WO2021218930A1 - 塞来昔布与普瑞巴林共无定型物及其制备方法 - Google Patents

塞来昔布与普瑞巴林共无定型物及其制备方法 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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PCT/CN2021/090017
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English (en)
French (fr)
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罗欢
路苹
陈叶明
蒋钰
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江苏恩华药业股份有限公司
苏州恩华生物医药科技有限公司
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Priority to CN202180028486.8A priority Critical patent/CN115551834B/zh
Publication of WO2021218930A1 publication Critical patent/WO2021218930A1/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

提供塞来昔布与普瑞巴林的共无定形物及其制备方法。所述共无定形物，尤其是塞来昔布与普瑞巴林摩尔比为2:1的共无定形物结构稳定，改善了塞来昔布的水溶性，为两者联合给药提供了方便的物理形态。

Description

塞来昔布与普瑞巴林共无定型物及其制备方法
相关专利申请的交叉引用
本专利申请要求2020年4月30日向中国国家知识产权局提交的申请号为202010365541.X，发明名称为“塞来昔布与普瑞巴林共无定型物及其制备方法”的在先发明专利申请的优先权。该在先申请的全文通过引用方式纳入本申请中。
技术领域
本发明属于医药技术领域，具体涉及塞来昔布与普瑞巴林按摩尔比2:1结合形成的塞来昔布普瑞巴林共无定形物(通常也称为“无定型物”)及其制备方法。
背景技术
根据物理成因，疼痛可分为三类：伤害型、神经病理型与混合型。
伤害型疼痛通常是由伤害性刺激引起，例如身体/内脏的炎症或机械性引起的疼痛。因此可进一步分为躯体性疼痛和内脏性疼痛。伤害型疼痛通常持续时间短，伴随损伤的恢复而消失。伤害性疼痛包括术后痛、炎症痛、出血痛、癌症痛等。
神经病理性疼痛源自中枢或外周神经***中自发的异常神经元放电。由于潜在的病因不可逆，多数神经性疼痛为慢性疼痛。神经病理性疼痛根据病因部位通常分为外周神经病理性疼痛和中枢神经病理性疼痛。外周神经病理性疼痛包括后背神经痛、糖尿病周围神经病变、带状疱疹后神经痛等。中枢神经病理性疼痛包括中风后中枢神经痛、脊髓损伤、多发性硬化、神经功能障碍性疼痛、纤维肌痛综合征等。
混合型疼痛的特征为伤害性疼痛与神经病理性疼痛共存。例如，有神经损伤的后背痛、偏头痛等。
存在许多已知的适用于治疗或控制各类疼痛的药物。非甾体消炎镇痛药(NSAID)通过抑制环氧酶(cyclooxygenase,COX)从而抑制***素生物合成达到消炎镇痛的效果。阿片类镇痛药，通过激动或阻滞阿片受体达到镇痛效果，包括弱阿片类镇痛药和强阿片类镇痛药。
临床上通常使用多模式镇痛(multimodal analgesics)，推荐联合使用不同镇痛机理的镇痛药 物达到镇痛目的。
WHO“3-步骤”准则提供了处理疼痛的指导原则。“3-步骤”是通过疼痛强度和药物的镇痛活性确定的，包括轻度、中度、重度。
塞来昔布(Celecoxib)，化学名称是4-[5-(4-苯甲基)-3-(三氟甲基)-1氢-1-吡唑-1-基]苯磺酰胺，属于非甾体类抗炎药(NSAIDs)，其作用机理是通过选择性抑制环氧化酶2(COX-2)抑制***素的生物合成，从而达到消炎镇痛的效果。通常用于关节炎、类风湿性关节炎以及各种类型的痛觉缓解。因其对COX-2的高度选择性，使其常见的胃肠不良药物反应(例如胃溃疡)最少。塞来昔布呈长针状晶体，导致其堆密度低、可压性较差等，使其很难制备成理想固体剂型。而且塞来昔布属于BCS II的弱酸性药物，pKa为11.1，在水中几乎不溶，口服后生物利用度较低，可通过改善其溶解性改善其吸收。
普瑞巴林(Pregabalin)，化学名称是(S)-3-氨甲基-5-甲基己酸，为γ-氨基丁酸(GABA)类似物，结构和作用与加巴喷丁相似，其作用机制主要是通过电压依赖性钙通道的I型α2-δ亚基相结合，减少钙离子内流，从而减少兴奋性神经递质的释放，进而有效控制神经性疼痛。主要用于治疗带状疱疹后神经痛、糖尿病性神经病变、纤维肌痛综合征等。
发明内容
本发明的第一个目的是提供一种塞来昔布与普瑞巴林的共无定形物。
本发明的另一目的是提供一种塞来昔布与普瑞巴林的共无定形物，其用于治疗或缓解中度或中重度疼痛患者的疼痛。
根据本发明，所述塞来昔布与普瑞巴林的共无定形物中，塞来昔布与普瑞巴林的摩尔比为1:2～2:1，优选为2:1。
根据本发明，所述塞来昔布与普瑞巴林共无定形物的玻璃化转变温度为47.17℃～59.50℃。
根据本发明，在一个具体实施方式中，所述塞来昔布与普瑞巴林共无定形物的玻璃化转变温度为56.50±3℃。
根据本发明，在一个具体实施方式中，所述塞来昔布与普瑞巴林的共无定形物具有基本如图8所示的DSC谱图。更优选，所述塞来昔布与普瑞巴林的共无定形物具有如图8所示的DSC谱图。
根据本发明，在一个具体实施方式中，所述塞来昔布与普瑞巴林的共无定形物具有基本如图4所示的XRPD谱图。更优选，所述塞来昔布与普瑞巴林的共无定形物具有如图4所示的 XRPD谱图。
根据本发明，在一个具体实施方式中，所述塞来昔布与普瑞巴林共无定形物的红外光谱在以下位置(cm -1±2cm -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具有吸收峰。优选，所述塞来昔布与普瑞巴林共无定形物的红外光谱吸收峰(cm -1±2cm -1)为：691.11，717.03，722.02，742.67，759.74，805.40，825.72，841.89，912.21，970.59，976.27，1017.51，1039.60，1094.90，1129.82，1159.91，1201.15，1234.90，1271.44，1292.93，1306.50，1332.31，1373.10，1406.24，1448.04，1471.27，1500.39，1550.61，1598.22，2867.73，2898.66，2927.26，2954.34。
在一个实施方案中，TGA分析显示，所述塞来昔布与普瑞巴林共无定形物在约30～150℃的失重比例为约1.23±0.5％。
根据本发明，在一个具体实施方式中，所述塞来昔布与普瑞巴林共无定形物的拉曼光谱在以下位置(cm -1±2cm -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具有散射峰。优选，所述塞来昔布与普瑞巴林共无定形物的拉曼光谱的散射峰(cm -1±2cm -1)为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。
在本发明优选的具体实施方案中，所述塞来昔布与普瑞巴林共无定形物具有如下一个或多个特征：
Ⅰ.基本上符合图4的X-射线粉末衍射图谱或者符合图4的X-射线粉末衍射图谱；
Ⅱ.基本上符合图12的FT-IR光谱或者符合图12的FT-IR光谱图；
Ⅲ.基本上符合图8的DSC谱图或者符合图8的DSC谱图；
Ⅳ.基本上符合图17的TGA谱图或者符合图17的TGA谱图；
V.基本上符合图16的拉曼光谱图或者符合图16的拉曼光谱图。
本发明的另一目的是提供制备所述塞来昔布与普瑞巴林共无定形物的方法。
一种所述塞来昔布与普瑞巴林共无定形物的制备方法，将塞来昔布和普瑞巴林溶解于有 机溶剂中，得到澄清液体，采用喷雾干燥制得终产品。
根据本发明，将塞来昔布和普瑞巴林溶解于有机溶剂后，任选还包括过滤所得溶液的步骤。
本发明另外一个具体的实施例方案中，将塞来昔布和普瑞巴林溶解于有机溶剂的过程中还包括搅拌步骤。
本发明优选的具体实施的方案中，所述有机溶剂选自C1-5的醇类、酮类以及砜类，所述C1-5的醇类优选甲醇、乙醇的一种或两种，优选甲醇；所述酮类选自丙酮、丁酮或甲基异丁基酮中的一种或多种，优选丙酮；所述砜类选自二甲基亚砜。
本发明优选的具体实施方案中，塞来昔布和普瑞巴林的投料摩尔比选自1:2～2:1，优选2:1。
本发明优选的具体实施方案中，塞来昔布和普瑞巴林的投料总质量与有机溶剂的体积比为2-20mg/ml，优选4-15mg/ml，例如为5-6mg/ml，10-12mg/ml，12-14mg/ml。
本发明优选的具体实施例方案中，搅拌步骤的持续时间选自0～1h，优选1～30min，更优选15～30min。
在本发明优选的实施方式中，喷雾干燥的条件为：进口温度选自50～65℃，优选60℃；抽气机70-100％，泵5％～20％，冷却温度选自-7℃～-20℃。
在本发明的具体实施方式中，所采用的喷雾干燥仪器是步琦小型喷雾干燥仪B-290，配惰性气体循环装置B-295。
本发明中公开的塞来昔布与普瑞巴林共无定形物与已有专利报道的塞来昔布晶体和普瑞巴林晶体的粉末X射线衍射图谱、DSC图谱、红外光谱均不同，因此所述固体形态是一种完全不同于现有技术的塞来昔布和普瑞巴林的形态。
本发明的再一个目的是提供一种药物组合物，其含有本发明所述的塞来昔布与普瑞巴林的共无定形物。
根据本发明，所述药物组合物进一步含有药学可接受的辅料。
根据本发明，所述药物组合物中所述的塞来昔布普瑞巴林共无定形物的含量为100-400mg，优选为150-300mg。
根据本发明，所述药物组合物中所述的塞来昔布普瑞巴林共无定形物占所述药物组合物的质量百分比为20-85％，优选为30-80％，更优选为40-60％。
根据本发明，所述药学可接受的辅料在固体剂型的情况下，包括但不限于：稀释剂，例如淀粉、预胶化淀粉、乳糖、粉状纤维素、微晶纤维素、磷酸氢钙、磷酸三钙、甘露醇、山 梨醇、糖等；粘合剂，例如***胶、瓜尔胶、明胶、聚乙烯吡咯烷酮、羟丙基纤维素、羟丙基甲基纤维素、聚乙二醇等；崩解剂，例如淀粉、羟基乙酸淀粉钠、预胶化淀粉、交联聚维酮、交联羧甲基纤维素钠、胶体二氧化硅等；润滑剂，例如硬脂酸、硬脂酸镁、硬脂酸锌、苯甲酸钠、乙酸钠等；助流剂，例如胶体二氧化硅等；复合物形成剂，例如各种级别的环糊精和树脂；释放速度控制剂，例如羟丙基纤维素、羟甲基纤维素、羟丙基甲基纤维素、乙基纤维素、甲基纤维素、甲基丙烯酸甲酯、蜡等。可用的其他药学上可接受的辅料包括但不限于成膜剂、增塑剂、着色剂、调味剂、粘度调节剂、防腐剂、抗氧化剂等。任选地，对固体剂型中的片剂可以涂覆包衣层，例如提供虫胶隔离包衣、糖衣或聚合物包衣，包衣层中的聚合物例如羟丙基甲基纤维素、聚乙烯醇、乙基纤维素、甲基丙烯酸类聚合物、羟丙基纤维素或淀粉，还可以包括抗粘着剂如二氧化硅、滑石粉，乳浊剂如二氧化钛，着色剂如氧化铁类着色剂。在液体剂型的情况下，合适的辅料包括水、油类、醇类、二醇类、调味剂、防腐剂、稳定剂、着色剂、增溶剂、抗氧化剂等；水或非水的无菌混悬剂可含有悬浮剂和增稠剂；适用于水性混悬剂的辅料包括合成胶或天然胶例如***树胶、苍耳树胶、藻酸盐、葡聚糖、羧甲基纤维素钠、甲基纤维素、聚乙烯吡咯烷酮或明胶。在胃肠外给药剂型的情况下，水或非水的无菌注射溶液的辅料通常为无菌水、生理盐水或葡萄糖水溶液，可以含有缓冲剂、抗氧化剂、抑菌剂和能够使该药物组合物与血液等渗的溶质。每一种辅料必须是可接受的，能与配方中的其他成分兼容并且对于患者无害。
根据本发明，所述药物组合物可制成一定的剂型，通过适合的途径给药。例如口服、肠胃外(包括皮下、肌肉、静脉或皮内)、直肠、透皮、经鼻、***等途径。适合口服给药的剂型包括片剂、胶囊剂、颗粒剂、散剂、丸剂、粉剂、锭剂、溶液、糖浆剂或混悬剂，根据需要，可适于药物活性成分的快速释放、延迟释放或调节释放；适合肠胃外给药的剂型包括水性或非水性的无菌注射溶液、乳液或混悬液；适合直肠给药的剂型包括栓剂或灌肠剂；适合透皮给药的剂型包括软膏、霜剂、贴剂；适合经鼻给药的剂型包括气雾剂、喷剂、滴鼻剂；适合***给药的剂型包括栓剂、塞剂、凝胶、糊剂或喷剂。
所述药物组合物可以使用本领域公知的方法来制备。在本发明的一个实施方式中，所述药物组合物是混悬剂，通过将所述共无定形物分散于药学上可接受的辅料中制备获得。
本发明的再一个目的是提供所述的塞来昔布与普瑞巴林的共无定形物在制备治疗或缓解中度或中重度疼痛患者疼痛的药物中的用途。
本发明还涉及治疗或缓解中度或中重度疼痛患者疼痛的方法。
根据本发明，所述方法包括给予有需要的患者，治疗有效量的本发明所述的塞来昔布与普瑞巴林的共无定形物，或者含有本发明所述的塞来昔布与普瑞巴林的共无定形物的药物组合物。
根据本发明，所述治疗有效量、给药频次以及给药方式根据患者的身体状态、年龄和疼痛程度可由医生进行合理调整，通常而言，治疗有效量为每人每天100-400mg，优选为每人每天150-300mg；给药频次为每日一次或每日两次；给药方式优选为口服。
根据本发明，所述中度或中重度疼痛是伤害性疼痛、神经病理性疼痛或混合型疼痛。
根据本发明，所述中度或中重度疼痛包括但不限于：术后痛、炎症痛、出血痛、癌症痛、外周神经病理性疼痛(包括但不限于：后背神经痛、糖尿病周围神经病变、带状疱疹后神经痛等)、中枢神经病理性疼痛(包括但不限于：中风后中枢神经痛、脊髓损伤、多发性硬化、神经功能障碍性疼痛、纤维肌痛综合征等)、有神经损伤的后背痛、偏头痛等。
根据本发明，优选所述中度或中重度疼痛是混合型疼痛。
根据本发明，优选所述中度或中重度疼痛是手术后痛、后背痛、癌症痛等。
本发明的共无定形物含有塞来昔布和普瑞巴林，两者镇痛机制不同，联合使用能够缓解中度或中重度疼痛，尤其是对伤害性疼痛和神经病理性疼痛的混合型疼痛起到治疗或缓解的作用；并且两者的联合使用具有明显的协同效果，可以显著降低每种活性物质的剂量，而达到相同的药效，使副作用最小化。
而塞来昔布普瑞巴林共无定形物又进一步提供了两种单独药物联合使用所不具有的优点，包括：(1)减少每种活性药物的剂量达到相同药效，使副作用最小化；(2)与母体药物相比改善水溶性，提高生物利用度。
附图说明
图1是塞来昔布晶体I的粉末X射线衍射图。
图2是普瑞巴林晶体I的粉末X射线衍射图。
图3是塞来昔布晶体I和普瑞巴林晶体I物理混合物的粉末X射线衍射图。
图4是塞来昔布普瑞巴林共无定形物(摩尔比2:1)的粉末X射线衍射图。
图5是塞来昔布晶体I的DSC图。
图6是普瑞巴林晶体I的DSC图。
图7是塞来昔布晶体I和普瑞巴林晶体I物理混合物的DSC图。
图8是塞来昔布普瑞巴林共无定形物(摩尔比2:1)的DSC图。
图9是塞来昔布无定形物的红外光谱图。
图10是普瑞巴林喷雾干燥样品的红外光谱图。
图11是喷雾干燥后的塞来昔布和喷雾干燥后的普瑞巴林的摩尔比2:1物理混合物的红外光谱图。
图12是塞来昔布普瑞巴林共无定形物(摩尔比2:1)的红外光谱图。
图13是塞来昔布无定形物的拉曼光谱图。
图14是普瑞巴林喷雾干燥样品的拉曼光谱图。
图15是喷雾干燥后的塞来昔布和喷雾干燥后的普瑞巴林的摩尔比2:1物理混合物的拉曼光谱图。
图16是塞来昔布普瑞巴林共无定形物(摩尔比2:1)的拉曼光谱图。
图17是塞来昔布普瑞巴林共无定形物(摩尔比2:1)的TGA图。
图18是喷雾干燥塞来昔布晶型I后的稳定性图。
图19是喷雾干燥和研磨普瑞巴林晶型I后的稳定性图。
图20是喷雾干燥制得的塞来昔布/普瑞巴林(1:2)无定形物的晶型稳定性图。
图21是喷雾干燥制得的塞来昔布/普瑞巴林(1:1)无定形物的晶型稳定性图。
图22是塞来昔布普瑞巴林(2:1)共无定形物的晶型稳定性图。
具体实施方式
以下结合实施例对本发明做进一步描述。需要说明的是，实施例不能作为对本发明保护范围的限制，本领域的技术人员理解，任何在本发明基础上所作的改进和变化都在本发明的保护范围之内。
以下实施例所用到的常规化学试剂均可商购获得。
下述实施例中，所述的试验方法按照常规条件或制造厂商建议的条件实施。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射分析
TGA：热重分析
DSC：差示扫描量热分析
FT-IR：傅里叶变换红外分析
HPLC：高效液相色谱
以下实施例的X射线粉末衍射图在帕纳科X’Pert锐影X射线粉末衍射仪(PW3040/60)上采集，测试温度为常规温度，例如25℃。所述的X射线粉末衍射的方法参数如下：
X射线反射参数：Cu，Kα
波长：
Figure PCTCN2021090017-appb-000001
管压：45KV
管流：40mA
步长：0.01313°
扫描速度：0.0416°/s
扫描范围：自2.0至40.0度
以下实施例的热重分析(TGA)图在TA Q500上采集。所述的热重分析(TGA)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
以下实施例的差示扫描量热分析(DSC)图在TA Q2000上采集。所述的差示扫描量热分析(DSC)的方法参数如下：
模式：调制模式
升温速率：3℃/min，每40s调制±0.5℃
保护气体：氮气
以下实施例的傅里叶变换红外光谱(FTIR)图在FTIR-650上采集。所述的傅里叶变换红外的方法参数如下：
分辨率：1cm -1
扫描次数：32
以下实施例的喷雾干燥仪是步琦小型喷雾干燥仪B-290，配惰性气体循环装置B-295。设定条件为：进口温度50℃-60℃，抽气机70％-100％，泵5％/10％/20％，冷却温度-7℃、-15℃或-20℃。
以下实施例的拉曼(Raman)图在雷尼绍inVia拉曼显微光谱仪(配置近红外二极管激光源和Rencam电荷耦合器件(CCD)硅检测器)上采集。所述拉曼的方法参数如下：
检测波长：785nm
检测范围：200cm -1-1800cm -1
刺激强度：100％
曝光时间：1s
数据分析：wire4.3
实施例1：塞来昔布普瑞巴林共无定形物(摩尔比2:1)的制备
制备塞来昔布晶体和普瑞巴林晶体的摩尔比1:1的物理混合物：
将原料塞来昔布晶体I型和普瑞巴林晶体I型按摩尔比1:1加入研钵中，充分研磨混合后进行固态表征。将物理混合物的XRPD(图3)与塞来昔布、普瑞巴林起始原料对比(图1-2)，可以看出制备的物理混合物中两种成分的信号良好，可作为参比用于后续实验结果的比对。
1)称取120.16mg塞来昔布晶型I(购于苏州天马精细化学品股份有限公司，3A251807031)和25.04mg普瑞巴林晶型I(来源于江苏恩华，E05-20180501)，加入25mL甲醇，搅拌溶解；
2)应用步琦小型喷雾干燥仪B-290，配惰性气体循环装置B-295。按设定条件对步骤1)获得的溶液进行喷雾干燥，得到样品。设定条件如下：进口温度60℃，抽气机100％，泵为10％，冷却温度为-15℃。
所述样品的XRPD结果如图4，DSC结果如图8，FTIR结果如图12，Raman结果如图16，TGA结果如图17。
由结果可知：塞来昔布普瑞巴林共无定形物的XRPD谱图没有尖锐的衍射峰，30℃至150℃失重为1.23％，玻璃化转变温度为56.50℃。
红外光谱吸收峰(cm -1)为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。
Raman光谱的散射峰(cm -1)为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。
制备塞来昔布无定形物与喷雾干燥后的普瑞巴林摩尔比2:1的物理混合物：
采用喷雾干燥方法(条件同上)制备塞来昔布无定形物、喷雾干燥后的普瑞巴林，并将两者以摩尔比2:1比例充分混合后得到物理混合物，分别进行固态表征，IR(图9-11)与Raman(图13-15)。与以上制备的共无定形样品的IR(图12)与Raman(图16)进行比对。
IR结果显示，与塞来昔布和普瑞巴林相比，喷雾干燥的塞来昔布与喷雾干燥的普瑞巴林的物理混合物仅是两化合物的信号的叠加，未检测到两化合物的分子间作用力；共无定形物与物理混合物相比明显不同，具体表现为普瑞巴林-OH、-NH在2600cm -1、2690cm -1、2765cm -1、2845cm -1处的吸收峰变得不明显，在2898cm -1、2923cm -1处的峰变宽，可能是普瑞巴林的氢键供体-OH、-NH与塞来昔布的氢键受体基团-S＝O产生了分子间氢键，普瑞巴林-C＝O在1643cm -1处的伸缩吸收谱带消失，可能是普瑞巴林的氢键受体-C＝O与氢键供体-NH产生了分子内氢键，使峰变宽，且与塞来昔布的-NH产生了分子间氢键，进一步使峰变宽，最终表现为共无定形物在1643cm -1处的基线向上漂移而没有吸收峰；塞来昔布氢键受体-S＝O的对称、不对称伸缩振动产生的吸收峰由1337cm -1和1159cm -1降为1333cm -1和1157cm -1，氢键供体-NH在3000-3400cm -1处有两个吸收峰和肩峰，但共无定形物在此区域的肩峰不明显。说明两化合物间存在作用力，而且是氢键，导致以上氢键受体、供体基团的吸收峰发生改变。
Raman结果显示以摩尔比2:1混合的物理混合物除主要含喷雾干燥的塞来昔布，还可见喷雾干燥的普瑞巴林的信号，共无定形物与喷雾干燥的塞来昔布与喷雾干燥的普瑞巴林的物理混合物相比不同。综上，实施例1制得的样品为共无定形物。
实施例2：塞来昔布普瑞巴林共无定形物(摩尔比2:1)的制备
1)称取5.3774g塞来昔布和1.1243g普瑞巴林，加入500mL甲醇，搅拌溶解；
2)应用步琦小型喷雾干燥仪B-290，配惰性气体循环装置B-295。按设定条件对步骤1)获得的溶液进行喷雾干燥，得到样品。设定条件如下：进口温度60℃，抽气机100％，泵为10％，冷却温度为-15℃。塞来昔布普瑞巴林共无定形物的XRPD谱图没有尖锐的衍射峰。
实施例3：塞来昔布普瑞巴林共无定形物(摩尔比2:1)的制备
1)称取5.8736g塞来昔布和1.2483g普瑞巴林，加入600mL甲醇，搅拌溶解；
2)应用步琦小型喷雾干燥仪B-290，配惰性气体循环装置B-295。按设定条件对步骤1)获得的溶液进行喷雾干燥，得到样品。设定条件如下：进口温度50℃，抽气机70％，泵为20％， 冷却温度为-7℃。塞来昔布普瑞巴林共无定形物的XRPD谱图没有尖锐的衍射峰。
实施例4：塞来昔布普瑞巴林共无定形物稳定性研究
单一塞来昔布晶型I在相同喷雾干燥制备条件下可得到无定形物，将该无定形物在室温干燥器中放置17小时，经测试，该无定形物转变为起始塞来昔布样品的晶型I，如图18。图18中XRPD图从上至下依次为：塞来昔布喷雾干燥获得的无定形物，无定形物放置17小时后，塞来昔布晶型I。无定形物放置17小时后的物质的XRPD中出现了衍射峰，所述衍射峰与塞来昔布晶型I的衍射峰位置相同。
单一普瑞巴林晶型I在相同喷雾干燥制备条件下仍有很大程度保持晶型I的晶型，采用干法球磨，对普瑞巴林晶型I球磨3小时，仍观察到普瑞巴林晶型I的衍射峰，如图19。图19中XRPD图从上至下依次为：普瑞巴林喷雾干燥并球磨3小时后，普瑞巴林晶型I。
按照实施例1中共无定形物的制备方法，改变塞来昔布晶型I和普瑞巴林晶型I的摩尔比例至1:2投料，在相同喷雾干燥制备条件下可得到无定形物，玻璃化转变温度为50.17℃，在室温干燥器中放置22小时后测试转为晶型，如图20。图20中XRPD图从上至下依次为：喷雾干燥获得无定形物，无定形物放置22小时后。
按照实施例1中共无定形物的制备方法，改变塞来昔布晶型I和普瑞巴林晶型I的摩尔比例至1:1投料，在相同喷雾干燥制备条件下可得到无定形物，玻璃化转变温度为53.15℃，在室温干燥器中放置30小时后测试转为晶型，如图21。图21中XRPD图从上至下依次为：喷雾干燥获得无定形物，无定形物放置30小时后。
将实施例1中喷雾干燥制得的塞来昔布/普瑞巴林(2:1)共无定形物在室温干燥器中放置25天后测试仍为无定形；转至实验室环境下(20-25℃，45-50％RH)放置17小时后测试仍为无定形，如图22。图22中XRPD图从上至下依次为：喷雾干燥后获得的无定形物，无定形物在室温干燥器中放置25天后，转至实验室环境下放置17小时后。
实施例5：塞来昔布普瑞巴林共无定形物溶解度检测
溶解度检测方法：
取塞来昔布普瑞巴林共无定形物(摩尔比2:1)约1.5g，塞来昔布晶型I与普瑞巴林晶型I的混合物(按摩尔比2:1混合)约1.5g分别置于pH1.2盐酸溶液、pH4.0醋酸盐缓冲液、pH7.4磷酸盐缓冲液4ml中，搅拌，于1h、24h取样，离心，取上清液过0.45μm滤膜，取样稀释后测定含量， 结果如下：
Figure PCTCN2021090017-appb-000002
实施例6：塞来昔布和普瑞巴林联合用药，以及两者共无定形物的药效实验
将塞来昔布晶型I、普瑞巴林晶型I、塞来昔布晶型I和普瑞巴林晶型I物理混合物(摩尔比2:1)、塞来昔布普瑞巴林共无定形物(摩尔比2:1)按照设计好的给药剂量分别混悬于注射级别的大豆油中。
均采用灌胃给药。
术后痛
实验步骤
大鼠初筛，测试基础值(至少测两次，如果两次结果差异太大，测试第三次，取平均值)，剔除敏感型动物；7％水合氯醛作为麻醉剂，腹腔注射体积1ml/250g，碘伏对大鼠脚底手术部位进行表面消毒，从足跟部边缘0.5cm处向前作一1cm纵向切口，包括皮肤、筋膜及跖肌，缝合皮肤两针，按压止血及清洁伤口。术后第一天再次测试基础值，平均分组，每组8只动物，使得每组基础值尽可能保持一致；造模后第二天，给药，120min后检测大鼠机械触痛缩足阈值(MWT)。
结果计算
痛阈值提高率(％)＝(给药组痛阈值-溶媒组痛阈值)*100％/溶媒组痛阈值
实验结果
受试物与剂量(mg/kg) 痛阈值提高率(％)
芬太尼组0.04 103.16
塞来昔布24 6.43
塞来昔布48 11.52
塞来昔布96 34.45***
普瑞巴林10 0.48
普瑞巴林20 20.05**
普瑞巴林40 35.67***
物理混合物14.5 -4.57
物理混合物29 16.28*
物理混合物58 38.29***
共无定形物14.5 23.42**/#
共无定形物29 21.11*
共无定形物58 35.64***
与溶媒组机械触痛缩足阈值比，*：p≤0.05；**：p≤0.01；***：p≤0.001；具有统计学意义；
与相同剂量的物理混合组机械触痛缩足阈值比，#：p≤0.05，具有统计学意义。
结论：在术后痛模型中，塞来昔布普瑞巴林的物理混合物以及塞来昔布普瑞巴林共无定形物的各剂量组提高率高于普瑞巴林与塞来昔布相应剂量单药，通过减低两组分的给药量，能够达到相似或更优药效，因此临床上可能通过减少药物使用量，不改变药效的同时减少药物副作用。在该模型中，共无定形物的低剂量组与相同剂量的物理混合物组相比，共无定形组仍有显著药效，说明共无定形物的药效在该模型中相对物理混合物的药效较优。
大鼠药代动力学
制备塞来昔布晶型I、普瑞巴林晶型I、塞来昔布晶型I和普瑞巴林晶型I物理混合物(摩尔比2:1)、塞来昔布普瑞巴林共无定形物(摩尔比2:1)混悬液
分别将塞来昔布晶型I、普瑞巴林晶型I、塞来昔布晶型I和普瑞巴林晶型I物理混合物、塞来昔布普瑞巴林共无定形物混悬于大豆油(注射级)中，制得供试品。
此研究采用LC-MS方法，考察塞来昔布普瑞巴林共无定形物在大鼠体内的药代动力学特征。
实验设计：
动物给药
四组(每组4只动物)SD大鼠于实验前禁食12h，自由饮水，按照设定剂量(塞来昔布24mg/kg，普瑞巴林5mg/kg，物理混合物29mg/kg，共无定形物29mg/kg)灌胃给予药液，分别于给药后5min,15min,30min,1,2,4,6,8,12,24h眼眶采血0.3ml，置离心管中，离心分离血浆，冷冻保存在-20℃冰箱中待测。
结果
在此研究中，塞来昔布普瑞巴林共无定形物/塞来昔布晶型I普瑞巴林晶型I物理混合物/塞来昔布/普瑞巴林在大鼠体内的药代动力学参数如表所示。
表：各组大鼠药代动力学参数
Figure PCTCN2021090017-appb-000003
与共无定形组比，*：p≤0.05；
结论
对于塞来昔布：共无定形物暴露量略低于单独给药，但无明显差异；共无定形暴露量高于物理混合物，且有显著性差异。对于普瑞巴林：共无定形物暴露量高于单独给药和物理混合物，但均无明显差异。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能一次限制本发明的保护范围。凡根据本发明精神是指所做的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (10)

  1. 一种塞来昔布与普瑞巴林的共无定形物，优选，其中塞来昔布与普瑞巴林的摩尔比为1:2～2:1，更优选为2:1。
  2. 如权利要求1所述的塞来昔布与普瑞巴林的共无定形物，其特征在于，所述共无定形物的玻璃化转变温度为47.17℃～59.50℃，优选为56.50±3℃。
  3. 如权利要求1或2所述的塞来昔布与普瑞巴林的共无定形物，其特征在于，所述共无定形物的拉曼光谱在以下位置(cm -1±2cm -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具有散射峰；
    优选，所述共无定形物的拉曼光谱的散射峰(cm -1±2cm -1)为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。
  4. 如权利要求1-3任一项所述的塞来昔布与普瑞巴林的共无定形物，其特征在于，所述共无定形物具有基本如图8所示的DSC谱图。
  5. 如权利要求1-4任一项所述的塞来昔布与普瑞巴林的共无定形物，其特征在于，所述共无定形物具有基本如图4所示的XRPD谱图。
  6. 如权利要求1-5任一项所述的塞来昔布与普瑞巴林的共无定形物，其特征在于，所述共无定形物的红外光谱在以下位置(cm -1±2cm -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具有吸收峰；
    优选，所述共无定形物的红外光谱吸收峰(cm -1±2cm -1)为：691.11，717.03，722.02，742.67，759.74，805.40，825.72，841.89，912.21，970.59，976.27，1017.51，1039.60，1094.90，1129.82，1159.91，1201.15，1234.90，1271.44，1292.93，1306.50，1332.31，1373.10，1406.24，1448.04，1471.27，1500.39，1550.61，1598.22，2867.73，2898.66，2927.26，2954.34。
  7. 如权利要求1-6任一项所述的塞来昔布与普瑞巴林的共无定形物，其特征在于，所述 共无定形物具有如下一个或多个特征：
    Ⅰ.基本上符合图4的X-射线粉末衍射图谱或者符合图4的X-射线粉末衍射图谱；
    Ⅱ.基本上符合图12的FT-IR光谱或者符合图12的FT-IR光谱图；
    Ⅲ.基本上符合图8的DSC谱图或者符合图8的DSC谱图；
    Ⅳ.基本上符合图17的TGA谱图或者符合图17的TGA谱图；
    V.基本上符合图16的拉曼光谱图或者符合图16的拉曼光谱图。
  8. 权利要求1-7任一项所述的塞来昔布与普瑞巴林的共无定形物的制备方法，其特征在于，将塞来昔布和普瑞巴林溶解于有机溶剂中，得到澄清液体，采用喷雾干燥制备；
    优选，将塞来昔布和普瑞巴林溶解于有机溶剂后，任选还包括过滤所得溶液的步骤；
    优选，所述有机溶剂选自C1-5的醇类、酮类以及砜类；所述C1-5的醇类优选甲醇、乙醇的一种或两种，优选甲醇；所述酮类选自丙酮、丁酮或甲基异丁基酮中的一种或多种，优选丙酮；所述砜类选自二甲基亚砜；
    优选，塞来昔布和普瑞巴林的投料摩尔比为1:2～2:1，优选为2:1；
    优选，塞来昔布和普瑞巴林的投料总质量与有机溶剂的体积比为2-20mg/ml，优选4-15mg/ml；
    优选，喷雾干燥的条件为：进口温度为50～65℃；抽气机70-100％，泵5％～20％，冷却温度为-7℃～-20℃。
  9. 权利要求1-7任一项所述的塞来昔布与普瑞巴林的共无定形物在制备治疗或缓解中度或中重度疼痛患者疼痛的药物中的用途；
    优选，所述中度或中重度疼痛是伤害性疼痛、神经病理性疼痛或混合型疼痛；
    优选，所述中度或中重度疼痛选自术后痛、炎症痛、出血痛、癌症痛、、后背神经痛、糖尿病周围神经病变、带状疱疹后神经痛、中风后中枢神经痛、脊髓损伤、多发性硬化、神经功能障碍性疼痛、纤维肌痛综合征、有神经损伤的后背痛、偏头痛；
    优选，所述中度或中重度疼痛是混合型疼痛；
    优选，所述中度或中重度疼痛是手术后痛、后背痛、癌症痛。
  10. 一种药物组合物，其特征在于含有权利要求1-7任一项所述的塞来昔布与普瑞巴林的共无定形物。
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