CN115551834B - Celecoxib and pregabalin co-amorphous substance and preparation method thereof - Google Patents

Celecoxib and pregabalin co-amorphous substance and preparation method thereof Download PDF

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CN115551834B
CN115551834B CN202180028486.8A CN202180028486A CN115551834B CN 115551834 B CN115551834 B CN 115551834B CN 202180028486 A CN202180028486 A CN 202180028486A CN 115551834 B CN115551834 B CN 115551834B
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celecoxib
pregabalin
amorphous
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pain
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CN115551834A (en
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罗欢
路苹
陈叶明
蒋钰
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Suzhou Enhua Biomedical Technology Co ltd
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Abstract

Co-amorphous forms of celecoxib and pregabalin and methods of making the same are provided. The co-amorphous substance, especially the co-amorphous substance with the molar ratio of celecoxib to pregabalin of 2:1, has stable structure, improves the water solubility of celecoxib, and provides a convenient physical form for the combined administration of celecoxib and pregabalin.

Description

Celecoxib and pregabalin co-amorphous substance and preparation method thereof
Cross-reference to related patent applications
The patent application claims priority of the prior patent application with the application number of 202010365541.X, the name of celecoxib and pregabalin co-amorphous substance and the preparation method thereof, which are submitted to the China national intellectual property agency on the 30 th month of 2020. The entire disclosure of this prior application is incorporated by reference herein.
Technical Field
The application belongs to the technical field of medicines, and particularly relates to a celecoxib and pregabalin co-amorphous substance (commonly referred to as an 'amorphous substance') formed by combining celecoxib and pregabalin according to a molar ratio of 2:1 and a preparation method thereof.
Background
Pain can be divided into three categories depending on the physical cause: nociceptive, neuropathic, and mixed forms.
Nociceptive pain is generally pain caused by noxious stimuli, such as inflammation of the body/viscera or mechanically. Thus, it can be further classified into somatic pain and visceral pain. Nociceptive pain is usually short in duration and disappears with recovery from injury. Nociceptive pain includes postoperative pain, inflammatory pain, bleeding pain, cancer pain, and the like.
Neuropathic pain results from spontaneous abnormal neuronal firing in the central or peripheral nervous system. Most neuropathic pain is chronic pain due to irreversible underlying etiology. Neuropathic pain is generally classified into peripheral neuropathic pain and central neuropathic pain according to the site of etiology. Peripheral neuropathic pain includes back neuralgia, diabetic peripheral neuropathy, post-herpetic neuralgia, and the like. Central neuropathic pain includes post-stroke central neuralgia, spinal cord injury, multiple sclerosis, neuropathic pain, fibromyalgia syndrome, and the like.
Mixed pain is characterized by the coexistence of nociceptive pain and neuropathic pain. For example, there are back pain, migraine, etc. of nerve injury.
There are many known drugs that are suitable for the treatment or management of various types of pain. Non-steroidal anti-inflammatory analgesics (NSAIDs) achieve anti-inflammatory and analgesic effects by inhibiting the biosynthesis of prostaglandins by inhibiting Cyclooxygenase (COX). Opioid analgesics achieve analgesic effects by agonizing or blocking opioid receptors, including weak opioid analgesics and strong opioid analgesics.
In clinic, multi-mode analgesia (multimodal analgesics) is generally used, and it is recommended to combine analgesic drugs with different analgesic mechanisms to achieve the analgesic purpose.
WHO "3-step" guidelines provide guidelines for the management of pain. The "3-step" is determined by the intensity of pain and analgesic activity of the drug, including mild, moderate, severe.
Celecoxib (4- [5- (4-benzyl) -3- (trifluoromethyl) -1 hydrogen-1-pyrazol-1-yl ] benzenesulfonamide belongs to non-steroidal anti-inflammatory drugs (NSAIDs) and has the action mechanism that the biosynthesis of prostaglandin is inhibited by selectively inhibiting cyclooxygenase 2 (COX-2), so that the effects of diminishing inflammation and easing pain are achieved. Is commonly used for arthritis, rheumatoid arthritis and various types of pain relief. Because of its high selectivity for COX-2, its common adverse gastrointestinal drug reactions (e.g., gastric ulcers) are minimized. Celecoxib is in long needle-shaped crystals, so that the celecoxib has low bulk density, poor compressibility and the like, and is difficult to prepare into an ideal solid dosage form. And celecoxib belongs to a weak acid drug of BCS II, has a pKa of 11.1, is almost insoluble in water, has low bioavailability after oral administration, and can improve the absorption by improving the solubility.
Pregabalin (Pregabalin), known by the chemical name (S) -3-aminomethyl-5-methylhexanoic acid, is a gamma-aminobutyric acid (GABA) analog, and has a structure and action similar to gabapentin, and its mechanism of action is mainly through the binding of the type I α2- δ subunit of voltage-dependent calcium channels, reducing calcium influx, thereby reducing the release of excitatory neurotransmitters, and thus effectively controlling neuropathic pain. Is mainly used for treating postherpetic neuralgia, diabetic neuropathy, fibromyalgia syndrome and the like.
Disclosure of Invention
A first object of the present application is to provide a co-amorphous form of celecoxib and pregabalin.
It is another object of the present application to provide a co-amorphous form of celecoxib and pregabalin for use in treating or alleviating pain in patients with moderate or moderately severe pain.
According to the application, in the co-amorphous substance of celecoxib and pregabalin, the molar ratio of celecoxib to pregabalin is 1:2-2:1, preferably 2:1.
According to the application, the glass transition temperature of the celecoxib and pregabalin co-amorphous substance is 47.17-59.50 ℃.
According to the application, in a specific embodiment, the glass transition temperature of the celecoxib and pregabalin co-amorphous is 56.50+ -3 ℃.
In one embodiment according to the present application, the co-amorphous form of celecoxib and pregabalin has a DSC profile substantially as shown in figure 8. More preferably, the co-amorphous form of celecoxib and pregabalin has a DSC profile as shown in figure 8.
In one embodiment according to the present application, the co-amorphous form of celecoxib and pregabalin has an XRPD pattern substantially as shown in figure 4. More preferably, the co-amorphous form of celecoxib and pregabalin has an XRPD pattern as shown in figure 4.
According to the present application, in one embodiment, the infrared spectrum of the celecoxib and pregabalin co-amorphous is in the following position (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 have absorption peaks. Preferably, the celecoxib and pregabalin co-amorphous material has an infrared spectrum absorption peak (cm) -1 ±2cm -1 ) The method comprises the following steps: 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。
In one embodiment, TGA analysis shows that the weight loss ratio of celecoxib and pregabalin co-amorphous is about 1.23±0.5% at about 30-150 ℃.
According to the present application, in one embodiment, the raman spectrum of the celecoxib and pregabalin co-amorphous is in the following position (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 have scattering peaks. Preferably, the celecoxib and pregabalin co-amorphous has a raman spectrum with a scattering peak (cm -1 ±2cm -1 ) Is 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.
In preferred embodiments of the present application, the celecoxib and pregabalin co-amorphous form has one or more of the following characteristics:
I. an X-ray powder diffraction pattern substantially in accordance with figure 4 or an X-ray powder diffraction pattern in accordance with figure 4;
substantially in accordance with the FT-IR spectrum of fig. 12 or in accordance with the FT-IR spectrum of fig. 12;
a DSC profile substantially in accordance with figure 8 or a DSC profile in accordance with figure 8;
substantially in accordance with the TGA profile of fig. 17 or in accordance with the TGA profile of fig. 17;
v. substantially in accordance with the raman spectrum of fig. 16 or in accordance with the raman spectrum of fig. 16.
It is another object of the present application to provide a process for preparing the celecoxib and pregabalin co-amorphous.
The preparation method of the celecoxib and pregabalin co-amorphous substance comprises the steps of dissolving celecoxib and pregabalin in an organic solvent to obtain clear liquid, and spray-drying to obtain a final product.
According to the present application, after dissolution of celecoxib and pregabalin in an organic solvent, the step of filtering the resulting solution is optionally further included.
In another embodiment of the present application, the process of dissolving celecoxib and pregabalin in an organic solvent further comprises a stirring step.
In a preferred embodiment of the present application, the organic solvent is selected from the group consisting of C1-5 alcohols, ketones and sulfones, wherein the C1-5 alcohols are preferably one or two of methanol and ethanol, preferably methanol; the ketone is selected from one or more of acetone, butanone or methyl isobutyl ketone, preferably acetone; the sulfones are selected from dimethyl sulfoxide.
In a preferred embodiment of the present application, the molar ratio of celecoxib to pregabalin is selected from the group consisting of 1:2 to 2:1, preferably 2:1.
In a preferred embodiment of the application, the ratio of the total mass of the celecoxib and pregabalin dosed to the volume of organic solvent is 2-20mg/ml, preferably 4-15mg/ml, for example 5-6mg/ml,10-12mg/ml,12-14mg/ml.
In a preferred embodiment of the application, the duration of the stirring step is chosen from 0 to 1 hour, preferably from 1 to 30 minutes, more preferably from 15 to 30 minutes.
In a preferred embodiment of the application, the spray drying conditions are: the inlet temperature is selected from 50-65 ℃, preferably 60 ℃; 70-100% of air extractor, 5-20% of pump and cooling temperature of-7 deg.C to-20 deg.C.
In the specific embodiment of the application, the adopted spray drying instrument is a small-sized step-type spray drying instrument B-290 which is provided with an inert gas circulating device B-295.
The celecoxib and pregabalin co-amorphous substance disclosed by the application is different from the powder X-ray diffraction patterns, DSC patterns and infrared spectra of celecoxib crystals and pregabalin crystals reported in the prior patent, so that the solid form is completely different from the celecoxib and pregabalin in the prior art.
It is a further object of the present application to provide a pharmaceutical composition comprising the co-amorphous form of celecoxib and pregabalin according to the present application.
According to the present application, the pharmaceutical composition further comprises pharmaceutically acceptable excipients.
According to the present application, the content of celecoxib pregabalin co-amorphous in said pharmaceutical composition is 100-400mg, preferably 150-300mg.
According to the application, the celecoxib and pregabalin co-amorphous substance in the pharmaceutical composition accounts for 20-85% of the mass of the pharmaceutical composition, preferably 30-80%, and more preferably 40-60%.
According to the present application, the pharmaceutically acceptable excipients in the case of solid dosage forms include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dibasic calcium phosphate, tribasic calcium phosphate, mannitol, sorbitol, sugar, and the like; binders such as acacia, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate, and the like; glidants, such as colloidal silicon dioxide and the like; complex forming agents, such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl methacrylate, waxes, and the like. Other pharmaceutically acceptable excipients that may be used include, but are not limited to, film forming agents, plasticizers, colorants, flavoring agents, viscosity modifiers, preservatives, antioxidants, and the like. Optionally, the tablets in the solid dosage form may be coated with a coating layer, for example providing a shellac barrier coating, a sugar coating or a polymer coating, the polymers in the coating layer, for example hydroxypropyl methylcellulose, polyvinyl alcohol, ethylcellulose, methacrylic polymers, hydroxypropyl cellulose or starch, may also include anti-adherent agents such as silica, talc, opacifying agents such as titanium dioxide, colorants such as iron oxide type colorants. In the case of liquid dosage forms, suitable excipients include water, oils, alcohols, glycols, flavoring agents, preservatives, stabilizers, coloring agents, solubilizing agents, antioxidants and the like; the aqueous or nonaqueous sterile suspension may contain suspending agents and thickening agents; suitable adjuvants for aqueous suspensions include synthetic or natural gums such as gum arabic, xanthan gum, alginates, dextran, sodium carboxymethyl cellulose, methylcellulose, polyvinylpyrrolidone or gelatin. In the case of parenteral dosage forms, the aqueous or nonaqueous sterile injection solution will typically be in the form of a sterile aqueous, physiological saline or dextrose solution, and may contain buffers, antioxidants, bacteriostats and solutes which render the pharmaceutical composition isotonic with the blood. Each adjuvant must be acceptable, compatible with the other ingredients of the formulation, and not deleterious to the patient.
According to the present application, the pharmaceutical composition may be formulated into a dosage form for administration by a suitable route. Such as oral, parenteral (including subcutaneous, intramuscular, intravenous, or intradermal), rectal, transdermal, nasal, vaginal, and the like. Dosage forms suitable for oral administration include tablets, capsules, granules, powders, pills, powders, lozenges, solutions, syrups or suspensions, which may be adapted for rapid, delayed or modified release of the pharmaceutically active ingredient as desired; formulations suitable for parenteral administration include aqueous or non-aqueous sterile injectable solutions, emulsions or suspensions; dosage forms suitable for rectal administration include suppositories or enemas; formulations suitable for transdermal administration include ointments, creams, patches; formulations suitable for nasal administration include aerosols, sprays, nasal drops; dosage forms suitable for vaginal administration include suppositories, tampons, gels, pastes or sprays.
The pharmaceutical compositions may be prepared using methods well known in the art. In one embodiment of the application, the pharmaceutical composition is a suspension prepared by dispersing the co-amorphous material in a pharmaceutically acceptable adjuvant.
It is a further object of the present application to provide the use of the co-amorphous form of celecoxib and pregabalin in the manufacture of a medicament for treating or alleviating pain in patients suffering from moderate or moderately severe pain.
The application also relates to methods of treating or alleviating pain in patients suffering from moderate or moderately severe pain.
According to the present application, the method comprises administering to a patient in need thereof a therapeutically effective amount of a co-amorphous form of celecoxib and pregabalin according to the present application, or a pharmaceutical composition comprising a co-amorphous form of celecoxib and pregabalin according to the present application.
According to the present application, the therapeutically effective amount, the frequency of administration and the mode of administration can be reasonably adjusted by a doctor according to the physical state, age and pain degree of a patient, and generally, the therapeutically effective amount is 100-400mg per day, preferably 150-300mg per day; the administration frequency is once daily or twice daily; the mode of administration is preferably oral.
According to the application, the moderate or moderately severe pain is nociceptive pain, neuropathic pain or mixed pain.
According to the present application, the moderate or moderately severe pain includes, but is not limited to: postoperative pain, inflammatory pain, hemorrhagic pain, cancer pain, peripheral neuropathic pain (including but not limited to back neuralgia, diabetic peripheral neuropathy, post-herpetic neuralgia, etc.), central neuropathic pain (including but not limited to post-stroke central neuralgia, spinal cord injury, multiple sclerosis, neuropathic pain, fibromyalgia syndrome, etc.), back pain with nerve injury, migraine, etc.
According to the application, it is preferred that the moderate or moderately severe pain is mixed pain.
According to the present application, it is preferable that the moderate or moderately severe pain is postoperative pain, back pain, cancer pain, or the like.
The co-amorphous substance contains celecoxib and pregabalin, the analgesic mechanisms of the celecoxib and the pregabalin are different, and the co-amorphous substance can relieve moderate or moderately severe pain when used in combination, and particularly has the effects of treating or relieving mixed pain of nociceptive pain and neuropathic pain; and the combination of the two has obvious synergistic effect, can obviously reduce the dosage of each active substance, achieves the same drug effect and minimizes side effects.
Whereas celecoxib pregabalin co-amorphous still further provides advantages not associated with the use of two separate drugs, including: (1) The dosage of each active drug is reduced to achieve the same efficacy, so that side effects are minimized; (2) Improving water solubility and bioavailability compared with parent medicine.
Drawings
Fig. 1 is a powder X-ray diffraction pattern of celecoxib crystal I.
Fig. 2 is a powder X-ray diffraction pattern of pregabalin crystal I.
Fig. 3 is a powder X-ray diffraction pattern of a physical mixture of celecoxib crystals I and pregabalin crystals I.
FIG. 4 is a powder X-ray diffraction pattern of celecoxib pregabalin co-amorphous (molar ratio 2:1).
Fig. 5 is a DSC diagram of celecoxib crystal I.
Fig. 6 is a DSC diagram of pregabalin crystal I.
Fig. 7 is a DSC diagram of a physical mixture of celecoxib crystal I and pregabalin crystal I.
FIG. 8 is a DSC of celecoxib pregabalin co-amorphous (molar ratio 2:1).
Fig. 9 is an infrared spectrum of celecoxib amorphous form.
Fig. 10 is an infrared spectrum of a pregabalin spray-dried sample.
FIG. 11 is an infrared spectrum of a physical mixture of celecoxib after spray drying and pregabalin after spray drying in a molar ratio of 2:1.
FIG. 12 is an infrared spectrum of celecoxib pregabalin co-amorphous (molar ratio 2:1).
FIG. 13 is a Raman spectrum of celecoxib amorphous material.
Fig. 14 is a raman spectrum of a pregabalin spray dried sample.
Fig. 15 is a raman spectrum of a physical mixture having a molar ratio of celecoxib after spray drying to pregabalin after spray drying of 2:1.
FIG. 16 is a Raman spectrum of celecoxib pregabalin co-amorphous (molar ratio 2:1).
FIG. 17 is a TGA plot of celecoxib pregabalin co-amorphous (molar ratio 2:1).
Figure 18 is a graph of stability after spray drying of crystalline form I of celecoxib.
Fig. 19 is a graph of stability after spray drying and milling of pregabalin form I.
FIG. 20 is a graph showing the stability of crystalline forms of celecoxib/pregabalin (1:2) amorphous form produced by spray drying.
FIG. 21 is a graph showing the stability of crystalline forms of celecoxib/pregabalin (1:1) amorphous form produced by spray drying.
Figure 22 is a graph of the stability of the crystalline form of celecoxib pregabalin (2:1) co-amorphous.
Detailed Description
The application is further described below with reference to examples. It should be noted that the examples should not be construed as limiting the scope of the present application, and those skilled in the art will understand that any modifications and variations based on the present application are within the scope of the present application.
The conventional chemicals used in the examples below are all commercially available.
In the examples described below, the test methods were carried out under conventional conditions or conditions recommended by the manufacturer.
The abbreviations used in the present application are explained as follows:
XRPD: powder diffraction analysis by X-ray
TGA: thermogravimetric analysis
DSC: differential scanning calorimetric analysis
FT-IR: fourier transform infrared analysis
HPLC: high performance liquid chromatography
The X-ray powder diffraction patterns of the following examples were collected on a Panace X' Pert sharp X-ray powder diffractometer (PW 3040/60) at a conventional temperature, e.g., 25 ℃. The X-ray powder diffraction method has the following parameters:
x-ray reflection parameters: cu, K alpha
Wavelength:
tube pressure: 45KV
Tube flow: 40mA
Step size: 0.01313 DEG
Scanning speed: 0.0416 DEG/s
Scanning range: from 2.0 to 40.0 DEG
Thermogravimetric analysis (TGA) plots of the following examples were collected on TA Q500. The method parameters of thermogravimetric analysis (TGA) are as follows:
scanning rate: 10 ℃/min
Protective gas: nitrogen gas
Differential Scanning Calorimetric (DSC) plots of the following examples were collected on TA Q2000. The method parameters of the differential scanning calorimetric analysis (DSC) are as follows:
mode: modulation mode
Rate of temperature rise: 3 ℃/min, every 40s modulation + -0.5 DEG C
Protective gas: nitrogen gas
Fourier Transform Infrared (FTIR) images of the following examples were collected on FTIR-650. The Fourier transform infrared method parameters are as follows:
resolution ratio: 1cm -1
Number of scans: 32
The spray dryer of the following example is a Miniqi small spray dryer B-290 equipped with an inert gas circulation device B-295. The setting conditions are as follows: inlet temperature 50-60 deg.c, air pump 70-100%, pump 5%/10%/20%, cooling temperature-7 deg.c, 15 deg.c or 20 deg.c.
Raman (Raman) plots of the following examples were collected on a rani shaoxinvia Raman micro-spectrometer (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:
detection wavelength: 785nm
Detection range: 200cm -1 -1800cm -1
Stimulation intensity: 100 percent of
Exposure time: 1s
Data analysis: wire4.3
Example 1: preparation of celecoxib-pregabalin co-amorphous (molar ratio 2:1)
Preparing a physical mixture of celecoxib crystals and pregabalin crystals in a molar ratio of 1:1:
adding raw materials of celecoxib crystal form I and pregabalin crystal form I into a mortar according to a molar ratio of 1:1, and fully grinding and mixing to perform solid state characterization. Comparing the XRPD of the physical mixture (fig. 3) with celecoxib, pregabalin starting materials (fig. 1-2), it can be seen that the signals of the two components in the prepared physical mixture are good, and can be used as a reference for comparison of the results of subsequent experiments.
1) 120.16mg of celecoxib form I (available from Suzhou Tianma Fine chemical Co., ltd., 3A 251807031) and 25.04mg of pregabalin form I (from Jiangsu Enhua, E05-20180501) were weighed, 25mL of methanol was added, and stirred for dissolution;
2) The Miniqi spray dryer B-290 is used, and an inert gas circulation device B-295 is arranged. And (3) spray drying the solution obtained in the step (1) according to set conditions to obtain a sample. The setting conditions are as follows: inlet temperature 60 ℃, air extractor 100%, pump 10%, cooling temperature-15 ℃.
The XRPD results of the samples are shown in fig. 4, dsc results are shown in fig. 8, ftir results are shown in fig. 12, raman results are shown in fig. 16, and tga results are shown in fig. 17.
From the results, it can be seen that: the XRPD pattern of the celecoxib pregabalin co-amorphous has no sharp diffraction peaks, a weight loss of 1.23% at 30 ℃ to 150 ℃ and a glass transition temperature of 56.50 ℃.
Absorption peak of infrared spectrum (cm) -1 ) 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.
Scattering peak (cm) of Raman spectrum -1 ) Is 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.
Preparing a physical mixture of celecoxib amorphous material and pregabalin after spray drying in a molar ratio of 2:1:
the celecoxib amorphous substance and the pregabalin after spray drying are prepared by a spray drying method (the conditions are the same as above), and the celecoxib amorphous substance and the pregabalin after spray drying are fully mixed according to the mol ratio of 2:1 to obtain a physical mixture, and the physical mixture is respectively subjected to solid state characterization, IR (shown in figures 9-11) and Raman (shown in figures 13-15). IR (fig. 12) and Raman (fig. 16) of the co-amorphous samples prepared above were compared.
IR results showed that the physical mixture of spray dried celecoxib and spray dried pregabalin was only a superposition of the signals of the two compounds, no intermolecular forces were detected, compared to celecoxib and pregabalin; the co-amorphous material is significantly different from the physical mixture, and is characterized by pregabalin-OH, -NH being 2600cm -1 、2690cm -1 、2765cm -1 、2845cm -1 The absorption peak at 2898cm becomes insignificant -1 、2923cm -1 The peak at which is broadened, possiblyThe hydrogen bond donor-OH, -NH of pregabalin and the hydrogen bond acceptor group-S=O of celecoxib generate intermolecular hydrogen bonds, and pregabalin-C=O is 1643cm -1 The telescopic absorption band at the site disappeared, probably the hydrogen bond acceptor-c=o of pregabalin and the hydrogen bond donor-NH produced an intramolecular hydrogen bond, widening the peak, and the-NH of celecoxib produced an intermolecular hydrogen bond, further widening the peak, finally appearing as co-amorphous at 1643cm -1 The baseline at which drifts upward without an absorption peak; the absorption peak of celecoxib hydrogen bond acceptor-S=O symmetrical and asymmetrical telescopic vibration is formed by 1337cm -1 And 1159cm -1 Down to 1333cm -1 And 1157cm -1 Hydrogen bond donor-NH is between 3000 and 3400cm -1 There are two peaks of absorption and shoulders, but the co-amorphous is not evident in the shoulder in this region. Indicating that there is a force between the two compounds and hydrogen bonds, resulting in a change in the absorption peaks of the above hydrogen bond acceptors and donor groups.
The Raman results show that physical mixtures mixed in a molar ratio of 2:1, in addition to predominantly spray dried celecoxib, also show a sign of spray dried pregabalin, the co-amorphous material being different compared to the physical mixture of spray dried celecoxib and spray dried pregabalin. In summary, the sample prepared in example 1 was co-amorphous.
Example 2: preparation of celecoxib-pregabalin co-amorphous (molar ratio 2:1)
1) 5.3774g of celecoxib and 1.1243g of pregabalin are weighed, 500mL of methanol is added, and stirring and dissolution are carried out;
2) The Miniqi spray dryer B-290 is used, and an inert gas circulation device B-295 is arranged. And (3) spray drying the solution obtained in the step (1) according to set conditions to obtain a sample. The setting conditions are as follows: inlet temperature 60 ℃, air extractor 100%, pump 10%, cooling temperature-15 ℃. The XRPD pattern of the celecoxib-pregabalin co-amorphous has no sharp diffraction peaks.
Example 3: preparation of celecoxib-pregabalin co-amorphous (molar ratio 2:1)
1) 5.8736g of celecoxib and 12483g of pregabalin are weighed, 600mL of methanol is added, and stirring and dissolution are carried out;
2) The Miniqi spray dryer B-290 is used, and an inert gas circulation device B-295 is arranged. And (3) spray drying the solution obtained in the step (1) according to set conditions to obtain a sample. The setting conditions are as follows: the inlet temperature was 50 ℃, the pump was 70%, the pump was 20%, and the cooling temperature was-7 ℃. The XRPD pattern of the celecoxib-pregabalin co-amorphous has no sharp diffraction peaks.
Example 4: stability study of celecoxib pregabalin co-amorphous
Single celecoxib form I gives an amorphous form under the same spray-drying preparation conditions, which is placed in a room temperature dryer for 17 hours, and tested to convert to form I of the starting celecoxib sample, as shown in fig. 18. The XRPD pattern in fig. 18 is, in order from top to bottom: celecoxib is spray-dried to obtain an amorphous substance, and the amorphous substance is placed for 17 hours, so that the celecoxib is in a crystal form I. The XRPD of the material after 17 hours of amorphous placement showed diffraction peaks that were identical in position to the diffraction peaks of celecoxib form I.
The single pregabalin form I still remained largely crystalline form of form I under the same spray-drying preparation conditions, and the diffraction peak of pregabalin form I was still observed by dry ball milling for 3 hours for pregabalin form I, as shown in fig. 19. The XRPD pattern in fig. 19 is, in order from top to bottom: pregabalin crystalline form I after spray drying and ball milling for 3 hours.
According to the preparation method of the common amorphous substance in the example 1, the molar ratio of celecoxib crystal form I and pregabalin crystal form I is changed to 1:2, the amorphous substance can be obtained under the same spray drying preparation condition, the glass transition temperature is 50.17 ℃, and the crystalline substance is converted into the crystal form after being placed in a room temperature dryer for 22 hours, as shown in figure 20. The XRPD pattern in fig. 20 is in the order from top to bottom: spray drying to obtain an amorphous material, and standing for 22 hr.
According to the preparation method of the co-amorphous material in example 1, the molar ratio of celecoxib crystal form I and pregabalin crystal form I is changed to 1:1, the amorphous material can be obtained under the same spray drying preparation condition, the glass transition temperature is 53.15 ℃, and the crystalline material is tested to be changed into the crystal form after being placed in a room temperature dryer for 30 hours, as shown in figure 21. The XRPD pattern in fig. 21 is, in order from top to bottom: spray drying to obtain an amorphous material, and standing for 30 hr.
The celecoxib/pregabalin (2:1) co-amorphous material prepared in example 1 by spray drying was left in a room temperature dryer for 25 days and was still amorphous; the test remained amorphous after 17 hours of standing in a laboratory environment (20-25 ℃,45-50% rh) as shown in fig. 22. The XRPD pattern in fig. 22 is in the order from top to bottom: the amorphous material obtained after spray drying was left in a room temperature dryer for 25 days, and then transferred to a laboratory environment for 17 hours.
Example 5: celecoxib pregabalin co-amorphous solubility detection
The solubility detection method comprises the following steps:
about 1.5g of celecoxib and pregabalin co-amorphous substance (molar ratio 2:1) is taken, about 1.5g of mixture of celecoxib crystal form I and pregabalin crystal form I (molar ratio 2:1 is mixed) is respectively placed in 4ml of pH1.2 hydrochloric acid solution, pH4.0 acetate buffer solution and pH7.4 phosphate buffer solution, and stirred, sampling is carried out for 1h and 24h, centrifugation is carried out, supernatant fluid is taken, and filtered through a 0.45 mu m filter membrane, and the content is measured after sampling dilution, and the result is as follows:
example 6: pharmaceutical efficacy experiment of celecoxib and pregabalin combined drug
Celecoxib crystal form I, pregabalin crystal form I, physical mixture of celecoxib crystal form I and pregabalin crystal form I (molar ratio 2:1) and celecoxib pregabalin co-amorphous substance (molar ratio 2:1) are respectively suspended in soybean oil of injection grade according to designed administration dosage.
The medicine is administered by stomach irrigation.
Postoperative pain
Experimental procedure
Primary screening of rats, testing basic values (testing at least twice, testing for the third time if the difference between the results of the two times is too large, taking an average value), and eliminating sensitive animals; 7% chloral hydrate was used as anesthetic, the volume of intraperitoneal injection was 1ml/250g, iodophor was used to surface disinfect the rat plantar surgical site, a 1cm longitudinal incision was made from the 0.5cm edge of the heel, including skin, fascia and plantar muscle, two needles were sutured to the skin, hemostasis was pressed and the wound was cleaned. The basic values are tested again on the first day after operation, and the basic values are grouped evenly, wherein 8 animals are in each group, so that the basic values in each group are kept consistent as much as possible; the following day after molding, the rats were tested for mechanical tenderness and footshrink threshold (MWT) after 120 min.
Result calculation
Pain threshold increase (%) = (dosing group pain threshold-vehicle group pain threshold) ×100%/vehicle group pain threshold
Experimental results
Ratio to vehicle group mechanical tenderness to foot reduction threshold,: p is less than or equal to 0.05; * *: p is less than or equal to 0.01; * **: p is less than or equal to 0.001; has statistical significance;
mechanical tenderness to foot threshold ratio with physical mix group at the same dose, #: p is less than or equal to 0.05, and has statistical significance.
Conclusion: in a postoperative pain model, the improvement rate of each dosage group of the physical mixture of celecoxib and the common amorphous substance of celecoxib is high Yu Purui, and similar or better drug effects can be achieved by reducing the dosage of the two components, so that the drug side effects can be reduced while the drug effects are not changed by reducing the dosage of the drugs clinically. In this model, the low dose group of the co-amorphous substance has a significant efficacy compared to the same dose of the physical mixture group, indicating that the efficacy of the co-amorphous substance is superior to the efficacy of the physical mixture in this model.
Rat pharmacokinetics
Preparation of celecoxib form I, pregabalin form I, physical mixture of celecoxib form I and pregabalin form I (molar ratio 2:1), celecoxib pregabalin co-amorphous (molar ratio 2:1) suspension
And respectively suspending celecoxib crystal form I, pregabalin crystal form I, a physical mixture of celecoxib crystal form I and pregabalin crystal form I and a celecoxib pregabalin co-amorphous substance in soybean oil (injection grade) to prepare a test sample.
This study examined the pharmacokinetic profile of celecoxib pregabalin co-amorphous in rats using LC-MS method.
Experiment design:
animal administration
Four groups (4 animals in each group) of SD rats were fasted for 12h before the experiment, were freely drunk, were dosed with the set doses (celecoxib 24mg/kg, pregabalin 5mg/kg, physical mixture 29mg/kg, total amorphous 29 mg/kg) and were dosed with the drug solution by stomach, and were collected with 0.3ml blood at 5min,15min,30min,1,2,4,6,8, 12, 24h orbit after dosing, placed in centrifuge tubes, centrifuged to separate plasma, and frozen for storage in a-20deg.C refrigerator.
Results
In this study, the pharmacokinetic parameters of celecoxib pregabalin co-amorphous/celecoxib crystalline form I pregabalin form I physical mixture/celecoxib/pregabalin in rats are shown in the table.
Table: pharmacokinetic parameters of rats in each group
Ratio to co-amorphous group,: p is less than or equal to 0.05;
conclusion(s)
For celecoxib: the co-amorphous exposure was slightly lower than that administered alone, but without significant differences; the total amorphous exposure was higher than the physical mixture and was significantly different. For pregabalin: the co-amorphous exposure was higher than the single administration and physical mixture, but there was no significant difference.
The above embodiments are only for illustrating the technical concept and features of the present application, and are not intended to limit the scope of the present application once, since those skilled in the art can understand the content of the present application and implement the same. All changes and modifications that come within the meaning and range of equivalency of the application are to be embraced within their scope.

Claims (13)

1. A preparation method of a co-amorphous substance of celecoxib and pregabalin, which is characterized in that celecoxib and pregabalin are dissolved in an organic solvent to obtain clear liquid, and the clear liquid is prepared by spray drying;
wherein the organic solvent is selected from alcohols, ketones and sulfones of C1-5;
the spray drying conditions are as follows: the inlet temperature is 50-65 ℃; 70-100% of air extractor, 5-20% of pump, and cooling temperature of-7-20 ℃;
the molar ratio of celecoxib to pregabalin in the co-amorphous is 2:1.
2. The method of claim 1, wherein the co-amorphous material has a glass transition temperature of 56.50 ± 3 ℃.
3. The method of claim 1, wherein the co-amorphous material has a raman spectrum at the following positions (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 have scattering peaks.
4. The method of claim 1, wherein the co-amorphous material has a raman spectrum with a scattering peak (cm -1 ±2cm -1 ) 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。
5. The method of claim 1, wherein the co-amorphous material has an infrared spectrum at the following position (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 have absorption peaks.
6. The method of claim 1, wherein the co-amorphous material has an infrared spectral absorption peak (cm -1 ±2cm -1 ) The method comprises the following steps: 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. The method of claim 1, wherein the co-amorphous material has one or more of the following characteristics:
substantially conforming to the X-ray powder diffraction pattern of figure 4 or to the X-ray powder diffraction pattern of figure 4;
substantially conforming to the FT-IR spectrum of FIG. 12 or to the FT-IR spectrum of FIG. 12;
a DSC profile substantially in accordance with figure 8 or a DSC profile in accordance with figure 8;
IV. A TGA spectrum substantially corresponding to FIG. 17 or a TGA spectrum corresponding to FIG. 17;
v. substantially in accordance with the raman spectrum of fig. 16 or in accordance with the raman spectrum of fig. 16.
8. The process according to any one of claims 1 to 7, wherein the step of filtering the resulting solution is optionally further comprised after dissolution of celecoxib and pregabalin in an organic solvent.
9. The process according to any one of claims 1 to 7, wherein the C1-5 alcohol is one or both of methanol and ethanol; the ketone is selected from one or more of acetone, butanone or methyl isobutyl ketone; the sulfones are selected from dimethyl sulfoxide.
10. The process according to any one of claims 1 to 7, wherein the organic solvent is selected from methanol, acetone or dimethyl sulfoxide.
11. The process according to any one of claims 1 to 7, wherein the molar ratio of celecoxib to pregabalin is 2:1.
12. The preparation method according to any one of claims 1 to 7, wherein the volume ratio of the total mass of the feed of celecoxib and pregabalin to the organic solvent is 2-20mg/ml.
13. The preparation method according to any one of claims 1 to 7, wherein the volume ratio of the total mass of the feed of celecoxib and pregabalin to the organic solvent is 4-15mg/ml.
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