WO2021218930A1 - Substance co-amorphe de célécoxib et de prégabaline et son procédé de préparation - Google Patents

Substance co-amorphe de célécoxib et de prégabaline et son procédé de préparation Download PDF

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WO2021218930A1
WO2021218930A1 PCT/CN2021/090017 CN2021090017W WO2021218930A1 WO 2021218930 A1 WO2021218930 A1 WO 2021218930A1 CN 2021090017 W CN2021090017 W CN 2021090017W WO 2021218930 A1 WO2021218930 A1 WO 2021218930A1
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celecoxib
pregabalin
pain
amorphous substance
spectrum
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Chinese (zh)
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罗欢
路苹
陈叶明
蒋钰
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Suzhou Nhwa Pharmaceutical Research Co Ltd
Nhwa Pharmaceutical Corp
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Suzhou Nhwa Pharmaceutical Research Co Ltd
Nhwa Pharmaceutical Corp
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Priority to CN202180028486.8A priority Critical patent/CN115551834B/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention belongs to the technical field of medicine, and specifically relates to a celecoxib pregabalin co-amorphous substance formed by the 2:1 combination of celecoxib and pregabalin at a molar ratio (usually also referred to as "amorphous substance") and Preparation.
  • pain can be divided into three categories: injury, neuropathology, and mixed.
  • Nociceptive pain is usually caused by noxious stimuli, such as body/visceral inflammation or mechanical pain. Therefore, it can be further divided into somatic pain and visceral pain. Nociceptive pain usually lasts for a short time and disappears with the recovery of the injury. Nociceptive pain includes postoperative pain, inflammatory pain, bleeding pain, cancer pain and so on.
  • Neuropathic pain results from spontaneous abnormal neuronal firing in the central or peripheral nervous system. Since the underlying cause is irreversible, most neuropathic pain is chronic pain. Neuropathic pain is usually divided into peripheral neuropathic pain and central neuropathic pain according to the location of the cause. Peripheral neuropathic pain includes back neuralgia, diabetic peripheral neuropathy, and post-herpetic neuralgia. Central nervous system pathological pain includes post-stroke central neuralgia, spinal cord injury, multiple sclerosis, neurological dysfunction pain, fibromyalgia syndrome and so on.
  • Mixed pain is characterized by the coexistence of nociceptive pain and neuropathic pain. For example, back pain with nerve damage, migraine, etc.
  • Non-steroidal anti-inflammatory and analgesic drugs achieve anti-inflammatory and analgesic effects by inhibiting cyclooxygenase (COX) to inhibit prostaglandin biosynthesis.
  • Opioid analgesics which achieve analgesic effects by stimulating or blocking opioid receptors, include weak opioid analgesics and strong opioid analgesics.
  • Multimodal analgesics are usually used clinically, and it is recommended to use analgesic drugs with different analgesic mechanisms to achieve analgesia.
  • the WHO "3-step” guidelines provide guidelines for dealing with pain.
  • the “3-step” is determined by the intensity of pain and the analgesic activity of the drug, including mild, moderate, and severe.
  • Celecoxib (Celecoxib), whose chemical name is 4-[5-(4-benzyl)-3-(trifluoromethyl)-1hydro-1-pyrazole-1-yl]benzenesulfonamide, belongs to Non-steroidal anti-inflammatory drugs (NSAIDs), whose mechanism of action is to inhibit the biosynthesis of prostaglandins by selectively inhibiting cyclooxygenase 2 (COX-2), thereby achieving anti-inflammatory and analgesic effects.
  • NSAIDs Non-steroidal anti-inflammatory drugs
  • COX-2 cyclooxygenase 2
  • Celecoxib is long needle-like crystals, resulting in low bulk density and poor compressibility, making it difficult to prepare an ideal solid dosage form.
  • Celecoxib is a weakly acidic drug of BCS II. It has a pKa of 11.1 and is almost insoluble in water. After oral administration, its bioavailability is low, and its absorption can be improved by improving its solubility.
  • Pregabalin whose chemical name is (S)-3-aminomethyl-5-methylhexanoic acid, is an analog of ⁇ -aminobutyric acid (GABA). Its structure and function are similar to that of gabapentin, and its mechanism of action is mainly It is through the combination of the type I ⁇ 2- ⁇ subunits of the voltage-dependent calcium channel to reduce the influx of calcium ions, thereby reducing the release of excitatory neurotransmitters, thereby effectively controlling neuropathic pain. Mainly used for the treatment of post-herpetic neuralgia, diabetic neuropathy, fibromyalgia syndrome, etc.
  • GABA ⁇ -aminobutyric acid
  • the first object of the present invention is to provide a co-amorphous form of celecoxib and pregabalin.
  • Another object of the present invention is to provide a co-amorphous form of celecoxib and pregabalin, which is used to treat or relieve the pain of patients with moderate or moderate to severe pain.
  • the molar ratio of celecoxib to pregabalin is 1:2 to 2:1, preferably 2:1.
  • the glass transition temperature of the co-amorphous celecoxib and pregabalin is 47.17°C to 59.50°C.
  • the glass transition temperature of the co-amorphous celecoxib and pregabalin is 56.50 ⁇ 3°C.
  • the co-amorphous form of celecoxib and pregabalin has a DSC spectrum substantially as shown in FIG. 8. More preferably, the co-amorphous form of celecoxib and pregabalin has a DSC spectrum as shown in FIG. 8.
  • the co-amorphous form of celecoxib and pregabalin has an XRPD spectrum substantially as shown in FIG. 4. More preferably, the co-amorphous form of celecoxib and pregabalin has an XRPD spectrum as shown in FIG. 4.
  • the infrared spectrum of the co-amorphous celecoxib and pregabalin is at the following positions (cm -1 ⁇ 2 cm -1 ) 691.11, 742.67, 759.74, 805.40, 841.89, 976.27,1094.90,1129.82,1159.91,1234.90,1271.44,1332.31,1373.10,1406.24,1471.27,1500.39,1550.61,2867.73,2954.34 have absorption peaks.
  • the infrared spectrum absorption peaks (cm -1 ⁇ 2 cm -1 ) of the co-amorphous celecoxib and pregabalin are: 691.11, 717.03, 722.02, 742.67, 759.74, 805.40, 825.72, 841.89, 912.21. 970.59,976.27,1017.51,1039.60,1094.90,1129.82,1159.91,1201.15,1234.90,1271.44,1292.93,1306.50,1332.31,1373.10,1406.24,1448.04,1471.27,1500.39,1550.61,1598.22,2867.73,2898.66.2927.26,2954.32
  • TGA analysis shows that the weight loss ratio of the co-amorphous celecoxib and pregabalin at about 30 to 150° C. is about 1.23 ⁇ 0.5%.
  • the Raman spectra of the co-amorphous celecoxib and pregabalin are at the following positions (cm -1 ⁇ 2 cm -1 ) 206.95, 242.05, 296.65, 353.87, 378.44 , 409.52, 563.55, 628.57, 642.70, 718.78, 743.25, 798.41, 974.42, 1063.36, 1098.29, 1159.66, 1187.85, 1202.32, 1238.17, 1312.99, 1375.07, 1449.92, 1473.17, 1520.65, 1557.10, 1599.00, 1617.66 have scattering peaks.
  • the scattering peaks (cm -1 ⁇ 2 cm -1 ) of the Raman spectrum of the co-amorphous celecoxib and pregabalin are 206.95, 242.05, 269.83, 296.65, 353.87, 378.44, 409.52, 440.73, 462.86 , 482.30, 500.07, 513.33, 544.08, 563.55, 628.57, 642.70, 689.05, 718.78, 743.25, 760.39, 798.41, 842.27, 974.42, 1021.20, 1063.36, 1098.29, 1159.66, 1187.85, 1202.32, 1238.17, 1280.26, 1293.46, 1312.99 , 1411.10, 1449.92, 1473.17, 1499.88, 1520.65, 1557.10, 1599.00, 1617.66.
  • the co-amorphous form of celecoxib and pregabalin has one or more of the following characteristics:
  • V Basically conform to the Raman spectrum of FIG. 16 or conform to the Raman spectrum of FIG. 16.
  • Another object of the present invention is to provide a method for preparing the co-amorphous form of celecoxib and pregabalin.
  • a method for preparing the co-amorphous substance of celecoxib and pregabalin is to dissolve celecoxib and pregabalin in an organic solvent to obtain a clear liquid, and spray drying to prepare the final product.
  • the step of filtering the resulting solution is optionally included.
  • the process of dissolving celecoxib and pregabalin in the organic solvent further includes a stirring step.
  • the organic solvent is selected from C1-5 alcohols, ketones and sulfones, and the C1-5 alcohols are preferably one or two of methanol and ethanol, preferably methanol
  • the ketones are selected from one or more of acetone, methyl ethyl ketone or methyl isobutyl ketone, preferably acetone; the sulfones are selected from dimethyl sulfoxide.
  • the molar ratio of celecoxib and pregabalin is selected from 1:2 to 2:1, preferably 2:1.
  • the volume ratio of the total mass of celecoxib and pregabalin to the organic solvent is 2-20 mg/ml, preferably 4-15 mg/ml, for example 5-6 mg/ml, 10 -12mg/ml, 12-14mg/ml.
  • the duration of the stirring step is selected from 0 to 1 h, preferably 1 to 30 min, more preferably 15 to 30 min.
  • the spray drying conditions are as follows: inlet temperature is selected from 50 to 65°C, preferably 60°C; 70-100% for aspirator, 5% to 20% for pump, and cooling temperature is selected from -7°C ⁇ -20°C.
  • the spray drying instrument used is Buqi Small Spray Dryer B-290, equipped with inert gas circulation device B-295.
  • the powder X-ray diffraction pattern, DSC pattern and infrared spectrum of the celecoxib and pregabalin co-amorphous substances disclosed in the present invention are different from the powder X-ray diffraction patterns, DSC patterns and infrared spectra of the celecoxib crystals and pregabalin crystals reported in the patents.
  • the solid form is completely different from the form of celecoxib and pregabalin in the prior art.
  • Another object of the present invention is to provide a pharmaceutical composition containing the co-amorphous form of celecoxib and pregabalin of the present invention.
  • the pharmaceutical composition further contains pharmaceutically acceptable excipients.
  • the content of the celecoxib and pregabalin co-amorphous substance in the pharmaceutical composition is 100-400 mg, preferably 150-300 mg.
  • the celecoxib pregabalin co-amorphous in the pharmaceutical composition accounts for 20-85% by mass of the pharmaceutical composition, preferably 30-80%, more preferably 40%. -60%.
  • the pharmaceutically acceptable excipients include, but are not limited to: diluents, such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, calcium hydrogen phosphate, Tricalcium phosphate, mannitol, sorbitol, sugar, etc.; binders, such as gum arabic, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, etc.
  • diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, calcium hydrogen phosphate, Tricalcium phosphate, mannitol, sorbitol, sugar, etc.
  • binders such as gum arabic, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, etc.
  • Disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide, etc.
  • lubricants such as stearic acid, stearic acid Magnesium, zinc stearate, sodium benzoate, sodium acetate, etc.
  • glidants such as colloidal silicon dioxide, etc.
  • complex forming agents such as various grades of cyclodextrin and resin
  • release rate control agents such as hydroxypropyl Cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, methyl methacrylate, wax, etc.
  • the tablets in the solid dosage form may be coated with a coating layer, for example, shellac isolation coating, sugar coating or polymer coating is provided.
  • the polymer in the coating layer is such as hydroxypropyl methylcellulose, poly Vinyl alcohol, ethyl cellulose, methacrylic polymers, hydroxypropyl cellulose or starch, and may also include anti-adhesive agents such as silicon dioxide, talc, opacifiers such as titanium dioxide, coloring agents such as iron oxides Agent.
  • suitable excipients include water, oils, alcohols, glycols, flavoring agents, preservatives, stabilizers, coloring agents, solubilizers, antioxidants, etc.; water or non-aqueous sterile mixtures
  • Suspensions may contain suspending agents and thickening agents;
  • suitable auxiliary materials for aqueous suspensions include synthetic gums or natural gums such as gum arabic, xanthium gum, alginate, dextran, sodium carboxymethyl cellulose, methyl Cellulose, polyvinylpyrrolidone or gelatin.
  • auxiliary materials of aqueous or non-aqueous sterile injection solutions are usually sterile water, physiological saline or aqueous glucose solution, which may contain buffers, antioxidants, bacteriostatic agents and can make the drug
  • the composition is a solute that is isotonic with blood.
  • Each excipient must be acceptable, compatible with the other ingredients in the formula, and harmless to the patient.
  • the pharmaceutical composition can be made into a certain dosage form and administered through a suitable route.
  • a suitable route for example, oral, parenteral (including subcutaneous, intramuscular, intravenous or intradermal), rectal, transdermal, nasal, and vaginal routes.
  • Dosage forms suitable for oral administration include tablets, capsules, granules, powders, pills, powders, lozenges, solutions, syrups or suspensions, and can be suitable for rapid release, delayed release or suspension of active pharmaceutical ingredients as required.
  • dosage forms suitable for parenteral administration include aqueous or non-aqueous sterile injection solutions, emulsions or suspensions; dosage forms suitable for rectal administration include suppositories or enemas; dosage forms suitable for transdermal administration include ointments and creams Preparations, patches; dosage forms suitable for nasal administration include aerosols, sprays, and nasal drops; dosage forms suitable for vaginal administration include suppositories, suppositories, gels, pastes or sprays.
  • the pharmaceutical composition can be prepared using methods known in the art.
  • the pharmaceutical composition is a suspension, which is prepared by dispersing the co-amorphous substance in a pharmaceutically acceptable excipient.
  • Another object of the present invention is to provide the use of the co-amorphous substance of celecoxib and pregabalin in the preparation of a medicine for treating or relieving pain in patients with moderate or moderate to severe pain.
  • the present invention also relates to a method for treating or relieving pain in patients with moderate or moderate to severe pain.
  • the method includes administering to a patient in need, a therapeutically effective amount of the co-amorphous substance of celecoxib and pregabalin of the present invention, or containing celecoxib and pregabalin of the present invention.
  • the therapeutically effective amount, frequency of administration and manner of administration can be reasonably adjusted by a doctor according to the patient's physical condition, age and pain degree.
  • the therapeutically effective amount is 100-400 mg per person per day, preferably 150-300 mg per person per day; the frequency of administration is once a day or twice a day; the mode of administration is preferably oral.
  • the moderate or moderately severe pain is nociceptive pain, neuropathic pain or mixed pain.
  • the moderate or moderate to severe pain includes but is not limited to: postoperative pain, inflammatory pain, bleeding pain, cancer pain, peripheral neuropathic pain (including but not limited to: back neuralgia, diabetic peripheral neuropathy, Post-herpetic neuralgia, etc.), central nervous system pathological pain (including but not limited to: post-stroke central neuralgia, spinal cord injury, multiple sclerosis, neurological dysfunction pain, fibromyalgia syndrome, etc.), nerve damage Back pain, migraine, etc.
  • peripheral neuropathic pain including but not limited to: back neuralgia, diabetic peripheral neuropathy, Post-herpetic neuralgia, etc.
  • central nervous system pathological pain including but not limited to: post-stroke central neuralgia, spinal cord injury, multiple sclerosis, neurological dysfunction pain, fibromyalgia syndrome, etc.
  • nerve damage Back pain migraine, etc.
  • the moderate or moderate to severe pain is mixed type pain.
  • the moderate or moderate to severe pain is postoperative pain, back pain, cancer pain, and the like.
  • the co-amorphous substance of the present invention contains celecoxib and pregabalin, both of which have different analgesic mechanisms.
  • the combined use can relieve moderate or moderate to severe pain, especially for mixed pain of nociceptive pain and neuropathic pain. To treat or relieve the effect; and the combined use of the two has a significant synergistic effect, which can significantly reduce the dose of each active substance, while achieving the same efficacy and minimizing side effects.
  • the celecoxib and pregabalin co-amorphous substance further provides advantages that the two separate drugs do not have in the combined use, including: (1) reducing the dose of each active drug to achieve the same efficacy and minimize side effects; (2) Compared with the parent drug, the water solubility is improved and the bioavailability is improved.
  • Figure 1 is a powder X-ray diffraction pattern of celecoxib crystal I.
  • Figure 2 is a powder X-ray diffraction pattern of pregabalin crystal I.
  • Figure 3 is a powder X-ray diffraction pattern of a physical mixture of celecoxib crystal I and pregabalin crystal I.
  • Figure 4 is a powder X-ray diffraction pattern of the co-amorphous celecoxib and pregabalin (molar ratio 2:1).
  • Figure 5 is a DSC chart of celecoxib crystal I.
  • Fig. 6 is a DSC chart of pregabalin crystal I.
  • Figure 7 is a DSC chart of the physical mixture of celecoxib crystal I and pregabalin crystal I.
  • Figure 8 is a DSC chart of celecoxib and pregabalin co-amorphous (molar ratio 2:1).
  • Figure 9 is the infrared spectrum of the amorphous celecoxib.
  • Figure 10 is an infrared spectrum of a pregabalin spray-dried sample.
  • Figure 11 is an infrared spectrogram of a physical mixture of 2:1 molar ratio of celecoxib after spray drying and pregabalin after spray drying.
  • Figure 12 is the infrared spectrum of the co-amorphous celecoxib and pregabalin (molar ratio 2:1).
  • Figure 13 is the Raman spectrum of the amorphous celecoxib.
  • Figure 14 is a Raman spectrum of a spray-dried sample of pregabalin.
  • Figure 15 is a Raman spectrum of a physical mixture of 2:1 molar ratio of celecoxib after spray drying and pregabalin after spray drying.
  • Figure 16 is a Raman spectrum of the co-amorphous celecoxib and pregabalin (molar ratio 2:1).
  • Figure 17 is a TGA graph of celecoxib and pregabalin co-amorphous (molar ratio 2:1).
  • Figure 18 is a graph showing the stability of celecoxib crystal form I after spray drying.
  • Figure 19 is a graph showing the stability of pregabalin crystal form I after spray drying and grinding.
  • Figure 20 is a graph of the crystal stability of celecoxib/pregabalin (1:2) amorphous prepared by spray drying.
  • Figure 21 is a graph of the crystal stability of celecoxib/pregabalin (1:1) amorphous obtained by spray drying.
  • Figure 22 is a graph showing the crystal stability of celecoxib and pregabalin (2:1) co-amorphous form.
  • test methods described are implemented in accordance with conventional conditions or conditions recommended by the manufacturer.
  • the X-ray powder diffraction patterns of the following examples were collected on a PANalytical X’Pert sharp shadow X-ray powder diffractometer (PW3040/60), and the test temperature was a conventional temperature, such as 25°C.
  • the parameters of the X-ray powder diffraction method are as follows:
  • Scan range: from 2.0 to 40.0 degrees
  • thermogravimetric analysis (TGA) graphs of the following examples were collected on TA Q500.
  • TGA thermogravimetric analysis
  • the differential scanning calorimetry (DSC) graphs of the following examples were collected on TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) are as follows:
  • Heating rate 3°C/min, modulate ⁇ 0.5°C every 40s
  • FTIR Fourier Transform Infrared Spectroscopy
  • the spray dryer in the following embodiment is a Buqi small spray dryer B-290, equipped with an inert gas circulation device B-295.
  • the setting conditions are: inlet temperature 50°C-60°C, aspirator 70%-100%, pump 5%/10%/20%, cooling temperature -7°C, -15°C or -20°C.
  • the Raman images of the following examples were collected on a Renishaw inVia Raman microscope (equipped with a near-infrared diode laser source and a Rencam charge-coupled device (CCD) silicon detector).
  • the parameters of the Raman method are as follows:
  • step 2) Use Buqi small spray dryer B-290, equipped with inert gas circulation device B-295.
  • the solution obtained in step 1) is spray-dried according to the set conditions to obtain a sample.
  • the setting conditions are as follows: the inlet temperature is 60°C, the aspirator is 100%, the pump is 10%, and the cooling temperature is -15°C.
  • the XRPD result of the sample is shown in Fig. 4, the DSC result is shown in Fig. 8, the FTIR result is shown in Fig. 12, the Raman result is shown in Fig. 16, and the TGA result is shown in Fig. 17.
  • the infrared spectrum absorption peak (cm -1 ) is 691.11, 717.03, 722.02, 742.67, 759.74, 805.40, 825.72, 841.89, 912.21, 970.59, 976.274, 1017.51, 1039.60, 1094.89, 1129.82, 1159.91, 1201.15, 1234.90, 1271.44, 1292.93, 1306.50,1332.31,1373.10,1406.24,1448.04,1471.27,1500.39,1550.61,1598.22,2867.73,2898.66,2927.26,2954.34.
  • the scattering peaks (cm -1 ) of the Raman spectrum are 206.95, 242.05, 269.83, 296.65, 353.87, 378.44, 409.52, 440.73, 462.86, 482.30, 500.07, 513.33, 544.08, 563.55, 628.57, 642.70, 689.05, 718.78, 743.25, 760.39 , 798.41, 842.27, 974.42, 1021.20, 1063.36, 1098.29, 1159.66, 1187.85, 1202.32, 1238.17, 1280.26, 1293.46, 1312.99, 1375.07, 1411.10, 1449.92, 1473.17, 1499.88, 1520.65, 1557.10, 1599.00, 1617.66.
  • the celecoxib amorphous substance and the spray-dried pregabalin were prepared by spray-drying method (the same conditions as above), and the two were thoroughly mixed at a molar ratio of 2:1 to obtain a physical mixture, and the solid-state characterization was performed respectively.
  • the IR ( Figure 12) and Raman ( Figure 16) of the co-amorphous sample prepared above were compared.
  • the peak is broadened, and intermolecular hydrogen bonds are formed with -NH of celecoxib, which further broadens the peak, and finally shows that the baseline of the co-amorphous substance at 1643cm -1 drifts upward without an absorption peak;
  • celecoxib hydrogen bond acceptor -S O symmetric, asymmetric stretching vibration absorption peak of 1333cm -1 and 1157cm -1, a hydrogen bond donor and 1159cm -1 1337cm -1 -NH reduced at 3000-3400cm -
  • step 2) Use Buqi small spray dryer B-290, equipped with inert gas circulation device B-295.
  • the solution obtained in step 1) is spray-dried according to the set conditions to obtain a sample.
  • the setting conditions are as follows: the inlet temperature is 60°C, the aspirator is 100%, the pump is 10%, and the cooling temperature is -15°C.
  • the XRPD spectrum of the co-amorphous celecoxib and pregabalin has no sharp diffraction peaks.
  • step 2) Use Buqi small spray dryer B-290, equipped with inert gas circulation device B-295.
  • the solution obtained in step 1) is spray-dried according to the set conditions to obtain a sample.
  • the setting conditions are as follows: the inlet temperature is 50°C, the aspirator is 70%, the pump is 20%, and the cooling temperature is -7°C.
  • the XRPD spectrum of the co-amorphous celecoxib and pregabalin has no sharp diffraction peaks.
  • a single celecoxib crystal form I can obtain an amorphous substance under the same spray drying preparation conditions.
  • the amorphous substance is placed in a room temperature desiccator for 17 hours. After testing, the amorphous substance is transformed into the starting celecoxib
  • the crystal form I of the sample is shown in Figure 18.
  • the XRPD patterns in Figure 18 from top to bottom are: the amorphous substance obtained by spray drying of celecoxib, the amorphous substance is placed for 17 hours, the crystal form I of celecoxib.
  • a diffraction peak appeared in the XRPD of the substance after the amorphous substance was placed for 17 hours, and the diffraction peak was at the same position as the diffraction peak of celecoxib crystal form I.
  • Single pregabalin crystal form I still maintains the crystal form of crystal form I to a large extent under the same spray drying preparation conditions. Dry ball milling is used. For pregabalin crystal form I ball milling for 3 hours, pregabalin crystals are still observed The diffraction peaks of Form I are shown in Figure 19. The XRPD patterns in Figure 19 from top to bottom are: pregabalin crystal form I after spray drying and ball milling for 3 hours.
  • the molar ratio of celecoxib crystal form I and pregabalin crystal form I was changed to 1:2, and the amorphous substance can be obtained under the same spray drying preparation conditions.
  • the transformation temperature is 50.17°C, and the crystal form is tested after being placed in a room temperature desiccator for 22 hours, as shown in Figure 20.
  • the XRPD patterns in Figure 20 from top to bottom are: spray drying to obtain an amorphous substance, and the amorphous substance is left for 22 hours.
  • the molar ratio of celecoxib crystal form I and pregabalin crystal form I was changed to 1:1.
  • the amorphous substance and glass can be obtained under the same spray drying preparation conditions.
  • the transformation temperature is 53.15°C, and the crystal form is tested after being placed in a desiccator at room temperature for 30 hours, as shown in Figure 21.
  • the XRPD patterns in Figure 21 from top to bottom are: spray drying to obtain an amorphous substance, and the amorphous substance is left for 30 hours.
  • the celecoxib/pregabalin (2:1) co-amorphous substance prepared by spray drying in Example 1 was still amorphous after being placed in a room temperature desiccator for 25 days; transferred to a laboratory environment (20- 25°C, 45-50% RH) is still amorphous after being placed for 17 hours, as shown in Figure 22.
  • the XRPD patterns in Figure 22 from top to bottom are: the amorphous material obtained after spray drying, the amorphous material is placed in a room temperature desiccator for 25 days, and then transferred to a laboratory environment for 17 hours.
  • celecoxib pregabalin co-amorphous substance Take about 1.5 g of celecoxib pregabalin co-amorphous substance (molar ratio 2:1), and the mixture of celecoxib crystal form I and pregabalin crystal form I (mixed by molar ratio 2:1) is about 1.5 g Put in 4ml of pH1.2 hydrochloric acid solution, pH4.0 acetate buffer solution, pH7.4 phosphate buffer solution, stir, take samples at 1h and 24h, centrifuge, take the supernatant through a 0.45 ⁇ m filter membrane, and sample After dilution, the content is determined, and the results are as follows:
  • Example 6 Combination medication of celecoxib and pregabalin, and the efficacy experiment of the two amorphous substances
  • celecoxib crystal form I The physical mixture of celecoxib crystal form I, pregabalin crystal form I, celecoxib crystal form I and pregabalin crystal form I (molar ratio 2:1), celecoxib and pregabalin are totally amorphous
  • the substance (molar ratio 2:1) was suspended in injection-grade soybean oil according to the designed dosage.
  • Rats are initially screened, and the basic value is tested (at least twice, if the two results are too different, test the third time, take the average value), exclude sensitive animals; 7% chloral hydrate is used as an anesthetic, and the intraperitoneal injection volume is 1ml/ 250g, iodophor was used to disinfect the surface of the surgical site on the sole of the rat.
  • a 1cm longitudinal incision was made from the edge of the heel 0.5cm forward, including the skin, fascia and plantaris muscle, sutured with two stitches of the skin, pressed to stop bleeding and clean the wound.
  • the basic value was tested again on the first day after the operation and divided into groups with 8 animals in each group so that the basic value of each group was kept as consistent as possible; the second day after the model was made, the administration was performed, and the mechanical tenderness withdrawal threshold of the rats was measured 120 minutes later. (MWT).
  • Pain threshold increase rate (%) (administration group pain threshold-vehicle group pain threshold) * 100% / vehicle group pain threshold
  • Celecoxib 48 11.52 Celecoxib 96 34.45*** Pregabalin 10 0.48 Pregabalin 20 20.05** Pregabalin 40 35.67*** Physical mixture 14.5 -4.57 Physical mixture 29 16.28* Physical mixture 58 38.29*** Co-amorphous 14.5 23.42**/# Co-amorphous 29 21.11* Co-amorphous 58 35.64***
  • the co-amorphous exposure is slightly lower than that of single administration, but there is no significant difference; the co-amorphous exposure is higher than the physical mixture, and there is a significant difference.
  • the exposure of co-amorphous substance is higher than that of single administration and physical mixture, but there is no significant difference.

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Abstract

La présente invention concerne une substance co-amorphe de célécoxib et de prégabaline et son procédé de préparation. La substance co-amorphe, en particulier la substance co-amorphe, dont le rapport molaire de célécoxib à la prégabaline est de 2 : 1, est stable en structure, ce qui permet d'améliorer la solubilité dans l'eau du célécoxib et de fournir une forme physique pratique pour une administration combinée de célécoxib et de prégabaline.
PCT/CN2021/090017 2020-04-30 2021-04-26 Substance co-amorphe de célécoxib et de prégabaline et son procédé de préparation Ceased WO2021218930A1 (fr)

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