CN112300086A - Clozapine and quetiapine fumarate co-amorphous compound and preparation method thereof - Google Patents
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Abstract
The invention relates to a clozapine and quetiapine fumarate co-amorphous compound and a preparation method thereof. The invention finds that the combination of clozapine and quetiapine fumarate has a synergistic effect, and can be used for treating various schizophrenia, even including refractory schizophrenia. The invention provides a co-amorphous substance formed by clozapine and quetiapine fumarate, which has good bioavailability, therapeutic effect, stability of drug effect, developability of process and storability, and particularly has the therapeutic effect obviously superior to that of a simple mixture of clozapine and quetiapine fumarate.
Description
Technical Field
The application belongs to the technical field of medicines, and particularly relates to a clozapine and quetiapine fumarate amorphous substance (also called as a common amorphous substance) and a preparation method thereof.
Background
Schizophrenia is a chronic and serious mental disorder. Clinical symptoms are mainly classified into positive symptoms (hallucinations, delusions, and the like), negative symptoms (apathy, anhedonia, and the like), and cognitive symptoms (inattention, working memory deficiency, and the like). Typical schizophrenia drugs are directed at dopamine receptors and have good therapeutic effects on positive symptoms of schizophrenia, but have large side effects and are ineffective on negative symptoms. Atypical schizophrenia acts by acting on dopamine and serotonin receptors, and has affinity for serotonin higher than that of dopamine, little side effect, and is effective on both positive and negative symptoms.
Refractory schizophrenia refers to the undesirable outcome of treatment with at least 2 doses of a comparable course of treatment of a chemically different antipsychotic agent over the last 5 years.
At present, the clinical use of the drugs for schizophrenia is common, and the purposes are as follows: 1/5-1/3, the patient discontinued clozapine because the side effects or positive symptoms were not effective; the patient who is prone to violence needs to respond quickly; reducing side effects caused by overdose; other symptoms besides psychotic symptoms can be controlled.
Clozapine (Clozapine) has the chemical name 8-chloro-11- (4-methyl-1-piperazinyl) -5H-dibenzo [ B, E][1,4]Diaza derivatives
The structural formula is as follows:
belongs to the benzodiazepine
Antipsychotic-like drugs, the first atypical anti-schizophrenia drug found on the market. The traditional Chinese medicine composition is effective to both positive symptoms and negative symptoms of schizophrenia and also improves cognitive symptoms, and is the only accepted medicine capable of treating intractable schizophrenia. In addition, clozapine is the only reducible extractAn anti-schizophrenia drug for suicide risk of schizophrenia. But it is widely used because of its serious side effects that may lead to granulocytopenia.
Quetiapine Fumarate (Quetiapine Fumarate) is chemically 11- [4- [2- (2-hydroxyethoxy) ethyl]-1-piperazinyl]Dibenzo [ b, f ]][1,4]Sulfoazazepine
Hemifumarate salt of the formula:
are atypical antipsychotics. Can be used for treating schizophrenia, with positive and negative symptoms, and relieving symptoms related to schizophrenia such as depression, anxiety, mania, violence tendency and cognitive deficit.
The co-amorphous drug refers to a single-phase amorphous binary system with a single glass transition temperature formed by combining an active drug ingredient with other small-molecule solid substances (drugs or auxiliary materials). As a new solid form of a drug, the co-amorphous substance may improve the solubility, dissolution rate, stability and bioavailability of the drug. The co-amorphous substance formed by the active pharmaceutical ingredients and the active pharmaceutical ingredients has the advantages and can also have a synergistic effect, improve the clinical curative effect, reduce the toxic and side effects of the drugs and further increase the administration safety window. At present, no report about the preparation of two psychotropic active ingredients into a co-amorphous substance and the research of the curative effect of the co-amorphous substance is found.
Disclosure of Invention
The invention finds that the combination of two anti-schizophrenia drugs clozapine and quetiapine fumarate achieves the synergistic effect, and can be used for treating various schizophrenia, even including refractory schizophrenia.
Through extensive experimental research, the inventor of the invention finds that the active ingredients of the two psychotropic drugs, namely clozapine and quetiapine fumarate, can form a co-amorphous substance, and the co-amorphous substance has obvious advantages in aspects of production, application and the like.
The invention aims to provide a co-amorphous substance of clozapine and quetiapine fumarate, which has good stability and improved bioavailability of medicines.
According to the invention, the co-amorphous substance of clozapine and quetiapine fumarate is prepared, wherein the molar ratio of clozapine to quetiapine fumarate is 1: 1.
According to the invention, the amorphous substance of clozapine and quetiapine fumarate is a co-amorphous substance, wherein the molar ratio of clozapine to quetiapine fumarate is 2: 1.
According to the invention, the glass transition temperature of the co-amorphous substance with the molar ratio of clozapine to quetiapine fumarate of 1:1 is 50.44 ℃.
According to the invention, the infrared spectrum wave number (cm) of the co-amorphous substance (potassium bromide tablet) with the molar ratio of clozapine to quetiapine fumarate being 1:1-1) Is characterized in particular by the following peaks: 3278.3, 1714.8.
According to the invention, the infrared spectrum wave number (cm) of the co-amorphous substance (potassium bromide tablet) with the molar ratio of clozapine to quetiapine fumarate being 1:1-1) Comprises the following steps: 3278.3, 3052.5, 2916.9, 2849.5, 1714.8, 1600.8, 1573.9, 1458.0, 1376.9, 1303.8, 1243.9, 1120.5, 1082.6, 1062.7, 1003.3, 981.9, 953.2, 894.7, 875.5, 814.6, 762.2, 742.1, 694.9, 668.4, 597.0, 568.9, 546.3, 522.8, and 462.4.
Error of + -2 cm for all wavenumbers of infrared spectrum-1。
According to the invention, the co-amorphous substance with the molar ratio of clozapine to quetiapine fumarate being 1:1 has an XRPD pattern as shown in figure 4.
According to the invention, the glass transition temperature of the co-amorphous substance with the molar ratio of clozapine to quetiapine fumarate of 2:1 is 50.97 ℃.
According to the invention, the infrared spectrum wave number (cm) of the co-amorphous substance (potassium bromide tablet) with the molar ratio of clozapine to quetiapine fumarate being 2:1-1) Is characterized in particular by the following peaks: 3272.7, 1784.0, 1703.1.
According to the invention, the infrared spectrum wave number (cm) of the co-amorphous substance (potassium bromide tablet) with the molar ratio of clozapine to quetiapine fumarate being 2:1-1) Comprises the following steps: 3272.7, 3212.6, 3117.7, 3053.6, 2996.2, 2934.6, 2849.7, 2801.7, 1784.0, 1703.1, 1601.9, 1573.5, 1560.4, 1459.6, 1428.1, 1367.4, 1303.3, 1257.5, 1243.4, 1140.5, 1120.6, 1105.7, 1082.4, 1063.3, 1028.5, 1013.9, 1004.2, 981.6, 952.2, 924.7, 894.5, 875.0, 813.7, 761.9, 742.5, 694.3, 669.2, 596.9, 569.2, 523.0, and 463.4.
Error of + -2 cm for all wavenumbers of infrared spectrum-1。
According to the invention, the co-amorphous substance with the molar ratio of clozapine to quetiapine fumarate being 2:1 has an XRPD pattern as shown in figure 13.
The invention also aims to provide a preparation method of the clozapine-quetiapine fumarate co-amorphous substance, which is simple and low in cost and has important value for clinical application and development of future clozapine-quetiapine fumarate combined drugs.
A preparation method of the clozapine and quetiapine fumarate co-amorphous substance comprises the steps of grinding and uniformly mixing the clozapine and quetiapine fumarate, heating for melting, and then quenching for cooling.
According to the invention, in the preparation method, the molar ratio of clozapine to quetiapine fumarate is 1: 1.
According to the invention, in the preparation method, the molar ratio of clozapine to quetiapine fumarate is 2: 1.
According to the invention, the clozapine is a crystal of clozapine having the XRPD diffraction pattern shown in figure 1.
According to the invention, the quetiapine fumarate is a quetiapine fumarate crystal with an XRPD diffraction pattern shown in figure 2.
According to the invention, the melting temperature is from 180 ℃ to 190 ℃ and preferably the melting temperature is 185 ℃.
The third purpose of the invention is to provide a pharmaceutical composition, which comprises an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient comprises the clozapine fumarate quetiapine co-amorphous substance.
According to the invention, in the pharmaceutical composition, the clozapine and quetiapine fumarate co-amorphous substance is formed by mixing clozapine and quetiapine fumarate in a molar ratio of 1:1, or clozapine and quetiapine fumarate in a molar ratio of 2:1, or a mixture of both.
According to the invention, the pharmaceutical composition further comprises pharmaceutically acceptable auxiliary materials.
In the case of solid dosage forms, the 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, 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, for example by providing a shellac barrier coating, sugar coating or polymer coating, the polymers in the coating such as hydroxypropyl methylcellulose, polyvinyl alcohol, ethyl cellulose, methacrylic polymers, hydroxypropyl cellulose or starch, and may also include anti-adherent agents such as silicon dioxide, talc, opacifying agents such as titanium dioxide, colouring agents such as iron oxide based colouring agents. In the case of liquid dosage forms, suitable adjuvants include water, oils, alcohols, glycols, flavoring agents, preservatives, stabilizers, coloring agents, solubilizers, antioxidants, and the like; aqueous or non-aqueous sterile suspensions may contain suspending agents and thickening agents; suitable excipients for aqueous suspensions include synthetic or natural gums such as acacia, xanthan gum, alginates, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin. In the case of parenteral dosage forms, the excipients for sterile injectable solutions, aqueous or non-aqueous, are generally sterile water, physiological saline or aqueous dextrose, 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 injurious to the patient.
According to the present invention, the pharmaceutical composition may be formulated for administration by a suitable route. For example, 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, as desired, for the rapid, delayed or modified release of the active pharmaceutical ingredient; formulations 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, creams, patches; dosage forms suitable for nasal administration include aerosols, sprays, nasal drops; dosage forms suitable for vaginal administration include suppositories, tampons, gels, pastes or sprays.
The fourth purpose of the invention is to provide the application of the clozapine and quetiapine fumarate co-amorphous substance in preparing a medicine for treating schizophrenia.
According to the invention, the clozapine and quetiapine fumarate co-amorphous is a co-amorphous with a molar ratio of clozapine to quetiapine fumarate of 1: 1.
According to the invention, the clozapine and quetiapine fumarate co-amorphous is a co-amorphous with a molar ratio of clozapine to quetiapine fumarate of 2: 1.
The fifth purpose of the invention is to provide the clozapine quetiapine fumarate co-amorphous substance for use in treating schizophrenia.
According to the invention, the clozapine and quetiapine fumarate co-amorphous is a co-amorphous with a molar ratio of clozapine to quetiapine fumarate of 1: 1.
According to the invention, the clozapine and quetiapine fumarate co-amorphous is a co-amorphous with a molar ratio of clozapine to quetiapine fumarate of 2: 1.
A sixth object of the present invention is to provide a method for treating schizophrenia comprising administering the clozapine quetiapine fumarate co-amorphous form as described above or a pharmaceutical composition comprising the co-amorphous form to a patient.
Further, the schizophrenia includes refractory schizophrenia.
According to the present invention, the treatment of schizophrenia includes the treatment or amelioration of affective symptoms associated with schizophrenia, such as depression, anxiety, mania, violence tendency, suicidal tendency, cognitive deficits.
The invention has the beneficial effects that:
the invention provides the co-amorphous form of clozapine and quetiapine fumarate for the first time, and shows that the co-amorphous form has good bioavailability, therapeutic effect, pharmacodynamic stability, process developability and storability, and particularly the therapeutic effect of the co-amorphous form is obviously better than that of a simple mixture of clozapine and quetiapine fumarate.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of clozapine;
FIG. 2 is an X-ray powder diffraction pattern of quetiapine fumarate;
FIG. 3 is an X-ray powder diffraction pattern of a physical mixture of clozapine crystals and quetiapine fumarate crystals;
FIG. 4 is an X-ray powder diffraction pattern of clozapine quetiapine fumarate molar ratio 1:1 co-amorphous;
FIG. 5 is a DSC of clozapine crystals;
FIG. 6 is a DSC of quetiapine fumarate crystals;
FIG. 7 is a DSC of a physical mixture of clozapine crystals and quetiapine fumarate crystals;
FIG. 8 is a mDSC of clozapine quetiapine fumarate molar ratio 1:1 co-amorphous;
FIG. 9 is an infrared spectrum of a crystal of clozapine;
FIG. 10 is an infrared spectrum of a crystalline quetiapine fumarate;
FIG. 11 is a graph of the infrared spectrum of clozapine quetiapine fumarate in a 1:1 molar ratio co-amorphous form;
fig. 12 is an XRPD comparison of clozapine quetiapine fumarate co-amorphous for stability under different temperature and humidity conditions, in order from top to bottom: XRPD after 1 week at 40 ℃/75% RH for a 1:1 molar ratio co-amorphous, after 1 week at 25 ℃/60% RH for a 1:1 molar ratio co-amorphous, and XRPD of as-prepared 1:1 molar ratio co-amorphous;
FIG. 13 is an X-ray powder diffraction pattern of clozapine quetiapine fumarate molar ratio 2:1 co-amorphous;
FIG. 14 is a DSC of clozapine quetiapine fumarate molar ratio 2:1 co-amorphous;
FIG. 15 is a mDSC of clozapine quetiapine fumarate molar ratio 2:1 co-amorphous;
FIG. 16 is a graph of the infrared spectrum of clozapine quetiapine fumarate molar ratio 2:1 co-amorphous;
FIG. 17 is a comparison of infrared spectra for clozapine crystals, quetiapine fumarate crystals, 1:1 co-amorphous and 2:1 co-amorphous. The infrared spectrum of the clozapine crystal, the quetiapine fumarate crystal, the 1:1 co-amorphous substance and the 2:1 co-amorphous substance is shown in the figure from top to bottom;
FIG. 18 is a graph of mean time of administration of clozapine over time for different experimental groups;
FIG. 19 is a graph of the mean time course of quetiapine fumarate over time for different experimental groups.
Detailed Description
The present invention is further described below with reference to examples. It should be noted that the examples are not intended to limit the scope of the present invention, and those skilled in the art will appreciate that any modifications and variations based on the present invention are within the scope of the present invention.
Conventional chemicals used in the following examples are commercially available.
The clozapine crystals and quetiapine fumarate crystals used in the following experiments were all in the form of crystals used in marketed drugs, and the XRPD thereof are shown in FIGS. 1 and 2, respectively, and were obtained from Jiangsu Enwawa pharmaceutical research institute, clozapine lot No. SC05-20170802, and quetiapine fumarate lot No. 0903-20170904.
Comparative example 1: preparation of a 1:1 molar ratio physical mixture of clozapine crystals and quetiapine fumarate crystals
Weighing clozapine crystals and quetiapine fumarate crystals with a molar ratio of 1:1, grinding for 2min, and mixing on a shaker for 20min to mix them uniformly.
Example 1: preparation method of 1:1 molar ratio clozapine fumarate quetiapine co-amorphous
Weighing clozapine crystals and quetiapine fumarate crystals in a molar ratio of 1:1, grinding to mix uniformly, heating on a hot table at 185 ℃ for 0.5-1 min to melt, taking down the sample, placing the sample on an aluminum disc for quenching treatment to obtain a light yellow block-shaped product, and grinding into powder.
Example 2: preparation method of 2:1 molar ratio clozapine fumarate quetiapine co-amorphous
Weighing clozapine crystals and quetiapine fumarate crystals in a molar ratio of 2:1, grinding to mix uniformly, heating on a hot table at 185 ℃ for 0.5-1 min to melt, taking down the sample, placing the sample on an aluminum disc for quenching treatment to obtain a light yellow block-shaped product, and grinding into powder.
Example 3: example 1 characterization of the prepared 1:1 molar Co-amorphous
The X-ray powder diffraction pattern is collected on a D8 advanced X-ray powder diffractometer, and the test temperature is the conventional ambient temperature. The X-ray powder diffraction method has the following parameters:
target: Cu-Kalpha radiation
Wavelength:
pipe pressure: 40kV
Pipe flow: 40mA
Step length: 0.02 degree
Scanning speed: 0.3 DEG/s
The results show that: the spectrum of the clozapine-quetiapine fumarate co-amorphous substance is shown in figure 4, and the clozapine-quetiapine fumarate co-amorphous substance is broad in peak shape and has no sharp diffraction peak.
The Differential Scanning Calorimetry (DSC) chart of the invention is collected on a TA Q2000 chart, and the parameters of the Differential Scanning Calorimetry (DSC) method of the invention are as follows:
the range is as follows: -40-400 deg.C
Temperature rise rate: 10 ℃/min
The glass transition temperature of clozapine quetiapine fumarate co-amorphous is 50.44 ℃. Tg values between those of amorphous clozapine and quetiapine fumarate, with the Gordon-Taylor empirical equation (T)gmix≈[W1×Tg,1+K×W2×Tg,2]/[W1+K×W2]，K＝ρ1×Tg,1/ρ2×Tg,2) The calculated Tg values (49.67 ℃) were similar.
The infrared spectrum (IR) diagram of the invention is collected on a Fourier infrared spectrometer of Bruker Tensor 27, and the method parameters of the infrared spectrum (IR) of the invention are as follows:
tabletting conditions are as follows: potassium bromide tablet
Infrared spectrum wave number (cm) of clozapine-quetiapine fumarate co-amorphous substance-1)(±2cm-1): 3278.3, 3052.5, 2916.9, 2849.5, 1714.8, 1600.8, 1573.9, 1458.0, 1376.9, 1303.8, 1243.9, 1120.5, 1082.6, 1062.7, 1003.3, 981.9, 953.2, 894.7, 875.5, 814.6, 762.2, 742.1, 694.9, 668.4, 597.0, 568.9, 546.3, 522.8, and 462.4.
The clozapine and quetiapine fumarate are similar in structure, groups are basically the same, and IR spectrums are also basically similar, while the clozapine quetiapine fumarate co-amorphous substance has an IR spectrum of 3300-3500 cm-1The peak shape is relatively blunt, and the peak shape is relatively blunt,it is possible that the chemical environment is changed due to the formation of chemical bonds by hydroxyl or secondary amine groups in the co-amorphous form; at 1715cm-1The occurrence of a carbonyl peak indicates that the group attached to the carbonyl group is cleaved or less conjugated than the individual API molecule.
Example 4: example 2 characterization of the prepared 2:1 molar ratio Co-amorphous
The same test conditions as in example 3 were used to obtain the XRPD pattern shown in fig. 13, which is broad and has no sharp diffraction peaks.
The DSC plots shown in FIGS. 14 and 15 were obtained, and the glass transition temperature of clozapine quetiapine fumarate 2:1 co-amorphous was 50.97 ℃.
Obtaining the infrared spectrum chart of FIG. 16, the infrared spectrum wave number (cm) of clozapine quetiapine fumarate 2:1 co-amorphous substance-1)(±2cm-1): 3272.7, 3212.6, 3117.7, 3053.6, 2996.2, 2934.6, 2849.7, 2801.7, 1784.0, 1703.1, 1601.9, 1573.5, 1560.4, 1459.6, 1428.1, 1367.4, 1303.3, 1257.5, 1243.4, 1140.5, 1120.6, 1105.7, 1082.4, 1063.3, 1028.5, 1013.9, 1004.2, 981.6, 952.2, 924.7, 894.5, 875.0, 813.7, 761.9, 742.5, 694.3, 669.2, 596.9, 569.2, 523.0, and 463.4.
The diffraction peak of the co-amorphous substance is 3300-3500 cm-1The blunter peak shape may be due to a change in chemical environment caused by chemical bonding of hydroxyl or secondary amine groups in the co-amorphous form. At 1783cm-1And 1700cm-1A smaller diffraction peak appears, and the combination of the structure of the raw material medicine and the infrared common group data supposes that the small amount of quetiapine fumarate forms anhydride.
Example 5: stability study of Co-amorphous Material
Two samples of the co-amorphous material prepared in examples 1 and 2 of the present invention were exposed to 25 deg.C/60% humidity and 40 deg.C/75% humidity, and after 7 days, the samples were sampled for XRPD and HPLC, and the test results are shown in Table 1, and the corresponding XRPD is shown in FIG. 12.
The HPLC method was as follows: analyzing the sample with a SHIMADZU high performance liquid chromatograph (SPD-20A detector, SIL-20A pump, LC-Solution chromatography workstation)The content of clozapine and quetiapine fumarate. A chromatographic column: agilent Eclipse plus C18 chromatography column (4.6 × 250mm, 5 μm), mobile phase: 0.03mol/L NH4Ac acetonitrile 28:72, detection wavelength: 254nm, column temperature: 40 ℃, flow rate: 1mL/min, sample injection volume: 10 μ l.
A standard curve was plotted with the concentration X (mg/mL) and the peak area Y. The standard curve for clozapine is Y32823991.6074X +1944.6334, R21.0000, linear range 0.001-0.1mg/mL, detection wavelength 254 nm; the standard curve of quetiapine fumarate is 19125728.5110X +11870.4533, R2 is 1.0000, the linear range is 0.003-0.3mg/mL, and the detection wavelength is 254 nm.
TABLE 1
| Starting sample | Conditions of standing | Time of standing | Crystal form change | Purity of |
| 1:1 |
25℃/60 |
7 days | Without change | 97.2％ |
| 1:1 |
40℃/75 |
7 days | Without change | 96.7％ |
| 2:1 |
25℃/60 |
7 days | Without change | 94.8％ |
| 2:1 |
40℃/75 |
7 days | Without change | 97.4％ |
The 1:1 co-amorphous starting purity was 95.8% and the 2:1 co-amorphous starting purity was 96.8%. The results show that the 1:1 and 2:1 molar ratio of the co-amorphous substance of the invention is not changed in crystal form and is not changed in chemical purity when the co-amorphous substance is placed for 7 days under the conditions of 25 ℃/60% humidity and 40 ℃/75% humidity.
Example 6: animal model evaluation of synergistic effect of clozapine and quetiapine fumarate
1. Model for evaluating high-activity efficacy of mouse with single and combined application of clozapine and quetiapine fumarate
The objective of this study was to administer to mice an intraperitoneal injection of 0.3mg/kg MK-801 ((+) -MK-801 hydrogene maleate) resulting in a high activity model in mice, and to observe the effect of 3mg/kg clozapine administered alone and in combination with 20mg/kg quetiapine fumarate on this model.
The solvent preparation method comprises the following steps: taking a certain amount of CMC-Na, adding pure water, stirring and dissolving to prepare a pure water mixed solution with the concentration of 0.5 percent of CMC-Na.
Quetiapine fumarate was suspended in pure water, clozapine was suspended in 0.5% CMC-Na;
design of experiments
Animal(s) production
All animals received 4 days of quarantine and acclimation during which general observations were made on the animals each day. Day and night light and shade alternation time of animal rooms: 12h/12h, air change times: not less than 8 times/h, temperature: 16-26 ℃ and 40-70% of relative humidity. Animals were stratified by body weight and randomly divided into a blank group, a model group (vehicle treatment only), and each test article group, 8 mice per group.
Animal administration
The mice were gavaged with clozapine, quetiapine fumarate, or a combination of both. The dosage is 10 ml/kg. After 1h of administration, 0.3mg/kg MK-801 was intraperitoneally injected, and the mice were placed in an autonomous activity box (black polyethylene box with a specification of 29cm × 29cm × 30 cm) and video-recorded for 60min, video analysis was performed after video recording was completed, and the activity of the mice was evaluated.
Evaluation of inhibition of hyperactivity in mice after administration
Calculating the high activity inhibition rate of the model group mice by analyzing the moving distance of the mice after administration: the inhibition ratio in the drug group was 100- (distance traveled by drug group mouse/distance traveled by model group mouse) × 100.
Results
In this study, the range of action and inhibition results for clozapine and quetiapine fumarate used alone and in combination are shown in Table 2
TABLE 2 high motility distance and inhibition rate in mice administered alone or in combination after gavage
| Group of | Distance of movement (mm) | Inhibition rate |
| Blank group | 81349.75±22129.18 | -- |
| Model set | 255471.54±66449.67 | -- |
| Clozapine 3mg/kg | 181976.61±73997.93 | 28.77 |
| Quetiapine fumarate 20mg/kg | 143663.67±53163.31 | 43.77 |
| Combined administration group (clozapine 3mg/kg + quetiapine fumarate 20mg/kg) | 39874.52±18457.82 | 84.30 |
2. Comparison of drug effects of clozapine-quetiapine fumarate co-amorphous substance and physical mixture
The purpose is as follows: mouse high-activity animal model for evaluating whether clozapine-quetiapine fumarate co-amorphous substance has better drug effect than physical mixture
Preparation of a suspension of a physical mixture of clozapine Quetiapine fumarate, a suspension of Co-amorphous
A physical mixture of clozapine crystals and quetiapine fumarate crystals was prepared according to the molar ratio of the two drugs in clozapine quetiapine fumarate co-amorphous form (1: 1). The co-amorphous form and the physical mixture were separately suspended in sesame oil and gavaged at a volume of 10ml/kg per mouse. Both the co-amorphous material and the physical mixture maintained their respective solid forms in sesame oil.
Inhibition in mouse high activity schizophrenia model
The objective of this study was to administer to mice an intraperitoneal injection of 0.3mg/kg MK-801 ((+) -MK-801 hydrogen maleate) resulting in a high activity model of mice and to observe the effect of clozapine-quetiapine co-amorphous and physical mixtures on this model.
Experiment design:
animal(s) production
All animals received 4 days of quarantine and acclimation during which general observations were made on the animals each day. Day and night light and shade alternation time of animal rooms: 12h/12h, air change times: not less than 8 times/h, temperature: 16-26 ℃ and 40-70% of relative humidity. Animals were stratified by weight and randomly divided into blank groups, model groups (treated with sesame oil only), and each test article group, 15 mice in blank groups, and 8 mice in other groups.
Animal administration
The mice were fully gavaged with clozapine quetiapine fumarate in a 1:1 molar co-amorphous form or in a 1:1 molar physical mixture. After 1h of administration, 0.3mg/kg MK-801 was intraperitoneally injected, and the mice were placed in an autonomous activity box (black polyethylene box with a specification of 29cm × 29cm × 30 cm) and video-recorded for 60min, video analysis was performed after video recording was completed, and the activity of the mice was evaluated.
Evaluation of inhibition of hyperactivity in mice after administration
Calculating the high activity inhibition rate of the model group mice by analyzing the moving distance of the mice after administration: the inhibition ratio in the drug group was 100- (distance traveled by drug group mouse/distance traveled by model group mouse) × 100.
Results
In this study, clozapine quetiapine fumarate at a 1:1 molar ratio co-amorphous versus 1:1 molar ratio physical mixture range and inhibition results are shown in tables 3 and 4.
TABLE 3 high range of motion in mice co-amorphous and physical mixtures after intragastric administration
| Group of | Distance of movement (mm) |
| Blank group | 67556.1±28545.20 |
| Model set | 217404.02±119602.71## |
| Physically mix Low dose (mg/kg) (clozapine 1.9+ Quetiapine fumarate 5) | 222862.10±60992.04 |
| Physical mixing of Medium dose (mg/kg) (clozapine 3.7+ Quetiapine fumarate 10) | 178526.35±85931.80 |
| Physical mixing of high dose (mg/kg) (clozapine 7.4+ Quetiapine fumarate 20) | 146044.33±146044.33 |
| Co-amorphous Low dose (mg/kg) (clozapine 1.9+ Quetiapine fumarate 5) | 222563.17±60609.88 |
| Co-amorphous Medium dose (mg/kg) (clozapine 3.7+ Quetiapine fumarate 10) | 118223.67±70616.27* |
| High dose (mg/kg) of co-amorphous (clozapine 7.4+ quetiapine fumarate 20) | 63312.68±84642.34** |
Note: comparison with blank group##P is less than 0.01; p < 0.05 compared to model group; p < 0.01.
TABLE 4 high Activity inhibition in mice of Co-amorphous and physically mixed compositions after intragastric administration
Conclusion
In a mouse high-activity model, clozapine and quetiapine fumarate are jointly used, the high-activity inhibition rate of the clozapine and quetiapine fumarate is higher than the simple addition of the single inhibition rate of the clozapine and quetiapine fumarate, and the clozapine and quetiapine fumarate have a synergistic effect on the anti-schizophrenia drug effect; the drug effect of the clozapine and quetiapine fumarate co-amorphous substance is further superior to that of a physical mixture.
3. Clozapine quetiapine fumarate co-amorphous pharmacokinetics
The purpose of the test is as follows: the pharmacokinetic characteristics of clozapine quetiapine fumarate co-amorphous are examined in rats by using an LC-MS method.
Chromatographic conditions of clozapine and quetiapine fumarate: the column was an Agilent extended C18 column (150 mm. times.4.6 mm,5 μm, Agilent Corp.); pre-column: a C18 guard column (4 mm. times.3.0 mm,5 μm, Phenomenex, USA); mobile phase: acetonitrile-10 mM aqueous ammonium acetate 50: 50 (v/v); flow rate: 1.0 mL/min-1(ii) a Column temperature: at 30 ℃.
Mass spectrum conditions of clozapine and quetiapine fumarate: an ionization mode: electrospray ionization (ESI); the temperature is 350 ℃; selective-ion monitoring (SIM), positive ion detection; dryer temperature: 350 ℃; fragmentation voltage: 70V; atomizer pressure (psi): 35; the drying airflow rate is 8.0L/min; high vacuum 1.3E-005 Torr. The detected ions are: clozapine [ M + H]+(mass-to-charge ratio, m/z): 327, quetiapine [ M + H]+(mass-to-charge ratio, m/z): 384, internal standard YHK180625[ M + H]+(mass-to-charge ratio, m/z): 438.
treatment of plasma samples: a plasma sample (80. mu.L) was taken and placed in a 1.5mL centrifuge tube, and an internal standard solution (5.0. mu.g. mL) was added thereto-1YHK180625 solution) 10. mu.L, mobile phase solution 10. mu.L, mixing, adding 300. mu.L of precipitant-methanol, vortexing for 5min, centrifuging at 4 deg.C (12,000rpm) for 10min, and collecting supernatant 10. mu.L for LC-MS analysis.
Preparing a test sample:
preparation of intragastric administration solution (physical mixture of-clozapine 11.1mg/kg + quetiapine fumarate 30 mg/kg): 11.mg of clozapine and 30mg of quetiapine fumarate are weighed respectively, physically mixed, ultrasonically mixed by 10mL of sesame oil, and prepared into suspension.
Preparation of intragastric administration solution (co-amorphous-clozapine fumarate co-amorphous-41.1 mg/kg): 41.1mg of clozapine-quetiapine fumarate amorphous substance is weighed and mixed with 10mL of sesame oil by ultrasound to prepare a suspension.
Preparation of a solution for intragastric administration (clozapine crystals-11.1 mg/kg): 11.1mg of clozapine compound is weighed and mixed with 10mL of sesame oil by ultrasound to prepare a suspension.
Preparation of intragastric administration solution (quetiapine fumarate crystal-30 mg/kg): 30mg of quetiapine fumarate compound is weighed and mixed evenly with 10mL of sesame oil by ultrasound to prepare suspension.
And (3) experimental design:
grouping method of experimental animals: 12 healthy male SD rats were of uniform body weight and were randomly divided into four groups of 3 rats each.
The administration route and the method are as follows: intragastric administration;
frequency and duration of administration: single administration;
the administration time is as follows: the uniform speed is proper;
sprague Dawley rats were each 3, male. Fasting was performed for 12h before the test, water was freely drunk, and physical mixtures of 11.1mg/kg of clozapine + 30mg/kg of quetiapine fumarate, 41.1mg/kg of clozapine-quetiapine fumarate co-amorphous, and chlorine were administered by gavage as a doseRespectively taking 0.3mL of azone-11.1 mg/kg and quetiapine fumarate-30 mg/kg liquid medicine before and after administration for 15min, 30min, 60min, 2h, 4h, 6h, 8h, 12h and 24h, placing in a centrifuge tube, and collecting blood at 8000 r.min-1Centrifuging for 10min, separating plasma, freezing and storing in a refrigerator at-80 deg.C for testing. In the experiment, the result of one animal is abnormal at the blood sampling point of 6h in the clozapine group, so that the data of three animal experiments at the point are abandoned; quetiapine data points were retained.
Before administration, about 0.5mL blood samples were collected from the experimental animals, transferred to sample tubes containing heparin sodium as an anticoagulant, and placed in wet ice for preparing blank plasma. The prepared blank plasma was mixed for development of analytical methods and sample analysis. Within 1 hour (including 1 hour) after administration, blood collection time of ± 1 minute was considered as an acceptable range. Blood collection times after 1 hour of no more than 5% of the standard time are acceptable and are not considered experimental deviations. Plasma was centrifuged within 60 minutes after blood collection. The animals were closely observed during the experiment, and the general state and appearance of the animals were observed.
Determination of unknown plasma samples: when unknown plasma samples are determined, the plasma sample processing method is used, and the concentration of clozapine and quetiapine fumarate in each sample is calculated according to the following standard. Samples with concentrations below the lower limit of quantitation when assayed for unknown plasma samples are calculated as zero values, if zero is indicated before peak arrival and n.d. (not detected) after peak arrival.
And substituting the data of the plasma concentration and time of clozapine and quetiapine fumarate measured by intragastric administration into a DAS 3.2.8 program to calculate main pharmacokinetic parameters. Tmax and Cmax were measured by the trapezoidal method to calculate AUC0-t value and AUC0- ∞ value, and t1/2 was calculated from the concentration point at the end of elimination phase by the semilogarithmic plot method.
The experimental data are represented by x +/-SD, SPSS statistical software is adopted, homogeneity of variance test is firstly carried out, single-factor analysis of variance is firstly carried out if the variance is uniform, Welch's ANOVA is adopted if the variance is irregular, and the difference is significant when P is less than 0.05.
And (3) test results:
pharmacokinetic parameters of clozapine and quetiapine fumarate in rats are given in table 5 below:
and (4) conclusion: after single intragastric administration of physically mixed clozapine and quetiapine fumarate, co-amorphous clozapine and quetiapine fumarate, the AUC (0- ∞) of physically mixed clozapine, co-amorphous clozapine and clozapine are 1830.099, 3517.363 and 1277.02, respectively, and the AUC (0- ∞) of co-amorphous clozapine is highest; peak concentrations (Cmax) of 220.22, 423.19 and 103.17, respectively, were highest for clozapine as the amorphous form; the peak time of arrival (Tmax) is 6.67, 4.67 and 2.00h respectively, the Tmax of clozapine is the fastest, the clozapine is the co-amorphous substance, and the slowest peak time is the physical mixture of clozapine; the elimination half-lives (t1/2z) were 9.60, 24.133 and 10.15h, respectively, and the clearance of the co-amorphous clozapine was slower.
The AUC (0- ∞) of quetiapine fumarate, and quetiapine fumarate of the physical mixture is 878.30, 524.84, and 948.81, respectively, the AUC (0- ∞) of quetiapine fumarate and quetiapine fumarate of the physical mixture is almost equal, and the AUC (0- ∞) of quetiapine fumarate of the co-amorphous compound is relatively lower; peak concentrations (Cmax) were 182.51, 124.09, and 223.07, respectively, with quetiapine fumarate having the highest Cmax and the amorphous form, quetiapine fumarate, having the lowest Cmax; the peak reaching time (Tmax) is 0.25h, and the absorption is relatively quick; the elimination half-lives (t1/2z) were 1.10, 1.13 and 5.64h, respectively, and the elimination half-lives of physically mixed-quetiapine fumarate and co-amorphous-quetiapine fumarate were almost equal, whereas the t1/2z of quetiapine fumarate was relatively long.
In conclusion, the bioavailability of the co-amorphous substance is improved, and particularly, the relative bioavailability of clozapine in the co-amorphous substance is higher than that in the physically mixed group and the single administration group, and is 1.7 times and 2.5 times of that in the physically mixed group and the single administration group respectively.
Claims (10)
1. A co-amorphous form of clozapine and quetiapine fumarate;
preferably, in the co-amorphous substance of clozapine and quetiapine fumarate, the molar ratio of clozapine to quetiapine fumarate is 1: 1;
preferably, in the co-amorphous substance of clozapine and quetiapine fumarate, the molar ratio of clozapine to quetiapine fumarate is 2: 1.
2. The co-amorphous form according to claim 1, wherein the co-amorphous form with a 1:1 molar ratio of clozapine and quetiapine fumarate has a glass transition temperature of 50.44 ℃;
preferably, the infrared spectrum wave number (cm) of the co-amorphous substance with the molar ratio of clozapine to quetiapine fumarate of 1:1-1)(±2cm-1) Is characterized in particular by the following peaks: 3278.3, 1714.8;
preferably, the infrared spectrum wave number (cm) of the co-amorphous substance with the molar ratio of clozapine to quetiapine fumarate of 1:1-1)(±2cm-1) Comprises the following steps: 3278.3, 3052.5, 2916.9, 2849.5, 1714.8, 1600.8, 1573.9, 1458.0, 1376.9, 1303.8, 1243.9, 1120.5, 1082.6, 1062.7, 1003.3, 981.9, 953.2, 894.7, 875.5, 814.6, 762.2, 742.1, 694.9, 668.4, 597.0, 568.9, 546.3, 522.8, and 462.4.
3. The co-amorphous form according to claim 2, wherein the co-amorphous form has a 1:1 molar ratio of clozapine and quetiapine fumarate has an XRPD pattern as shown in figure 4.
4. The co-amorphous form according to claim 1, wherein the co-amorphous form with a 2:1 molar ratio of clozapine and quetiapine fumarate has a glass transition temperature of 50.97 ℃;
preferably, the infrared spectrum wave number (cm) of the co-amorphous substance with the molar ratio of clozapine to quetiapine fumarate of 2:1-1)(±2cm-1) Is characterized in particular by the following peaks: 3272.7, 1784.0, 1703.1;
preferably, said clozapineInfrared spectrum wavenumber (cm) of co-amorphous substance with quetiapine fumarate molar ratio of 2:1-1)(±2cm-1) Comprises the following steps: 3272.7, 3212.6, 3117.7, 3053.6, 2996.2, 2934.6, 2849.7, 2801.7, 1784.0, 1703.1, 1601.9, 1573.5, 1560.4, 1459.6, 1428.1, 1367.4, 1303.3, 1257.5, 1243.4, 1140.5, 1120.6, 1105.7, 1082.4, 1063.3, 1028.5, 1013.9, 1004.2, 981.6, 952.2, 924.7, 894.5, 875.0, 813.7, 761.9, 742.5, 694.3, 669.2, 596.9, 569.2, 523.0, and 463.4.
5. The co-amorphous form of claim 4, wherein the co-amorphous form has a 2:1 molar ratio of clozapine to quetiapine fumarate has an XRPD pattern as shown in figure 13.
6. The preparation method of clozapine quetiapine fumarate co-amorphous substance as claimed in any one of claims 1 to 5, characterized in that clozapine and quetiapine fumarate are ground and mixed uniformly, heated and melted, and then cooled down by quenching;
preferably, the molar ratio of clozapine to quetiapine fumarate is 1: 1;
preferably, the molar ratio of clozapine to quetiapine fumarate is 2: 1;
preferably, the melting temperature is 180 ℃ to 190 ℃.
7. A pharmaceutical composition comprising an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient comprises clozapine fumarate quetiapine co-amorphous form as claimed in any one of claims 1 to 5;
preferably, the clozapine-quetiapine fumarate co-amorphous substance is a co-amorphous substance with a molar ratio of clozapine to quetiapine fumarate of 1:1, or a co-amorphous substance with a molar ratio of clozapine to quetiapine fumarate of 2:1, or a mixture of the two substances.
8. Use of clozapine quetiapine fumarate co-amorphous form according to any of claims 1 to 5 in the manufacture of a medicament for the treatment of schizophrenia.
9. The use according to claim 8, wherein the schizophrenia is refractory schizophrenia.
10. The use according to claim 8 or 9, wherein the treatment of schizophrenia comprises the treatment or amelioration of affective symptoms associated with schizophrenia; preferably the affective symptom is selected from: depression, anxiety, mania, violence tendency, suicidal tendency, and/or cognitive deficits.
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