CN104415042A - Co-amorphous system and preparation method thereof - Google Patents
Co-amorphous system and preparation method thereof Download PDFInfo
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- CN104415042A CN104415042A CN201310393189.0A CN201310393189A CN104415042A CN 104415042 A CN104415042 A CN 104415042A CN 201310393189 A CN201310393189 A CN 201310393189A CN 104415042 A CN104415042 A CN 104415042A
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- glimepiride
- pioglitazone hydrochloride
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- amorphous
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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Abstract
The invention discloses a co-amorphous system and a preparation method thereof. The co-amorphous system comprises pioglitazone hydrochloride and glimepiride. The analysis by the powder X-ray diffraction technology confirms that the pioglitazone hydrochloride and the glimepiride exist in an amorphous form. The analysis by the differential scanning calorimetry finds that the pioglitazone hydrochloride and the glimepiride have strong intermolecular interaction. By using the co-amorphous matter, a new idea is provided for the combined medication. The co-amorphous matter is easy to smash and is convenient to preserve. The invention further provides a compound medicinal preparation containing the co-amorphous system.
Description
Technical field
The invention belongs to medical art, the common unformed system being specifically related to a kind of pioglitazone hydrochloride and glimepiride with and preparation method thereof and compound medicament composition containing this system.
Background technology
Diabetes (Diabetes) are mainly manifested in lasting hyperglycemia feature.Diabetes be by immunologic function disorder, inherited genetic factors, free radical toxin, infected by microbes and the various paathogenic factor such as toxin, Nervous and Mental Factors thereof act on body cause hypoinsulinism, insulin resistant etc. and cause a series of metabolism disorder syndrome such as sugar, protein, fat, water and eletrolytes.Clinically, the performance such as polydipsia, polyphagia, polyuria can appear in the model case of diabetes, become thin, i.e. " three-many-one-little " symptom, diabetes (blood glucose) are once control badly can cause complication, cause the exhaustion pathological changes at the positions such as kidney, eye, foot, and cannot cure, the life of serious threat patient.At present, global diabetics more than 100,000,000, and presents the trend increased year by year.Diabetes are divided into type i diabetes and type ii diabetes.In diabetics, type ii diabetes patient occupies more than 90%.Type ii diabetes is also Adult Onset's patients with type Ⅰ DM, produces the ability of insulin in patient body and non-fully is still lost, and in some patient bodies, insulin even produces more.But the action effect of insulin is had a greatly reduced quality, therefore the insulin of patient is in the state relatively lacked.Therefore particularly urgent to the treatment of type ii diabetes.
The chemistry of pioglitazone hydrochloride (Pioglitazone Hydrochloride) (±) 5-by name [[4-[2-(5-ethyl-2-pyridine radicals) ethyoxyl] benzyl]-2,4-thiophene alkane dione hydrochlorides.Molecular structure is as follows:
Pioglitazone hydrochloride belongs to thiazolidinedione oral sugar-lowering drug thing, is a kind of euglycemic agent.It does not stimulate the secretion of insulin, but by the onset to the sensitivity of insulin of intensifier target tissue.The resistance around insulin can be reduced in liver, strengthen the utilization of insulin, excite antidiabetic effect.Pioglitazone hydrochloride is the agonist of the Peroxisome proliferator-activated receptor-α (PPAR γ) of high selectivity, can activate PPAR γ, regulates the insulin related gene of many control glucoses and lipid metabolism to transcribe.After receptor, level increases the sensitivity of tissue to insulin, reduces insulin resistant, thus reaches and fall hypoglycemic object.Pioglitazone hydrochloride is the thiazolidinedione class medicine going on the market more late after rosiglitazone, and the hypoglycemic effect of pioglitazone hydrochloride is than troglitazone strong ten times.
The chemistry of glimepiride (Glimepiride) is called 1-[4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrrolin-1-formamido)-ethyl]-benzene sulfonyl] trans-4-methylcyclohexyl of-3-()-urea.Molecular structure is as follows:
Glimepiride is sulfonylurea oral hypoglycaemic medicine, and its hypoglycemic main mechanism is that (relative molecular mass is 6.5 × 10 by the sulfonylureas receptor with pancreas beta cell surface
4protein) combine, the K of this receptor and ATP sensitivity
+(KATP) passage is mutually coupling, impels KATP pathway closure, causes the depolarization of cell membrane, makes voltage dependent channel open, Ga
2+interior stream and impel the release of insulin, and suppress the synthesis of hepatic glucose, thus promote that muscle is to the picked-up of periphery glucose and the effect promoting insulin secretion, plays hypoglycemic activity.Because the effect of glimepiride to cardiovascular KATP passage is weaker than glibornuride, gliclazide and glipizide.Therefore cardiovascular untoward reaction is also little.
At present, there is report that pioglitazone hydrochloride and glimepiride are made compound preparation and carried out drug combination.Compound preparation by increasing the secretory volume of insulin and improving target tissue to the sensitivity of insulin, can have good cooperative effect.Chinese patent (CN1857264A) discloses a kind of with pioglitazone hydrochloride and glimepiride Pharmaceutical composition that is active component and preparation method thereof, for the treatment of type ii diabetes.There is DEVELOPMENT PROSPECT comparatively widely.
But pioglitazone hydrochloride and glimepiride are insoluble drug, in the body of such medicine, bioavailability is all lower.Pioglitazone hydrochloride in vivo maximum plasma concentration is 30%-50%.Overall bioavailability is 20%-25%, and bioavailability is on the low side.And glimepiride is insoluble in many Conventional solvents such as water, methanol, ethanol, in chloroform and dichloromethane, have a small amount of dissolving, bioavailability is in vivo also lower.
Unformed form is the method more effectively increasing drug absorption at present, medicine is made the contact area that unformed form can increase medicine and aqueous medium potentially, improves wettability and dissolubility, improves stripping in vivo and bioavailability.These two kinds of medicines are crystalline drug, and absorbing poor main cause is that drug molecule exists with crystal form, and wettability is in an aqueous medium poor.How adopting new technology to change its crystal structure or existing way to increase the wettability of medicine is the key increasing bioavailability in its body.The ordered arrangement of crystalline pharmaceutical molecule is mainly broken by the principle of the amorphous forms increase wettability of medicine, become the lack of alignment of molecule, the surface energy that this unformed form overcomes when can greatly reduce medicine dissolution, rapid moistening, improves and absorbs.
The present invention refer to new concept, is namely total to unformed system (Co-amorphous).Unformed system is that two kinds of crystalline drug are all become amorphous forms altogether, can make compound preparation further, also not have pertinent literature to report at present.The proposition of unformed system has great significance for compound preparation altogether.Special more important for the body absorption of two or more insoluble drug.Unformed system can solve the absorption of two kinds of medicines in compound preparation body potentially altogether.
Summary of the invention
The object of the present invention is to provide a kind of unformed system altogether.
An also object of the present invention there are provided the preparation method that this is total to unformed system.
Another object of the present invention there are provided a kind of pharmaceutical composition containing this common unformed system.
Described common unformed system is made up of pioglitazone hydrochloride and glimepiride.Two kinds of medicines are all hypoglycemic drug.Two kinds of medicines all exist with amorphous forms.There is stronger intermolecular force to each other.Determine that two kinds of medicines all exist with amorphous forms by powder x-ray diffraction technology.By differential canning calorimetry, we find that two kinds of medicines itself have very strong intermolecular interaction, and this common amorphous article is that drug combination provides new thinking.This common amorphous article, pulverizes easily, and it is convenient to preserve, and easily makes compound medicinal formulation.
The unformed system altogether that the present invention relates to comprises unformed pioglitazone hydrochloride and unformed glimepiride, and the part by weight of pioglitazone hydrochloride and glimepiride is 1:0.01 ~ 50, is preferably 1:0.1 ~ 10.
Described this unformed system altogether mainly exists in powder form.
The particle diameter of described this unformed system is altogether less than 200 μm.The particle microscopic pattern of this unformed system is strip and block.
The preparation method of described this unformed system altogether, pioglitazone hydrochloride and glimepiride are joined in solvent dissolve, be placed in a heated condition on Rotary Evaporators, under reduced pressure, mixed solvent is volatilized rapidly, drying obtains the common unformed system containing pioglitazone hydrochloride and glimepiride, and pioglitazone hydrochloride and glimepiride molecule all exist with amorphous forms.
Described dissolving pioglitazone hydrochloride and the solvent load of glimepiride are 2-100 times of drug alone weight, and described multiple is envelope-bulk to weight ratio, and unit is mL/g.Heating-up temperature when volatilizing solvent is 35-60 DEG C.
Described dissolution solvent can be any one in ethanol, methanol, normal propyl alcohol, n-butyl alcohol, oxolane, chloroform, isopropyl alcohol, dichloromethane, petroleum ether, glycerol, acetonitrile, ether, ethyl acetate, acetone.
The invention also discloses containing this altogether unformed compound, comprise pioglitazone hydrochloride and glimepiride altogether amorphous article, pharmaceutically acceptable adjuvant as filler, binding agent, disintegrating agent and lubricant.Further disclose the compositing formula of this compound.
It is emphasized that the Preparation method and use of this amorphous article altogether, be not only applicable to crystalline drug pioglitazone hydrochloride of the present invention and glimepiride, the administering drug combinations of other slightly solubility crystalline drug can also be applicable to further.Common unformed system prepared by the present invention has for the drug combination solving other insoluble drugs the effect of giving instructions and set examples.
Accompanying drawing explanation
Fig. 1 pioglitazone hydrochloride and glimepiride are total to the environmental scanning electronic microscope photo (amplifying 100 times) of amorphous article;
Fig. 2 pioglitazone hydrochloride and glimepiride are total to the environmental scanning electronic microscope photo (amplifying 250 times) of amorphous article;
The x-ray diffractogram of powder spectrum of Fig. 3 pioglitazone hydrochloride;
The x-ray diffractogram of powder spectrum of Fig. 4 glimepiride;
Fig. 5 pioglitazone hydrochloride and glimepiride are total to the x-ray diffractogram of powder spectrum of amorphous article;
The Differential Scanning Calorimetry of Fig. 6 pioglitazone hydrochloride, glimepiride and both mixture.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described further, and embodiment is only indicative, never means that it limits the scope of the invention by any way.
embodiment 1
Claim pioglitazone hydrochloride 1g, add methanol 5mL and dissolve.Take glimepiride 0.1g, add chloroform 10mL and dissolve.Both dissolution homogeneity are mixed.Put into the Rotary Evaporators of 50mL, heat in 35 DEG C of water-baths, rotary evaporation is carried out in decompression, complete to mixed solvent volatilization, dry that pioglitazone hydrochloride-glimepiride is total to amorphous article.
embodiment 2
Claim pioglitazone hydrochloride 0.2g, add methanol 3mL and dissolve.Take glimepiride 2g, add dichloromethane 30mL and dissolve.Both dissolution homogeneity are mixed.Put into the Rotary Evaporators of 50mL, heat in 45 DEG C of water-baths, rotary evaporation is carried out in decompression, complete to mixed solvent volatilization, dry that pioglitazone hydrochloride-glimepiride is total to amorphous article.
embodiment 3
Claim pioglitazone hydrochloride 2g, add methanol 10mL and dissolve.Take glimepiride 2g, add dichloromethane 20mL and dissolve.Both dissolution homogeneity are mixed.Put into the Rotary Evaporators of 50mL, heat in 60 DEG C of water-baths, rotary evaporation is carried out in decompression, complete to mixed solvent volatilization, dry that pioglitazone hydrochloride-glimepiride is total to amorphous article.
embodiment 4
The preparation of compound medicament composition
Make the tablet formulation that 1000 every sheets contain 15mg pioglitazone hydrochloride and 1mg glimepiride
embodiment 5
Environmental scanning electron microscope test (ESEM)
Pioglitazone hydrochloride of the present invention and glimepiride are total to amorphous article observes particle surface microscopic pattern by environmental scanning electron microscope (XL-30ESEM, Philips, Holland).The operating voltage of environmental scanning electron microscope is 20kV, and the sample that takes a morsel is coated on the sheet glass with two-sided adhesive gel, and under ar gas environment metal spraying.The photo amplifying different multiples is observed under ESEM.
Fig. 1 and Fig. 2 amplification is respectively 100 times (accompanying drawings 1) and 250 times (accompanying drawing 2), and from scale (100 μm and 200 μm), the particle diameter of this pioglitazone hydrochloride amorphous article is within 200 μm.Tested by ESEM, finding that pioglitazone hydrochloride and glimepiride are total to amorphous article microscopic pattern is rectangular block distribution (see accompanying drawing 1 and accompanying drawing 2).
embodiment 6
Powder x-ray diffraction test (PXRD)
Pioglitazone hydrochloride of the present invention and glimepiride are total to amorphous article measures medicine unformed state by D/Max-2500 type x-ray diffractometer (Rigaku, Tokyo, Japan), this instrument uses Cu K alpha ray to be emission source
.Standard to operate in voltage be 40kV and electric current is carry out under 100mA.Scanning speed is 8 DEG C/min, and sweep limits is 10 ~ 90 ° of 2 θ.Get this sample powder of about 50mg, be pressed into thin slice, put into X-ray diffraction instrument and measure.PXRD result of the test as shown in Figure 3.Be the PXRD collection of illustrative plates of pioglitazone hydrochloride in fig. 3, accompanying drawing 4 is the PXRD collection of illustrative plates of glimepiride, and accompanying drawing 5 is the PXRD collection of illustrative plates that pioglitazone hydrochloride and glimepiride are total to amorphous article.
Tested by PXRD, we find that independent crystalline state pioglitazone hydrochloride and glimepiride are in 10 ~ 90 ° of 2 θ angle range, there will be obvious crystal diffraction peak.And the crystal peak being total to two kinds of medicines in amorphous article all disappears, further demonstrate two kinds of medicines and all exist with unformed form.
embodiment 7
Differential scanning calorimetry (DSC)
The interaction force that may exist between two kinds of medicines is measured by differential scanning calorimeter (DSC822e, prunus mume (sieb.) sieb.et zucc. Teller, Sweden).DSC instrument is interior mark with indium, and the test sample of 5mg is placed in aluminum dish, puts into DSC instrument, and heating rate is 10 DEG C/min, and temperature range is 30-220 DEG C.Get independent pioglitazone hydrochloride, each 5mg of glimepiride puts into DSC instrument and tests.Again pioglitazone hydrochloride and glimepiride are mixed by 1:1 mol ratio, after mix homogeneously, get 5mg and put into DSC instrument and test.DSC result of the test is shown in shown in accompanying drawing 6.
Need understand background knowledge be: 1. when between two kinds of material molecules without any active force time, at the fusing point peak remaining two kinds of independent materials that DSC shows, can not there is any change in the position at fusing point peak.Be inclined to during often kind of material melts and self interact; When 2. there is interaction force when between two kinds of material molecules, what show at DSC is possible be the independent fusing point peak of two kinds of materials, the position at the independent fusing point peak of each material there occurs decline, also may be the coincidence fusing point peak of two kinds of materials, the position at mixed melting point peak be all lower than the fusing point peak of any one material independent.Intermolecular interaction is stronger, and fusing point peak declines lower.Intermolecular force is stronger, is more prone to the fusing point peak occurring overlapping.During often kind of material melts, tendency and another kind of material interact.
Tested by DSC, we find that the fusing point peak of independent pioglitazone hydrochloride is at 197.4 DEG C, and glimepiride goes out peak at 215.4 DEG C.And both mixed fusing point peaks appear at 176.4 DEG C, and the fusing point peak for overlapping.This also illustrates between pioglitazone hydrochloride and glimepiride and there is stronger intermolecular interaction, pioglitazone hydrochloride and the intermolecular existence of glimepiride comparatively strong interaction after the common amorphous substance formed, this formation for unformed system is altogether most important.
Claims (8)
1. be total to a unformed system, it is characterized in that, described common unformed system is made up of pioglitazone hydrochloride and glimepiride, and described pioglitazone hydrochloride and the weight ratio of glimepiride are 1:0.01 ~ 50; In described common unformed system, the drug molecule of pioglitazone hydrochloride and glimepiride all exists with amorphous forms.
2. unformed system altogether according to claim 1, it is characterized in that, described pioglitazone hydrochloride and the weight ratio of glimepiride are 1:0.1 ~ 10.
3. unformed system altogether according to claim 1, it is characterized in that, described amorphous article particle diameter is less than 200 μm.
4. the preparation method of the common unformed system according to any one of claim 1-3, is characterized in that, pioglitazone hydrochloride and glimepiride is dissolved, and under heating condition, decompression volatilizes solvent.
5. preparation method according to claim 4, is characterized in that, the solvent load dissolving pioglitazone hydrochloride and glimepiride is 2-100 times of drug alone weight, and described multiple is envelope-bulk to weight ratio, and unit is mL/g.
6. preparation method according to claim 4, is characterized in that, described heating-up temperature is 35-60 DEG C.
7. preparation method according to claim 4, it is characterized in that, any one in the solvent selected from ethanol adopted, methanol, normal propyl alcohol, n-butyl alcohol, oxolane, chloroform, isopropyl alcohol, dichloromethane, petroleum ether, glycerol, acetonitrile, ether, ethyl acetate, acetone.
8. a pharmaceutical composition, containing, for example unformed system and the pharmaceutically acceptable pharmaceutic adjuvant altogether of the one described in any one of claim 1-3.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310393189.0A CN104415042A (en) | 2013-08-30 | 2013-08-30 | Co-amorphous system and preparation method thereof |
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| CN201310393189.0A CN104415042A (en) | 2013-08-30 | 2013-08-30 | Co-amorphous system and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104288161A (en) * | 2014-09-19 | 2015-01-21 | 四川海思科制药有限公司 | Pharmaceutical composition containing pioglitazone and glimepiride |
| CN105646353A (en) * | 2016-03-02 | 2016-06-08 | 中国药科大学 | Celecoxib and irbesartan coamorphous substance |
| CN113214121A (en) * | 2020-01-21 | 2021-08-06 | 江苏恒瑞医药股份有限公司 | Glibenclamide-arginine co-amorphous |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1857264A (en) * | 2006-04-14 | 2006-11-08 | 北京润德康医药技术有限公司 | Medicine composition with pioglitazone hydrochloride and glimepiride as active components and its preparing method and use |
| CN101969766A (en) * | 2007-10-17 | 2011-02-09 | 托德·F·奥沃凯泰斯 | Process for the modification of the solid state of a compound and co-amorphous compositions produced with same |
-
2013
- 2013-08-30 CN CN201310393189.0A patent/CN104415042A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1857264A (en) * | 2006-04-14 | 2006-11-08 | 北京润德康医药技术有限公司 | Medicine composition with pioglitazone hydrochloride and glimepiride as active components and its preparing method and use |
| CN101969766A (en) * | 2007-10-17 | 2011-02-09 | 托德·F·奥沃凯泰斯 | Process for the modification of the solid state of a compound and co-amorphous compositions produced with same |
Non-Patent Citations (2)
| Title |
|---|
| 姚静等: "共无定型药物系统的研究进展", 《药学学报》 * |
| 应剑等: "固体药物无定型状态的研究进展", 《药学学报》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104288161A (en) * | 2014-09-19 | 2015-01-21 | 四川海思科制药有限公司 | Pharmaceutical composition containing pioglitazone and glimepiride |
| CN105646353A (en) * | 2016-03-02 | 2016-06-08 | 中国药科大学 | Celecoxib and irbesartan coamorphous substance |
| CN113214121A (en) * | 2020-01-21 | 2021-08-06 | 江苏恒瑞医药股份有限公司 | Glibenclamide-arginine co-amorphous |
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