boehringer Ingelheim and marketed in Europe under the brand names Melox, Movalis, and Recoxa for the treatment of rheumatoid arthritis, short-term use for osteoarthritis, and ankylosing spondylitis.
  • Meloxicam is commercialized as tablets, orally disintegrating tablets, and capsules in 7.5 and 15 mg doses, and an oral suspension in 7.5 mg/5 mL doses.
  • Bupivacaine/meloxicam extended-release solution (trade name: Zynrelef, research and development code: HTX-011) was developed by Heron Therapeutics and was approved by the FDA on May 13, 2021. It is instilled into the soft tissue or around the joints in the surgical area after bunionectomy, open inguinal hernia repair, and total knee replacement in adult patients to produce postoperative analgesia. The product was approved by the European Union as early as September 2020 for the treatment of postoperative pain in the body caused by small and medium-sized surgical wounds in adults.
  • Zynrelef is a fixed-dose combination of bupivacaine and meloxicam in a ratio of 33:1.1.
  • meloxicam as a non-steroidal anti-inflammatory drug (NSAID)
  • NSAID non-steroidal anti-inflammatory drug
  • Zynrelef is the only dual-acting local anesthetic (DALA) currently on the market, but its preparation is
  • DALA local anesthetic
  • POE fourth-generation polyorthoesters
  • the polyorthoester material is actually a composite material, including diethylene tetraoxaspiroundecane, triethylene glycol, and triethylene glycol polyglycolide.
  • DMSO diethylene tetraoxaspiroundecane
  • triethylene glycol triethylene glycol polyglycolide
  • a bupivacaine meloxicam salt crystal form A and a single crystal thereof, a preparation method and an application thereof are provided.
  • a crystalline form A of bupivacaine meloxicam salt wherein the X-ray powder diffraction pattern thereof has characteristic diffraction peaks at the following 2 ⁇ (°) angles:
  • the second aspect of the present application provides a method for preparing the A crystal form of the bupivacaine meloxicam salt described in the first aspect, comprising the following steps: Steps:
  • Bupivacaine, meloxicam and an organic solvent are mixed, heated under reflux until dissolved, and then the reaction solution is concentrated until solid is precipitated, an anti-solvent is added, solid is further precipitated, and the solid is collected and dried to prepare the A crystal form of the bupivacaine meloxicam salt.
  • the third aspect of the present application provides a single crystal of the A-form of the bupivacaine meloxicam salt described in the first aspect, wherein in the unit cell structure of the single crystal, one unit cell contains 4 single crystal molecules of the bupivacaine meloxicam salt.
  • the fourth aspect of the present application provides a pharmaceutical composition, comprising one or more of the single crystals of the A crystal form of the bupivacaine meloxicam salt described in the first aspect and the A crystal form of the bupivacaine meloxicam salt described in the third aspect, and a pharmaceutically acceptable carrier and/or excipient.
  • the fifth aspect of the present application provides the use of the A crystal form of the bupivacaine meloxicam salt described in the first aspect, the single crystal of the A crystal form of the bupivacaine meloxicam salt described in the third aspect, or the pharmaceutical composition described in the fourth aspect in the preparation of a drug having an effect of treating local pain.
  • FIG1 is an X-ray diffraction pattern of Form A obtained in Example 1 of the present application.
  • FIG2 is a DSC spectrum of Form A obtained in Example 1 of the present application.
  • FIG3 is a TG spectrum of Form A obtained in Example 1 of the present application.
  • FIG4 is an IR spectrum of Form A obtained in Example 1 of the present application.
  • FIG5 is a HPLC spectrum of Form A obtained in Example 1 of the present application.
  • FIG6 is a stability test comparison diagram of Form A obtained in Example 1 of the present application.
  • FIG7 is a comparison chart of the bioavailability of Form A obtained in Example 1 of the present application and bupivacaine in animals;
  • FIG8 is the crystal morphology of the single crystal obtained in Example 20 of the present application.
  • FIG9 is a molecular structure and atomic number (ball-and-stick diagram) of a single crystal obtained in Example 20 of the present application.
  • FIG10 is a molecular structure and atomic number (line diagram) of a single crystal obtained in Example 20 of the present application.
  • FIG11 is a unit cell structure of a single crystal obtained in Example 20 of the present application (color-coded by atomic type);
  • FIG12 is a unit cell structure of a single crystal obtained in Example 20 of the present application (color-coded according to symmetry);
  • FIG13 is the absolute configuration of the single crystal obtained in Example 20 of the present application (wherein the black C is a chiral C atom).
  • first aspect”, “second aspect”, “third aspect”, “fourth aspect”, etc. are used only for descriptive purposes and cannot be understood as indicating or implying relative importance or quantity, nor can they be understood as implicitly indicating the importance or quantity of the indicated technical features. Moreover, “first”, “second”, “third”, “fourth”, etc. only serve the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation on quantity.
  • the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.
  • the temperature parameters in this application allow for both constant temperature treatment and treatment within a certain temperature range.
  • the constant temperature treatment allows the temperature to fluctuate within the accuracy range of instrument control.
  • the room temperature in the present application generally refers to 4°C to 30°C, preferably 22°C to 27°C.
  • bupivacaine meloxicam salt in this application refers to the salt formed by the reaction of bupivacaine and meloxicam, which has the following structural characteristics:
  • bupivacaine meloxicam salt 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide and 1-n-butyl-2-(2,6-dimethylcarbamoyl)piperidine.
  • the present application provides a crystal form A of bupivacaine meloxicam salt, whose X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2 ⁇ (°) angles:
  • crystal form A of 1-n-butyl-2-(2,6-dimethylaminoformyl)piperidine and 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide crystalline compound.
  • the crystal form A has a stable morphology and a definite melting point, good chemical stability, high temperature resistance and light resistance, and has the properties required for preparing solid preparations, with a high dosing concentration, good dissolution, good compressibility and disintegration, and convenient storage, making the production operation of the preparation simpler and the quality easier to control.
  • the A crystal form also has good bioavailability.
  • the radiation source used in the X-ray powder diffraction spectrum is a Cu radiation source.
  • the X-ray powder diffraction spectrum refers to a PXRD spectrum.
  • the X-ray powder diffraction pattern of the A crystal form has characteristic diffraction peaks at the following 2 ⁇ (°) angles:
  • the relative intensities (I/I 0 ) of the above characteristic diffraction peaks are all greater than or equal to 30%.
  • the A crystal form also includes one or more characteristic diffraction peaks selected from the following 2 ⁇ (°) angles: 18.9 ⁇ 0.2, 10.1 ⁇ 0.2, 17.3 ⁇ 0.2, 18.9 ⁇ 0.2, 21.0 ⁇ 0.2 and 25.2 ⁇ 0.2.
  • the radiation source used in the X-ray powder diffraction spectrum is a Cu radiation source.
  • the X-ray powder diffraction spectrum refers to a PXRD spectrum.
  • the A crystal form also includes one or more characteristic diffraction peaks selected from the following 2 ⁇ (°) angles: 18.9 ⁇ 0.1, 10.1 ⁇ 0.1, 17.3 ⁇ 0.1, 18.9 ⁇ 0.1, 21.0 ⁇ 0.1 and 25.2 ⁇ 0.1.
  • the relative intensities (I/I 0 ) of the above characteristic diffraction peaks are all greater than or equal to 20%.
  • the A crystal form also includes one or more characteristic diffraction peaks selected from the following 2 ⁇ (°) angles: 18.1 ⁇ 0.2, 20.2 ⁇ 0.2, 22.7 ⁇ 0.2, 23.8 ⁇ 0.2, 24.0 ⁇ 0.2, 25.8 ⁇ 0.2, 26.4 ⁇ 0.2 and 26.5 ⁇ 0.2.
  • the radiation source used in the X-ray powder diffraction spectrum is a Cu radiation source.
  • the X-ray powder diffraction spectrum refers to a PXRD spectrum.
  • the A crystal form also includes one or more characteristic diffraction peaks selected from the following 2 ⁇ (°) angles: 18.1 ⁇ 0.1, 20.2 ⁇ 0.1, 22.7 ⁇ 0.1, 23.8 ⁇ 0.1, 24.0 ⁇ 0.1, 25.8 ⁇ 0.1, 26.4 ⁇ 0.1 and 26.5 ⁇ 0.1.
  • the relative intensities (I/I 0 ) of the above characteristic diffraction peaks are all greater than or equal to 10%.
  • the main parameters of the X-ray powder diffraction pattern of the crystal form A are as follows:
  • the relative intensity value is an approximate value, and "approximate” refers to the uncertainty of the intensity measurement value.
  • the uncertainty of the relative intensity is related to the measurement conditions and can be changed within the range of ⁇ 25% or further within the range of ⁇ 10%.
  • the X-ray powder diffraction pattern of the A crystal form is substantially as shown in Figure 1.
  • the radiation source used in the X-ray powder diffraction pattern is a Cu radiation source.
  • the X-ray powder diffraction pattern refers to a PXRD pattern.
  • the differential scanning calorimetry curve of the A crystal form has an endothermic peak at 189.6°C ⁇ 3°C. Further, the differential scanning calorimetry curve of the A crystal form has an endothermic peak at 189.6°C ⁇ 1°C.
  • the differential scanning calorimetry curve of the A crystal form is substantially as shown in FIG2 .
  • thermogravimetric spectrum of the A crystal form has a weight loss of 57% ⁇ 1% in the range of 210°C to 300°C.
  • thermogravimetric spectrum of the A crystal form is substantially as shown in Figure 3.
  • thermogravimetric spectrum (TGA) shows that there is a weight loss of 0.4% ⁇ 1% in the range of 50°C to 150°C, which is the loss caused by the residual solvent.
  • the infrared spectrum of the A crystal form includes the following absorption peaks:
  • the infrared spectrum of the A crystal form is substantially as shown in FIG4 .
  • the present application also provides a method for preparing the above-mentioned crystal form A of bupivacaine meloxicam salt, comprising the following steps:
  • Bupivacaine, meloxicam and an organic solvent are mixed, heated under reflux until dissolved, and then the reaction solution is concentrated until solid is precipitated, an anti-solvent is added, solid is further precipitated, and the solid is collected and dried to prepare the A crystal form of the bupivacaine meloxicam salt.
  • the organic solvent is one or more of butanone, acetone, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, ethyl acetate and isopropyl acetate; further, the organic solvent is acetone.
  • the anti-solvent is one or more of water, isopropanol and n-heptane. Further, the anti-solvent is water.
  • the volume ratio of the organic solvent to the anti-solvent is 1 to 4: 1. Furthermore, the volume ratio of the organic solvent to the anti-solvent is 1.5 to 2.5:1.
  • the molar ratio of meloxicam to bupivacaine is 1:1 to 5. Further, the molar ratio of meloxicam to bupivacaine is 1:1 to 2.
  • the ratio between the total mass of bupivacaine and meloxicam and the total volume of the organic solvent and the anti-solvent is 5 mg to 20 mg: 1 ml. Further, the ratio is 7 mg to 11 mg: 1 ml.
  • the temperature of the heating reflux is 30° C. to 80° C. Further, the temperature of the heating reflux is 58° C. to 62° C.
  • the solid precipitation time is 2 to 8 hours. Further, the solid precipitation time is 3 to 5 hours.
  • the temperature at which solids continue to precipitate is 0 to 40° C. Further, the temperature at which solids continue to precipitate is 20 to 30° C.
  • the drying temperature is 30°C to 60°C. Further, the drying temperature is 45°C to 55°C.
  • the concentration temperature is 40°C to 50°C and the pressure is -0.2MPa to -0.1MPa.
  • the present application also provides a single crystal of the A-form of the bupivacaine meloxicam salt as described above, wherein in the unit cell structure of the single crystal, one unit cell contains 4 single crystal molecules of the bupivacaine meloxicam salt.
  • the independent symmetry elements are a double helical axis and an n slip plane.
  • the crystallographic structure parameters of the single crystal are as follows:
  • the present application also provides a method for preparing a single crystal of the A crystal form of the bupivacaine meloxicam salt as described above, comprising the following steps:
  • Bupivacaine, meloxicam and an organic solvent are mixed, heated under reflux until dissolved, and then the organic solvent in the reaction solution is evaporated until solid is precipitated, and the solid is collected to prepare the single crystal.
  • the organic solvent is one or more of butanone, acetone, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, ethyl acetate and isopropyl acetate. Further, the organic solvent is acetone.
  • the molar ratio of meloxicam to bupivacaine is 1:1 to 5. Further, the molar ratio of meloxicam to bupivacaine is 1:1 to 2.
  • the ratio between the total mass of bupivacaine and meloxicam and the volume of the organic solvent is 5 mg to 20 mg: 1 ml. Further, the ratio is 7 mg to 11 mg: 1 ml.
  • the heating reflux temperature is 30°C to 80°C; further, the heating reflux temperature is 58°C to 62°C.
  • volatilizing the organic solvent in the reaction solution includes the following steps: placing the reaction solution in a glass bottle, sealing it with a sealing layer, and providing a vent on the sealing layer.
  • the sealing layer is a sealing film.
  • the ventilation holes are formed by piercing 1 to 2 holes with the needle of a 10 ml syringe.
  • the organic solvent in the reaction solution is volatilized for 2 to 10 days at room temperature.
  • the present application also provides a pharmaceutical composition, comprising one or more of the above-mentioned crystal form A of bupivacaine meloxicam salt and the above-mentioned single crystal of crystal form A of bupivacaine meloxicam salt, and a pharmaceutically acceptable carrier and/or excipient.
  • the pharmaceutical composition can be further formulated into a form for administration according to conventional preparation methods, including oral or parenteral administration.
  • a therapeutically effective amount of the crystal form A of the bupivacaine meloxicam salt and/or a single crystal of the crystal form A of the bupivacaine meloxicam salt should be included.
  • the so-called "therapeutically effective amount” means that at this dose, the crystal form A of the bupivacaine meloxicam salt and the single crystal of the crystal form A of the bupivacaine meloxicam salt described in the present application not only have improved therapeutic activity for relieving pain, but also show greatly improved solubility when used for intra- and extra-gastric administration, and greatly improved transdermal permeability when used for local treatment.
  • the pharmaceutical composition is suitable for use in topical treatment, and its preparation forms include but are not limited to the form of solution, gel, emulsion gel, cream, ointment, lotion, skin patch or eye drops.
  • the pharmaceutical composition is also suitable for parenteral injection.
  • the present application also provides the use of the above-mentioned pharmaceutical composition in the preparation of a drug having the effect of treating local pain.
  • the local pain includes but is not limited to muscle pain, joint pain, pain associated with herpes infection, wound pain (such as surgical pain or burn pain), etc.
  • the pharmaceutical composition of the present application is particularly suitable for treating patients with local pain. Without limitation, it is to treat these patients topically and parenterally by an effective amount of the pharmaceutical preparation.
  • Detection conditions X-ray tube voltage 40 kV, X-ray tube current 40 mA, scanning range 3-40° (2 ⁇ ), step size 0.02°, scanning speed 5°/min.
  • Test sample mass 2.906 mg (alumina sample pan)
  • Test sample mass 1.68 mg (alumina sample pan)
  • Example 1 The dissolution crystallization method was used to scale up the preparation of bupivacaine/meloxicam salt A crystal form.
  • the stability of the bupivacaine meloxicam salt Form A of Example 1 under high temperature (50°C), light, and accelerated (40°C, 75% RH) conditions was investigated, and samples were taken for PXRD and HPLC detection at 5 days and 10 days, respectively, and the results are shown in Table 2 and Figure 6.
  • the results show that the moisture, purity, and crystal form of the bupivacaine meloxicam salt Form A under high temperature, light, and accelerated conditions were compared with the data of 0 day, and the results show that the obtained Form A is stable.
  • Preparation method The above ingredients are mixed and directly compressed into tablets according to conventional preparation methods.
  • Preparation method The bupivacaine meloxicam salt form A of Example 1 is mixed evenly with mannitol, lactose, and cross-linked polyvinylpyrrolidone by the equal amount doubling method, and the pre-prepared HPMC solution is added to make a soft material, granulated with a 20-mesh sieve, dried at 60°C for 30 minutes, granulated with an 18-mesh sieve, added with micro-powder silica gel, and loaded into 2# capsules.
  • Preparation method The above ingredients are mixed and directly compressed into tablets according to conventional preparation methods.
  • Prescriptions 1 to 2 and the control prescription were tested for solubility, compressibility and disintegration.
  • the dissolution test method was the first or second method of ⁇ Dissolution and Release Determination Method 0931> in Part IV of the 2020 edition of the "Chinese Pharmacopoeia”; the disintegration test method was ⁇ Disintegration Time Test Method 0921> in Part IV of the 2020 edition of the "Chinese Pharmacopoeia”; compressibility was generally judged by whether the tablet had cracks, whether the lid was removed, and hardness.
  • the dissolution test showed that the dissolution rates of prescriptions 1 to 2 were all above 80% in 15 minutes.
  • the dissolution rate of the comparative prescription was only 70% in 15 minutes.
  • the compressibility and disintegration were also better than those of the comparative prescription.
  • the A crystal form of the bupivacaine meloxicam salt of the present application is superior not only in terms of various evaluation indicators such as preparation solubility, compressibility, and disintegration, but also in terms of melting point, solubility, crystal solubility, etc.
  • Bupivacaine, bupivacaine meloxicam salt form A and bupivacaine in Example 1 were administered to rats by gavage at a dose of 1.5 mg/kg, respectively; plasma was collected from each group of animals at different time points (0, 0.0833, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 30, and 48 hours) of administration, and the blood drug concentrations at different time points were measured.
  • the obtained single crystal was analyzed by X-ray single crystal diffraction to obtain the crystallographic data table and structure diagram
  • Figures 9 and 10 show the molecular structure in the unit cell of a single crystal of bupivacaine meloxicam salt, in which the numbers of the atoms in the molecule are marked, and hydrogen is not numbered for the sake of clarity. For ease of explanation, this application refers to each atom by the atomic number in the figure.
  • the crystal unit cell structure is shown in Figures 11 and 12, where one unit cell contains four single crystal molecules of bupivacaine/meloxicam salt.
  • the independent symmetry elements in the crystal are the two-fold helical axis and the n-slip plane.
  • the absolute configuration indicates the real arrangement relationship of each group in the chiral molecule in space, that is, the absolute spatial relationship.
  • Figure 13 shows the absolute configuration of a single crystal molecule of bupivacaine meloxicam salt in a unit cell.
  • Each single crystal molecule of bupivacaine meloxicam salt includes one chiral carbon atom (black mark), and the absolute configuration of the chiral carbon atom is C24 (R).
  • anisotropic displacement factor index is: -2 ⁇ [h 2 a* 2U11 +...+2h k a*b*U 12 ], where a*, b*, c* are the unit lengths of the reciprocal lattice; U 11 , U 22 , U 33 , U 23 , U 13 and U 12 are anisotropic displacement parameters, also known as temperature factors; h, k, l are diffraction indices; the parallel X-ray direction size is suitable for a perfect single crystal, and diffraction occurs when the optical path difference meets the conditional integer multiple of the wavelength.
  • h, k, and l are all integers.
  • a set of h, k, and l is called a diffraction index, which specifies a specific diffraction direction.

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Abstract

Sont divulgués une forme cristalline A d'un sel de bupivacaïne-méloxicam, un monocristal de celui-ci, un procédé de préparation correspondant et une utilisation associée. Un diagramme de diffraction de rayons X sur poudre de la forme cristalline A du sel de bupivacaïne-méloxicam présente des pics de diffraction caractéristiques aux angles 2θ (°) suivants : 7,5 ± 0,2, 8,3 ± 0,2, 12,7 ± 0,2, 15,1 ± 0,2, 16,1 ± 0,2, 16,6 ± 0,2, 24,9 ± 0,2 et 25,0 ± 0,2.
PCT/CN2023/120714 2022-10-19 2023-09-22 Forme cristalline d'un sel de bupivacaine-meloxicam, monocristal de celui-ci, procédé de préparation correspondant et utilisation associée WO2024082917A1 (fr)

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CN115894340A (zh) * 2022-10-19 2023-04-04 加立(深圳)生物科技有限公司 布比卡因美洛昔康盐的a晶型及其单晶、制备方法和应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102007030695A1 (de) * 2007-07-01 2009-01-08 Sciconcept Gmbh Co-Kristalle aus Harnstoff mit Amid- und/oder Harnstoffderivaten
CN102036946A (zh) * 2008-05-21 2011-04-27 埃斯蒂文博士实验室股份有限公司 用于治疗疼痛的度洛西汀和Cox-抑制剂的共晶体
CN111747947A (zh) * 2020-07-30 2020-10-09 山东第一医科大学(山东省医学科学院) 美洛昔康-尿素共晶及其制备方法
CN113614077A (zh) * 2018-11-05 2021-11-05 迈兰实验室有限公司 美洛昔康共晶
CN115894340A (zh) * 2022-10-19 2023-04-04 加立(深圳)生物科技有限公司 布比卡因美洛昔康盐的a晶型及其单晶、制备方法和应用
CN116041342A (zh) * 2022-12-30 2023-05-02 加立(深圳)生物科技有限公司 罗哌卡因/美洛昔康盐的一水合物i晶型、药物组合物及其制备方法和应用

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8124603B2 (en) * 2008-01-22 2012-02-28 Thar Pharmaceuticals In vivo studies of crystalline forms of meloxicam
CN110117250A (zh) * 2018-02-06 2019-08-13 四川科伦药物研究院有限公司 一种布比卡因晶型的制备方法
CN113827547A (zh) * 2020-06-23 2021-12-24 南京清普生物科技有限公司 一种缓释制剂组合物

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102007030695A1 (de) * 2007-07-01 2009-01-08 Sciconcept Gmbh Co-Kristalle aus Harnstoff mit Amid- und/oder Harnstoffderivaten
CN102036946A (zh) * 2008-05-21 2011-04-27 埃斯蒂文博士实验室股份有限公司 用于治疗疼痛的度洛西汀和Cox-抑制剂的共晶体
CN113614077A (zh) * 2018-11-05 2021-11-05 迈兰实验室有限公司 美洛昔康共晶
CN111747947A (zh) * 2020-07-30 2020-10-09 山东第一医科大学(山东省医学科学院) 美洛昔康-尿素共晶及其制备方法
CN115894340A (zh) * 2022-10-19 2023-04-04 加立(深圳)生物科技有限公司 布比卡因美洛昔康盐的a晶型及其单晶、制备方法和应用
CN116041342A (zh) * 2022-12-30 2023-05-02 加立(深圳)生物科技有限公司 罗哌卡因/美洛昔康盐的一水合物i晶型、药物组合物及其制备方法和应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ACS: "RN2561486-80-2", REGISTRY(STN), 17 December 2020 (2020-12-17) *
陈彤 等 (CHEN, TONG ET AL.): "布比卡因/美洛昔康复方缓释溶液的研究进展 (Research Progress of Bupivacaine/Meloxicam Sustained Release Solution)", 中国医院药学杂志 (CHINESE JOURNAL OF HOSPITAL PHARMACY), vol. 42, no. 18, 30 September 2022 (2022-09-30) *

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