CN107174571A - A kind of Li Gelieting and its salt, ester, the pharmaceutical composition of derivative and preparation method thereof - Google Patents
A kind of Li Gelieting and its salt, ester, the pharmaceutical composition of derivative and preparation method thereof Download PDFInfo
- Publication number
- CN107174571A CN107174571A CN201710131664.5A CN201710131664A CN107174571A CN 107174571 A CN107174571 A CN 107174571A CN 201710131664 A CN201710131664 A CN 201710131664A CN 107174571 A CN107174571 A CN 107174571A
- Authority
- CN
- China
- Prior art keywords
- gelieting
- composition
- pharmaceutical compositions
- prepared
- diluent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- 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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to a kind of Li Gelieting pharmaceutical compositions, it, which is included, includes a kind of diluent in Li Gelieting or its salt, ester, derivative, diluent, adhesive, disintegrant and lubricant, the diluent, significantly reduce cost of supplementary product.Present invention also offers the preparation technology of the Li Gelieting pharmaceutical compositions, traditional preparation section is simplified, production efficiency is improved.
Description
Technical field
Li Gelieting and its salt, ester, the pharmaceutical composition of derivative and preparation method thereof, category are included the present invention relates to a kind of
In drug field.
Background technology
Incretin (GLP-1) has a variety of functions such as the differentiation of promotion beta cell, suppression gastric emptying because of it, it is considered to be control
One of very promising new drug of diabetes is treated, but because the DPP IV (dipeptidyl peptidase 4) in human body rapidly can lose GLP-1
It is living, so its application is restricted.In recent years, research finds that the inhibitor of DPP IV can successfully suppress the activity of DPP IV, promotes
Beta cell regenerates, and suppresses beta cell apoptosis, and therefore DPP IV becomes the new target spot for the treatment of type II diabetes, the inhibitor of DPP IV
New drug as treatment diabetes.
Li Gelieting is a kind of inhibitor of selective d PP IV of Boehringer Ingelheim company research and development.Listed with other
The inhibitor of DPP IV is compared, and the medicine has obvious advantage：Mainly drained through excrement, therefore its user need not inspect periodically
Renal function and corresponding adjustment dosage, all drug users can unify fixed dosage, be more convenient for prescribing；Tolerance is good, no
Drug drug interaction risk can be increased；And what is more important, its is alone or will not increase with the combination of other hypoglycemic medicines
Risk of hypoglycemia, and potent effect can be produced during with co-administrated metformin.
The content of the invention
The invention provides a kind of Li Gelieting pharmaceutical compositions.For defect present in prior art, the present invention is kept away
The use of pregelatinized starch, copovidone is exempted from, while solving former prilling process tedious process and adhesive
Not the problems such as addition is not known.
The Li Gelieting pharmaceutical compositions of the present invention, include Li Gelieting or its salt, ester, derivative and pharmaceutically useful dilute
Agent, adhesive, disintegrant and lubricant are released, wherein the diluent includes a kind of diluent.
Composition of the present invention mainly includes the supplementary material of following weight percent：
Li Gelieting or its salt, ester, derivative 0.5-20%
Preferably：
Li Gelieting or its salt, ester, derivative 0.5-10%
Wherein, diluent of the present invention is cellulose powder, calcium phosphate dibasic anhydrous, calcium phosphate dibasic dihydrate, xylose
It is a kind of in one kind in alcohol, hydroxypropyl cellulose, mannitol or xylitol, preferably mannitol or xylitol；The lubrication
Agent is the one or more in talcum powder, polyethylene glycol, behenic acid calcium, calcium stearate, rilanit special or magnesium stearate, preferably
For two kinds or one kind of magnesium stearate or talcum powder；Described adhesive is starch, hydroxypropyl methyl cellulose or hydroxy propyl cellulose
One or more in element；The disintegrant is starch, carboxyrnethyl starch sodium, Ac-Di-Sol or hydroxypropyl cellulose
In one or more.
Further, above-mentioned Li Gelieting pharmaceutical compositions are prepared from by the supplementary material of following weight percent：
Or,
Or,
Or
Or
Or
Or
Or
Li Gelieting pharmaceutical compositions of the present invention can also be prepared from by the supplementary material of following weight percent：
Or
Or
Or
Or
Or
Or
Or
Or
Or
Or
It should be noted that above-mentioned percentage of the invention is weight percentage.
The pharmaceutical composition of the present invention can be oral formulations, optionally capsule, granule, tablet or film-coated tablet,
Preferably tablet.
The Li Gelieting pharmaceutical compositions of the present invention are used for the purposes for preparing the medicine for the treatment of diabetes, Li Ge of the invention
Treatment diabetes optionally can be used in combination with melbine and/or sulfonylurea drugs in row spit of fland pharmaceutical composition.The diabetes are special
It is not type ii diabetes, especially with renal function or the type ii diabetes of liver function damage patient；
Present invention also offers a kind of preparation method of Li Gelieting pharmaceutical compositions is as follows：
1) by Li Gelieting or its salt, ester, derivative, diluent, adhesive, disintegrant mixing are prepared into pre-composition；Adopt
Granulation processing is carried out to pre-composition with optional wetting agent；Then lubricant is added into obtained particle, mixed；Most afterwards through pressure
Piece, is coated, that is, Ge Lieting pharmaceutical compositions of getting profit；
Or 2) by Li Gelieting or its salt, ester, derivative, diluent, disintegrant, lubricant, adhesive are mixed successively, no
Tabletting is directly carried out by granulation processing, is coated, and then obtains Li Gelieting pharmaceutical compositions；
Further, the production technology is comprised the following steps：
A, pre-composition：Li Gelieting, diluent, adhesive, disintegrant are mixed, pre-composition is prepared into；
B, granulation：Optional wetting agent wetting is added into pre-composition, is prepared by steps such as granulation, dry and whole grains
Particle；Wherein described wetting agent is one or more, preferably water in optional water, ethanol, methanol, isopropanol or acetone；Should
Illustrate, wetting agent is volatile component, it is not remained in final product.Step b mixtures are pelletized by wet-mixing
Machine is pelletized, and drying process is carried out optionally in fluidized bed dryer；The drying temperature is 40-75 DEG C.
Optionally comprising step c, sieving：The pellet through sieves that step b is prepared；
D, mixing：Lubricant is added into particle, is well mixed；
E, tabletting：Mixture in step d is suppressed into tablet；
Optional, the tablet can also be comprised the following steps：
F, Coating Suspension is prepared, be coated；Wherein, film forming agent, plasticizer, opacifier, coloring are mainly included in Coating Suspension
Agent；
In step c, the screen size of the sieving is no more than 0.6mm；
In step f, the weight percentage of the Coating Suspension is the 2-5% of Li Gelieting compositions；The film forming agent
One kind or many in the fine element of hydroxypropyl methylcellulose, hydroxypropyl cellulose, propyl methocel, methylcellulose and ethyl
Kind；Plasticizer is selected from the one or more in polyethylene glycol, propane diols, triethyl citrate, glyceryl triacetate；Opacifier is selected
From titanium dioxide；Colouring agent is selected from pigment, inorganic pigment, FD＆C red No. 3, FD＆C red 20, FD＆C yellow 6, FD＆C
In blueness 2, D＆C greens 5, orange No. 5 of D＆C, D＆C red No. 8, caramel, iron oxide red, iron oxide yellow and ferrous oxide
It is one or more；
Further.Opadry I or Opadry II is mainly included in Coating Suspension；
Alternatively, the part excipient as additional particle, such as partial disintegration agent are added before step f mixing
And/or diluent.
In another alternative form of the method, step a to d particle produced in one pot of high shear stress prilling process and
Then dried in one pot of comminutor.
For preparing capsule, the mixture obtained by step d is further filled into capsule.
In trial prepares the pharmaceutical composition of the inhibitor of DPP IV, inventor has found the inhibitor of DPP IV in production process
In occur in that different degrees of stability problem, such as degraded or extraction problem, the DPP particularly with primary amino radical or secondary amino group
The performance of IV inhibitor is particularly evident, and the Li Gelieting of the present invention possesses this kind of chemical combination as one kind in the inhibitor of DPP IV
The core skeleton of thing, the functional group such as amino, secondary amine, tertiary amine groups present in its structure Ge Lieting that makes to get profit is same in preparation
It is faced with above-mentioned difficulty.Therefore, select suitable auxiliary material or optimize the technique of preparation to become one and urgently to be resolved hurrily ask
Topic.
Pharmaceutical composition of the inhibitor of DPP IV and preparation method thereof disclosed in CN101437493A, wherein existing substantially
Defect.
First, inventor has found, the diluent species used in CN101437493A composition is more, especially second
The risk that diluent pregelatinized starch not only increases preparation also add preparation cost.Although pregelatinized starch is used as a kind of property
Good multi-functional auxiliary material of fine quality is widely applied in the production of the solid pharmaceutical preparations such as tablet and capsule, but is due to existing skill
It is not strict to pregelatinated extent control in art, cause the pregelatinated degree of the pregelatinized starch of different manufacturers production different, cause
Drug-eluting is larger by the species of pregelatinized starch, source impact, and quality control is more difficult, and external pregelatinized starch valency
Lattice are higher, using can substantially increase cost.
Secondly, inventor has found what is used as adhesive during the inhibitor formulations stability of DPP IV is studied
Contain a large amount of amide groups in copovidone, the group can be with the formation intramolecular of the N atoms in the inhibitor of DPP IV
Hydrogen bond, so as to influence the dissolution of medicine；, also can be to the stability of medicine and molten in addition, the aldehyde radical contained in copolyvidone impurity
Go out and produce certain influence.
Finally, inventor is in production process, and discovery prior art needs first that adhesive is molten when preparing the pharmaceutical composition
Solution, to produce granulation liquid, is then then granulated in solvent with granulation liquid wetting pre-composition.This granulation mode lack
Fall into, one is that process is more, influence production efficiency；Two be that the addition that possible cause adhesive is not known.
The defect of three aspects brings such as production cost and process increase, production for preparation more than present in prior art
The problems such as quality and production efficiency decline.
The present invention mainly brings following beneficial effect by improvements over the prior art：
The present invention combines bulk drug Li Gelieting physics and chemistry feature, and auxiliary material is screened, by diluent, bonding
The ingenious selection of agent, disintegrant and lubricant, reduce the species of auxiliary material, it is to avoid the use of pregelatinized starch, overcomes pre-
Risk that gelling starch is brought is big, the unmanageable defect of quality；
Present invention overcomes domestic copolyvidone source less, the expensive defect of import price, in prescription of the present invention
Avoid replacing with hydroxypropyl cellulose using copolyvidone or by the almost full copolyvidone by import, its price is less than altogether
The 1/4 of PVP, significantly reduces cost, it is to avoid the quality problems that copolyvidone is brought to inventive compound；.
Prior art usual way when preparing same type pharmaceutical composition is first to be dissolved in solvent to produce by adhesive
Raw granulation liquid, then soaks pre-composition with granulation liquid, is then granulated.Because pre-composition is dissolved in the speed in a small amount of solvent
Degree is slower, spends the time long, the production cycle can be caused to extend, and reduces production efficiency；In addition, being needed in preparation process to solvent
Consumption is adjusted, and can so cause the addition of adhesive in the pre-composition that has been mixed with part granulation liquid inaccurate.This
Invention in the preparation directly mixes adhesive with Li Gelieting, diluent and disintegrant, then adds wetting agent, it is to avoid
Multiple wet operation, simplifies process, improves production efficiency and product quality.
Li Gelieting pharmaceutical compositions prepared by the present invention are shown with preferably dissolution rate, are conducive to improving Li Gelieting
The bioavilability of medicine；Li Gelieting contents are higher in pharmaceutical composition, after 60 DEG C of temperature are placed 10 days, prepared by the present invention
Li Gelieting pharmaceutical compositions the miscellaneous and total miscellaneous content rise of list it is seldom, reduce drug toxicity, improve drug safety；This
Li Gelieting pharmaceutical compositions, preparation prescription and its process of preparing of application are stable, favorable reproducibility, the one of multiple batches of production
Cause property is high, it can be ensured that product quality is stably and controllable；Improving different batches of product, (such as gastric acid secretion is not enough for different crowd
Patient) difference of body absorption is likely to result in, it is advantageously implemented preparation amplification industrialization.
Obviously, according to the above of the present invention, according to the ordinary technical knowledge and customary means of this area, do not departing from
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification of other diversified forms can also be made, replaces or changes.
Brief description of the drawings
The stripping curve of Li Gelieting drug composition products prepared by Fig. 1 comparative examples 1 in different dissolution mediums
The stripping curve of Li Gelieting drug composition products prepared by Fig. 2 embodiments 3 in different dissolution mediums
Stripping curve of the commercially available Li Gelieting formulation products of Fig. 3 different batches in 0.1N HCl solution
The Li Gelieting drug composition products of different batches prepared by Fig. 4 embodiments 3 are molten in 0.1N HCl solution
Go out curve
Embodiment
The embodiment of form, further specifically to the above work of the present invention by the following examples
It is bright.But the scope that this should not be interpreted as to above-mentioned theme of the invention is only limitted to following example.It is all to be based on the above of the present invention
The technology realized belongs to the scope of the present invention.
Wetting agent is water in following examples；Hydroxypropyl methylcellulose, talcum powder, titanium dioxide are mainly included in Coating Suspension
Titanium, polyethylene glycol.
The preparation of the pharmaceutical composition of the present invention of embodiment 1
[preparation technology]
A, Li Gelieting, mannitol, hydroxypropyl cellulose be prepared by mixing into pre-composition；
B, magnesium stearate finally mixed more than in mixed powder；
C, the final mixture is pressed into label；
D, prepare Coating Suspension；
E, the label is coated to weightening about 2-4% to produce film-coated tablet with the film coating suspension.
The preparation of the pharmaceutical composition of the present invention of embodiment 2
[preparation technology]
A, Li Gelieting, mannitol, hydroxypropyl methyl cellulose and starch is prepared by mixing into pre-composition；
B, the pre-composition for preparing a steps, add wetting agent wetting, granulation；
C, sieving：Particle prepared by b step is sieved by the sieve of the mesh of screen size 20, by particle in about 60 DEG C with
Lower drying, untill the loss on drying value needed for is reached in the range of 0.5-2%, dry particle is sieved through 20 mesh sieves；
D, by magnesium stearate be added to particle in finally mixed；
E, the final mixture is pressed into label；
F, Coating Suspension is prepared, the label is coated to weightening about 2-4% with the film coating suspension to produce film coating piece
Agent.
The preparation of the pharmaceutical composition of the present invention of embodiment 3
[preparation technology]
A, Li Gelieting, mannitol, hydroxypropyl methyl cellulose and starch is prepared by mixing into pre-composition；
B, the pre-composition for preparing a steps, add wetting agent wetting, granulation；
C, sieving：Particle prepared by b step is sieved by the sieve of the mesh of screen size 20, by particle in about 60 DEG C with
Lower drying, untill the loss on drying value needed for is reached in the range of 0.5-2%, dry particle is sieved through 20 mesh sieves；
D, by magnesium stearate be added to particle in finally mixed；
E, the final mixture is pressed into label；
F, Coating Suspension is prepared, the label is coated to weightening about 2-4% with the film coating suspension to produce film coating piece
Agent.
The preparation of the pharmaceutical composition of the present invention of embodiment 4
[preparation technology]
A, Li Gelieting, mannitol, hydroxypropyl methyl cellulose be prepared by mixing into pre-composition；
B, starch, which adds water, is made as about 10% concentration starch slurry, and starch slurry granulation is added into pre-composition；
C, sieving：Particle prepared by b step is sieved by the sieve of the mesh of screen size 20, by particle in about 60 DEG C with
Lower drying, untill the loss on drying value needed for is reached in the range of 0.5-2%, dry particle is sieved through 20 mesh sieves；
D, by magnesium stearate be added to particle in finally mixed；
E, the final mixture is pressed into label；
F, Coating Suspension is prepared, the label is coated to weightening about 2-4% with the film coating suspension to produce film coating piece
Agent.
The preparation of the pharmaceutical composition of the present invention of embodiment 5
[preparation technology]
A, Li Gelieting, mannitol, HPMC, hydroxypropyl cellulose be prepared by mixing into pre-composition；
B, the pre-composition for preparing a steps, add wetting agent wetting, granulate,
C, sieving：Particle prepared by b step is sieved by the sieve of the mesh of screen size 20, by particle in about 60 DEG C with
Lower drying, untill the loss on drying value needed for is reached in the range of 0.5-2%, dry particle is sieved through 20 mesh sieves；
D, by magnesium stearate be added to particle in finally mixed；
E, the final mixture is pressed into label；
F, Coating Suspension is prepared, the label is coated to weightening about 3-4% with the film coating suspension to produce film coating piece
Agent.
The preparation of the pharmaceutical composition of the present invention of embodiment 6
[preparation technology]
A, Li Gelieting, mannitol, HPMC, sodium carboxymethyl starch be prepared by mixing into pre-composition；
B, the pre-composition for preparing a steps, add wetting agent wetting, granulation；
C, sieving：Particle prepared by b step is sieved by the sieve of the mesh of screen size 20, by particle in about 60 DEG C with
Lower drying, untill the loss on drying value needed for is reached in the range of 0.5-2%, dry particle is sieved through 20 mesh sieves；
D, by magnesium stearate be added to particle in finally mixed；
E, the final mixture is pressed into label；
F, Coating Suspension is prepared, the label is coated to weightening about 3-4% with the film coating suspension to produce film coating piece
Agent
The preparation of the pharmaceutical composition of the present invention of embodiment 7
[preparation technology]
A, Li Gelieting, mannitol, hydroxypropyl methylcellulose, Ac-Di-Sol be prepared by mixing into pre-composition；
B, the pre-composition for preparing a steps, add wetting agent wetting, granulation；
C, sieving：Particle prepared by b step is sieved by the sieve of the mesh of screen size 20, by particle in about 60 DEG C with
Lower drying, untill the loss on drying value needed for is reached in the range of 0.5-2%, dry particle is sieved through 20 mesh sieves；
D, by magnesium stearate be added to particle in finally mixed；
E, the final mixture is pressed into label；
F, Coating Suspension is prepared, the label is coated to weightening about 3-4% with the film coating suspension to produce film coating piece
Agent
The preparation of the pharmaceutical composition of the present invention of embodiment 8
[preparation technology]
A, Li Gelieting, xylitol, low-substituted hydroxypropyl cellulose and starch is mixed with pre-composition；
B, the pre-composition for preparing a steps, add wetting agent wetting, granulation；
C, sieving：Particle prepared by b step is sieved by the sieve of the mesh of screen size 20, by particle in about 60 DEG C with
Lower drying, untill the loss on drying value needed for is reached in the range of 0.5-2%, dry particle is sieved through 20 mesh sieves；
D, by magnesium stearate be added to particle in finally mixed；
E, the final mixture is pressed into label；
F, Coating Suspension is prepared, the label is coated to weightening about 3-4% with the film coating suspension to produce film coating piece
Agent.
The preparation of the pharmaceutical composition of the present invention of embodiment 9
[preparation technology]
A, Li Gelieting, xylitol, hydroxypropyl methyl cellulose and starch is mixed with pre-composition；
B, the pre-composition for preparing a steps, add wetting agent wetting, granulation；
C, sieving：Particle prepared by b step is sieved by the sieve of the mesh of screen size 20, by particle in about 60 DEG C with
Lower drying, untill the loss on drying value needed for is reached in the range of 0.5-2%, dry particle is sieved through 20 mesh sieves；
D, by magnesium stearate be added to particle in finally mixed；
E, the final mixture is pressed into label；
F, Coating Suspension is prepared, the label is coated to weightening about 2-4% with the film coating suspension to produce film coating piece
Agent.
The preparation of the pharmaceutical composition of the present invention of embodiment 10
[preparation technology]
A, Li Gelieting, xylitol, hydroxypropyl cellulose and Ac-Di-Sol be mixed with pre-composition；
B, the pre-composition for preparing a steps, add wetting agent wetting, granulation；
C, sieving：Particle prepared by b step is sieved by the sieve of the mesh of screen size 20, by particle in about 60 DEG C with
Lower drying, untill the loss on drying value needed for is reached in the range of 0.5-2%, dry particle is sieved through 20 mesh sieves；
D, by magnesium stearate be added to particle in finally mixed；
E, the final mixture is pressed into label；
F, Coating Suspension is prepared, the label is coated to weightening about 3-4% with the film coating suspension to produce film coating piece
Agent.
The preparation of the pharmaceutical composition of the present invention of embodiment 11
[preparation technology]
A, Li Gelieting, xylitol, hydroxypropyl methyl cellulose and carboxyrnethyl starch sodium be mixed with pre-composition；
B, the pre-composition for preparing a steps, add wetting agent wetting, granulation；
C, sieving：Particle prepared by b step is sieved by the sieve of the mesh of screen size 20, by particle in about 60 DEG C with
Lower drying, untill the loss on drying value needed for is reached in the range of 0.5-2%, dry particle is sieved through 20 mesh sieves；
D, by magnesium stearate be added to particle in finally mixed；
E, the final mixture is pressed into label；
F, Coating Suspension is prepared, the label is coated to weightening about 2-4% with the film coating suspension to produce film coating piece
Agent.
Comparative example 1
[preparation technology]
A, Li Gelieting, mannitol, starch, pregelatinized starch be mixed with pre-composition；Copolyvidone is dissolved in pure water
It is middle to be used as adhesive；
B, the pre-composition for preparing a steps, are granulated after adding adhesive wetting；
C, sieving：Particle prepared by b step is sieved by the sieve of the mesh of screen size 20, by particle in about 60 DEG C with
Lower drying, untill the loss on drying value needed for is reached in the range of 0.5-2%, dry particle is sieved through 20 mesh sieves；
D, by magnesium stearate be added to particle in finally mixed；
E, the final mixture is pressed into label；
F, Coating Suspension is prepared, the label is coated to weightening about 2-4% with the film coating suspension to produce film coating piece
Agent.
The correlated quality parameter of Li Gelieting compositions of the present invention and comparative example 1 is contrasted below by way of testing inspection, with
Prove beneficial effects of the present invention.
1. dissolution detection method：Tested with reference to the method for four annex of Chinese Pharmacopoeia version in 2015 0931 first.China
The method of four annex of pharmacopeia version in 2015 0931 first is basket method, and rotating speed is 50rpm.
2. content and impurity determination method：Determined with reference to two annex V D of Chinese Pharmacopoeia version in 2010.
Test example 1：
According to above-mentioned detection method, in the HCl solution that dissolution medium is 0.1N, to the Li Gelieting prepared by the present invention
The dissolution rate and Li Gelieting contents of Li Gelieting pharmaceutical compositions prepared by pharmaceutical composition and comparative example 1 are detected, are examined
Survey the results are shown in Table 1.
Table 1
| Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | Comparative example 1 | |
| Dissolution rate (%) | 98.0 | 98.9 | 98.6 | 99.1 | 95.3 |
| Li Gelieting contents (%) | 99.6 | 99.7 | 99.8 | 99.6 | 98.7 |
The test data of table 1 is shown, in 0.1N HCl solution, Li Gelieting pharmaceutical composition dissolutions prepared by the present invention
Degree is more than 98%, better than 95.3% dissolution rate of comparative example 1；Sharp lattice in Li Gelieting pharmaceutical compositions prepared by the present invention
Spit of fland content is arranged more than 99.5%, higher than 98.7% content of comparative example 1.
According to above-mentioned detection method, by taking the embodiment of the present invention 4 as an example, the Li Gelieting drug regimens that will be prepared by the present invention
Li Gelieting pharmaceutical compositions prepared by thing and comparative example 1 are (relevant to impurity content after at a temperature of 60 DEG C place 10 days
Material) detected that impurity growth rate when impurity content was compared to 0 day in com-parison and analysis composition the results are shown in Table 2.
It is maximum single during maximum single miscellaneous growth rate %=(at 10 days maximum single miscellaneous content -0 day when maximum single miscellaneous content)/0 day
Miscellaneous content %；
Total miscellaneous content % during total miscellaneous growth rate %=(at 10 days total miscellaneous content -0 day when total miscellaneous content)/0 day；
Table 2
| Embodiment 4 | Comparative example 1 | |
| Maximum single miscellaneous growth rate：(%) | 0 | 200 |
| Total miscellaneous growth rate (%) | 33.3 | 100 |
The test data of table 2 is shown, after 60 DEG C of temperature are placed 10 days, the Li Gelieting medicines prepared relative to comparative example 1
In composition, maximum single miscellaneous content increases 200%, and total miscellaneous content increases 100%；Li Ge prepared by the embodiment of the present invention 4
The single miscellaneous content of maximum in the pharmaceutical composition of spit of fland is arranged without growth, total miscellaneous content increases 33.3%；Prepared by the embodiment of the present invention 4
The single miscellaneous and total miscellaneous content growth rate of maximum of Li Gelieting pharmaceutical compositions is significantly lower than Li Gelieting medicines prepared by comparative example 1
Maximum single miscellaneous and total miscellaneous content growth rate in compositions.
Comprehensive Tables 1 and 2 result shows prepared by the Li Gelieting pharmaceutical compositions prepared relative to comparative example 1, the present invention
Li Gelieting pharmaceutical compositions show with preferably dissolution rate；Li Gelieting contents are higher in pharmaceutical composition；At 60 DEG C
After temperature is placed 10 days, the growth rate of the miscellaneous and total miscellaneous content of the list of Li Gelieting pharmaceutical compositions prepared by the present invention is substantially less than
The growth rate of the miscellaneous and total miscellaneous content of Li Gelieting pharmaceutical composition lists prepared by comparative example 1.Be conducive to improving Li Gelieting medicines
Bioavilability, reduce drug toxicity, improve drug safety；The preparation for being advantageously implemented Li Gelieting pharmaceutical compositions is put
Big industrialization.
The Li Gelieting pharmaceutical compositions of technical scheme have dissolution rate and impurity content similar to the above
Characteristic, is equally beneficial for the bioavilability of Li Gelieting medicines, reduces drug toxicity, improves drug safety and realizes preparation
Amplification industrialization.
Test example 2：
According to above-mentioned detection method, the profit prepared to the Li Gelieting pharmaceutical compositions and comparative example 1 prepared by the present invention
Ge Lieting pharmaceutical compositions and commercially available Li Gelieting formulation products carry out the detection of stripping curve in different medium.
Li Gelie prepared by Li Gelieting pharmaceutical compositions and the embodiment of the present invention 3 prepared by the comparative example 1 of same batch
Spit of fland pharmaceutical composition, divides in 0.1N HCl solution (pH1.0), pH4.5 acetate buffers and pH6.8 phosphate buffers
Not carry out stripping curve measure, as depicted in figs. 1 and 2.
Take the commercially available Li Gelieting formulation products of different batches, and three batches the profit that is prepared with embodiment 3 of the present invention
The said goods are carried out stripping curve measure by Ge Lieting pharmaceutical compositions in 0.1N HCl solution, investigate product different batches
Batch between uniformity, as shown in Figure 3 and Figure 4.
Fig. 1 stripping curve shows that the Li Gelieting pharmaceutical compositions with the preparation of a batch of comparative example 1 are in different dissolutions
Deposited in medium 0.1N HCl solution (pH1.0), pH4.5 acetate buffers and pH6.8 phosphate buffers between stripping curve
In larger difference.
Fig. 2 stripping curve shows that the Li Gelieting pharmaceutical compositions with the preparation of a batch of embodiment of the present invention 3 are not
With stripping curve in dissolution medium 0.1N HCl solution (pH1.0), pH4.5 acetate buffers and pH6.8 phosphate buffers
It is basically identical.
Fig. 3 stripping curve is shown, in 0.1N HCl solution, the commercially available Li Gelieting preparations production of three batches of different batches
The stripping curve of product has notable difference, and differences between batches are larger.
Fig. 4 stripping curve is shown, in 0.1N HCl solution, the Li Gelie of the preparation of the embodiment of the present invention 3 of three batches
The stripping curve of spit of fland pharmaceutical composition is basically identical.
Complex chart 1 to Fig. 4 stripping curve illustrates, the Li Gelieting pharmaceutical compositions and commercially available prepared with comparative example 1
Li Gelieting formulation products compare, the embodiment of the present invention 3 prepare Li Gelieting drug composition products, the profit of different batches
Ge Lieting drug composition product dissolved corrosions have good uniformity；Li Gelieting drug composition products with batch exist
Dissolved corrosion equally has preferable uniformity in different medium.Illustrate the Li Gelieting pharmaceutical compositions of the application, at preparation
Side and its process of preparing are stable, favorable reproducibility, and the uniformity of multiple batches of production is high, it can be ensured that product quality is stable can
Control；Improve different batches of product and be likely to result in the difference of body absorption for different crowd (such as gastric acid secretion deficiency patient).
The Li Gelieting pharmaceutical compositions of technical scheme have Dissolution behaviours similar to the above.
Claims (10)
1. a kind of Li Gelieting pharmaceutical compositions, it is characterised in that：Include Li Gelieting or its salt, ester, derivative and can medicine
Diluent, adhesive, disintegrant and lubricant, wherein the diluent only includes a kind of diluent.
2. Li Gelieting pharmaceutical compositions as claimed in claim 1, it is characterised in that：The composition includes following weight hundred
Divide the supplementary material of content：
Preferably：
3. Li Gelieting pharmaceutical compositions as claimed in claim 1 or 2, it is characterised in that：Described diluent is cellulose
One in powder, calcium phosphate dibasic anhydrous, calcium phosphate dibasic dihydrate, xylitol, hydroxypropyl cellulose, mannitol or xylitol
Plant, preferably one kind in mannitol or xylitol；The lubricant is talcum powder, polyethylene glycol, behenic acid calcium, stearic acid
One or more, preferably magnesium stearate and/or talcum powder in calcium, rilanit special or magnesium stearate；Described adhesive is shallow lake
It is one or more in powder, hydroxypropyl methyl cellulose or hydroxypropyl cellulose；The disintegrant is starch, carboxyrnethyl starch sodium, friendship
Join one or more in sodium carboxymethylcellulose or hydroxypropyl cellulose.
4. Li Gelieting pharmaceutical compositions as claimed in claim 3, it is characterised in that：The composition is by following weight percentage
The supplementary material of content is prepared from：
Or,
Or,
Or
Or
Or
Or
Or
5. Li Gelieting pharmaceutical compositions as claimed in claim 4, it is characterised in that：The composition is by following weight percentage
The supplementary material of content is prepared from：
Or
Or
Or
Or
Or
Or
Or
Or
Or
6. the Li Gelieting pharmaceutical compositions as described in claim 1-5 any one, it is characterised in that：Described composition is
Oral formulations, optionally capsule, granule, tablet or film-coated tablet, preferably tablet.
7. Li Gelieting pharmaceutical compositions described in claim 1-6 any one individually and/or with melbine and/or sulphur
Carbamide type medicine combines the purposes for preparing treatment diabetes medicament, and the diabetes are preferably type ii diabetes, more preferably
With renal function or the type ii diabetes of liver function damage patient.
8. a kind of method for preparing the Li Gelieting pharmaceutical compositions described in claim 1-6 any one, it is characterised in that：
1) by Li Gelieting or its salt, ester, derivative, diluent, adhesive, disintegrant mixing are prepared into pre-composition；Using appoint
Wetting agent is selected to carry out granulation processing to pre-composition；Then lubricant is added into obtained particle, mixed；Most afterwards through tabletting, bag
Clothing, that is, Ge Lieting pharmaceutical compositions of getting profit；
Or 2) by Li Gelieting or its salt, ester, derivative, diluent, disintegrant, lubricant, adhesive are mixed successively, without
Granulation processing directly carries out tabletting, is coated, and then obtains Li Gelieting pharmaceutical compositions.
9. method as claimed in claim 8, is comprised the following steps：
A, pre-composition：Li Gelieting, diluent, adhesive, disintegrant are mixed, pre-composition is prepared into；
B, granulation：Wetting agent wetting is optionally added into pre-composition, particle is prepared by granulation, dry and whole grain step；
Optional c containing step, sieving：The pellet through sieves that step b is prepared；
D, mixing：Lubricant is added into particle, is well mixed；
E, tabletting：Mixture in step d is suppressed into tablet；
Optional, the tablet is also comprised the following steps：
F, Coating Suspension is prepared, be coated.
10. the method for Li Gelieting pharmaceutical compositions as claimed in claim 9, it is characterised in that：In step b, pass through wet method
Mixer-granulator is granulated, and the drying is optionally carried out in fluidized bed dryer；Drying temperature is 40-75 DEG C；The profit
Humectant is that optional water, ethanol, methanol, isopropanol or acetone are one or more, preferably water；Wherein, in step c, in step c,
The screen size of the sieving is no more than 0.6mm；In step f, the weight percentage of the Coating Suspension is Li Gelieting
The 2-5% of composition.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2016101346275 | 2016-03-09 | ||
| CN201610134627 | 2016-03-09 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107174571A true CN107174571A (en) | 2017-09-19 |
| CN107174571B CN107174571B (en) | 2021-01-08 |
Family
ID=59829856
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710131664.5A Active CN107174571B (en) | 2016-03-09 | 2017-03-07 | Pharmaceutical composition of linagliptin and salts, esters and derivatives thereof and preparation method of pharmaceutical composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107174571B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110840856A (en) * | 2019-12-20 | 2020-02-28 | 青岛黄海制药有限责任公司 | Composition containing linagliptin and application thereof |
| CN115227661A (en) * | 2022-09-22 | 2022-10-25 | 北京惠之衡生物科技有限公司 | Linagliptin tablet and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102316861A (en) * | 2009-02-13 | 2012-01-11 | 贝林格尔.英格海姆国际有限公司 | Pharmaceutical composition comprising linagliptin and optionally a sglt2 inhibitor, and uses thereof |
| WO2014080384A1 (en) * | 2012-11-26 | 2014-05-30 | Ranbaxy Laboratories Limited | Pharmaceutical composition of linagliptin |
| EP2853257A1 (en) * | 2013-09-12 | 2015-04-01 | Sanovel Ilac Sanayi ve Ticaret A.S. | Pharmaceutical formulations of linagliptin |
| US20150283248A1 (en) * | 2014-04-02 | 2015-10-08 | Aurobindo Pharma Ltd. | Pharmaceutical compositions of Linagliptin and process for preparation thereof |
-
2017
- 2017-03-07 CN CN201710131664.5A patent/CN107174571B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102316861A (en) * | 2009-02-13 | 2012-01-11 | 贝林格尔.英格海姆国际有限公司 | Pharmaceutical composition comprising linagliptin and optionally a sglt2 inhibitor, and uses thereof |
| CN103751193A (en) * | 2009-02-13 | 2014-04-30 | 勃林格殷格翰国际有限公司 | Pharmaceutical composition comprising linagliptin and optional SGLT2 inhibitor and uses thereof |
| CN103751192A (en) * | 2009-02-13 | 2014-04-30 | 勃林格殷格翰国际有限公司 | Pharmaceutical composition comprising linagliptin and optional SGLT2 inhibitor and uses thereof |
| WO2014080384A1 (en) * | 2012-11-26 | 2014-05-30 | Ranbaxy Laboratories Limited | Pharmaceutical composition of linagliptin |
| EP2853257A1 (en) * | 2013-09-12 | 2015-04-01 | Sanovel Ilac Sanayi ve Ticaret A.S. | Pharmaceutical formulations of linagliptin |
| US20150283248A1 (en) * | 2014-04-02 | 2015-10-08 | Aurobindo Pharma Ltd. | Pharmaceutical compositions of Linagliptin and process for preparation thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110840856A (en) * | 2019-12-20 | 2020-02-28 | 青岛黄海制药有限责任公司 | Composition containing linagliptin and application thereof |
| CN115227661A (en) * | 2022-09-22 | 2022-10-25 | 北京惠之衡生物科技有限公司 | Linagliptin tablet and preparation method thereof |
| CN115227661B (en) * | 2022-09-22 | 2022-12-13 | 北京惠之衡生物科技有限公司 | Linagliptin tablet and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107174571B (en) | 2021-01-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107669683B (en) | Pharmaceutical composition containing sitagliptin and metformin | |
| CN101252920A (en) | Stable fixed-dose unitary formulations containing tenofovir, a surfactant, efavirenz and emtricitabine | |
| CN105878202A (en) | Tofacitinib citrate tablet and preparation method thereof | |
| CN103610650B (en) | A kind of isosorbide mononitrate slow-release micro-pill and preparation, preparation method | |
| CN100490807C (en) | Cephalofruxin ester liposome, its preparation and medicinal composition containing it | |
| CN103340829A (en) | Enteric coating pellet of proton pump inhibitor | |
| CN101695480A (en) | Olopatadine hydrochloride dispersible tablets, preparation method thereof and quality control method thereof | |
| CN107174571A (en) | A kind of Li Gelieting and its salt, ester, the pharmaceutical composition of derivative and preparation method thereof | |
| CN106265641A (en) | A kind of pharmaceutical composition containing vildagliptin and metformin and preparation method thereof | |
| CN109674754B (en) | Flupentixol and melitracen pharmaceutical composition and preparation thereof | |
| CN107998097A (en) | A kind of tablet containing olmesartan medoxomil and preparation method thereof | |
| CN102727447A (en) | Florfenicol controlled release preparation and preparation method thereof | |
| CN107412198A (en) | Duloxetine hydrochloride enteric slow release granule and preparation method thereof | |
| CN107213130B (en) | A kind of Entecavir Pharmaceutical composition, preparation method and applications | |
| CN104138365B (en) | A kind of telmisartan capsules agent and preparation method thereof | |
| CN108125918A (en) | Everolimus pharmaceutical composition | |
| CN104546667A (en) | Solid dispersion containing posaconazole and preparation method thereof | |
| CN107536831A (en) | A kind of composition and preparation method containing vildagliptin and melbine | |
| CN113209036A (en) | Azilsartan tablets and preparation method and application thereof | |
| CN106236727B (en) | A kind of analgin effervescent tablet and preparation method thereof | |
| CN103565767B (en) | Ranolazine sustained release tablets label, coating tablet and preparation method thereof | |
| CN114652696A (en) | Cetirizine hydrochloride tablet and preparation method thereof | |
| CN106176642B (en) | A kind of Disket and preparation method thereof for treating respiratory disease | |
| CN103893185B (en) | A kind of valsartan and Hydrochlorothiade dispersible tablet and preparation method thereof | |
| CN107349185B (en) | A kind of emtricitabine tablet and preparation method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |