CN113943283B - Pioglitazone hydrochloride para aminobenzoic acid eutectic crystal and preparation, composition and application thereof - Google Patents
Pioglitazone hydrochloride para aminobenzoic acid eutectic crystal and preparation, composition and application thereof Download PDFInfo
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- CN113943283B CN113943283B CN202010678401.8A CN202010678401A CN113943283B CN 113943283 B CN113943283 B CN 113943283B CN 202010678401 A CN202010678401 A CN 202010678401A CN 113943283 B CN113943283 B CN 113943283B
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- aminobenzoic acid
- pioglitazone hydrochloride
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- GHUUBYQTCDQWRA-UHFFFAOYSA-N Pioglitazone hydrochloride Chemical compound Cl.N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 GHUUBYQTCDQWRA-UHFFFAOYSA-N 0.000 title claims abstract description 183
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
- C07C227/42—Crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C229/60—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in meta- or para- positions
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Health & Medical Sciences (AREA)
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- Hematology (AREA)
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Abstract
The invention belongs to the technical field of medicines, and discloses a pioglitazone hydrochloride and para aminobenzoic acid eutectic, a preparation method, a pharmaceutical composition and application thereof. Specifically, the invention discloses a solid substance state of a co-crystal of pioglitazone hydrochloride and para aminobenzoic acid; a preparation method of pioglitazone hydrochloride and para aminobenzoic acid eutectic solid substance samples; the application of pioglitazone hydrochloride and para aminobenzoic acid eutectic as active ingredients in preparing medicaments for reducing blood sugar and blood fat and reducing or preventing the degeneration of diabetic nephropathy and insulin cells.
Description
Technical Field
The invention discloses a pioglitazone hydrochloride and para aminobenzoic acid eutectic, a preparation method, a composition and application thereof. In particular, the invention discloses a eutectic formed by pioglitazone hydrochloride and p-aminobenzoic acid; a preparation method of a pioglitazone hydrochloride and para aminobenzoic acid eutectic; the application of pioglitazone hydrochloride and para aminobenzoic acid eutectic as the active components in preparing the medicine for reducing blood sugar, reducing blood fat, reducing or preventing diabetic nephropathy and insulin cell degeneration belongs to the field of medicine technology.
Background
Pharmaceutical co-crystals are crystals formed by intermolecular non-covalent interactions in a certain proportion of active drug molecules to co-crystal formations. The medicine can greatly enrich the crystal forms of the medicine through forming eutectic crystals, and can improve the physicochemical properties and clinical effects of the medicine. For the simulated medicine, the research of the co-crystal can break the crystal form patent of the original medicine, and improve the market competitiveness of the simulated medicine.
The invention adopts pioglitazone hydrochloride as active substance, and the chemical name of the pioglitazone hydrochloride is (+ -) 5- [4- [2- (5-ethyl-2-pyridine) ethoxy]Benzyl group]-2, 4-thiazolidinedione hydrochloride having formula C 19 H 20 N 2 O 3 S.HCl, white or off-white powder. The structural formula is shown as a. Para aminobenzoic acid is organic acid with molecular formula of C 7 H 7 NO 2 The structural formula is shown as b.
Pioglitazone hydrochloride is a thiazolidinedione antidiabetic drug, belongs to an insulin sensitizer, has an action mechanism related to the existence of insulin, can reduce insulin resistance of peripheral tissues and livers, increases the treatment of glucose dependent on insulin, and reduces the output of hepatic glucose. Pioglitazone hydrochloride has high selectivity to activate peroxisome growth factor activation receptor-gamma [ PPAR-gamma ], and the activation of PPAR-gamma can regulate the transcription of a plurality of insulin related genes controlling glucose and lipid metabolism. Experiments show that pioglitazone hydrochloride can reduce hyperglycemia, hyperinsulinemia and hypertriglyceridemia of insulin resistance. The metabolic changes caused by pioglitazone hydrochloride lead to an increase in the insulin dependent tissue response. Pioglitazone hydrochloride cannot lower blood glucose in the absence of endogenous insulin because it increases the action of circulating insulin (i.e. reduces insulin resistance). Pioglitazone hydrochloride is almost insoluble in water, belongs to insoluble medicines, and has the defects of low dissolution rate, low dissolution rate and low bioavailability because the pioglitazone hydrochloride is mainly used as an oral tablet at present.
It is known from domestic and foreign patent and literature search that other eutectic patent or literature report about pioglitazone hydrochloride para aminobenzoic acid is not found.
The invention discovers a solid state of a co-crystal of pioglitazone hydrochloride and para aminobenzoic acid and a preparation method which are different from the contents of the patent or literature research reports.
The invention aims to search and discover the existence type, state characteristics and new pharmacological activity of pioglitazone hydrochloride eutectic solid substances on the active ingredient raw material level of the medicine by virtue of a eutectic screening technology and a biological activity evaluation technology from the study of the existence state of pioglitazone hydrochloride and para-aminobenzoic acid eutectic solid substances. The eutectic substance is combined with pharmacodynamics research, so that basic scientific data is provided for searching, finding and developing pharmaceutical eutectic solid substances of pioglitazone hydrochloride with new pharmacological activity and clinical curative effect; meanwhile, scientific basis is provided for applying national or international intellectual property patent protection on the basis of pioglitazone hydrochloride eutectic solid drug raw material substances.
Disclosure of Invention
The invention aims to solve the technical problems:
one of the technical problems to be solved by the invention is as follows: provides the existence state and the characterization mode of the pioglitazone hydrochloride and para aminobenzoic acid eutectic.
The second technical problem to be solved by the invention is: provides a preparation method of pioglitazone hydrochloride and para aminobenzoic acid eutectic.
The third technical problem to be solved by the invention is: provides a mixed solid substance containing pure pioglitazone hydrochloride and para-aminobenzoic acid eutectic substance or any non-zero proportion pioglitazone hydrochloride and para-aminobenzoic acid eutectic substance and a pharmaceutical composition thereof.
The invention aims to solve the fourth technical problem: provided is a pharmaceutical composition using pioglitazone hydrochloride and para-aminobenzoic acid co-crystal as pharmaceutical active ingredients, the pharmaceutical specification of which is in the range of 1-200 mg. The pharmaceutical composition comprises tablets, capsules, pills, preparations for injection, granules, powder, micropills, dripping pills, suppositories, films, patches, aerosols, sprays, sustained-release preparations or controlled-release preparations.
The invention solves the technical problems: provides a substance of a co-crystal of pioglitazone hydrochloride and para aminobenzoic acid, and has superior characteristic in solubility compared with pioglitazone hydrochloride.
The invention solves the technical problems: provides the active pharmaceutical effects of the pioglitazone hydrochloride and the para aminobenzoic acid in the course of treating diseases, and simultaneously, the active pharmaceutical effects of the pioglitazone hydrochloride and the para aminobenzoic acid are exerted, and the bioavailability in the body is improved due to the eutectic substances, so that the effective therapeutic effects of the medicines are exerted.
The invention solves the technical problems: the application of pioglitazone hydrochloride and para aminobenzoic acid eutectic as the effective components in preparing the medicine for reducing blood sugar, reducing blood fat, and reducing or preventing diabetic nephropathy and insulin cell degeneration.
In order to solve the technical problems, the invention adopts the following technical scheme:
1. pioglitazone hydrochloride and para aminobenzoic acid eutectic sample morphological characteristics:
1.1 the co-crystal of pioglitazone hydrochloride and para-aminobenzoic acid related to the invention is a co-crystal formed by pioglitazone hydrochloride and para-aminobenzoic acid in a molar ratio of 1:1.
1.2 pioglitazone hydrochloride and para-aminobenzoic acid co-crystals according to the present invention, when powder X-ray diffraction is usedThe analysis adopts CuK α Diffraction peak position under radiation experimental conditions: 2-Theta value (°) or d valueDiffraction peak relative intensity: the peak Height value (Height%) or the peak Area value (Area%) has the following characteristics (table 1, fig. 1); powder X-ray diffraction patterns and data of physical mixtures of pioglitazone hydrochloride and para aminobenzoic acid eutectic are shown in table 2 and figure 2. The powder X-ray diffraction patterns of the physical mixtures of the eutectics of the pioglitazone hydrochloride and the para-aminobenzoic acid and the physical mixtures of the pioglitazone hydrochloride and the para-aminobenzoic acid have obvious differences in the aspects of diffraction peak number, diffraction peak position, diffraction peak intensity, diffraction peak topological graph and the like, which indicates that the physical mixtures of the eutectics of the pioglitazone hydrochloride and the para-aminobenzoic acid and the physical mixtures of the pioglitazone hydrochloride and the para-aminobenzoic acid are neither identical nor equivalent. TABLE 1 powder X-ray diffraction peak of pioglitazone hydrochloride and para-aminobenzoic acid co-crystals
TABLE 2 powder X-ray diffraction peak of physical mixing of pioglitazone hydrochloride and para-aminobenzoic acid
1.4 pioglitazone hydrochloride and para-aminobenzoic acid co-crystals according to the present invention are analyzed by attenuated total reflection Fourier infrared spectroscopy 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 -1 There is an infrared spectrum characteristic peak at the position,wherein the allowable deviation of the characteristic peak of the infrared spectrum is +/-2 cm -1 (FIG. 3).
1.5 pioglitazone hydrochloride and para-aminobenzoic acid co-crystals according to the present invention, when analyzed using differential scanning calorimetry, present 1 endothermic peak at 123 ℃ ± 3 ℃ in the DSC profile at a heating rate of 10 ℃ per minute (fig. 4). The DSC spectra of pioglitazone hydrochloride, para-aminobenzoic acid and the eutectic of pioglitazone hydrochloride and para-aminobenzoic acid are shown in figure 5. The DSC spectra of the pioglitazone hydrochloride and the para aminobenzoic acid eutectic substance and the pioglitazone hydrochloride and the para aminobenzoic acid have obvious differences in the aspects of the number, the position and the like of the absorption/release peaks, which indicates that the pioglitazone hydrochloride and the para aminobenzoic acid eutectic substance form new substances.
1.6 the co-crystal of pioglitazone hydrochloride and para aminobenzoic acid related by the invention is analyzed by using a thermogravimetric technology, when the temperature rising rate is 10 ℃ per minute, only the decomposition weightlessness peak of the co-crystal of pioglitazone hydrochloride and para aminobenzoic acid exists in a TG graph, which indicates that the co-crystal of pioglitazone hydrochloride and para aminobenzoic acid does not contain crystallization solvent or crystallization water. The TG profile of the co-crystal of pioglitazone hydrochloride and p-aminobenzoic acid is shown in fig. 6.
2. The preparation method of the pioglitazone hydrochloride and para aminobenzoic acid eutectic and mixed solid material is characterized in that:
2.1 the preparation method of the pioglitazone hydrochloride and para aminobenzoic acid eutectic substance related by the invention comprises the steps of feeding pioglitazone hydrochloride and para aminobenzoic acid according to a molar ratio of 1:1, and preparing the pioglitazone hydrochloride and para aminobenzoic acid eutectic substance by adopting a mechanochemical method with controlled pressure and temperature. The mechanochemical method can be selected from a liquid adding grinding method or a liquid adding ball milling method, wherein the types of liquid adding organic solvents are any one or more mixed solvents prepared by combining 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 per gram of sample; grinding time is 0.1-10 hours, drying temperature is 40-60 ℃, and drying time is 4-12 hours; the comprehensive filling rate of the bowl body by 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 by the liquid adding ball milling method is 10 kw-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 rotating speed is 20 r/min-400 r/min, preferably 300 r/min-400 r/min.
2.2 the preparation method of the pioglitazone hydrochloride and para aminobenzoic acid eutectic substance related by the invention comprises the steps of feeding pioglitazone hydrochloride and para aminobenzoic acid into a clean container according to a molar ratio of 1:1, adding an organic solvent to prepare a suspension, stirring for 1-4 days at room temperature, and obtaining the pioglitazone hydrochloride and para aminobenzoic acid eutectic substance through solvent evaporation drying, filtration and natural drying or filtration and vacuum drying of the obtained suspension. The organic solvent is preferably selected from methanol, ethanol, n-propanol, isopropanol, n-butanol and other alcoholic solvents, and any one or more of ethyl formate, ethyl acetate, propyl acetate and tetrahydrofuran is/are mixed according to different proportions to prepare a mixed solvent; the solid-to-liquid ratio of the total mass of the para-aminobenzoic acid and the pioglitazone hydrochloride to the organic solvent is kept within the range of 1mg/ml to 500 mg/ml.
2.3 the mixed solid substance of the pioglitazone hydrochloride and the para aminobenzoic acid eutectic substance is prepared by mixing pioglitazone hydrochloride and the para aminobenzoic acid eutectic substance component prepared by the method with other chemical substances according to any non-zero proportion and a conventional method.
3. Pharmaceutical formulation compositions containing pioglitazone hydrochloride and para aminobenzoic acid eutectic components, dosing characteristics and pharmaceutical use:
3.1 pharmaceutical compositions according to the invention comprise a co-crystal of pioglitazone hydrochloride and para-aminobenzoic acid and a pharmaceutically acceptable carrier.
3.2 the pharmaceutical composition of the invention comprises a mixed solid substance of pioglitazone hydrochloride and a para aminobenzoic acid eutectic substance and a pharmaceutically acceptable carrier.
3.3 the pharmaceutical composition related by the invention has the daily dosage of pioglitazone hydrochloride in the range of 1-200 mg.
The pharmaceutical composition is characterized by being various tablets, capsules, pills, preparations for injection, granules, powder, micropills, dripping pills, suppositories, films, patches, aerosols, sprays, sustained-release preparations or controlled-release preparations.
3.5 the invention relates to the application of pioglitazone hydrochloride and para aminobenzoic acid eutectic, pioglitazone hydrochloride and para aminobenzoic acid eutectic mixed solid substance or pharmaceutical composition in the preparation of medicaments for reducing blood sugar and blood fat and reducing or preventing diabetic nephropathy and degeneration of insulin cells.
The invention relates to a pharmaceutical composition taking pioglitazone hydrochloride and para aminobenzoic acid eutectic as active ingredients. The pharmaceutical compositions may be prepared according to methods well known in the art. Any dosage form suitable for human or animal use can be made by combining pioglitazone hydrochloride and para-aminobenzoic acid co-crystal components of the present invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the pioglitazone hydrochloride and para aminobenzoic acid eutectic in the pharmaceutical composition is within the range of 10-90% by weight.
The pioglitazone hydrochloride and the para-aminobenzoic acid eutectic can be administered in 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, lungs, respiratory tract, skin, vagina, rectum and the like.
The administration form of the present invention is preferably a solid dosage form. The solid dosage forms can be tablets (including common tablets, enteric coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules and enteric coated capsules), granules, powder, micropills, dripping pills, suppositories, films, patches, aerosol (powder) and spray.
The pioglitazone hydrochloride and para aminobenzoic acid eutectic can be prepared into common preparations, slow-release preparations, controlled-release preparations, targeted preparations and various particle administration systems.
For tableting the co-crystals of pioglitazone hydrochloride and p-aminobenzoic acid of the present invention, various excipients known in the art may 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 wetting agent can be water, ethanol, isopropanol, etc.; the binder may be starch slurry, dextrin, syrup, mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrating agent can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, 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 bilayer and multilayer tablets.
In order to prepare the administration unit into a capsule, the active ingredient pioglitazone hydrochloride and the para aminobenzoic acid eutectic substance of the invention can be mixed with a diluent and a glidant, and the mixture can be directly placed into a hard capsule or a soft capsule. The active ingredients of the invention, namely the pioglitazone hydrochloride and para aminobenzoic acid eutectic substance, can be prepared into particles or pellets by a diluent, an adhesive and a disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants and glidants used for preparing the pioglitazone hydrochloride and para aminobenzoic acid eutectic tablet can also be used for preparing the pioglitazone hydrochloride and para aminobenzoic acid eutectic capsule.
In addition, colorants, preservatives, fragrances, flavoring agents, or other additives may also be added to the pharmaceutical formulation, if desired.
For the purpose of administration, the medicament of the invention can be administered by any known administration method to enhance the therapeutic effect.
The dosage of the pharmaceutical composition of pioglitazone hydrochloride and para-aminobenzoic acid cocrystal of the present invention may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and dosage form, etc. The above-mentioned dosages may be administered in one dosage unit or in several dosage units, depending on the clinical experience of the physician and the dosage regimen involved in the application of other therapeutic means.
The pioglitazone hydrochloride and para-aminobenzoic acid eutectic or composition can be taken alone or combined with other therapeutic drugs or symptomatic drugs. When pioglitazone hydrochloride and para aminobenzoic acid co-crystal have synergistic effect with other therapeutic drugs, the dosage of pioglitazone hydrochloride and para aminobenzoic acid co-crystal should be adjusted according to actual conditions.
4. The beneficial technical effects of the invention are as follows: the safety and bioactivity advantage characteristics of the co-crystal of pioglitazone hydrochloride and para aminobenzoic acid.
4.1 the co-crystal of pioglitazone hydrochloride and para aminobenzoic acid of the invention does not contain any crystallization solvent, and has good safety and drug advantages.
4.2 the pioglitazone hydrochloride and para aminobenzoic acid eutectic has the advantage of solubility, and is specifically characterized in that: the solubility in 0.2% aqueous SDS was significantly better than pioglitazone hydrochloride (FIG. 7).
4.4 the pioglitazone hydrochloride and para aminobenzoic acid co-crystal solid substance of the invention has significant biological absorption advantage compared with pioglitazone hydrochloride (figure 8).
Drawings
FIG. 1 powder X-ray diffraction pattern of pioglitazone hydrochloride and para-aminobenzoic acid co-crystal
FIG. 2 powder X-ray diffraction pattern of physical mixture of pioglitazone hydrochloride and para-aminobenzoic acid
FIG. 3 is a chart showing the infrared absorption spectrum of pioglitazone hydrochloride and para-aminobenzoic acid co-crystal
FIG. 4 differential scanning calorimetric diagram of pioglitazone hydrochloride and para-aminobenzoic acid co-crystal
FIG. 5 differential scanning calorimetric diagram of pioglitazone hydrochloride and para-aminobenzoic acid co-crystal and raw materials
FIG. 6 thermogravimetric plot of pioglitazone hydrochloride and para aminobenzoic acid co-crystals
FIG. 7 comparison of the solubility of pioglitazone hydrochloride and co-crystal of para-aminobenzoic acid with pioglitazone hydrochloride in 0.2% SDS aqueous solution
FIG. 8 biological absorption spectra of pioglitazone hydrochloride and para-aminobenzoic acid cocrystal and pioglitazone hydrochloride
Detailed Description
The following examples are given for better illustration of the technical solution of the present invention, but the present invention is not limited thereto.
Example 1
Preparation method 1 of pioglitazone hydrochloride and para aminobenzoic acid eutectic:
according to the table below, pioglitazone hydrochloride and proper amount of p-aminobenzoic acid (molar ratio 1:1) are taken and put into a mortar, proper amount of organic solvent is added, and the mixture is manually ground for proper time and dried at a certain temperature. Powder X-ray diffraction analysis is carried out on the sample, and the diffraction pattern of the sample is consistent with that of figure 1, which shows that the obtained sample is a pioglitazone hydrochloride and para-aminobenzoic acid eutectic.
Table 3 experimental parameter examples of pioglitazone hydrochloride and para aminobenzoic acid co-crystal preparation method 1
Preparation method 2 of pioglitazone hydrochloride and para aminobenzoic acid eutectic:
according to the table below, pioglitazone hydrochloride and proper amount of para aminobenzoic acid (molar ratio 1:1) are taken and put into a ball milling tank, proper amount of organic solvent is added, proper ball material ratio is selected, proper rotation speed is set, grinding is carried out for proper time, and drying is carried out at a certain temperature. Powder X-ray diffraction analysis is carried out on the sample, and the diffraction pattern of the sample is consistent with that of figure 1, which shows that the obtained sample is a pioglitazone hydrochloride and para-aminobenzoic acid eutectic.
Table 4 experimental parameter examples of pioglitazone hydrochloride and para aminobenzoic acid co-crystal preparation method 2
Preparation method 3 of pioglitazone hydrochloride and para aminobenzoic acid eutectic:
according to the table below, pioglitazone hydrochloride and proper amount of para-aminobenzoic acid are taken and put into a clean container, proper amount of organic solvent is added, stirring is carried out for proper time under room temperature condition, the obtained suspension is filtered, and the solid matter is dried under certain temperature. Powder X-ray diffraction analysis is carried out on the sample, and the diffraction pattern of the sample is consistent with that of figure 1, which shows that the obtained sample is a pioglitazone hydrochloride and para-aminobenzoic acid eutectic.
Table 5 experimental parameter examples of pioglitazone hydrochloride and para aminobenzoic acid co-crystal preparation method 3
Example 2
Pioglitazone hydrochloride and para aminobenzoic acid eutectic solubility characteristics:
pioglitazone hydrochloride belongs to a medicine with poor water solubility, an experiment is carried out by using 0.2% SDS aqueous solution, and a solvent system has good differentiation degree on the dissolution rate of pioglitazone hydrochloride, para aminobenzoic acid eutectic substance and pioglitazone hydrochloride two substances (f 2 = 30.56) (fig. 7). The dissolution rate was measured by the method of measuring the solubility (general oral solid preparation dissolution test technical guidelines (first draft), 2012,10 pharmaceutical review center). Calculating the dissolved concentration of the sample by using the chromatographic peak area data of the sample by adopting a high performance liquid chromatography, and respectively drawing a solubility curve by taking time as an abscissa and the solvent concentration as an ordinate, wherein the data are shown in the following table:
TABLE 6 dissolution profile data for pioglitazone hydrochloride and co-crystals of para-aminobenzoic acid and pioglitazone hydrochloride in 0.2% SDS aqueous solution
The experimental data show that the dissolution behavior of the pioglitazone hydrochloride and the para aminobenzoic acid eutectic in a 0.2% SDS aqueous solution system is obviously superior to that of pioglitazone hydrochloride, the pioglitazone hydrochloride and the para aminobenzoic acid eutectic are particularly embodied to have a faster dissolution rate, the pioglitazone hydrochloride and the para aminobenzoic acid eutectic are easy to quickly absorb to reach an effective blood concentration, the disease treatment effect of the medicine is realized, meanwhile, the pioglitazone hydrochloride and the para aminobenzoic acid eutectic have greater solubility, and compared with the pioglitazone hydrochloride, the solubility is improved by more than 2 times, and the higher biological absorption in the disease treatment process can be ensured.
Example 3
Pioglitazone hydrochloride and para aminobenzoic acid eutectic compound have absorption characteristics and blood concentration characteristics in rats:
SD rats were randomly grouped, 5 rats per group were given free water, and after 12h of fasting, the rats were weighed and weighed according to 20mg.kg -1 The pioglitazone hydrochloride dosage calculation of (2) is carried out by loading pioglitazone hydrochloride and para aminobenzoic acid eutectic sample into solid dosage device, and directly placing medicinal powder into rat stomach through oral cavity. Blood is taken from inner canthus and placed in heparinized tube 15min,30min,1h, 1.5h, 2h,2.5h,3h,4h,6h,8h,10h,12h,24h and 36h after administration, and centrifuged at 6500rpm for 10min at 4deg.C, and frozen in refrigerator at-40deg.C for testing. Precisely sucking 40 mu L of heparin anticoagulated blood plasma, placing in a 1.5mL centrifuge tube, adding 10 mu L of internal standard carbamazepine working solution, adding 750 mu L of extractant (methanol), shaking for 3min, centrifuging (13400 rpm,10 min), taking 200 mu L of upper layer solution in the inner lining tube, and injecting 5 mu L. Quantitative analysis was performed as the ratio of drug to internal standard peak area.
Detection conditions: chromatographic column: agilent SB-C 18 (2.1X105 mm,2.7 μm, USA); methanol-0.05 mol.L －1 Ammonium acetate in water (formic acid ph=5.0) (60:40, v/v); the flow rate is 0.3mL/min; column temperature is 35 ℃; sample injection amount: 5. Mu.L; run time: 8min; mass spectrometrySignal: ESI source (positive ion detection mode), ion for quantitative analysis m/z=237 (carbamazepine), m/z=357 (pioglitazone), fragmentation voltage of 140V (pioglitazone), 105V (carbamazepine), gain factor of 1, dry gas flow of 110.0L/min, spray chamber voltage of 35psig, dryer temperature of 350 ℃, capillary voltage of 3000V (positive), 3000V (negative), respectively.
Table 7 shows the blood concentration at various time points in the blood of rats after oral administration of pioglitazone hydrochloride and a co-crystal of pioglitazone hydrochloride and para-aminobenzoic acid; table 8 shows pharmacokinetic parameters of rats over 0-24h of oral pioglitazone hydrochloride and paraaminobenzoic acid co-crystal samples; fig. 8 shows the bioabsorption pattern of pioglitazone hydrochloride and co-crystal of para aminobenzoic acid and pioglitazone hydrochloride.
Table 7 blood concentration at each time point (n=5,)
table 8 SD pharmacokinetic parameters of pioglitazone hydrochloride and co-crystal of pioglitazone hydrochloride and para-aminobenzoic acid taken orally in rats
From the above map data, compared with the raw material drug of pioglitazone hydrochloride, the co-crystal of pioglitazone hydrochloride and para aminobenzoic acid has obvious biological absorption advantage, and is specifically characterized in that the maximum blood concentration Cmax of the co-crystal of pioglitazone hydrochloride and para aminobenzoic acid is improved by about 1.8 times compared with that of pioglitazone hydrochloride, the absorption advantage of the absorption degree is improved, and unexpected advantageous technical effects are obtained.
Example 4
Preparation method of combination pharmaceutical formulation 1 (tablet):
a preparation method of a combined medicine tablet is characterized in that pioglitazone hydrochloride and para aminobenzoic acid eutectic substance are used, and a plurality of excipients are used as auxiliary material components for preparing the combined medicine tablet, and tablet samples containing 1-100 mg of pioglitazone hydrochloride and para aminobenzoic acid eutectic substance are prepared according to a certain proportion, wherein the tablet formula proportion is shown in table 9:
table 9 preparation formulation of pioglitazone hydrochloride and para aminobenzoic acid co-crystal combination pharmaceutical tablet
The method for preparing the tablet preparation by taking pioglitazone hydrochloride and para aminobenzoic acid eutectic as bulk drugs comprises the following steps: mixing several excipients with the raw materials, and tabletting directly; or mixing the auxiliary materials, granulating by a dry method, uniformly mixing with the raw materials, and tabletting.
Preparation method of combination pharmaceutical formulation 2 (tablet):
a preparation method of a combined medicine tablet is characterized in that pioglitazone hydrochloride and para aminobenzoic acid eutectic substance are used, a plurality of excipients are used as auxiliary material components for preparing the combined medicine tablet, a tablet sample containing 1-100 mg of eutectic is prepared according to a certain proportion, and the formula proportion of the tablet is shown in table 9:
table 9 preparation formulation of pioglitazone hydrochloride and para aminobenzoic acid co-crystal combination pharmaceutical tablet
The method for preparing the tablet preparation by taking pioglitazone hydrochloride and para aminobenzoic acid eutectic as bulk drugs comprises the following steps: mixing several excipients and raw materials, adding 1% sodium hydroxymethyl cellulose solution, making into soft material, sieving, granulating, oven drying, sieving, granulating, adding magnesium stearate and pulvis Talci, mixing, and tabletting.
Preparation method 3 of the combined pharmaceutical preparation (capsule):
a preparation method of a combined medicine capsule is characterized in that pioglitazone hydrochloride and para aminobenzoic acid eutectic 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 dosage of 1-100 mg of each tablet is prepared according to a certain proportion, and the formula proportion of the capsule is shown in a table 10:
table 10 raw material medicine and auxiliary material formulation of pioglitazone hydrochloride and para aminobenzoic acid eutectic compound medicine capsule preparation
The method for preparing the capsule by taking pioglitazone hydrochloride and para aminobenzoic acid eutectic as raw material medicines comprises the following steps: mixing several excipients with the raw materials, adding 1% sodium hydroxymethyl cellulose solution, making into wet granule, oven drying, sieving, grading, adding magnesium stearate, mixing, and making into capsule; or directly mixing pioglitazone hydrochloride and para aminobenzoic acid eutectic crude drug with several excipient auxiliary materials uniformly without granulating step, sieving, and directly encapsulating.
Example 4
Dose 1 (tablet) of pioglitazone hydrochloride and para-aminobenzoic acid co-crystal combination drug:
the pharmaceutical composition is characterized in that the pioglitazone hydrochloride and the para-aminobenzoic acid eutectic are used as active ingredients of medicines, the daily administration dosage is 50mg, and the pharmaceutical composition can be prepared into common tablets of 25mg for 2 times per day or 1 tablet of 50mg for 1 time per day.
Drug administration dose 2 (capsule) of pioglitazone hydrochloride and para-aminobenzoic acid eutectic compound drug:
the pharmaceutical composition is prepared and developed by using the co-crystal of pioglitazone hydrochloride and para aminobenzoic acid as the active ingredients, and is characterized in that the co-crystal of pioglitazone hydrochloride and para aminobenzoic acid is used as the active ingredients of the medicine, and the daily administration dosage is 100mg, and the pharmaceutical composition can be prepared into 25mg capsules for 2 times per time per day or 50mg capsules for 2 times per time per 1 time per day.
Problems to be described: the pharmaceutical composition of pioglitazone hydrochloride and para aminobenzoic acid cocrystal has a plurality of factors on the administration dosage of the active ingredients, such as: the age and body surface area of patients are different, and the dosage of each administration is different due to the different administration routes, administration times and treatment purposes; the presence of absorption and blood concentration differences between the samples also result in the present invention in the range of 0.02-5mg/kg body weight, preferably 0.1-2mg/kg body weight, per suitable dose of pioglitazone hydrochloride and paraaminobenzoic acid co-crystal composition. When in use, different total dosage schemes of active ingredients of the co-crystal of pioglitazone hydrochloride and the para aminobenzoic acid are formulated according to the actual requirements of different treatment conditions, and the administration can be completed in a mode of multiple times or one time.
Claims (13)
1. A co-crystal of pioglitazone hydrochloride and para-aminobenzoic acid, which is characterized in that the pioglitazone hydrochloride and the para-aminobenzoic acid form a co-crystal in a molar ratio of 1:1.
2. The co-crystal of pioglitazone hydrochloride and p-aminobenzoic acid as claimed in claim 1, wherein CuK is employed when powder X-ray diffraction analysis is used α Diffraction peak position under radiation experimental conditions: 2-Theta value (°), d valueDiffraction peak relative intensity: peak Height value (Height%), peak Area value (Area%) and the likeThe method has the following characteristics:
3. the co-crystal of pioglitazone hydrochloride and p-aminobenzoic acid as claimed in claim 1, wherein the analysis is carried out by attenuated total reflection fourier infrared spectroscopy 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 -1 There is an infrared spectrum characteristic peak, wherein the allowable deviation of the infrared spectrum characteristic peak is + -2 cm -1 。
4. The co-crystal of pioglitazone hydrochloride and p-aminobenzoic acid as claimed in claim 1, wherein when the temperature rise rate is 10 ℃ per minute, there are 1 endothermic peaks in the DSC profile at 123 ℃ ± 3 ℃ when analyzed using differential scanning calorimetry.
5. The method for preparing the co-crystal of pioglitazone hydrochloride and p-aminobenzoic acid according to any one of claims 1-4, which is characterized in that pioglitazone hydrochloride and p-aminobenzoic acid are fed according to a molar ratio of 1:1, the co-crystal of pioglitazone hydrochloride and p-aminobenzoic acid is prepared by adopting a mechanochemical method with controlled pressure and temperature, the mechanochemical method is selected from a liquid adding grinding method or a liquid adding ball milling method, and the types of liquid adding organic solvents are any one or a plurality of mixed solvents prepared by combining 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 per gram of sample; grinding time is 0.1-10 hours, drying temperature is 40-60 ℃, and drying time is 4-12 hours; the comprehensive filling rate of the bowl body by 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 by the liquid adding ball milling method is 10 kw-800 kw, and the comprehensive filling rate is 20-60%; the ball-material ratio is 1:1-10:1, and the ball milling rotating speed is 20 r/min-400 r/min.
6. The preparation method of the co-crystal of pioglitazone hydrochloride and p-aminobenzoic acid according to any one of claims 1-4, wherein pioglitazone hydrochloride and p-aminobenzoic acid are fed 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 for 1-4 days at room temperature, the obtained suspension is evaporated and dried by solvent, filtered and naturally dried or filtered and dried in vacuum to obtain the co-crystal of pioglitazone hydrochloride and p-aminobenzoic acid, and the organic solvent is selected from one or more solvents selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, ethyl formate, ethyl acetate, propyl acetate or tetrahydrofuran, and the mixed solvents are prepared by combining the solvents according to different proportions; the solid-liquid ratio of the total mass of pioglitazone hydrochloride and p-aminobenzoic acid to the organic solvent is kept within the range of 1 mg/ml-500 mg/ml.
7. A mixed solid substance comprising a co-crystal of pioglitazone hydrochloride and p-aminobenzoic acid, characterized in that the amount of the co-crystal of pioglitazone hydrochloride and p-aminobenzoic acid as defined in any one of claims 1 to 4 is 1 to 99.9%.
8. A mixed solid substance comprising a co-crystal of pioglitazone hydrochloride and p-aminobenzoic acid, characterized in that the amount of the co-crystal of pioglitazone hydrochloride and p-aminobenzoic acid as defined in any one of claims 1 to 4 is 50 to 99.9%.
9. A mixed solid substance containing a co-crystal of pioglitazone hydrochloride and p-aminobenzoic acid, characterized in that the amount of the co-crystal of pioglitazone hydrochloride and p-aminobenzoic acid as defined in any one of claims 1 to 4 is 85 to 99.9%.
10. A pharmaceutical composition comprising an effective amount of a co-crystal of pioglitazone hydrochloride and p-aminobenzoic acid as claimed in any one of claims 1 to 4 and a pharmaceutically acceptable carrier.
11. A pharmaceutical composition comprising an effective amount of a mixed solid material comprising a co-crystal of pioglitazone hydrochloride and p-aminobenzoic acid as claimed in any one of claims 7 to 9 and a pharmaceutically acceptable carrier.
12. Pharmaceutical composition according to claim 10 or 11, characterized in that the dosage form of the pharmaceutical composition is a tablet, capsule, pill, injectable preparation, granule, powder, pellet, drop pill, suppository, film, patch, aerosol, spray, sustained release preparation or controlled release preparation.
13. Use of a co-crystal of pioglitazone hydrochloride and p-aminobenzoic acid as defined in any one of claims 1 to 4 or a mixed solid substance comprising a co-crystal of pioglitazone hydrochloride and p-aminobenzoic acid as defined in any one of claims 7 to 9 or a pharmaceutical composition as defined in claim 10 or 11 for the manufacture of a medicament for reducing blood glucose, reducing blood lipid, 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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| Publication number | Priority date | Publication date | Assignee | Title |
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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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| 药物共晶的筛选技术及热力学研究进展;马坤;药学进展;第第34卷卷(第第12期期);第529-534页 * |
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