CN114886862B - Compound hypoglycemic medicine preparation and its preparing process - Google Patents
Compound hypoglycemic medicine preparation and its preparing process Download PDFInfo
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- CN114886862B CN114886862B CN202210535868.6A CN202210535868A CN114886862B CN 114886862 B CN114886862 B CN 114886862B CN 202210535868 A CN202210535868 A CN 202210535868A CN 114886862 B CN114886862 B CN 114886862B
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- 238000000034 method Methods 0.000 title claims abstract description 48
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- 230000002218 hypoglycaemic effect Effects 0.000 title claims abstract description 10
- 230000008569 process Effects 0.000 title claims description 28
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- 229960001254 vildagliptin Drugs 0.000 claims abstract description 103
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 claims abstract description 98
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- 101100232079 Arabidopsis thaliana HSR4 gene Proteins 0.000 description 1
- 101150007734 BCS1 gene Proteins 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 1
- 101100004264 Homo sapiens BCS1L gene Proteins 0.000 description 1
- 102100027891 Mitochondrial chaperone BCS1 Human genes 0.000 description 1
- 101100219120 Theobroma cacao BTS1 gene Proteins 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
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- 210000004211 gastric acid Anatomy 0.000 description 1
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- 230000002401 inhibitory effect Effects 0.000 description 1
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- 229940035752 metformin and vildagliptin Drugs 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- ALSCEGDXFJIYES-UHFFFAOYSA-N pyrrolidine-2-carbonitrile Chemical compound N#CC1CCCN1 ALSCEGDXFJIYES-UHFFFAOYSA-N 0.000 description 1
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- 239000012498 ultrapure water Substances 0.000 description 1
- 229940102889 vildagliptin 100 mg Drugs 0.000 description 1
- 229940102877 vildagliptin 50 mg Drugs 0.000 description 1
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- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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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- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a compound hypoglycemic pharmaceutical preparation and a preparation method thereof, wherein vildagliptin and an external adhesive are dissolved in ethanol to obtain an ethanol solution of the vildagliptin and the external adhesive; then mixing the mixed soft material with ethanol solution of metformin hydrochloride, an internal adhesive and an external adhesive of vildagliptin to prepare a mixed soft material; granulating by extrusion and spheronization, drying, mixing with lubricant, and tabletting. According to the method, the specific adhesive type is selected, the adhesive and the vildagliptin are dissolved in ethanol to prepare the composite adhesive, and extrusion, spheronization and granulation are matched, so that the using amount of auxiliary materials is reduced to the greatest extent, the stability of the vildagliptin is improved, the condition that the product content uniformity caused by uneven mixing does not meet the standard is avoided, and the medication compliance of a patient is ensured.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and in particular relates to a compound hypoglycemic pharmaceutical preparation and a preparation method thereof.
Background
The use of metformin vildagliptin tablets for metformin monotherapy for maximum tolerated dose glycemic control is still poor or in adult type 2 diabetics undergoing vildagliptin in combination with metformin. Vildagliptin was marketed in the european union under the trade name of jiawile in 9 of 2007, metformin was marketed in the european union since 1959, and the metformin vildagliptin tablet was approved by the european union for marketing in 11 of 2007 at 14 of No. 11, and the trade name is "yihe rui". The specification comprises: metformin-vildagliptin tablet (I) (500 mg/50 mg), metformin-vildagliptin tablet (II) (850 mg/50 mg), metformin-vildagliptin tablet (III) (1000 mg/50 mg).
Studies have shown that in patients with poor glycemic control with metformin monotherapy, a statistically significant decrease in HbA1c value occurred after 6 months of vildagliptin addition compared to the metformin monotherapy group (the differences between the dose groups of vildagliptin 50mg and 100mg were-0.7% to-1.1%, respectively). The ratio of HbA1c values in the metformin single drug treatment group to the vildagliptin and metformin combined treatment group to patients with a decrease of not less than 0.7% relative to the baseline is 46% and 60% respectively, and the vildagliptin and metformin combined treatment group is significantly higher than the metformin single drug treatment group (20%), which is statistically significant. The above results indicate that the combination of metformin and vildagliptin is of greater clinical value than metformin alone.
Metformin hydrochloride, having the chemical name 1, 1-dimethyldiguanide hydrochloride, a relative molecular mass of 165.63 and a molecular formula of C 4 H 11 N 5 HCl. Vildagliptin chemical name: (-) - (2S) -1- [ [ (3-hydroxytricyclo [3.3.1.1[3,7 ]]]Silane-1-yl) amino groups]Acetyl group]Pyrrolidine-2-carbonitrile having a formula of C 17 H 25 N 3 O 2 The relative molecular mass was 303.40.
The prior investigation results show that the prior metformin vildagliptin tablet has the following problems in the preparation process:
1. metformin hydrochloride is a BCS3 drug, and is soluble in water and poorly soluble in ethanol. Vildagliptin is a BCS1 type drug, is soluble in water and also in ethanol. Vildagliptin is sensitive to moisture and is easy to degrade, so that related substances and impurities exceed standards, and the stability of the medicine is poor.
Wherein, after the direct dry powder of the binder such as metformin hydrochloride, hydroxypropyl cellulose and the vildagliptin is mixed by wet granulation (such as CN 101277688A), the wet granulation is carried out by the wet granulation with water as a wetting agent, the preparation method accelerates the standard exceeding result of impurities caused in the stability test process, particularly 209-01 impurities (impurity I%) (chemical name: 2- (3-hydroxy-tricyclo [ 3.3.1.1) (3,7) ]Decane-1-yl) -1-imino-hexahydro-pyrrolo [1,2-a]Pyrazin-4-one) of formula C 17 H 25 N 3 O 2 303.40) are the most serious relative molecular masses, and the content exceeds the limit of mass standard. Overrun of the above impurities is related to the participation of vildagliptin in wet granulation during granulation. Thus, the wet granulation process creates a greater quality risk.
In patent CN 107536831a, the granulation process is performed by fluid bed granulation, thereby improving the compressibility of the granules. However, the above process still falls into the category of wet granulation, which still leads to the risk of overstandard substances during the later storage of vildagliptin.
If dry granulation (for example CN 105769796 a) is adopted, because of poor compressibility of vildagliptin, cracking can be generated during secondary compression in the subsequent tabletting process, so that friability is not qualified, and related substances have the risk of easily increasing exceeding standard during powder mixing and direct compression, so that the stability of subsequent products is affected.
In addition, the technical scheme for optimizing and adding the prescription comprises the following steps: other diluents, lubricants, disintegrants, etc. are added, but the modification of these publicly added excipients does not fundamentally improve the core risks expressed by the original developed patents. For example, patent WO2021262115A1 changes the stability of the raw materials by salifying the raw materials, and on the basis of this, screening and optimization of the auxiliary materials are performed. However, the technical means of the salt formation method can solve the problem of raw material stability to a certain extent, but the salt formation process changes the components and physical and chemical properties of the raw material medicine, and belongs to the research category of new medicine. And the solubility of the raw materials after salification is suddenly increased, the result is probably positive from the point of research on new drugs, however, the formation of salts with concomitant changes in solubility may mean alterations in transmembrane absorption and bioequivalence. In the preparation, the imitation medicine needs to be subjected to reference regulation and control on auxiliary materials, tabletting and other processes, and the medicine is required to have precise dissolution and acid-base coefficient, so that the imitation medicine can be disintegrated in the right time under the condition of reaching gastric acid, and can be dissolved at the right speed, and the right absorption rate can be obtained. If the disintegration and dissolution are too early, mucous membrane stimulation to esophagus and stomach can be caused; if the disintegration and dissolution are too late, the disintegration and dissolution are not fully absorbed in the stomach, the disintegration and dissolution are not easy to absorb when entering the pH environment of the intestinal tract, the dosage of the medicine is difficult to reach, and the treatment effect is likely to be affected. Only if the above standard is realized, the preparation requirements of the imitation medicine can be met. Therefore, the original grinding and salifying means can not fundamentally solve the technical problem of stability related to the field of the simulated pharmaceutical of the vildagliptin hydrochloride and the metformin hydrochloride.
2. In the prior art, the technological process of firstly granulating the metformin hydrochloride by a wet method, then mixing the metformin hydrochloride with the vildagliptin and tabletting the mixture comprises the fine powder of the metformin hydrochloride and the metformin granules prepared in advance, so that the mixed powder is uneven, and further the quality problems of uniform content of products and the like are caused.
In the patent CN107007579A, the two medicines are firstly granulated by a wet method respectively in the granulating process, and then the step-by-step process of total mixed tabletting is adopted, so that the mixing uniformity is improved. However, said method not only causes the risk of exceeding the standard of the relevant substances during the later storage of the vildagliptin, but also the very low content of the vildagliptin, still causes the risk of mixing the total mixture unless the particles of the vildagliptin are highly consistent with the particle size distribution of the metformin hydrochloride particles.
Because the vildagliptin raw materials are easy to agglomerate, the premixing before dry granulation is easy to generate uneven mixing, and the uniformity of the medicine is affected.
3. The total dosage of the metformin-vildagliptin tablet is large, the powder mobility of the metformin hydrochloride and vildagliptin is poor, and the relative proportion of the vildagliptin is low. If mixed powder direct compression or dry granulation is adopted, the processes must combine various excipients with raw material components, so as to facilitate the achievement of the indexes of the processes, and various auxiliary materials added into the mixed powder can further cause the increase of the total tablet weight of the medicine, and influence the medication compliance of patients.
For the above reasons, although there is a risk of delamination of the vildagliptin after mixing with the metformin granulate under the wet granulation process, the process risk is relatively smaller than the above drawbacks. Therefore, the wet granulation process is still the main means of the original drug grinding of the drug and the preparation process at the current stage.
In summary, in order to solve the problems of (1) poor stability caused by the sensitivity of vildagliptin to moisture, (2) the risk of uniformity of easy delamination due to the small dosage of vildagliptin in the wet granulation process, and (3) the reduced medication compliance caused by excessive dosage of auxiliary materials in the preparation process, it is necessary to develop a new preparation process of the metformin vildagliptin tablet preparation to reduce or eliminate the adverse effects.
Disclosure of Invention
Aiming at the problems, the invention adopts a specific preparation method and provides a compound hypoglycemic pharmaceutical preparation with good stability, uniformity and medication compliance.
Specifically, during the development of the metformin-vildagliptin tablet, through previous prescription investigation, the development of the preparation has several difficulties:
1) Stability: vildagliptin is sensitive to moisture, and is easy to cause poor stability of medicines and excessive impurities; meanwhile, vildagliptin has poor compressibility and high fracture probability in the tabletting process, so that the risk of impurity exceeding is increased;
2) And (3) uniformly: the vildagliptin has less content in the whole metformin vildagliptin tablet, and delamination is easy to cause, so that the content of the product is uniformly poor;
3) Compliance with medication: in the preparation process of the medicine, a large amount of auxiliary materials and auxiliary agents are required to be added, so that the tablet weight of the medicine is further increased, and the medication compliance of a patient is influenced.
In order to solve the above problems, the following modifications have been made:
1. through selecting the adhesive type with good solubility in ethanol, the vildagliptin and part of adhesive materials are dissolved in ethanol, so that the use of water is avoided, the problem that the impurity content of the vildagliptin is increased along with the extension of the medicine placement time is greatly improved, and the stability of the pharmaceutical preparation is improved.
2. After the medicine raw materials are mixed to prepare the soft material, the granulation in an extrusion and spheronization mode can be realized, the growth of related substances and impurities possibly generated in the high shearing process is further avoided, and the stability of the tablet is improved.
3. The mixed soft material is prepared by mixing the alcohol-soluble vildagliptin and the adhesive composite solution serving as a composite adhesive with the metformin hydrochloride, and the mixed soft material is matched with a strategy of granulating in an extrusion rolling way, so that the problem that the product content uniformity caused by uneven mixing of the metformin and the vildagliptin tablets does not meet the standard at one time is avoided.
4. The active substances contained in the metformin hydrochloride vildagliptin tablets prepared by the method are removed: besides metformin hydrochloride and vildagliptin, the auxiliary materials and auxiliary agents contained in the final tablet finished product only comprise adhesive, and lubricant and coating agent necessary in the tablet medicine, so that the medication compliance of patients is enhanced.
The invention is realized by the following modes:
a preparation method of a compound hypoglycemic drug preparation comprises the following steps:
1) Dissolving vildagliptin and an additional adhesive in ethanol to obtain an ethanol solution of the vildagliptin and the additional adhesive;
2) Mixing metformin hydrochloride, an internal adhesive and an ethanol solution of vildagliptin and an external adhesive to prepare a mixed soft material;
3) Granulating the mixed soft material by extrusion and spheronization, drying, mixing with lubricant, and tabletting.
The term "extrusion spheronization mode" includes a method of granulating by an extrusion spheronizer or an apparatus in the same principle as the extrusion spheronizer, and other methods in the same manner as the object of the present invention.
In some preferred embodiments, the additional binder is selected from one or more of the following: hydroxypropyl cellulose, povidone, polymethyl methacrylate, stearic acid;
the internal adhesive is selected from one or more of the following substances: hydroxypropyl cellulose, povidone, polymethyl methacrylate, stearic acid.
In some preferred embodiments, the ethanol content is 95-100vol.%, preferably 100vol.%.
The term "vol.%" refers to volume percent. In some embodiments, the ethanol is added in an amount of 6-12% of the prescribed amount, preferably 7-10% of the prescribed amount; more preferably 10% of the prescribed amount.
The term "prescribed amount" refers to the sum of the weights of the raw materials and auxiliary materials actually used in preparing a pharmaceutical preparation or a pharmaceutical composition; for example, the prescription amount of 600 tablets of pharmaceutical preparation is 596.6g (comprising 510g of metformin hydrochloride, 30.3g of vildagliptin, 3.9g of additional adhesive, 46.5g of internal adhesive, 5.9g of lubricant and 5.9g of magnesium stearate), and the addition amount of ethanol is 60g, the calculation method that the addition amount of ethanol is 10% of the prescription amount is as follows: (60/596.6) ×100% =10%.
In some embodiments, wherein the additional binder is added in an amount of 0.5 to 1.0% of the prescribed amount on a dry weight basis, preferably 0.7% of the prescribed amount; the amount of the internal adhesive added is 7.0 to 8.0% of the prescribed amount, preferably 7.7% of the prescribed amount.
In some embodiments, wherein step 2) mixes the soft material, the content ratio of metformin hydrochloride to vildagliptin on a dry weight basis is: (250-2000): 50, or the proportion relation of other dosage with the same specification in the corresponding bulk drug;
preferably, (500-1000): 50;
more preferably, the method further comprises the steps of, 500: 50. 850: 50. 1000:50.
in some preferred embodiments, wherein the lubricant in step 3) is selected from any one of magnesium stearate, aerosil, talc.
In some preferred embodiments, wherein the drying in step 3) is performed using room temperature fluid drying; dried to LOD of 0.5-1.0%.
In some preferred embodiments, after step 3) is completed, the compressed tablet product can also be coated with a lubricant to provide a coated tablet.
In some embodiments, the metformin hydrochloride is in the form of particles; the particle size of the metformin hydrochloride is d90=160-210 μm; preferably d90=179 μm.
The invention also relates to a compound hypoglycemic pharmaceutical preparation prepared by the method.
The invention also relates to a composition comprising only one active ingredient particle, wherein the active ingredient particle comprises:
1) The vildagliptin external adhesive mixture comprises vildagliptin and an external adhesive, wherein the additive amount of the external adhesive is 0.5-1.0% of the prescription amount;
2) Metformin hydrochloride;
3) An internal adhesive with the addition amount of 7.0-8.0% of the prescription amount;
wherein, the weight part ratio of the metformin hydrochloride to the vildagliptin is 250-2000:50.
in some embodiments, the vildagliptin plus binder mixture is formed from a vildagliptin plus binder ethanol solution by drying. In some embodiments, the additional binder is selected from one or more of the following: hydroxypropyl cellulose, povidone, polymethyl methacrylate, stearic acid; the internal adhesive is selected from one or more of the following substances: hydroxypropyl cellulose, povidone, polymethyl methacrylate, stearic acid.
In some embodiments, the ethanol content is 95-100vol.%, preferably 100vol.%.
In some preferred embodiments, the ethanol is added in an amount of 6-12% of the prescribed amount, preferably 7-10% of the prescribed amount; more preferably 10% of the prescribed amount.
In some preferred embodiments, the additional adhesive is added in an amount of 0.7% of the prescribed amount; the amount of the internal adhesive added was 7.7% of the prescribed amount.
In some embodiments, the ratio of metformin hydrochloride to vildagliptin is from 500 to 1000:50; preferably 500: 50. 850: 50. 1000:50.
In some embodiments, the active ingredient particles have a LOD of 0.5 to 1.0%.
In some embodiments, a lubricant selected from any one of magnesium stearate, colloidal silica fume, talc is also included.
In some embodiments, the composition is a tablet; preferably, the tablet is a coated tablet.
In some embodiments, the metformin hydrochloride is in the form of particles; the particle size of the metformin hydrochloride is d90=160-210 μm; preferably d90=179 μm.
In another aspect, the invention also relates to the use of the compound hypoglycemic pharmaceutical preparation or the composition in the preparation of a medicament for treating type 2 diabetes.
In some preferred embodiments, the type 2 diabetes is adult type 2 diabetes in which the maximum tolerated dose of metformin monotherapy is still poorly controlled in blood glucose or in the course of receiving vildagliptin in combination with metformin.
The beneficial effects of the invention are as follows:
1. the specific adhesive type is selected, and the specific adhesive type and the vildagliptin are dissolved in ethanol to prepare the composite adhesive, so that the use of water in the preparation process is avoided, and the increase of related substances, impurities and the like is reduced, so that the stability of the vildagliptin is improved.
2. In the preparation process, the raw materials are prepared into soft materials, and the granulation mode of extrusion and spheronization is matched, so that the impurity growth risk caused by a high shearing process during granulation is avoided, and the stability of the medicine is further improved.
3. By adopting the preparation process and the specific addition sequence, the vildagliptin and part of the adhesive are added into the pre-mixture of the metformin hydrochloride and the adhesive in a liquid state, so that the vildagliptin is ensured to be uniformly distributed in the pre-mixture, and good uniformity of the product content is realized.
4. The invention greatly reduces the adding types and the adding amounts of substances such as auxiliary materials, auxiliary agents and the like, ensures that the tablet has acceptable tablet size and ensures the medication compliance of patients; while maintaining good tablet properties including hardness, friability, etc.
Drawings
FIG. 1 is a process flow diagram of a preparation method of the invention;
FIG. 2 is a process flow diagram of the preparation method of comparative example 1;
fig. 3 is a process flow diagram of the preparation method of comparative example 2.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The raw materials and auxiliary materials used in the following examples were commercially available unless otherwise specified.
According to the preparation method, ethanol is used as an adhesive to replace water, vildagliptin and part of the adhesive are fully dissolved in ethanol, and then the obtained solution is used as a liquid adhesive to be mixed with metformin hydrochloride and the rest part of the adhesive in a mixer to prepare a mixed soft material; the ethanol can inhibit the growth of impurities and improve the stability of the tablet; however, the prepared particles have poor agglomeration force and are loose, and a cracking phenomenon can be generated, so that the product is brittle and unqualified. On the basis, the aggregation of particles can be increased through an extrusion and spheronization process, the compressibility of the tablet is improved, the adverse effect of ethanol on the tabletting process caused by an adhesive is improved, the uniformity of the pharmaceutical preparation is improved on the basis of ensuring the appearance and hardness properties, and the dual effect of inhibiting the growth of impurities is realized. In addition, the addition of auxiliary materials is reduced to the greatest extent in the preparation process, and the medication compliance of patients is improved.
In the following specific examples:
wherein D90 represents: the particle size corresponding to the cumulative particle size distribution number of a sample reaching 90% is physically smaller than 90% of its particles.
1. Granulating parameters:
mixing rotation speed 3r/s; the rotating speed of the cutter is 15r/s; granulating for 3min; fluidized bed drying, and drying weight loss is 0.5-1.0%; and (5) finishing the granules by using a screen 30 mesh.
2. Tabletting parameters:
a main pressure scale 8500; the tabletting speed is 5000 tablets/hour.
3. Tablet weight 994mg + -5%
Example 1:
according to the preparation process flow chart shown in fig. 1, the raw materials required in the preparation process are screened in advance:
metformin hydrochloride is sieved by a 10-mesh sieve; and controlling the particle size of metformin hydrochloride to d90=179 μm;
sieving vildagliptin with 16 mesh sieve;
sieving hydroxypropyl cellulose with 16 mesh sieve;
sieving magnesium stearate with 16 mesh sieve;
commercially available film coating premixes do not require sieving.
1) Selecting hydroxypropyl cellulose as an adhesive, and dissolving 30.3g of vildagliptin and 3.9g of additional hydroxypropyl cellulose into 60g of absolute ethyl alcohol to obtain a solution;
2) Mixing 510g of metformin hydrochloride and 46.5g of internal hydroxypropyl cellulose with the solution obtained in the step 1) to prepare a mixed soft material; the solution plays a role of a liquid adhesive and is mixed with metformin hydrochloride in a mixer to prepare a mixed soft material;
3) The mixed soft material is granulated by extrusion and spheronization to avoid the growth of related substances possibly generated in the high shear process. Then fluidized and dried at room temperature until lod=0.5-1.0%; mixing with magnesium stearate lubricant, tabletting to obtain mixed tabletting product (i.e. tablet).
And 3) after the step 3), coating the mixed tabletting product to obtain a finished tablet, and effectively avoiding the generation of impurities.
Table 1 product recipe
Examples 2 to 4:
referring to the preparation method of example 1, both the additional binder and the additional binder in step 1) and step 2) were replaced with povidone (both the additional binder and the additional binder were replaced with povidone, example 2), polymethyl methacrylate (both the additional binder and the additional binder were replaced with polymethyl methacrylate, example 3), stearic acid (both the additional binder and the additional binder were replaced with stearic acid, example 4), and the other steps were unchanged.
Comparative examples 1-2:
referring to the components and preparation method of example 1, the absolute ethanol in step 1) was replaced with ultrapure water (comparative example 1) and 50vol% ethanol (comparative example 2), respectively, and the other steps were the same as in example 1, to obtain a mixed compressed tablet product (i.e., a plain tablet).
Comparative examples 3 to 4:
with reference to the components and the preparation method of example 1, hydroxypropyl methylcellulose (both the additional binder and the additional binder are replaced with hydroxypropyl methylcellulose, comparative example 3), sodium carboxymethyl cellulose (both the additional binder and the additional binder are replaced with sodium carboxymethyl cellulose, comparative example 4) are used to replace the hydroxypropyl cellulose binder in step 1) and step 2), respectively, wherein both the additional binder and the additional binder are replaced, and the other steps are the same as in example 1, to obtain a mixed tablet (i.e., a green sheet).
Comparative example 5:
wet granulation: original grinding process
According to the preparation process flow chart shown in fig. 2, the raw materials required in the preparation process are screened in advance:
hydrochloric acid dimethyl sieving biguanide with 10 mesh sieve; and controlling the particle size of metformin hydrochloride to d90=179 μm;
sieving vildagliptin with 16 mesh sieve;
sieving hydroxypropyl cellulose with 16 mesh sieve;
sieving magnesium stearate with 16 mesh sieve;
commercially available film coating premixes do not require sieving.
1) Hydroxypropyl cellulose is selected as an adhesive, and 3.9g of additional hydroxypropyl cellulose is dissolved in 60g of water to obtain an adhesive solution;
2) Mixing 510g of metformin hydrochloride and 46.5g of internal hydroxypropyl cellulose for 10min, and then mixing with the solution obtained in the step 1) to prepare a mixed soft material; the solution plays a role of a liquid adhesive, is mixed with metformin hydrochloride and internal hydroxypropyl cellulose in a mixer to prepare a mixed soft material, and is subjected to high-shear granulation for 5 minutes at a stirring rotating speed of 3r/s and a cutter rotating speed of 30 r/s; the mixture was fluidized and dried at room temperature for 5min until lod=0.5-1.0%. Finishing grains (30 meshes) and discharging;
3) The dry granules are fully mixed with the prescribed proportion of vildagliptin, and then are subjected to total mixing with magnesium stearate lubricant and tabletting to obtain a mixed tabletting product (i.e. a plain tablet).
And 3) after the step 3), coating the mixed tabletting product to obtain a finished tablet, and effectively avoiding the generation of impurities.
Table 2 product recipe
Comparative example 6:
wet granulation: the difference from the present invention is that the mixing step of the preparation process is different
According to the preparation process flow chart shown in fig. 3, the raw materials required in the preparation process are screened in advance:
metformin hydrochloride is sieved by a 10-mesh sieve; and controlling the particle size of metformin hydrochloride to d90=179 μm;
sieving vildagliptin with 16 mesh sieve;
sieving hydroxypropyl cellulose with 16 mesh sieve;
sieving magnesium stearate with 16 mesh sieve;
commercially available film coating premixes do not require sieving.
1) Hydroxypropyl cellulose is selected as an adhesive, and 3.9g of additional hydroxypropyl cellulose is dissolved in 60g of water to obtain an adhesive solution;
2) Fully mixing 510g of metformin hydrochloride, 30.3g of vildagliptin and 46.5g of internal hydroxypropyl cellulose for 20min, and then mixing with the solution obtained in the step 1) to prepare a mixed soft material; the solution plays a role of a liquid binder and is mixed with the mixture to prepare a mixed soft material; then, granulating for 5 minutes under high shearing at the stirring rotating speed of 3r/s and the cutter rotating speed of 30 r/s; the mixture was fluidized and dried at room temperature for 5min until lod=0.5-1.0%. Finishing grains (30 meshes) and discharging;
3) Mixing the above granules with magnesium stearate lubricant, and tabletting to obtain mixed tabletting product (i.e. tablet).
And 3) after the step 3), coating the mixed tabletting product to obtain a finished tablet.
TABLE 3 product prescriptions
Comparative example 7:
the vildagliptin (non-salified compound) is used as raw material, and other raw materials and auxiliary materials are mixed in the same proportion as in the prior art patent WO20212621115A1, so as to press the tablet.
Table 4 product recipe
Experimental example 1: stability evaluation
By measuring the content of each impurity in the pharmaceutical tablets of examples and comparative examples, 4 batches of tablet products were prepared separately for each method, and the stability of the pharmaceutical tablets was evaluated.
Experimental conditions: the impurity contents of freshly prepared tablets and the impurity contents of the packaged tablets after 30 days at 40 ℃ and 60 ℃ were measured respectively, and the stability was examined.
TABLE 5 definition criteria for impurities
The limit of impurities is formulated by the limit standard of original ground medicines and related marketed products.
1-1 Effect of different adhesive types on stability
The finished tablets prepared in examples 1-4 with different binders were subjected to stability tests, the test results are shown in table 6.
TABLE 6 selection of adhesive types
| Name of the name | Adhesive type | Proportion (%) |
| Example 1 | Hydroxypropyl cellulose | 8.5 |
| Example 2 | Povidone | 8.5 |
| Example 3 | Polymethyl methacrylate | 8.5 |
| Example 4 | Stearic acid | 8.5 |
TABLE 7 evaluation of stability-Effect of different adhesive class selections on vildagliptin impurity
Analysis of results: as is clear from the above table, in example 1, the addition of hydroxypropylcellulose as a binder gave a pharmaceutical tablet having impurity H, impurity I, impurity K and unknown maximum mono-and total impurity contents of 0.03%, 0.09%, 0.01% and 0.03% and 0.17%, respectively, wherein the presence of impurity J was not detected.
The packed tablet is placed for 30 days at the temperature of 40 ℃, and the increase of impurity H, impurity K and unknown maximum single impurity is not obvious; impurity J was not detected; the impurity I is increased from 0.09% to 0.55%, but is still smaller than the impurity limit standard 1%, so that the tablet prepared by the method has good stability, and the phenomenon that the content of the impurity I exceeds the standard can be greatly inhibited; the total impurity content is increased to 0.65%, which is far smaller than the total impurity limiting standard of 3.5%, so that the stability is good, and the remarkable effect is achieved.
The packed tablets are placed for 30 days at the temperature of 60 ℃, and the increase of impurity H and impurity K is not obvious; a small amount of impurity J (content 0.02%) was detected after standing, because: with the duration of the placement, the impurity I is partially converted into an impurity J; the impurity I is increased from 0.09% to 0.69%, but is still smaller than the impurity limit standard 1%, so that the tablet prepared by the method has good stability, and the phenomenon that the content of the impurity I exceeds the standard can be greatly inhibited; the unknown maximum single impurity content is 0.19 percent under the condition of being placed at 60 ℃ for 30 days, and the unknown maximum single impurity content is controlled within the impurity limiting standard; the total impurity content is increased to 1.07%, which is far smaller than the total impurity limiting standard of 3.5%, so that the high-stability composite material has good stability and achieves remarkable effect.
Tablets prepared by using povidone, polymethyl methacrylate and stearic acid in examples 2-4 as binders of different types are similar to example 1, and the impurities all meet the quality standard, and the pharmaceutical preparation shows remarkable stability.
1-2, influence of different solvent types on stability
The stability test was performed on the finished tablets prepared by dissolving the additional binder in different solvents in example 1 and comparative examples 1 and 2, and the test results are shown in the following table.
TABLE 8 selection of different solvent types
| Name of the name | Adhesive type |
| Example 1 | Absolute ethyl alcohol |
| Comparative example 1 | Purified water |
| Comparative example 2 | 50% ethanol |
TABLE 9 evaluation of stability-Effect of different solvent selections on vildagliptin impurities
Conclusion analysis:
from the above table results, it is clear that the absolute ethanol or the high-concentration ethanol of the present invention is adopted to fully dissolve the vildagliptin and the external binder, and compared with the water and the 50% ethanol which are used as solvents, the stability of the drug is significantly improved, the increase of various single impurities and the unknown maximum single impurity and total impurity contents in the drug tablet is inhibited, and the inhibition effects are significantly different.
Specifically, the content of the impurity I% is reduced from 3.2% to 0.69% compared with water as a solvent, and the content of the impurity I can be controlled within a good limit standard range when absolute ethyl alcohol is used as the solvent; the unknown maximum single impurity is reduced from 0.67% to 0.19%; the total impurity is reduced from 4.91% to 1.07%, and the reduction effect is obvious.
Compared with 50% ethanol as a solvent, the content of the impurity I% is reduced from 3.0% to 0.69%, and the content of the impurity I can be controlled within a good limit standard range when the absolute ethanol is used as the solvent; the unknown maximum single impurity is reduced from 0.59% to 0.19%; the total impurities are reduced from 4.57% to 1.07%, and the reduction effect reaches good significance.
In conclusion, the content of each impurity is far smaller than the limit standard of the impurity of the medicine, and the remarkable effect is achieved.
1-3, influence of different preparation processes on stability
The stability test was performed on the finished tablets obtained in example 1 and comparative examples 5 and 6 using different manufacturing processes, and the test results are shown in the following table.
Table 10 different preparation process selections
TABLE 11 evaluation of stability-influence of different preparation Process choices on vildagliptin impurities
Analysis of results: as can be seen from the above table, the preparation process of the present invention can significantly reduce the unknown maximum single impurity and total impurity content of the drug tablet after being placed at 60 ℃ for 30 days, and significantly inhibit the increase of impurity I after being placed at 40 ℃ and 60 ℃ for 30 days, so that the impurity I content after being placed can still be combined with the impurity content limit standard, and the drug stability of the drug tablet is significantly improved, compared with comparative example 5 (i.e., wet granulation: original grinding process) and comparative example 6 (i.e., mixed raw material co-wet granulation process).
Specifically: compared with comparative example 5, the preparation process of the invention has the advantages that the content of impurity I is reduced from 0.63% to 0.55% by placing the product for 30 days with the package at 40 ℃, the reduction effect is obvious, and the total impurity is reduced from 0.73% to 0.65%; the product is placed for 30 days at 60 ℃ with the package, the content of the impurity I is reduced to 0.69 percent from 1.31 percent, the unknown maximum single impurity is reduced to 0.19 percent from 0.43 percent, the total impurity is reduced to 1.07 percent from 2.12 percent, and the reduction of the content of the impurity is remarkable.
Compared with comparative example 6, the preparation process of the invention is placed for 30 days with package at 40 ℃, the content of impurity H is reduced from 0.36% to 0.02%, the content of impurity I is reduced from 0.73% to 0.55%, and the total impurity is reduced from 1.40% to 0.65%, so that the reduction effect is remarkable; the product is placed for 30 days with package at 60 ℃, the content of impurity H is reduced from 0.42% to 0.13%, the content of impurity I is reduced from 2.08% to 0.69%, the reduction degree is remarkable, the unknown maximum single impurity is reduced from 0.43% to 0.19%, the total impurity is reduced from 3.11% to 1.07%, and the reduction degree of impurity content is remarkably remarkable.
The preparation method proves that the impurity content of each related substance is obviously reduced compared with the tablets with the same components obtained by other preparation processes, the drug stability of the drug tablet is improved, and the remarkable effect is realized.
1-4, influence of different auxiliary materials on stability
The stability test was performed on the finished tablets prepared in example 1 and comparative example 7 using different adjuvant ingredients and types, and the test results are shown in the following table.
TABLE 12 selection of different adjuvant ingredients and species
TABLE 13 evaluation of stability-Effect of different adjuvant ingredients and species selections on vildagliptin impurities
Analysis of results: according to the invention, through optimizing research on auxiliary materials, on the basis of not adding a plurality of fillers, disintegrants, glidants and surfactants, various drug tablets with low impurity content and meeting the impurity limit in the field can be prepared, and under the condition of standing at 60 ℃ for 30 days, various impurities are not obviously increased, so that the stability of the preparation product is proved to be excellent, and the obvious difference is realized.
In particular, compared with the case of adding various auxiliary materials, the content of the impurity H is reduced from 0.16% to 0.13%, the content of the impurity I is reduced from 0.76% to 0.69%, the total impurity content is reduced from 1.20% to 1.07%, the reduction degree is remarkable, and the obvious drug stability advantage is shown.
Experimental example 2: uniformity investigation
Uniformity studies were performed on examples and comparative examples.
According to the content uniformity inspection method of the Chinese pharmacopoeia (2020 edition). Except for the other regulations, 10 samples were taken, and according to the methods specified under each variety item, the relative content x of each single dose was determined to be 100 i And (3) calculating the mean value X, the standard deviation S and the absolute value A of the difference between the marked quantity and the mean value, wherein if A+2.2S is less than or equal to 15, the content uniformity of the sample meets the regulation. Wherein S is standard deviation
The relative standard deviation is calculated as follows:
table 14 product content uniformity evaluation-selection of different preparation Process
Analysis of results: as is clear from the above table, the prepared tablets using the preparation process of the present invention have good uniformity and improved uniformity, compared with comparative example 5 (i.e., wet granulation: original grinding process) and comparative example 6 (i.e., mixed raw material co-wet granulation process), showing good significance.
In particular, the mean values of the metformin hydrochloride and the vildagliptin in the tablet of the method are both up to more than 99.0, wherein the mean value of the metformin hydrochloride is up to 99.6.
Compared with comparative example 5, the mean values of metformin hydrochloride and vildagliptin in the scheme are respectively improved from 99.5 to 99.6, 97.7 to 99.0, the uniformity degree is obviously higher than that of comparative example 5, and the improvement degree is remarkable. From the perspective of RSD and A+2.2S parameters, the RSD of the metformin hydrochloride is reduced from 0.5% to 0.2%; the A+2.2S parameter is reduced from 3.1 to 2.7, and the reduction result is significant; the RSD of vildagliptin is reduced from 3.6% to 0.5%; the a+2.2s parameter was reduced from 6.9% to 3.4% and the degree of reduction showed sufficient significance.
The mean value of vildagliptin in this protocol was increased from 98.3 to 99.0 compared to comparative example 6. From the perspective of RSD and A+2.2S parameters, the RSD of the metformin hydrochloride is reduced from 0.6% to 0.2%, and the A+2.2S parameters are reduced from 2.8 to 2.7; the RSD of vildagliptin is reduced from 0.6% to 0.5%; the A+2.2S parameter is reduced from 4.9 to 3.4, the reduction effect is remarkable, and the uniformity is improved.
The uniformity of the metformin hydrochloride in the pharmaceutical tablet prepared by the method is obviously improved. The RSD values of the metformin hydrochloride and the vildagliptin are smaller than those of the pharmaceutical preparations obtained by the processes of the comparative example 5 and the comparative example 6; and the A+2.2S values of the two main components in the tablet in the example 1 are obviously reduced compared with the tablet in the comparative example 5, so that the pharmaceutical tablet obtained by the preparation method has good uniformity.
Experimental example 3: evaluation of hardness and appearance
The hardness and appearance properties of the pharmaceutical tablets of examples and comparative examples were evaluated.
Appearance: visual appearance was smooth or rough.
Hardness: and (5) measuring the hardness of the prepared plain tablets by adopting a tablet hardness tester.
Friability: and (3) measuring friability of the prepared plain tablets by adopting a tablet friability tester.
3-1 influence of different solvents on hardness and appearance of tablets
Comparing example 1, comparative example 1 and comparative example 2, the hardness and appearance of the prepared tablets were examined when different kinds of solvents were used to dissolve vildagliptin and additional binders.
TABLE 15 evaluation of hardness and appearance Properties-different solvent selections
Conclusion analysis:
from the above table results, it is clear that the pharmaceutical tablet having smooth appearance and hardness and friability meeting the standards can be prepared by sufficiently dissolving vildagliptin and an additional binder with the absolute ethanol or the high-concentration ethanol of the present invention.
3-2 influence of different binder classes on tablet hardness and appearance Properties
Comparing example 1, comparative example 3 and comparative example 4, examining the hardness versus appearance properties of the tablets prepared when using different types of binders for step 1) and step 2).
TABLE 16 evaluation of hardness and appearance Properties-selection of different classes of Adhesives
Conclusion analysis:
although the hydroxypropyl methylcellulose and the sodium carboxymethylcellulose can be widely used as adhesives in the existing technological process for preparing vildagliptin and metformin hydrochloride tablets, the hydroxypropyl methylcellulose and the sodium carboxymethylcellulose are not suitable for the special preparation process of the application, and the prepared medicinal preparation has the advantages of rough appearance, fragility, difficult preservation and unqualified hardness and friability.
All adopt the binder type that has excellent solubility in ethanol in this application, overcome the restriction of the binder type that can not be used to this patent that is disclosed in current patent, obtain the tablet that outward appearance is smooth, its outward appearance's smoothness degree has apparent improvement.
Compared with hydroxypropyl methyl cellulose used as a binder, the hardness of the adhesive is improved from 40 to 60 to 110 to 150; the coarse fraction was also increased from 6.0% to 0.02%. Compared with sodium carboxymethyl cellulose as adhesive, the hardness is increased from 40-80 to 110-150; the coarse fraction was increased from 2.6% to 0.02%, and the hardness and friability were greatly improved, and the obtained product showed sufficient significance.
Therefore, the tablet prepared by the application of the binder has good hardness and appearance characteristics, and significant difference is realized.
Experimental example 4: evaluation of medication compliance
The finished tablets prepared in example 1 and comparative example 7 with different auxiliary material components were subjected to drug compliance testing.
Analysis of results: compared with the preparation process of the application, the preparation process of the comparative example 7 is added with various auxiliary materials, besides the adhesive, the lubricant and the coating agent, the filling agent, the disintegrating agent, the glidant, the surfactant and the like, and when the metformin hydrochloride and the vildagliptin with the same pharmaceutical specification are prepared, the weight of the tablet is increased due to the excessive auxiliary materials and auxiliary agent components, so that the medication compliance of patients is affected. The auxiliary materials only contain the necessary adhesive, lubricant and coating agent of the tablet medicine, so that the gram weight of the tablet is reduced, and the higher medication compliance is realized.
Claims (33)
1. A preparation method of a compound hypoglycemic drug preparation comprises the following steps:
1) Dissolving vildagliptin and an additional adhesive in ethanol to obtain an ethanol solution of the vildagliptin and the additional adhesive; the ethanol content is 95-100vol.%;
2) Mixing metformin hydrochloride, an internal adhesive and the vildagliptin external adhesive ethanol solution to prepare a mixed soft material; in the mixed soft material, the weight ratio of the metformin hydrochloride to the vildagliptin is 250-2000 based on dry weight: 50;
3) Granulating the mixed soft material in an extrusion rolling way, drying, and mixing with a lubricant for tabletting;
wherein:
the external adhesive and the internal adhesive are hydroxypropyl cellulose; or (b)
The external adhesive and the internal adhesive are povidone; or (b)
The external adhesive and the internal adhesive are polymethyl methacrylate; or (b)
The external adhesive and the internal adhesive are stearic acid;
the addition amount of the external adhesive is 0.5-1.0% of the prescription amount based on dry weight;
the addition amount of the internal adhesive is 7.0-8.0% of the prescription amount by dry weight.
2. The method for preparing a compound hypoglycemic pharmaceutical preparation according to claim 1, wherein the ethanol content is 100vol.%.
3. The production method according to claim 1 or 2, wherein the amount of ethanol added is 6 to 12% of the prescribed amount.
4. The preparation method according to claim 3, wherein the amount of ethanol added is 7-10% of the prescribed amount.
5. The method according to claim 4, wherein the amount of ethanol added is 10% of the prescribed amount.
6. The preparation method according to claim 1, wherein the addition amount of the additional adhesive is 0.7% of the prescribed amount.
7. The preparation method according to claim 1, wherein the amount of the internal adhesive added is 7.7% of the prescribed amount.
8. The preparation method according to claim 1, wherein the weight part ratio of the metformin hydrochloride to the vildagliptin is 500-1000:50.
9. the preparation method according to claim 8, wherein the weight part ratio of the metformin hydrochloride to the vildagliptin is 500: 50. 850: 50. 1000:50.
10. The preparation method according to claim 1 or 2, wherein the lubricant in step 3) is selected from any one of magnesium stearate, silica gel micropowder and talc.
11. The preparation method according to claim 1 or 2, wherein the drying mode in step 3) adopts room temperature fluidization drying; dried to LOD of 0.5-1.0%.
12. The process according to claim 1 or 2, wherein after the completion of step 3), the compressed product is further coated with a lubricant to obtain a coated tablet.
13. The production method according to claim 1 or 2, wherein the metformin hydrochloride is in the form of particles; the particle size of metformin hydrochloride is d90=160-210 μm.
14. The preparation method according to claim 13, wherein the metformin hydrochloride has a particle size d90=179 μm.
15. A compound hypoglycemic pharmaceutical preparation prepared by the method of any one of claims 1-14.
16. A composition comprising only one active ingredient particle, wherein the active ingredient particle comprises:
1) The vildagliptin external adhesive mixture comprises vildagliptin and an external adhesive, wherein the additive amount of the external adhesive is 0.5-1.0% of the prescription amount;
2) Metformin hydrochloride;
3) An internal adhesive with the addition amount of 7.0-8.0% of the prescription amount;
wherein, the weight part ratio of the metformin hydrochloride to the vildagliptin is 250-2000:50;
the external adhesive and the internal adhesive are hydroxypropyl cellulose; or the externally added adhesive and the internally added adhesive are povidone; or the external adhesive and the internal adhesive are polymethyl methacrylate; or the external adhesive and the internal adhesive are stearic acid;
the preparation method of the active ingredient particles comprises the following steps:
1) Dissolving vildagliptin and an additional adhesive in ethanol to obtain an ethanol solution of the vildagliptin and the additional adhesive; the ethanol content is 95-100vol.%;
2) Mixing metformin hydrochloride, an internal adhesive and the vildagliptin external adhesive ethanol solution to prepare a mixed soft material;
3) The mixed soft material is granulated by extrusion and spheronization.
17. The composition of claim 16, wherein the vildagliptin plus binder mixture is formed from a vildagliptin plus binder ethanol solution upon drying.
18. The composition of claim 17, wherein the ethanol content is 95-100vol.%.
19. The composition of claim 18, wherein the ethanol content is 100vol.%.
20. The composition of claim 16, wherein the ethanol is added in an amount of 6-12% of the prescribed amount.
21. The composition of claim 20, wherein the ethanol is added in an amount of 7-10% of the prescribed amount.
22. The composition of claim 21, wherein the ethanol is added in an amount of 10% of the prescribed amount.
23. The composition of any of claims 16-22, wherein the add-on adhesive is added in an amount of 0.7% of the prescribed amount; the amount of the internal adhesive added was 7.7% of the prescribed amount.
24. The composition according to any one of claims 16-22, wherein the content ratio of metformin hydrochloride to vildagliptin is 500-1000:50.
25. the composition according to claim 24, wherein the content ratio of metformin hydrochloride to vildagliptin is 500: 50. 850: 50. 1000:50.
26. The composition of any one of claims 16-22, wherein the active ingredient particles have a LOD of 0.5-1.0%.
27. The composition of any one of claims 16-22, further comprising a lubricant selected from any one of magnesium stearate, micro-powder silica gel, talc.
28. The composition of any one of claims 16-22, which is a tablet.
29. The composition of claim 28, wherein the tablet is a coated tablet.
30. The composition according to any one of claims 16-22, said metformin hydrochloride being in particulate form; the particle size of metformin hydrochloride is d90=160-210 μm.
31. The composition of claim 30, wherein the metformin hydrochloride has a particle size d90=179 μιη.
32. Use of a compound hypoglycemic pharmaceutical preparation according to claim 15 or a composition according to any one of claims 16-31 in the manufacture of a medicament for the treatment of type 2 diabetes.
33. The use of claim 32, wherein the type 2 diabetes is adult type 2 diabetes in which the maximum tolerated dose of metformin monotherapy is still poorly controlled in blood glucose or in which vildagliptin is being treated in combination with metformin.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103181923A (en) * | 2011-12-29 | 2013-07-03 | 北京韩美药品有限公司 | Medicinal preparation containing repaglinide and preparation of medicinal preparation |
| WO2015097234A1 (en) * | 2013-12-23 | 2015-07-02 | Krka, D. D. Novo Mesto | Pharmaceutical composition of dpp-iv inhibitor in combination with metformin |
| CN107536831A (en) * | 2016-06-29 | 2018-01-05 | 深圳翰宇药业股份有限公司 | A kind of composition and preparation method containing vildagliptin and melbine |
| WO2020064145A1 (en) * | 2018-09-25 | 2020-04-02 | Pharmathen S.A. | Pharmaceutical composition comprising vildagliptin and metformin and method of preparation thereof |
| WO2021045706A1 (en) * | 2019-09-06 | 2021-03-11 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A combination comprising vildagliptin and metformin |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103181923A (en) * | 2011-12-29 | 2013-07-03 | 北京韩美药品有限公司 | Medicinal preparation containing repaglinide and preparation of medicinal preparation |
| WO2015097234A1 (en) * | 2013-12-23 | 2015-07-02 | Krka, D. D. Novo Mesto | Pharmaceutical composition of dpp-iv inhibitor in combination with metformin |
| CN107536831A (en) * | 2016-06-29 | 2018-01-05 | 深圳翰宇药业股份有限公司 | A kind of composition and preparation method containing vildagliptin and melbine |
| WO2020064145A1 (en) * | 2018-09-25 | 2020-04-02 | Pharmathen S.A. | Pharmaceutical composition comprising vildagliptin and metformin and method of preparation thereof |
| WO2021045706A1 (en) * | 2019-09-06 | 2021-03-11 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A combination comprising vildagliptin and metformin |
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