CN113943283A - Pioglitazone hydrochloride p-aminobenzoic acid eutectic crystal, preparation, composition and application thereof - Google Patents
Pioglitazone hydrochloride p-aminobenzoic acid eutectic crystal, preparation, composition and application thereof Download PDFInfo
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- CN113943283A CN113943283A CN202010678401.8A CN202010678401A CN113943283A CN 113943283 A CN113943283 A CN 113943283A CN 202010678401 A CN202010678401 A CN 202010678401A CN 113943283 A CN113943283 A CN 113943283A
- Authority
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- China
- Prior art keywords
- pioglitazone hydrochloride
- aminobenzoic acid
- acid eutectic
- eutectic compound
- pioglitazone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
The invention belongs to the technical field of medicines, and discloses a pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound, a preparation method, a pharmaceutical composition and application thereof. Specifically, the invention discloses pioglitazone hydrochloride and p-aminobenzoic acidSolid matter state of eutectic substance; a preparation method of a solid substance sample of a pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound; the pioglitazone hydrochloride and p-aminobenzoic acid eutectic crystal is used as an active ingredient for preparing the medicines for reducing blood sugar, reducing blood fat and relieving or preventing diabetic nephropathy and insulin cell degeneration.
Description
Technical Field
The invention discloses a pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound, a preparation method, a composition and application thereof. Specifically, the invention discloses a eutectic compound formed by pioglitazone hydrochloride and p-aminobenzoic acid; a preparation method of a pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound; an application of a pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound as a medicinal active ingredient in preparing medicaments for reducing blood sugar, reducing blood fat and relieving or preventing diabetic nephropathy and insulin cell degeneration, which belongs to the technical field of medicines.
Background
Pharmaceutical co-crystals are crystals formed by non-covalent intermolecular interaction of active drug molecules with co-crystal formers in a certain ratio. The drug forms a eutectic crystal, so that the crystal form of the drug can be greatly enriched on one hand, and the physicochemical property and the clinical curative effect of the drug can be improved on the other hand. For the imitation drugs, the crystal form patent of the original drugs can be broken through the research of the co-crystal, and the market competitiveness of the imitation drugs is improved.
The invention adopts pioglitazone hydrochloride as an active substance, and the chemical name of the pioglitazone hydrochloride is (+/-) 5- [4- [2- (5-ethyl-2-pyridine) ethoxy]Benzyl radical]-2, 4-thiazolidinedione hydrochloride having the formula C19H20N2O3S.HCl, white or off-white powder. The structural formula is shown as a. P-aminobenzoic acid is organic acid with molecular formula of C7H7NO2The structural formula is shown as b.
Pioglitazone hydrochloride is a thiazolidinedione antidiabetic, belongs to an insulin sensitizer, has an action mechanism related to the existence of insulin, can reduce the insulin resistance of peripheral tissues and livers, increases the treatment of insulin-dependent glucose and reduces the output of glycogen. Pioglitazone hydrochloride is highly selective to activate the peroxisome growth factor-activated receptor-gamma [ PPAR-gamma ], and the activation of PPAR-gamma can regulate the transcription of a plurality of insulin-related genes controlling the metabolism of glucose and lipid. Experiments show that pioglitazone hydrochloride can reduce hyperglycemia, hyperinsulinemia and hypertriglyceridemia of insulin resistance. The metabolic changes caused by pioglitazone hydrochloride result in an increase in insulin-dependent tissue responses. Since pioglitazone hydrochloride increases the effect of circulating insulin (i.e., decreases insulin resistance), it does not reduce blood glucose in the absence of endogenous insulin. Pioglitazone hydrochloride is almost insoluble in water and belongs to insoluble drugs, and at present, pioglitazone hydrochloride is mainly taken as an oral tablet for medicine taking and has the defects of low dissolution rate, low dissolution rate and low bioavailability.
The research of patents and documents at home and abroad shows that no other eutectic patents or documents related to pioglitazone hydrochloride p-aminobenzoic acid are found.
The invention discloses a solid matter state of a pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound and a preparation method thereof, which are different from the contents of the patent or the literature research reports.
The invention aims to search and discover the existence type, state characteristics and new pharmacological activity of the pioglitazone hydrochloride eutectic solid substance on the level of active ingredient raw materials of the medicament by using a eutectic screening technology and a biological activity evaluation technology starting from the research on the existence state of the pioglitazone hydrochloride and p-aminobenzoic acid eutectic solid substance. The eutectic substance is combined with pharmacodynamic research, and basic scientific data is provided for searching, discovering and developing medicinal eutectic solid substance of pioglitazone hydrochloride with new pharmacological activity and clinical curative effect; meanwhile, a scientific basis is provided for applying for the patent protection of national or international intellectual property rights on the basis of the pioglitazone hydrochloride eutectic solid medicine raw material substance.
Disclosure of Invention
The technical problems to be solved by the invention are as follows:
the invention aims to solve one of the technical problems that: provides a existence state and a representation mode of a pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound.
The second technical problem to be solved by the present invention is: provides a preparation method of a pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound.
The invention aims to solve the third technical problem: provides a pure product containing the eutectic compound of pioglitazone hydrochloride and para aminobenzoic acid, or a mixed solid substance containing the eutectic compound of pioglitazone hydrochloride and para aminobenzoic acid in any non-zero proportion and a pharmaceutical composition thereof.
The fourth technical problem to be solved by the invention is: the pharmaceutical composition uses a pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound as a pharmaceutical active ingredient, and the pharmaceutical specification of the pharmaceutical composition is within the range of 1-200 mg. The medicine composition comprises tablets, capsules, pills, injection preparations, granules, powder, pellets, dropping pills, suppositories, films, patches, aerosols, sprays, sustained-release preparations or controlled-release preparations.
The fifth technical problem to be solved by the invention is as follows: provides a substance of the eutectic compound of the pioglitazone hydrochloride and the p-aminobenzoic acid, and has the advantage characteristic of better solubility than the pioglitazone hydrochloride.
The technical problems to be solved by the invention are as follows: provides a pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound which can play the role of effective treatment of medicaments by improving the bioavailability in vivo due to the eutectic compound while playing the combined drug effect of biological activity in the process of treating diseases.
The invention solves the technical problems: the pioglitazone hydrochloride and p-aminobenzoic acid eutectic crystal is used as the effective component of medicine in preparing medicine for lowering blood sugar, reducing blood fat, and preventing and treating diabetic nephropathy and insulin cell degeneration.
In order to solve the technical problems, the invention adopts the following technical scheme:
1. morphological characteristics of a pioglitazone hydrochloride and p-aminobenzoic acid eutectic crystal sample:
1.1 the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound is formed by the pioglitazone hydrochloride and the p-aminobenzoic acid in a molar ratio of 1: 1.
1.2 the pioglitazone hydrochloride and p-aminobenzoic acid eutectic crystal of the invention adopts CuK when powder X-ray diffraction analysis is usedαDiffraction peak position under irradiation test conditions: 2-Theta value (°) or d value
Diffraction peak relative intensity: the peak Height value (Height%) or peak Area value (Area%) had the following characteristics (table 1, fig. 1); the powder X-ray diffraction pattern and data of the physical mixture of the pioglitazone hydrochloride and the p-aminobenzoic acid eutectic compound are shown in the table 2 and the figure 2. The powder X-ray diffraction patterns of the physical mixture of the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound and the pioglitazone hydrochloride and the p-aminobenzoic acid are obviously different in the aspects of diffraction peak number, diffraction peak position, diffraction peak intensity, diffraction peak topological graph and the like, which shows that the physical mixture of the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound and the physical mixture of the pioglitazone hydrochloride and the p-aminobenzoic acid are different and different. TABLE 1 powder X-ray diffraction Peak of eutectic product of pioglitazone hydrochloride and p-aminobenzoic acid
TABLE 2 powder X-ray diffraction peaks of physical mixtures of pioglitazone hydrochloride and p-aminobenzoic acid
1.4 analysis of eutectic substance of pioglitazone hydrochloride and p-aminobenzoic acid by attenuated total reflection Fourier infrared spectroscopy is carried out at 2962, 2924, 2870, 2606, 2478, 1872, 1762, 1737, 1703, 1610, 1575, 1515, 1472, 1462, 1427, 1398, 1386, 1317, 1296, 1248, 1181, 1160, 1111, 1040, 1017, 964, 927, 903, 840, 822, 738, 721, 713, 657cm-1Has characteristic peaks of infrared spectrum, wherein the allowable deviation of the characteristic peaks of the infrared spectrum is +/-2 cm-1(FIG. 3).
1.5 when analyzed by differential scanning calorimetry, the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound of the present invention has 1 endothermic peak at 123 ℃ + -3 ℃ in a DSC spectrum when the temperature rise rate is 10 ℃ per minute (fig. 4). DSC spectra of pioglitazone hydrochloride, p-aminobenzoic acid, and eutectic product of pioglitazone hydrochloride and p-aminobenzoic acid are shown in figure 5. The DSC spectra of the eutectic compound of the pioglitazone hydrochloride and the p-aminobenzoic acid and the pioglitazone hydrochloride and the p-aminobenzoic acid have obvious difference in the quantity, the position and the like of heat absorption/release peaks, and the result shows that the eutectic compound of the pioglitazone hydrochloride and the p-aminobenzoic acid forms a new substance.
1.6 when the eutectic substance of the pioglitazone hydrochloride and the p-aminobenzoic acid related to the invention is analyzed by using thermogravimetric technology, when the heating rate is 10 ℃ per minute, only the decomposition weight loss peak of the eutectic substance of the pioglitazone hydrochloride and the p-aminobenzoic acid exists in a TG atlas, which shows that the eutectic substance of the pioglitazone hydrochloride and the p-aminobenzoic acid does not contain a crystallization solvent or crystal water. The TG spectrum of the pioglitazone hydrochloride and p-aminobenzoic acid eutectic is shown in figure 6.
2. The preparation method of the eutectic compound and the mixed solid substance of the pioglitazone hydrochloride and the para aminobenzoic acid is characterized by comprising the following steps:
2.1 the invention relates to a preparation method of a pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound, which comprises the steps of feeding pioglitazone hydrochloride and p-aminobenzoic acid according to the molar ratio of 1:1, and preparing the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound by a mechanochemical method for controlling pressure and temperature. The mechanochemical method can be selected from a liquid adding grinding method or a liquid adding ball grinding method, wherein the type of the organic solvent added with liquid is any one or more mixed solvents prepared by combining in different proportions; the organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, ethyl formate, ethyl acetate, propyl acetate, and tetrahydrofuran; the liquid adding amount is 0.01-100 ml added into each gram of sample; grinding for 0.1-10 hours, drying at 40-60 ℃ for 4-12 hours; the comprehensive pot filling rate of the liquid adding grinding method is 10-50%, and the reciprocating speed is 20-70 m/min; the shearing impact energy of the ball mill of the liquid adding ball milling method is 10-800 kw, and the comprehensive filling rate is 20-60%; the ball-material ratio is 1: 1-10: 1, preferably 6: 1-10: 1; the ball milling speed is 20r/min to 400r/min, preferably 300r/min to 400 r/min.
2.2 the invention relates to a preparation method of eutectic substance of pioglitazone hydrochloride and p-aminobenzoic acid, which comprises the steps of putting pioglitazone hydrochloride and p-aminobenzoic acid into a clean container according to the molar ratio of 1:1, adding an organic solvent to prepare a suspension, stirring at room temperature for 1-4 days, and carrying out solvent evaporation drying, filtering natural drying or filtering vacuum drying on the obtained suspension to obtain the eutectic substance of pioglitazone hydrochloride and p-aminobenzoic acid. The organic solvent is preferably selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, and other alcoholic solvents, and one or more of ethyl formate, ethyl acetate, propyl acetate, and tetrahydrofuran; keeping the solid-liquid ratio of the total mass of the p-aminobenzoic acid and the pioglitazone hydrochloride to the organic solvent within the range of 1mg/ml to 500 mg/ml.
2.3 the solid mixture of pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound of the present invention is prepared by mixing the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound prepared by the above method with other chemical substances according to any non-zero proportion and conventional method.
3. The pharmaceutical preparation composition containing the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound components has the following characteristics of administration dosage and pharmaceutical application:
3.1 the pharmaceutical composition contains a pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound and a pharmaceutically acceptable carrier.
3.2 the pharmaceutical composition comprises a mixed solid substance of pioglitazone hydrochloride and a p-aminobenzoic acid eutectic compound and a pharmaceutically acceptable carrier.
3.3 the pharmaceutical composition of the invention has a daily dose of pioglitazone hydrochloride within the range of 1-200 mg.
3.4 the invention relates to a pharmaceutical composition, which is characterized in that the pharmaceutical composition is various tablets, capsules, pills, injection preparations, granules, powder, pellets, dropping pills, suppositories, film agents, patches, aerosols, sprays, sustained-release preparations or controlled-release preparations.
3.5 the invention relates to the application of a pioglitazone hydrochloride and para aminobenzoic acid eutectic compound, a mixed solid substance of the pioglitazone hydrochloride and the para aminobenzoic acid eutectic compound or a pharmaceutical composition in preparing medicines for reducing blood sugar and blood fat and relieving or preventing diabetic nephropathy and insulin cell degeneration.
The invention relates to a pharmaceutical composition taking a pioglitazone hydrochloride and p-aminobenzoic acid eutectic crystal as an active ingredient. The pharmaceutical composition may be prepared according to methods well known in the art. The pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound can be combined with one or more pharmaceutically acceptable solid or liquid excipients and/or auxiliary agents to prepare any preparation formulation suitable for human or animal use. The content of the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound in the pharmaceutical composition is within the range of 10-90% by weight.
The pioglitazone hydrochloride and p-aminobenzoic acid eutectic crystal can be administered in a unit dosage form, and the administration route can be intestinal tract or parenteral tract, such as oral administration, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eyes, lung and respiratory tract, skin, vagina, rectum and the like.
The administration form according to the invention is preferably a solid form. The solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.
The pioglitazone hydrochloride and p-aminobenzoic acid eutectic crystal can be prepared into common preparations, sustained release preparations, controlled release preparations, targeted preparations and various particle drug delivery systems.
In order to tablet the eutectic crystal of pioglitazone hydrochloride and p-aminobenzoic acid of the present invention, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
In order to prepare the administration unit into a capsule, the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound, which is an effective ingredient, can be mixed with a diluent and a glidant, and the mixture is directly placed into a hard capsule or a soft capsule. Or the active ingredients of the eutectic compound of pioglitazone hydrochloride and p-aminobenzoic acid can be prepared into granules or pellets with a diluent, an adhesive and a disintegrating agent, and then the granules or pellets are placed into hard capsules or soft capsules. Various diluents, adhesives, wetting agents, disintegrating agents and glidants for preparing the pioglitazone hydrochloride and p-aminobenzoic acid eutectic substance tablet can also be used for preparing capsules of the pioglitazone hydrochloride and p-aminobenzoic acid eutectic substance.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
For the purpose of administration and enhancing the therapeutic effect, the drug of the present invention can be administered by any known administration method.
The administration dosage of the pharmaceutical composition of the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound can be widely changed according to the nature and severity of diseases to be prevented or treated, individual conditions of patients or animals, administration routes, dosage forms and the like. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
The pioglitazone hydrochloride and p-aminobenzoic acid eutectic crystal or the composition can be taken alone or combined with other treatment medicines or symptomatic medicines. When the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound has synergistic effect with other therapeutic drugs, the dosage of the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound is adjusted according to actual conditions.
4. The invention has the beneficial technical effects that: the safety and the biological activity of the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound are characterized by the advantages.
4.1 the pioglitazone hydrochloride and p-aminobenzoic acid eutectic crystal does not contain any crystallization solvent, and has good safety and patent medicine advantages.
4.2 the pioglitazone hydrochloride and p-aminobenzoic acid eutectic crystal has the characteristic of solubility advantage, and is specifically embodied in that: the solubility in 0.2% SDS aqueous solution is obviously better than that of pioglitazone hydrochloride (FIG. 7).
4.4 compared with pioglitazone hydrochloride, the solid matter of the eutectic compound of pioglitazone hydrochloride and p-aminobenzoic acid of the invention has obvious biological absorption advantage (figure 8).
Drawings
FIG. 1 powder X-ray diffraction spectrum of pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound
FIG. 2 powder X-ray diffraction Pattern of physical mixture of pioglitazone hydrochloride and p-aminobenzoic acid
FIG. 3 is an infrared absorption spectrum of a pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound
FIG. 4 is a differential scanning calorimetry spectrum of a pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound
FIG. 5 Differential Scanning Calorimetry (DSC) spectrum of eutectic product of pioglitazone hydrochloride and p-aminobenzoic acid and raw materials
FIG. 6 thermogravimetric spectrum of pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound
FIG. 7 is a graph comparing the solubility of eutectic compound of pioglitazone hydrochloride and p-aminobenzoic acid and pioglitazone hydrochloride in 0.2% SDS aqueous solution
FIG. 8 is a biological absorption spectrum of a pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound and pioglitazone hydrochloride
Detailed Description
The following examples are given to better illustrate the technical aspects of the present invention, but the present invention is not limited thereto.
Example 1
The preparation method of the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound comprises the following steps:
according to the following table, appropriate amount (molar ratio 1:1) of pioglitazone hydrochloride and p-aminobenzoic acid are put into a mortar, appropriate amount of organic solvent is added, and the mixture is manually ground for appropriate time and dried at a certain temperature. Powder X-ray diffraction analysis is carried out on the crystal, the diffraction pattern of the crystal is consistent with that of figure 1, and the obtained sample is a pioglitazone hydrochloride and p-aminobenzoic acid eutectic crystal.
TABLE 3 Experimental parameter examples for preparation of pioglitazone hydrochloride and p-aminobenzoic acid cocrystals method 1
The preparation method of the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound comprises the following steps:
according to the table shown below, a proper amount (molar ratio is 1:1) of pioglitazone hydrochloride and p-aminobenzoic acid is put into a ball milling tank, a proper amount of organic solvent is added, a proper ball-material ratio is selected, a proper rotating speed is set, grinding is carried out for a proper time, and drying is carried out at a certain temperature. Powder X-ray diffraction analysis is carried out on the crystal, the diffraction pattern of the crystal is consistent with that of figure 1, and the obtained sample is a pioglitazone hydrochloride and p-aminobenzoic acid eutectic crystal.
TABLE 4 Experimental parameter examples for preparation of pioglitazone hydrochloride and p-aminobenzoic acid cocrystals method 2
The preparation method of the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound comprises the following steps:
according to the table shown below, a proper amount of pioglitazone hydrochloride and p-aminobenzoic acid are put into a clean container, a proper amount of organic solvent is added, stirring is carried out for a proper time at room temperature, the obtained suspension is filtered, and the solid matter is dried at a certain temperature. Powder X-ray diffraction analysis is carried out on the crystal, the diffraction pattern of the crystal is consistent with that of figure 1, and the obtained sample is a pioglitazone hydrochloride and p-aminobenzoic acid eutectic crystal.
TABLE 5 Experimental parameter examples for preparation of pioglitazone hydrochloride and p-aminobenzoic acid cocrystals method 3
Example 2
Solubility characteristics of a pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound:
pioglitazone hydrochloride belongs to a drug with poor water solubility, and a 0.2% SDS aqueous solution is used for carrying out experiments, and a solvent system is used for the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound and the pioglitazone hydrochlorideThe dissolution rates of the two substances are well differentiated (f)230.56) (fig. 7). The determination is carried out by referring to a solubility determination method (guiding principles of dissolution test technology of common oral solid preparations (first draft), 2012,10 center for drug evaluation). By adopting the high performance liquid chromatography, the concentration of the dissolved sample is calculated by utilizing the chromatographic peak area data of the sample, a solubility curve is respectively drawn by taking time as an abscissa and solvent concentration as an ordinate, and the data are shown in the following table:
TABLE 6 dissolution curve data of eutectic product of pioglitazone hydrochloride and p-aminobenzoic acid and pioglitazone hydrochloride in 0.2% SDS aqueous solution
The experimental data show that the dissolution behavior of the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound in a 0.2% SDS aqueous solution system is obviously superior to that of the pioglitazone hydrochloride, and the dissolution is particularly characterized in that the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound have higher dissolution rate, are easy to quickly absorb to reach effective blood concentration, realize the disease treatment effect of the medicament, have higher solubility compared with the pioglitazone hydrochloride, improve the solubility by more than 2 times, and ensure higher biological absorption in the disease treatment process.
Example 3
The absorption characteristics and the blood concentration characteristics of the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound in a rat body are as follows:
randomly grouping SD rats, each group comprises 5 rats, freely drinking water, fasting for 12 hr, weighing the weight of the rats according to 20 mg/kg-1The dose of the pioglitazone hydrochloride is calculated, the pioglitazone hydrochloride and p-aminobenzoic acid eutectic crystal sample is put into a solid administration device, and the medicinal powder is directly put into the stomach of a rat through the oral cavity. Respectively taking blood from inner canthus of eye 15min,30min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h after administration, placing in heparinized tube, centrifuging at 4 deg.C and 6500rpm for 10min, freezing and storingThe test was carried out in a refrigerator at-40 ℃. Precisely sucking 40 mu L of blood plasma anticoagulated by heparin, placing the blood plasma anticoagulated by heparin into a 1.5mL centrifuge tube, adding 10 mu L of internal standard carbamazepine working solution, adding 750 mu L of extracting agent (methanol), fully shaking for 3min, centrifuging (13400rpm, 10min), taking 200 mu L of upper layer solution, placing the upper layer solution into an inner lining tube, and injecting 5 mu L of sample. Quantitative analysis was performed as the ratio of peak areas of drug and internal standard.
Detection conditions are as follows: a chromatographic column: agilent SB-C18(2.1X 50mm,2.7 μm, USA); 0.05 mol/L of methanol－1Ammonium acetate in water (pH 5.0 adjusted with formic acid) (60: 40, v/v); the flow rate is 0.3 mL/min; the column temperature is 35 ℃; sample introduction amount: 5 mu L of the solution; operating time: 8 min; mass spectrum signal: ESI source (positive ion detection mode), ions for quantitative analysis m/z 237 (carbamazepine), m/z 357 (pioglitazone), fragmentation voltage 140V (pioglitazone), 105V (carbamazepine), gain factor 1, drying gas flow 110.0L/min, spray chamber voltage 35psig, dryer temperature 350 ℃, capillary voltage 3000V (positive), 3000V (negative).
Table 7 shows the plasma concentrations at various time points in blood of rats after oral administration of pioglitazone hydrochloride and samples of pioglitazone hydrochloride and p-aminobenzoic acid cocrystals; table 8 shows the pharmacokinetic parameters of oral pioglitazone hydrochloride and p-aminobenzoic acid eutectic substance samples of 0 to 24 hours for rats; fig. 8 shows the biological absorption spectrum of the eutectic compound of pioglitazone hydrochloride and p-aminobenzoic acid and pioglitazone hydrochloride.
Table 7 blood concentration at each time point (n-5,
)
TABLE 8 pharmacokinetic parameters of orally administered pioglitazone hydrochloride and eutectic substance of pioglitazone hydrochloride and p-aminobenzoic acid in SD rat
From the map data, the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound has obvious biological absorption advantage compared with a pioglitazone hydrochloride raw material drug, and is specifically reflected in that the maximum blood concentration Cmax of the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound is improved by about 1.8 times compared with that of the pioglitazone hydrochloride, so that the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound has the absorption advantage of increased absorption degree, and unexpected advantageous technical effects are obtained.
Example 4
Method for the preparation of a combined pharmaceutical preparation 1 (tablet):
a preparation method of a combined drug tablet is characterized in that a pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound and a plurality of excipients are used as auxiliary material components for preparing the combined drug tablet, each tablet sample containing 1-100 mg of the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound is prepared according to a certain proportion, and the formula proportion of the tablet is given in Table 9:
TABLE 9 preparation formulation of pharmaceutical tablet of eutectic composition of pioglitazone hydrochloride and p-aminobenzoic acid
The method for preparing the tablet preparation by taking the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound as the raw material medicine comprises the following steps: mixing several excipients with the raw materials, and directly tabletting; or mixing the auxiliary materials, granulating by a dry method, uniformly mixing with the raw material medicines, and tabletting to obtain the traditional Chinese medicine.
Method for the preparation of a combined pharmaceutical preparation 2 (tablet):
a preparation method of a combined drug tablet is characterized in that a pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound and a plurality of excipients are used as auxiliary material components for preparing the combined drug tablet, tablet samples containing 1-100 mg of eutectic are prepared according to a certain proportion, and the formula proportion of the tablet is given in Table 9:
TABLE 9 preparation formulation of pharmaceutical tablet of eutectic composition of pioglitazone hydrochloride and p-aminobenzoic acid
The method for preparing the tablet preparation by taking the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound as the raw material medicine comprises the following steps: mixing several excipients with the raw materials, adding appropriate amount of 1% sodium carboxymethylcellulose solution, making into soft material, sieving, granulating, oven drying, sieving, grading, adding magnesium stearate and pulvis Talci, mixing, and tabletting.
Method for preparing a combined pharmaceutical preparation 3 (capsule):
a preparation method of a combined medicine capsule is characterized in that a pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound is used as a raw material medicine, a plurality of excipients are used as auxiliary material components for preparing the combined medicine capsule, a capsule sample with the medicine content of 1-100 mg is prepared according to a certain proportion, and the formula proportion of the capsule is given in a table 10:
TABLE 10 bulk drug and adjuvant formulation for pioglitazone hydrochloride and para aminobenzoic acid eutectic compound combined drug capsule preparation
The method for preparing the capsule by taking the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound as the raw material medicine comprises the following steps: mixing several excipients with the raw materials, adding appropriate amount of 1% sodium carboxymethylcellulose solution, making into wet granules, oven drying, sieving, grading, adding magnesium stearate, mixing, and making into capsule; or directly mixing the pioglitazone hydrochloride and p-aminobenzoic acid eutectic bulk drug with a plurality of excipient auxiliary materials without using a granulation step, sieving and directly encapsulating to obtain the pharmaceutical composition.
Example 4
Administration dosage 1 (tablet) of pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound combined drug:
the pharmaceutical composition is characterized in that the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound is used as the active ingredient of the medicine, the daily administration dosage is 50mg, and the pharmaceutical composition can be respectively prepared into common tablets with 25mg for 1 tablet 2 times a day or 50mg for 1 tablet 1 time a day.
The administration dosage of the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound combined medicine is 2 (capsules):
the pharmaceutical composition is prepared and developed by using the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound as active pharmaceutical ingredients, and is characterized in that the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound is used as the active pharmaceutical ingredients, the daily administration dosage is 100mg, and the pharmaceutical composition can be respectively prepared into 2 capsules with 25mg per time 2 times a day or 1 capsule with 50mg per time 2 times a day.
Problems to be explained are: the pharmaceutical composition of the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound has many factors on the administration dosage of the effective components, such as: the age and the body surface area of patients are different, and the administration route, the administration frequency and the treatment purpose are different, so that the dosage of each administration is different; the difference in absorption and blood concentration between samples also causes the suitable dosage range of the invention using the pioglitazone hydrochloride and p-aminobenzoic acid eutectic composition to be 0.02-5mg/kg of body weight, preferably 0.1-2mg/kg of body weight. When in use, different total dosage schemes of the active ingredients of the pioglitazone hydrochloride and p-aminobenzoic acid eutectic crystal are prepared according to different actual requirements of treatment on different conditions, and the administration can be completed in a mode of multiple times or one time.
Claims (14)
1. The pioglitazone hydrochloride and p-aminobenzoic acid eutectic crystal is characterized in that the pioglitazone hydrochloride and the p-aminobenzoic acid form the eutectic crystal at a molar ratio of 1: 1.
2. The pioglitazone hydrochloride and p-aminobenzoic acid cocrystal as claimed in claim 1, wherein CuK is used when powder X-ray diffraction analysis is usedαDiffraction peak position under irradiation test conditions: 2-Theta value (°) or d value
Diffraction peak relative intensity: the peak Height value (Height%) or peak Area value (Area%) has the following characteristics:
3. the pioglitazone hydrochloride and p-aminobenzoic acid cocrystal as claimed in claim 1, which is characterized by having a peak value at 2962, 2924, 2870, 2606, 2478, 1872, 1762, 1737, 1703, 1610, 1575, 1515, 1472, 1462, 1427, 1398, 1386, 1317, 1296, 1248, 1181, 1160, 1111, 1040, 1017, 964, 927, 903, 840, 738, 721, 713, 657cm when analyzed by attenuated total reflection fourier infrared spectroscopy-1Has characteristic peaks of infrared spectrum, wherein the allowable deviation of the characteristic peaks of the infrared spectrum is +/-2 cm-1。
4. The pioglitazone hydrochloride and p-aminobenzoic acid cocrystal as claimed in claim 1, characterized in that when analyzed by differential scanning calorimetry, there are 1 endothermic peak at 123 ℃ ± 3 ℃ in the DSC spectrum at a temperature rise rate of 10 ℃ per minute.
5. The method for preparing the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound as claimed in any one of claims 1 to 4, wherein the pioglitazone hydrochloride and the p-aminobenzoic acid are fed in a molar ratio of 1:1, and the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound is prepared by a mechanochemical method with controlled pressure and temperature.
6. The preparation method according to claim 5, wherein the mechanochemical method is selected from a liquid-adding grinding method or a liquid-adding ball-milling method, wherein the type of the liquid-adding organic solvent is any one or more mixed solvents prepared by combining according to different proportions; the organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, ethyl formate, ethyl acetate, propyl acetate and/or tetrahydrofuran; the liquid adding amount is 0.01-100 ml added into each gram of sample; grinding for 0.1-10 hours, drying at 40-60 ℃ for 4-12 hours; the comprehensive pot filling rate of the liquid adding grinding method is 10-50%, and the reciprocating speed is 20-70 m/min; the shearing impact energy of the ball mill of the liquid adding ball milling method is 10-800 kw, and the comprehensive filling rate is 20-60%; the ball-material ratio is 1: 1-10: 1, preferably 6: 1-10: 1; the ball milling speed is 20r/min to 400r/min, preferably 300r/min to 400 r/min.
7. The preparation method of the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound as claimed in any one of claims 1 to 4, characterized in that pioglitazone hydrochloride and p-aminobenzoic acid are added into a clean container according to a molar ratio of 1:1, an organic solvent is added to prepare a suspension, the suspension is stirred at room temperature for 1 to 4 days, and the obtained suspension is subjected to solvent evaporation drying, filtration natural drying or filtration vacuum drying to obtain the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound.
8. The preparation method of the pioglitazone hydrochloride and p-aminobenzoic acid eutectic crystal as claimed in claim 7, wherein the organic solvent is a mixed solvent prepared by combining any one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, ethyl formate, ethyl acetate, propyl acetate and tetrahydrofuran in different proportions; keeping the solid-liquid ratio of the total mass of the pioglitazone hydrochloride and the p-aminobenzoic acid to the organic solvent within the range of 1mg/ml to 500 mg/ml.
9. A solid substance mixed with a pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound, characterized by containing the pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound according to any one of claims 1 to 4 in an amount of 1 to 99.9%, preferably 10 to 99.9%, more preferably 50 to 99.9%, most preferably 85 to 99.9%.
10. A pharmaceutical composition comprising an effective amount of a pioglitazone hydrochloride and p-aminobenzoic acid cocrystal according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.
11. A pharmaceutical composition comprising an effective amount of pioglitazone hydrochloride in combination with a p-aminobenzoic acid cocrystal as claimed in claim 9 in a solid form and a pharmaceutically acceptable carrier.
12. Pharmaceutical composition according to claim 10 or 11, characterized in that the dose of pioglitazone hydrochloride administered daily is in the range of 1 to 200 mg.
13. The pharmaceutical composition according to claim 10 or 11, wherein the pharmaceutical composition is in the form of a tablet, capsule, pill, injection, granule, powder, pellet, dripping pill, suppository, film, patch, aerosol, spray, sustained release formulation or controlled release formulation.
14. Use of pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound as defined in any one of claims 1 to 4, or mixed solid matter of pioglitazone hydrochloride and p-aminobenzoic acid eutectic compound as defined in claim 9, or pharmaceutical composition as defined in claim 10 or 11 for preparing a medicament for lowering blood sugar, lowering blood lipid, and reducing or preventing diabetic nephropathy and insulin cell degeneration.
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| KR20110011409A (en) * | 2009-07-28 | 2011-02-08 | 대봉엘에스 주식회사 | Polymorphic form of pioglitazone potassium salt, process for preparing the same, and pharmaceutical composition containing the same |
| CN104055774A (en) * | 2013-03-22 | 2014-09-24 | 天津药物研究院 | Stable amorphous pioglitazone hydrochloride compound |
| CN110357871A (en) * | 2019-07-03 | 2019-10-22 | 天津大学 | Melbine-Pioglitazone salt and its preparation method and application |
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| KR20110011409A (en) * | 2009-07-28 | 2011-02-08 | 대봉엘에스 주식회사 | Polymorphic form of pioglitazone potassium salt, process for preparing the same, and pharmaceutical composition containing the same |
| CN104055774A (en) * | 2013-03-22 | 2014-09-24 | 天津药物研究院 | Stable amorphous pioglitazone hydrochloride compound |
| CN110357871A (en) * | 2019-07-03 | 2019-10-22 | 天津大学 | Melbine-Pioglitazone salt and its preparation method and application |
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