CN107019674A - The pharmaceutical composition of the inhibitor of DPP IV - Google Patents
The pharmaceutical composition of the inhibitor of DPP IV Download PDFInfo
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- CN107019674A CN107019674A CN201710052062.0A CN201710052062A CN107019674A CN 107019674 A CN107019674 A CN 107019674A CN 201710052062 A CN201710052062 A CN 201710052062A CN 107019674 A CN107019674 A CN 107019674A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
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Abstract
The invention belongs to field of pharmaceutical preparations, it is related to the pharmaceutical composition of DPP IV inhibitor, in particular to 8 (bases of (R) 3 amino piperidine 1) 1 ([1,2,5] the thiadiazoles simultaneously methyl of [3,4 b] pyridine 5) 7 (base of 2 butine 1) 3 methyl xanthines pharmaceutical composition and preparation method thereof.The pharmaceutical composition of the present invention had both substantially increased CT 383 stability, and CT 383 bioavilability is added again, in process in leaching, showed good dissolution rate and dissolution rate；With excellent dissolution characteristic, stability and bioavilability, the technical barrier of the compound patent medicine of CT 383 is solved, is easy to Clinical practice.
Description
The reference of related application
This application claims the application number submitted in 2016 to State Intellectual Property Office of the People's Republic of China for 29th for 01 month
For the rights and interests of 201610065856.6 Chinese invention patent application.
Technical field
The application belongs to field of pharmaceutical preparations, and it is related to pharmaceutical composition of DPP-IV inhibitor and preparation method thereof.
Background technology
DPP-IV (DPP IV) is a kind of serine protease, and it is responsible for internal endogenous peptide (GLP-1 (7-
36) metabolic cleavage).Suppress DPP-IV to can be used for preventing and/or treating diabetes, especially type ii diabetes.At present
There are a variety of DPP-IV inhibitors to list, such as Egelieting, sitagliptin, BMS-477118, vildagliptin, BI 1356.
China Patent Publication No. CN102807568 discloses the thiadiazoles derivative shown in formula 7, and it has extraordinary
DPP-IV inhibitory activity.
However, there is certain difficulty in terms of druggability in the compound of formula 7, it is poor into salt rear stability, therefore need badly open
Hair had not only had the pharmaceutical composition of good biological availability but also the DPP-IV inhibitor with good stability, and suitable clinic makes
With.
The content of the invention
On the one hand the application provides a kind of pharmaceutical composition for including the compound of formula 7, it is characterised in that the chemical combination of formula 7
The dosage of thing is about 0.2-20mg, even more preferably about preferably from about 0.5-10mg, 1-5mg.
In some embodiments of the application, the formulation of the pharmaceutical composition of the application is selected from granule, tablet, capsule
Agent, pill or micropill preparation.
In the certain preferred embodiments of the application, the formulation of the pharmaceutical composition of the application is capsule, the glue
Capsule is made up of multiple micropills, and the dosage of the compound of capsule Chinese style 7 is about 0.2-20mg, preferably from about 0.5-10mg, more excellent
Elect about 1-5mg as.
In some embodiments of the present invention, the micropill includes from inside to outside：Capsule core and compound layer, wherein chemical combination
Nitride layer includes the compound of formula 7, and the weight ratio of wherein compound layer and capsule core is about 1:2-40, preferably from about 1:2-30, more preferably
It is about 1:4-25.
The species of the capsule core is not particularly limited, and those skilled in the art can eligibly select according to actual conditions, preferably
, affiliated capsule core is selected from microcrystalline cellulose capsule core, sucrose capsule core, starch capsule core or lactose capsule core.
In some embodiments of the application, the compound layer also includes adhesive.In some implementations of the application
In scheme, described adhesive is selected from hydroxypropyl cellulose, HPMC, methylcellulose, ethyl cellulose, ethoxy
Cellulose, sodium carboxymethylcellulose, PVP, copolyvidone, N- vinylpyrrolidones, Arabic gum or its mixture；It is preferred that
Hydroxypropyl cellulose, HPMC, sodium carboxymethylcellulose, PVP, copolyvidone or Arabic gum, more preferably hydroxyl
Propyl cellulose or sodium carboxymethylcellulose.
In some embodiments of the application, the compound layer is also optionally adjusted comprising filler, dispersant and/or pH
Save agent.In some embodiments of the application, the filler is selected from microcrystalline cellulose, mannitol, lactose, pregelatinized starch
Or its mixture, more preferably microcrystalline cellulose or mannitol.In some embodiments of the application, the dispersant, which is selected from, to be slided
Stone flour, magnesium stearate, stearic acid, hydrogenated vegetable oil, Compritol 888 ATO or its mixture, preferably talc powder.The application's
In some embodiments, the pH adjusting agent is selected from arginine, lysine, histidine, magnesium carbonate, dimeglumine, sodium carbonate, carbon
Sour hydrogen sodium or calcium carbonate.
In the certain preferred embodiments of the application, the weight ratio of the compound of formula 7 and pH adjusting agent is about 1:0.2-4.
In the certain preferred embodiments of the application, the pH adjusting agent is arginine.
In the certain preferred embodiments of the application, the micropill can also further comprise separation layer and/or overcoat.
In some embodiments of the application, the separation layer is included or preferably by selected from talcum powder, microcrystalline cellulose
Element, mannitol, copolyvidone, magnesium stearate, HPMC, PVP, sodium carboxymethylcellulose, methylcellulose,
At least two components composition in pectin and Arabic gum.
In some embodiments of the application, the overcoat is included or preferably by selected from talcum powder, microcrystalline cellulose
Element, mannitol, copolyvidone, magnesium stearate, HPMC, PVP, sodium carboxymethylcellulose, methylcellulose,
At least two components composition in pectin and Arabic gum.
In some embodiments of the application, the weight ratio that the separation layer accounts for pharmaceutical composition is about 1-35%, excellent
Elect about 2-30%, even more preferably about 4-25% as.
In some embodiments of the application, the weight ratio that the overcoat accounts for pharmaceutical composition is about 1-25%, excellent
Elect about 4-15%, even more preferably about 7-9% as.
In the further preferred embodiment of the application, the micropill is from inside to outside by capsule core (such as microcrystalline cellulose
Plain capsule core, sucrose capsule core, starch capsule core or lactose capsule core) and compound layer composition, for example as shown in Figure 1.
In another further preferred embodiment of the application, by capsule core, (for example crystallite is fine from inside to outside for the micropill
The plain capsule core of dimension, sucrose capsule core, starch capsule core or lactose capsule core), the compound layer and overcoat composition, such as such as Fig. 2
It is shown.
In another further preferred embodiment of the application, by capsule core, (for example crystallite is fine from inside to outside for the micropill
The plain capsule core of dimension, sucrose capsule core, starch capsule core or lactose capsule core), the separation layer and compound layer composition, such as such as Fig. 3
It is shown.
In another further preferred embodiment of the application, by capsule core, (for example crystallite is fine from inside to outside for the micropill
The plain capsule core of dimension, sucrose capsule core, starch capsule core or lactose capsule core), the separation layer, the compound layer and the overcoat group
Into for example as shown in Figure 4.
In addition, the application also provides another pharmaceutical composition for including the compound of formula 7, it changes comprising organic acid and formula 7
Compound, wherein isolating between the organic acid and the compound of the formula 7 by physics mode, and is coated with pellicle on its surface
Layer.
In some embodiments of the application, the organic acid be selected from citric acid, tartaric acid, vitamin C, malic acid,
Butanedioic acid, fumaric acid, maleic acid, glutamic acid or aspartic acid；Preferably citric acid, tartaric acid or malic acid；More preferably citric acid.
In some embodiments of the application, the compound of formula 7 and the weight ratio of the organic acid are about 1:0.5~
30；Preferably from about 1:1~15；Even more preferably about 1:2~10.
In some embodiments of the application, by weight, the semi-transparent film layer accounts for the gross weight of described pharmaceutical composition
About the 1%~about 25% of amount, preferably from about 2%~about 15%；More preferably from about 3%~about 10%.
In some embodiments of the application, the semi-transparent film layer includes water soluble compound and water-insoluble chemical combination
The weight ratio of thing, wherein water soluble compound and water-insoluble compound is about 1:0.05~20；Preferably from about 1:0.1~10；
Even more preferably about 1:0.2~4.
In some embodiments of the application, the water soluble compound be selected from methylcellulose, hydroxypropyl cellulose,
HPMC, PVP, sodium carboxymethylcellulose, Hydroxypropyl Methylcellulose Phathalate, pectin, cyclodextrin,
Galactomannans, mean molecule quantity are more than 4000 polyethylene glycol, gelatin, water-soluble monose, water-soluble polysaccharide or it is mixed
Compound；It is preferred that lactose, sucrose, methylcellulose, hydroxypropyl cellulose, HPMC, PEG6000, PVP or carboxylic
Sodium carboxymethylcellulose pyce；More preferably HPMC or hydroxypropyl cellulose.
In some embodiments of the application, the water-insoluble compound be selected from ethyl cellulose, HPMCAS,
HPMCP, methacrylic acid copolymer (such as EudragitE, EudragitR, EudragitS, Eudragit L,
EudragitRS, EudragitLD) or its mixture, preferred, ethyl, HPMCAS, Eudragit S100, Eudragit
L100 or HPMCP；Further preferred ethyl cellulose.
In some embodiments of the application, the semi-transparent film layer can also include antiplastering aid and/or plasticizer.At some
In embodiment, the antiplastering aid is selected from talcum powder, magnesium stearate, stearic acid, hydrogenated vegetable oil, Compritol 888 ATO or it is mixed
Compound；Preferably talc powder.In some embodiments, the plasticizer is selected from triethyl citrate, ATBC, glycerine
Triacetate, polyethylene glycol or its mixture；It is preferred that polyethylene glycol.
In some embodiments of the application, the formulation of the pharmaceutical composition of the application is selected from granule, tablet, capsule
Agent, pill or micropill preparation.
In the certain preferred embodiments of the application, described pharmaceutical composition is capsule, and the capsule is by multiple micro-
Ball is constituted, and micropill includes organic acid layer containing organic acid and the compound layer containing the compound of formula 7, organic acid layer and compound
The isolation of physics mode is carried out between layer in the form of separation layer.
In the certain preferred embodiments of the application, described pharmaceutical composition is tablet, and the tablet is sandwich construction,
Wherein described organic acid is provided in the form of organic acid layer, and the physics mode isolation is provided in the form of separation layer, the formula 7
Compound is provided in the form of compound layer.
In some embodiments of the application, organic acid layer optionally also comprising lubricant, adhesive and/or is filled out
Fill agent.
In some embodiments of the application, the lubricant is selected from magnesium stearate, superfine silica gel powder, talcum powder or it is mixed
Compound, more preferably magnesium stearate.In some embodiments of the application, described adhesive is selected from hydroxypropyl cellulose, hydroxypropyl
Methylcellulose, copolyvidone, sodium carboxymethylcellulose, methylcellulose, pectin, Arabic gum or its mixture, preferably hydroxyl
Propyl cellulose, HPMC, copolyvidone or Arabic gum, more preferably hydroxypropyl cellulose or Arabic gum.
In some embodiments of the application, the filler be selected from microcrystalline cellulose, lactose, starch, mannitol, pregelatinized starch,
Dextrin or its mixture, preferably microcrystalline cellulose.
In some embodiments of the application, the compound layer also include filler, adhesive, dispersant and/or
PH adjusting agent.In some embodiments of the application, the filler is selected from microcrystalline cellulose, mannitol, lactose, pregelatinated
Starch or its mixture, more preferably microcrystalline cellulose or mannitol.In some embodiments of the application, described adhesive choosing
From hydroxypropyl cellulose, HPMC, methylcellulose, hydroxyethyl cellulose, sodium carboxymethylcellulose, PVP,
Copolyvidone, N- vinylpyrrolidones, Arabic gum or its mixture；It is preferred that hydroxypropyl cellulose, HPMC, carboxylic
Sodium carboxymethylcellulose pyce, PVP, copolyvidone or Arabic gum, more preferably hydroxypropyl cellulose or sodium carboxymethylcellulose.
In some embodiments of the application, the dispersant is selected from talcum powder, magnesium stearate, stearic acid, hydrogenated vegetable oil, behenic acid
Glyceride or its mixture, preferably talc powder.In some embodiments of the application, the pH adjusting agent be selected from arginine,
Magnesium carbonate, dimeglumine, sodium carbonate, sodium acid carbonate or calcium carbonate.
In some embodiments of the application, the separation layer is included or preferably by selected from talcum powder, microcrystalline cellulose
Element, mannitol, copolyvidone, magnesium stearate, HPMC, PVP, sodium carboxymethylcellulose, methylcellulose,
At least two components composition in pectin and Arabic gum.
In the further preferred embodiment of the application, the micropill is from inside to outside by capsule core (such as microcrystalline cellulose
Plain capsule core, sucrose capsule core or lactose capsule core), organic acid layer, the separation layer, the compound layer and the semi-transparent film layer
Composition, for example as shown in Figure 5.
In another further preferred embodiment of the application, by capsule core, (for example crystallite is fine from inside to outside for the micropill
The plain capsule core of dimension, sucrose capsule core or lactose capsule core), the compound layer, the separation layer, organic acid layer and the pellicle
Layer composition, for example as shown in Figure 7.
In another further preferred embodiment of the application, by capsule core, (for example crystallite is fine from inside to outside for the micropill
The plain capsule core of dimension, sucrose capsule core or lactose capsule core), organic acid layer, the separation layer, the compound layer, water-soluble polymeric
Nitride layer and the semi-transparent film layer composition, for example as shown in Figure 6.
In some embodiments of the application, the water-soluble polymer layer include or preferably by selected from talcum powder,
Microcrystalline cellulose, mannitol, copolyvidone, magnesium stearate, HPMC, PVP, sodium carboxymethylcellulose, methyl
At least two components composition in cellulose, pectin and Arabic gum.
Another further aspect, is used to treat the suppression for benefiting from DPP-IV this application provides the pharmaceutical composition of the application in preparation
Purposes in the medicine of the disease of system.
In some embodiments of the application, the disease is preferably diabetes, more preferably type ii diabetes.
In the description of the present application, outer unless stated otherwise, CT-383 refers to compound shown in formula 7.
In the description of the present application, fluidisation medicine-feeding refers to be coated on suspension with fluid bed the side on the surface of solid particle
Method.
In the description of the present application, HPMCP refers to hydroxypropyl methylcellulose phthalate.
In the description of the present application, HPMCAS refers to acetic acid HPMC succinate.
Term " about " used herein has conventional sense.In some embodiments, when related to numerical value, it can manage
Solve as numerical value ± 10% or ± 5% or ± 2% or ± 1% or ± 0.5% or ± 0.1%.In other embodiments,
Word " about " is omitted to show exact value.
In the description of the present application, outer unless stated otherwise, semi-transparent film layer refers in dissolution medium (such as water, 0.1M hydrochloric acid
Deng) in there is certain intensity, and the coatings in duct can be produced.
The pharmaceutical composition of the application had both substantially increased CT-383 stability, and CT-383 biological utilisation is added again
Degree, in process in leaching, shows good dissolution rate and dissolution rate.The pharmaceutical composition of the application has excellent dissolution special
Property, stability and bioavilability, solve the technical barrier of CT-383 compound patent medicine, are easy to Clinical practice.
Brief description of the drawings
A kind of exemplary schematic diagram of Fig. 1 the application micropills.
Another exemplary schematic diagram of Fig. 2 the application micropills.
Another exemplary schematic diagram of Fig. 3 the application micropills.
Another exemplary schematic diagram of Fig. 4 the application micropills.
Another exemplary schematic diagram of Fig. 5 the application micropills.
Another exemplary schematic diagram of Fig. 6 the application micropills.
Another exemplary schematic diagram of Fig. 7 the application micropills.
Embodiment
Below with the technical scheme of specific embodiment exemplary illustration the application, but the protection domain of the application is not limited to
The scope of described embodiment.The reagent used is commercially available prod.
The preparation of the micropill of embodiment 1
Prescription：
Preparation method：
1st, the preparation technology of separation layer
1) HPMC of separation layer recipe quantity is weighed, appropriate purified water is added, it is about 5% to be prepared into concentration
(W/W) aqueous solution of HPMC；The talcum powder of separation layer recipe quantity is added, lasting stirring makes it be suspended；
2) microcrystalline cellulose capsule core is placed in fluid bed, by step 1) suspension even application in the surface of capsule core；
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers, particle 1 is obtained.
2nd, the preparation technology of compound layer
1) hydroxypropyl cellulose of recipe quantity is weighed, appropriate purified water is added, the hydroxyl that concentration is 2.5% (W/W) is prepared into
The aqueous solution of propyl cellulose；The arginine of recipe quantity is added, it is dissolved；The CT-383 of recipe quantity is added, is stirred, is formed
The suspension of uniform fine particle.
2) take particle 1 to be placed in fluid bed, above-mentioned suspension is fluidized and added medicine to.
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers, particle 2 is obtained.
3rd, the preparation technology of overcoat
1) HPMC of overcoat recipe quantity is weighed, appropriate purified water is added, it is about 5% to be prepared into concentration
(W/W) aqueous solution of HPMC；The talcum powder of overcoat recipe quantity is added, lasting stirring makes it be suspended；
2) particle 2 is placed in fluid bed, by step 1) suspension even application in the surface of capsule core；
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers.
4th, it is total mixed
Whole micropills of gained in step 3 are taken, is placed in total blending bucket and is mixed 10 minutes with 15 revs/min of rotating speed.
The preparation of the micropill of embodiment 2
Prescription：
Preparation method：
1st, the preparation technology of separation layer
1) HPMC of separation layer recipe quantity is weighed, appropriate purified water is added, it is about 5% to be prepared into concentration
(W/W) aqueous solution of HPMC；The talcum powder of separation layer recipe quantity is added, lasting stirring makes it be suspended；
2) microcrystalline cellulose capsule core is placed in fluid bed, by step 1) suspension even application in the surface of capsule core；
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers, particle 1 is obtained.
2nd, the preparation technology of compound layer
1) hydroxypropyl cellulose of recipe quantity is weighed, appropriate purified water is added, the hydroxyl that concentration is 2.5% (W/W) is prepared into
The aqueous solution of propyl cellulose；The arginine of recipe quantity is added, it is dissolved；The CT-383 of recipe quantity is added, is stirred, is formed
The suspension of uniform fine particle.
2) take particle 1 to be placed in fluid bed, above-mentioned suspension is fluidized and added medicine to.
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers.
3rd, it is total mixed
Whole micropills of gained in step 2 are taken, is placed in total blending bucket and is mixed 10 minutes with 15 revs/min of rotating speed.
The preparation of the micropill of embodiment 3
Prescription：
Preparation method：
1st, the preparation technology of compound layer
1) hydroxypropyl cellulose of recipe quantity is weighed, appropriate purified water is added, the hydroxyl that concentration is 2.5% (W/W) is prepared into
The aqueous solution of propyl cellulose；The arginine of recipe quantity is added, it is dissolved；The CT-383 of recipe quantity is added, is stirred, is formed
The suspension of uniform fine particle.
2) take microcrystalline cellulose capsule core to be placed in fluid bed, above-mentioned suspension is fluidized and added medicine to.
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers, particle 1 is obtained.
2nd, the preparation technology of overcoat
1) HPMC of overcoat recipe quantity is weighed, appropriate purified water is added, it is about 5% to be prepared into concentration
(W/W) aqueous solution of HPMC；The talcum powder of overcoat recipe quantity is added, lasting stirring makes it be suspended；
2) particle 1 is placed in fluid bed, by step 1) suspension even application in the surface of capsule core；
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers.
3rd, it is total mixed
Whole micropills of gained in step 2 are taken, is placed in total blending bucket and is mixed 10 minutes with 15 revs/min of rotating speed.
The preparation of the micropill of embodiment 4
Prescription：
Preparation method：
1) hydroxypropyl cellulose of recipe quantity is weighed, appropriate purified water is added, the hydroxyl that concentration is 2.5% (W/W) is prepared into
The aqueous solution of propyl cellulose；The arginine of recipe quantity is added, it is dissolved；The CT-383 of recipe quantity is added, is stirred, is formed
The suspension of uniform fine particle.
2) take microcrystalline cellulose capsule core to be placed in fluid bed, above-mentioned suspension is fluidized and added medicine to.
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers.
4) take step 3) in gained whole micropills, be placed in total blending bucket and mix 10 points with 15 revs/min of rotating speed
Clock.
The preparation of the micropill of embodiment 5
Prescription：
Preparation method：
1) hydroxypropyl cellulose of recipe quantity is weighed, appropriate purified water is added, the hydroxyl that concentration is 2.5% (W/W) is prepared into
The aqueous solution of propyl cellulose；The arginine of recipe quantity is added, it is dissolved；The CT-383 of recipe quantity is added, is stirred, is formed
The suspension of uniform fine particle.
2) take microcrystalline cellulose capsule core to be placed in fluid bed, above-mentioned suspension is fluidized and added medicine to.
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers.
4) take step 3) in gained whole micropills, be placed in total blending bucket and mix 10 points with 15 revs/min of rotating speed
Clock.
The preparation of the micropill of embodiment 6
Prescription：
Preparation method：
1) hydroxypropyl cellulose of recipe quantity is weighed, appropriate purified water is added, the hydroxyl that concentration is 2.5% (W/W) is prepared into
The aqueous solution of propyl cellulose；The arginine of recipe quantity is added, it is dissolved；The CT-383 of recipe quantity is added, is stirred, is formed
The suspension of uniform fine particle.
2) take microcrystalline cellulose capsule core to be placed in fluid bed, above-mentioned suspension is fluidized and added medicine to.
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers.
4) take step 3) in gained whole micropills, be placed in total blending bucket and mix 10 points with 15 revs/min of rotating speed
Clock.
The preparation of the micropill of embodiment 7
Prescription：
Preparation method：
1st, the preparation technology of separation layer
1) HPMC of separation layer recipe quantity is weighed, appropriate purified water is added, it is about 5% to be prepared into concentration
(W/W) aqueous solution of HPMC；The talcum powder of separation layer recipe quantity is added, lasting stirring makes it be suspended；
2) microcrystalline cellulose capsule core is placed in fluid bed, by step 1) suspension even application in the surface of capsule core；
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers, particle 1 is obtained.
4) take step 3) in gained whole micropills, be placed in total blending bucket and mix 10 points with 15 revs/min of rotating speed
Clock.
2nd, the preparation technology of compound layer
1) hydroxypropyl cellulose of recipe quantity is weighed, appropriate purified water is added, the hydroxyl that concentration is 2.5% (W/W) is prepared into
The aqueous solution of propyl cellulose；The arginine of recipe quantity is added, it is dissolved；The CT-383 of recipe quantity is added, is stirred, is formed
The suspension of uniform fine particle.
2) take particle 1 to be placed in fluid bed, above-mentioned suspension is fluidized and added medicine to.
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers.
3rd, it is total mixed
Whole micropills of gained in step 2 are taken, is placed in total blending bucket and is mixed 10 minutes with 15 revs/min of rotating speed.
The preparation of the micropill of embodiment 8
Prescription：
Preparation method：
1st, the preparation technology of separation layer
1) HPMC of separation layer recipe quantity is weighed, appropriate purified water is added, it is about 5% to be prepared into concentration
(W/W) aqueous solution of HPMC；The talcum powder of separation layer recipe quantity is added, lasting stirring makes it be suspended；
2) microcrystalline cellulose capsule core is placed in fluid bed, by step 1) suspension even application in the surface of capsule core；
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers, particle 1 is obtained.
2nd, the preparation technology of compound layer
1) hydroxypropyl cellulose of recipe quantity is weighed, appropriate purified water is added, the hydroxyl that concentration is 2.5% (W/W) is prepared into
The aqueous solution of propyl cellulose；The arginine of recipe quantity is added, it is dissolved；The CT-383 of recipe quantity is added, is stirred, is formed
The suspension of uniform fine particle.
2) take particle 1 to be placed in fluid bed, above-mentioned suspension is fluidized and added medicine to.
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers, particle 2 is obtained.
3rd, the preparation technology of overcoat
1) HPMC of overcoat recipe quantity is weighed, appropriate purified water is added, it is about 5% to be prepared into concentration
(W/W) aqueous solution of HPMC；The talcum powder of overcoat recipe quantity is added, lasting stirring makes it be suspended；
2) particle 2 is placed in fluid bed, by step 1) suspension even application in the surface of capsule core；
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers.
4th, it is total mixed
Whole micropills of gained in step 3 are taken, is placed in total blending bucket and is mixed 10 minutes with 15 revs/min of rotating speed.
The preparation of the micropill of embodiment 9
Prescription：
Preparation method：
1st, the preparation technology of separation layer
1) HPMC of separation layer recipe quantity is weighed, appropriate purified water is added, it is about 5% to be prepared into concentration
(W/W) aqueous solution of HPMC；The talcum powder of separation layer recipe quantity is added, lasting stirring makes it be suspended；
2) microcrystalline cellulose capsule core is placed in fluid bed, by step 1) suspension even application in the surface of capsule core；
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers, particle 1 is obtained.
2nd, the preparation technology of compound layer
1) hydroxypropyl cellulose of recipe quantity is weighed, appropriate purified water is added, the hydroxyl that concentration is 2.5% (W/W) is prepared into
The aqueous solution of propyl cellulose；The arginine of recipe quantity is added, it is dissolved；The CT-383 of recipe quantity is added, is stirred, is formed
The suspension of uniform fine particle.
2) take particle 1 to be placed in fluid bed, above-mentioned suspension is fluidized and added medicine to.
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers.
3rd, it is total mixed
Whole micropills of gained in step 2 are taken, is placed in total blending bucket and is mixed 10 minutes with 15 revs/min of rotating speed.
The preparation of the micropill of embodiment 10
Prescription：
Preparation method：
1) hydroxypropyl cellulose of recipe quantity is weighed, appropriate purified water is added, the hydroxyl that concentration is 2.5% (W/W) is prepared into
The aqueous solution of propyl cellulose；The arginine of recipe quantity is added, it is dissolved；The CT-383 of recipe quantity is added, is stirred, is formed
The suspension of uniform fine particle.
2) take microcrystalline cellulose capsule core to be placed in fluid bed, above-mentioned suspension is fluidized and added medicine to.
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers.
4) take step 3) in gained whole micropills, be placed in total blending bucket and mix 10 points with 15 revs/min of rotating speed
Clock.
The preparation of the micropill of embodiment 11
Prescription：
Preparation method：
1) hydroxypropyl cellulose of recipe quantity is weighed, appropriate purified water is added, the hydroxyl that concentration is 2.5% (W/W) is prepared into
The aqueous solution of propyl cellulose；The CT-383 of recipe quantity is added, stirring forms the suspension of uniform fine particle.
2) take microcrystalline cellulose capsule core to be placed in fluid bed, above-mentioned suspension is fluidized and added medicine to.
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers.
4) take step 3) in gained whole micropills, be placed in total blending bucket and mix 10 points with 15 revs/min of rotating speed
Clock.
The preparation of the CT-383 capsules of embodiment 12
Prescription：
| Component | Total amount (mg/ capsules) |
| Microcrystalline cellulose | 44 |
| Mannitol | 44 |
| Ac-Di-Sol | 3 |
| Hydroxypropyl cellulose | 2.5 |
| Magnesium stearate | 1.5 |
| CT-383 | 5 |
| It is total | 100 |
Preparation method：
1st, pre-process：Microcrystalline cellulose, Ac-Di-Sol, mannitol are subjected to drying and processing.
2nd, CT-383, microcrystalline cellulose, mannitol, hydroxypropyl cellulose and Ac-Di-Sol are sieved and mixed
Uniformly.
The 3rd, above powder is added to the magnesium stearate of total recipe quantity, is well mixed.
4th, by above intermediate 100mg, it is filled into No. 1 plant hollow capsule, obtains 5mg specification CT-383 capsules.
The preparation of the CT-383 capsules of embodiment 13
Micropill 224.5mg in Example 1, is filled into No. 1 plant hollow capsule, obtains 5mg specification CT-383 capsules.
The preparation of the CT-383 capsules of embodiment 14
Micropill 188.5mg in Example 2, is filled into No. 1 plant hollow capsule, obtains 5mg specification CT-383 capsules.
The preparation of the CT-383 capsules of embodiment 15
Micropill 188.5mg in Example 3, is filled into No. 1 plant hollow capsule, obtains 5mg specification CT-383 capsules.
The preparation of the CT-383 capsules of embodiment 16
Micropill 152.5mg in Example 4, is filled into No. 1 plant hollow capsule, obtains 5mg specification CT-383 capsules.
The preparation of the CT-383 capsules of embodiment 17
Micropill 143.5mg in Example 5, is filled into No. 1 plant hollow capsule, obtains 2mg specification CT-383 capsules.
The preparation of the CT-383 capsules of embodiment 18
Micropill 140.5mg in Example 6, is filled into No. 1 plant hollow capsule, obtains 1mg specification CT-383 capsules.
The preparation of the CT-383 capsules of embodiment 19
Micropill 162.5mg in Example 7, is filled into No. 1 plant hollow capsule, obtains 5mg specification CT-383 capsules.
The preparation of the CT-383 capsules of embodiment 20
Micropill 203.5mg in Example 8, is filled into No. 1 plant hollow capsule, obtains 5mg specification CT-383 capsules.
The preparation of the CT-383 capsules of embodiment 21
Micropill 177.5mg in Example 9, is filled into No. 1 plant hollow capsule, obtains 5mg specification CT-383 capsules.
The preparation of the CT-383 capsules of embodiment 22
Micropill 147.5mg in Example 10, is filled into No. 1 plant hollow capsule, obtains 5mg specification CT-383 capsules.
The preparation of the CT-383 capsules of embodiment 23
Micropill 152.5mg in Example 11, is filled into No. 1 plant hollow capsule, obtains 5mg specification CT-383 capsules.
The preparation of the tablet of embodiment 24
Prescription：
Preparation method：
1st, the preparation of adhesive：By the hydroxypropyl cellulose of recipe quantity, add purified water dissolving, be configured to 3% it is water-soluble
Liquid.
2nd, pelletize：By CT-383, microcrystalline cellulose, mannitol and Ac-Di-Sol, wet granulator is placed in
Middle premix, after being well mixed, the hydroxypropyl cellulose aqueous solution for plus 3% is pelletized, after fluidisation drying, crosses the progress of 30 mesh sieves whole
Grain.
The 3rd, above particle is added to the magnesium stearate of total recipe quantity, is well mixed.
4th, above intermediate is subjected to tabletting, the circular scrobicula punchings of selection 6.5mm control tablet hardness in 50~80N.
The preparation of the tablet of embodiment 25
Prescription：
| Component | Total amount (mg/ pieces) |
| Microcrystalline cellulose | 44 |
| Mannitol | 44 |
| Ac-Di-Sol | 3 |
| Hydroxypropyl cellulose | 2.5 |
| Magnesium stearate | 1.5 |
| CT-383 | 5 |
| It is total | 100 |
Preparation method：
1st, pre-process：Microcrystalline cellulose, Ac-Di-Sol, mannitol are subjected to drying and processing.
2nd, by CT-383, microcrystalline cellulose, mannitol, hydroxypropyl cellulose and Ac-Di-Sol, sieving is mixed
Close uniform.
The 3rd, above powder is added to the magnesium stearate of total recipe quantity, is well mixed.
4th, above intermediate is subjected to tabletting, the circular scrobicula punchings of selection 6.5mm control tablet hardness in 80~120N.
The preparation of the tablet of embodiment 26
Prescription：
| Component | Total amount (mg/ pieces) |
| Mannitol | 125.5 |
| Starch | 36 |
| Polyvinylpyrrolidone (VA64) | 10.8 |
| Magnesium stearate | 2.7 |
| CT-383 | 5 |
| Plate core weight | 180 |
Preparation method：
1st, the preparation of adhesive：By the polyvinylpyrrolidone of recipe quantity, purified water dissolving is added, 3% water is configured to
Solution, obtains solution 1.
2nd, CT-383, mannitol, starch, polyvinylpyrrolidone is added after preheating and be sufficiently mixed in fluid bed, to
It sprays into solution 1 and carries out fluidized granulation, and dry particl passes through pelletizing machine whole grain, mesh size after dryingRotating speed：
800rpm。
The 3rd, above particle is added to the magnesium stearate of total recipe quantity, is well mixed.
4th, above intermediate is subjected to tabletting, the circular scrobicula punchings of selection 7mm control tablet hardness in 50~80N.
The preparation of the tablet of embodiment 27
Prescription：
| Component | Total amount (mg/ pieces) |
| Microcrystalline cellulose | 44 |
| Mannitol | 44 |
| Ac-Di-Sol | 3 |
| Hydroxypropyl cellulose | 2.5 |
| Magnesium stearate | 1.5 |
| CT-383 | 5 |
| It is total | 100 |
Preparation method：
1st, the preparation of raw material suspension：By the hydroxypropyl cellulose of recipe quantity, purified water dissolving is added, 2.5% is configured to
The aqueous solution；The CT-383 of recipe quantity is added, it is uniformly dispersed, obtains suspension 1.
5th, microcrystalline cellulose, mannitol, Ac-Di-Sol is added after preheating and be sufficiently mixed in fluid bed,
Suspension 1 is sprayed into it and carries out fluidized granulation, and dry particl passes through pelletizing machine whole grain, mesh size after dryingRotating speed：
800rpm。
The 6th, above particle is added to the magnesium stearate of total recipe quantity, is well mixed.
7th, above intermediate is subjected to tabletting, the circular scrobicula punchings of selection 6.5mm control tablet hardness in 50~80N.
The preparation of the CT-383 coating tablets of embodiment 28
1st, stomach dissolved film coating pre-mix dose is taken, purified water is added, 10% solid content coating solution is prepared.
2nd, the label of the gained of embodiment 24 is coated, it is 80 DEG C to control EAT, and atomizing pressure is 1.0bar, is entered
Air quantity is 35m3/ h, engine speed is 6 revs/min, and control leaving air temp is between 38~45 DEG C；Coating closes feed liquor after terminating
And atomizing pressure, dry 5 minutes, coating weight gain 2-3%.
The preparation of the CT-383 coating tablets of embodiment 29
1st, stomach dissolved film coating pre-mix dose is taken, purified water is added, 10% solid content coating solution is prepared.
2nd, the label of the gained of embodiment 25 is coated, it is 0 DEG C to control EAT, and atomizing pressure is 1.3bar, is entered
Air quantity is 33m3/ h, engine speed is 6 revs/min, and control leaving air temp is between 38~45 DEG C；Coating closes feed liquor after terminating
And atomizing pressure, dry 5 minutes, coating weight gain 2-3%.
The preparation of the CT-383 coating tablets of embodiment 30
1st, stomach dissolved film coating pre-mix dose is taken, purified water is added, 10% solid content coating solution is prepared.
2nd, the label of the gained of embodiment 26 is coated, it is 0 DEG C to control EAT, and atomizing pressure is 1.3bar, is entered
Air quantity is 33m3/ h, engine speed is 6 revs/min, and control leaving air temp is between 38~45 DEG C；Coating closes feed liquor after terminating
And atomizing pressure, dry 5 minutes, coating weight gain 2-3%.
The preparation of the CT-383 coating tablets of embodiment 31
1st, stomach dissolved film coating pre-mix dose is taken, purified water is added, 10% solid content coating solution is prepared.
2nd, the label of the gained of embodiment 27 is coated, it is 0 DEG C to control EAT, and atomizing pressure is 1.3bar, is entered
Air quantity is 33m3/ h, engine speed is 6 revs/min, and control leaving air temp is between 38~45 DEG C；Coating closes feed liquor after terminating
And atomizing pressure, dry 5 minutes, coating weight gain 2-3%.
The preparation of the micropill of embodiment 32
Prescription：
Preparation method：
1st, the preparation technology of organic acid layer
1) citric acid (monohydrate) of recipe quantity is weighed, appropriate purified water is added, it is 36% (W/W's) to be prepared into concentration
The aqueous solution of citric acid (monohydrate)；
2) the microcrystalline cellulose capsule core of recipe quantity is weighed, is placed in fluid bed, it is 70m to control intake3/h±10m3/ h,
EAT is 70 DEG C ± 5 DEG C, and temperature of charge scope is at 45 DEG C ± 4 DEG C, and atomizing pressure is 2.0bar, by a citric acid (hydration
Thing) aqueous solution even application in the surface of microcrystalline cellulose capsule core；
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers, particle 1 is obtained.
2nd, the preparation technology of separation layer
1) HPMC of separation layer recipe quantity is weighed, appropriate purified water is added, it is about 5% to be prepared into concentration
(W/W) aqueous solution of HPMC；The talcum powder of separation layer recipe quantity is added, lasting stirring makes it be suspended；
2) particle 1 is placed in fluid bed, it is 70m to control intake3/h±10m3/ h, EAT is 70 DEG C ± 5 DEG C,
Temperature of charge is at 46 DEG C ± 5 DEG C, and atomizing pressure is 2.3bar, by step 1) suspension even application in the surface of particle 1；
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers, particle 2 is obtained.
3rd, the preparation technology of compound layer
1) hydroxypropyl cellulose of recipe quantity is weighed, appropriate purified water is added, it is 2.5% (W/W's) to be prepared into concentration
The HPC-SL aqueous solution；The arginine of recipe quantity is added, it is dissolved；The CT-383 of recipe quantity is added, is stirred, forms uniform
Fine particle suspension.
2) take particle 2 to be placed in fluid bed, above-mentioned suspension is fluidized and added medicine to.Technological parameter：Intake is 70m3/h±
10m3/ h, 70 DEG C ± 5 DEG C of EAT, temperature of charge controls 45 DEG C ± 5 DEG C, atomizing pressure 2.2bar.
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers, particle 3 is obtained.
4th, the preparation technology of semi-transparent film layer
1) ethyl cellulose and HPMC of the recipe quantity of semi-transparent film layer are weighed, ethanol in proper amount, stirring is added
To fully dissolving/being swelled, ethyl cellulose concentration is configured to for 0.8% (W/W), and HPMC concentration is 3.2% (W/
W solution).The talcum powder of semi-transparent film layer recipe quantity is added, stirring makes it be suspended, cross 24 eye mesh screens, it is standby.
2) take particle 3 to be placed in fluid bed, the suspension of above-mentioned semi-transparent film layer is fluidized and added medicine to.Technological parameter：Intake
For 70m3/h±10m3/ h, EAT is between 50 DEG C ± 5 DEG C, and temperature of charge is controlled between 34 DEG C ± 8 DEG C, and atomizing pressure exists
Between 1.5~1.8bar.
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers.
5th, it is total mixed
Whole micropills of gained in step 4 are taken, is placed in total blending bucket and is mixed 10 minutes with 15 revs/min of rotating speed.
The preparation of the micropill of embodiment 33
Prescription：
Preparation method be the same as Example 32.
The preparation of the micropill of embodiment 34
Prescription：
Preparation method be the same as Example 32.
The preparation of the micropill of embodiment 35
Prescription：
Preparation method be the same as Example 32.
The preparation of the micropill of embodiment 36
Prescription：
Preparation method be the same as Example 32.
The preparation of the micropill of embodiment 37
Prescription：
Preparation method：
1st, the preparation technology of organic acid layer
1) citric acid (monohydrate) of recipe quantity is weighed, appropriate purified water is added, it is 36% (W/W's) to be prepared into concentration
The aqueous solution of citric acid (monohydrate)；
2) the microcrystalline cellulose capsule core of recipe quantity is weighed, is placed in fluid bed, it is 70m to control intake3/h±10m3/ h,
EAT is 70 DEG C ± 5 DEG C, and temperature of charge scope is at 45 DEG C ± 4 DEG C, and atomizing pressure is 2.0bar, by a citric acid (hydration
Thing) aqueous solution even application in the surface of microcrystalline cellulose capsule core；
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers, particle 1 is obtained.
2nd, the preparation technology of separation layer
1) HPMC of separation layer recipe quantity is weighed, appropriate purified water is added, it is about 5% to be prepared into concentration
(W/W) aqueous solution of HPMC；The talcum powder of separation layer recipe quantity is added, lasting stirring makes it be suspended；
2) particle 1 is placed in fluid bed, it is 70m to control intake3/h±10m3/ h, EAT is 70 DEG C ± 5 DEG C,
Temperature of charge is at 46 DEG C ± 5 DEG C, and atomizing pressure is 2.3bar, by step 1) suspension even application in the surface of particle 1；
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers, particle 2 is obtained.
3rd, the preparation technology of compound layer
1) hydroxypropyl cellulose of recipe quantity is weighed, appropriate purified water is added, the hydroxyl that concentration is 2.5% (W/W) is prepared into
The aqueous solution of propyl cellulose；The arginine of recipe quantity is added, it is dissolved；The CT-383 of recipe quantity is added, is stirred, is formed
The suspension of uniform fine particle.
2) take particle 2 to be placed in fluid bed, above-mentioned suspension is fluidized and added medicine to.Technological parameter：Intake is 70m3/h±
10m3/ h, 70 DEG C ± 5 DEG C of EAT, temperature of charge controls 45 DEG C ± 5 DEG C, atomizing pressure 2.2bar.
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers, particle 3 is obtained.
4th, the preparation technology of water-soluble polymer layer
1) HPMC of water-soluble polymer layer recipe quantity is weighed, appropriate purified water is added, is prepared into concentration
It is the aqueous solution of about 5% (W/W) HPMC；The talcum powder of water-soluble polymer layer recipe quantity is added, is persistently stirred
Mixing makes it be suspended；
2) particle 3 is placed in fluid bed, it is 70m to control intake3/h±10m3/ h, EAT is 70 DEG C ± 5 DEG C,
Temperature of charge is at 46 DEG C ± 5 DEG C, and atomizing pressure is 2.3bar, by step 1) suspension even application in the surface of particle 3；
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers, particle 4 is obtained.
5th, the preparation technology of semi-transparent film layer
1) ethyl cellulose and HPMC of semi-transparent film layer recipe quantity are weighed, ethanol in proper amount is added, stirring is extremely
Fully dissolve/be swelled, be configured to ethyl cellulose concentration for 0.8% (W/W), HPMC concentration is 3.2% (W/W)
Solution, add the talcum powder of semi-transparent film layer recipe quantity, stirring makes it be suspended, cross 24 eye mesh screens, it is standby；
2) take particle 4 to be placed in fluid bed, above-mentioned semi-transparent film layer suspension fluidisation is added medicine to.Technological parameter：Intake is
70m3/h±10m3/ h, EAT is between 50 DEG C ± 5 DEG C, and temperature of charge is controlled between 34 DEG C ± 8 DEG C, and atomizing pressure is 1.5
Between~1.8bar；
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers.
6th, it is total mixed
Whole micropills of gained in step 5 are taken, are placed in total blending bucket, are mixed 10 minutes with 15 revs/min of rotating speed.
The preparation of the micropill of embodiment 38
Prescription：
Preparation method be the same as Example 37.
The preparation of the micropill of embodiment 39
Prescription：
Preparation method：
1st, the preparation technology of compound layer
1) hydroxypropyl cellulose of recipe quantity is weighed, appropriate purified water is added, the hydroxyl that concentration is 2.5% (W/W) is prepared into
The aqueous solution of propyl cellulose；The arginine of recipe quantity is added, it is dissolved；The CT-383 of recipe quantity is added, stirring makes it
Uniformly, the suspension of uniform fine particle is formed；
2) the microcrystalline cellulose pellets core of recipe quantity is weighed, is placed in fluid bed, it is 70m to control intake3/h±10m3/
H, EAT is 70 DEG C ± 5 DEG C, and 45 DEG C ± 4 DEG C of temperature of charge, atomizing pressure is 2.0bar, by step 1) suspension it is uniform
The surface of microcrystalline cellulose pellets core is sprayed at, the capsule core containing compound layer is prepared；
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers, particle 1 is obtained.
2nd, the preparation technology of separation layer
1) HPMC of separation layer recipe quantity is weighed, appropriate purified water is added, it is about 5% to be prepared into concentration
(W/W) aqueous solution of HPMC；The talcum powder of separation layer recipe quantity is added, lasting stirring makes it be suspended；
2) particle 1 is placed in fluid bed, it is 70m to control intake3/h±10m3/ h, EAT is 70 DEG C ± 5 DEG C,
Temperature of charge is at 46 DEG C ± 5 DEG C, and atomizing pressure is 2.3bar, by step 1) suspension even application in the surface of particle 1；
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers, particle 2 is obtained.
3rd, the preparation technology of organic acid layer
1) citric acid (monohydrate) and purified water of recipe quantity are weighed, the citric acid that concentration is 36% (W/W) is prepared into
The aqueous solution of (monohydrate)；
2) take particle 2 to be placed in fluid bed, the aqueous solution of citric acid (monohydrate) is fluidized and added medicine to.Technological parameter：Enter
Air quantity is 70m3/h±10m3/ h, 70 DEG C ± 5 DEG C of EAT, temperature of charge controls 45 DEG C ± 5 DEG C, atomizing pressure 2.2bar；
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers, particle 3 is obtained.
4th, the preparation technology of semi-transparent film layer
1) ethyl cellulose and HPMC of semi-transparent film layer recipe quantity are weighed, ethanol in proper amount is poured into, stirring is extremely
Fully dissolve/be swelled, be configured to ethyl cellulose concentration for 0.8% (W/W), HPMC concentration is 4.0% (W/W)
Solution.The talcum powder of semi-transparent film layer recipe quantity is added, stirring makes it be suspended, cross 24 eye mesh screens, it is standby；
2) take particle 3 to be placed in fluid bed, above-mentioned semi-transparent film layer suspension fluidisation is added medicine to.Technological parameter：Intake is
70m3/h±10m3/ h, EAT is between 50 DEG C ± 5 DEG C, and temperature of charge is controlled between 34 DEG C ± 8 DEG C, and atomizing pressure is 1.5
Between~1.8bar；
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers.
5th, it is total mixed
The micropill obtained by step 4 is taken, is placed in total blending bucket, is mixed 10 minutes with 15 revs/min of rotating speed.
The extrusion spheronization of embodiment 40 prepares acid capsule core
Prescription：
Preparation method：
1st, tartaric acid is crushed into 120 mesh sieves, and prepares powder tartaric acid.
2nd, the hydroxypropyl cellulose of the powder tartaric acid of recipe quantity, microcrystalline cellulose and organic acid layer recipe quantity is mixed.
3rd, add purified water as wetting agent and prepare softwood.
4th, by the softwood by extrusion spheronization machine to prepare the capsule core of micropill, sieve takes between the mesh of 20 mesh~30 after drying
Grain 1.
5th, the preparation technology of separation layer
1) hydroxypropyl cellulose and purified water of separation layer recipe quantity are weighed, the hydroxypropyl that concentration is about 5% (W/W) is prepared into
The aqueous solution of base cellulose；The talcum powder of separation layer recipe quantity is added, lasting stirring makes it be suspended；
2) particle 1 is placed in fluid bed, it is 70m to control intake3/h±10m3/ h, EAT is 70 DEG C ± 5 DEG C,
Temperature of charge is at 46 DEG C ± 5 DEG C, and atomizing pressure is 2.3bar, by step 1) suspension even application in the surface of particle 1；
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers, particle 2 is obtained.
6th, the preparation technology of compound layer
1) hydroxypropyl cellulose and purified water of Weigh Compound layer recipe quantity, are prepared into the hydroxyl that concentration is 2.5% (W/W)
The aqueous solution of propyl cellulose；The calcium carbonate of recipe quantity is added, it is dissolved；The CT-383 of recipe quantity is added, is stirred, is formed
The suspension of uniform fine particle.
2) take particle 2 to be placed in fluid bed, above-mentioned suspension is fluidized and added medicine to.Technological parameter：Intake is 70m3/h±
10m3/ h, 70 DEG C ± 5 DEG C of EAT, temperature of charge controls 45 DEG C ± 5 DEG C, atomizing pressure 2.2bar.
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers, particle 3 is obtained.
7th, the preparation technology of semi-transparent film layer
1) HPMCP (HPMCP) and hydroxy propyl cellulose of semi-transparent film layer recipe quantity are weighed
Element, adds ethanol in proper amount, stirs to fully dissolving/being swelled, is configured to HPMCP (HPMCP)
Concentration is 2% (W/W), and hydroxypropyl cellulose concentration is 2% (W/W) solution.The talcum powder of semi-transparent film layer recipe quantity is added,
Stirring makes it be suspended, and crosses 24 eye mesh screens, standby.
2) take particle 3 to be placed in fluid bed, above-mentioned semi-transparent film layer suspension fluidisation is added medicine to.Technological parameter：Intake is
70m3/h±10m3/ h, EAT is between 50 DEG C ± 5 DEG C, and temperature of charge is controlled between 34 DEG C ± 8 DEG C, and atomizing pressure is 1.5
Between~1.8bar.
3) 18 mesh standard sieves (1mm) are crossed to weed out multiple polymers.
The preparation of the tablet of embodiment 41
Prescription：
Preparation method：
1st, that citric acid (monohydrate) was crushed into 80 mesh sieves was standby.
2nd, it is the microcrystalline cellulose of organic acid layer recipe quantity, citric acid (monohydrate), copolyvidone and magnesium stearate is mixed
Cooperate as intermediate 1, it is standby.
3rd, the microcrystalline cellulose of separation layer recipe quantity, mannitol, copolyvidone and magnesium stearate are mixed and is used as intermediate
2, it is standby.
4th, by the CT-383 of compound layer recipe quantity, arginine, microcrystalline cellulose, mannitol, copolyvidone and stearic acid
Magnesium is mixed as intermediate 3, standby.
5th, the charging quantity of above intermediate 1 is set to 71mg, is used as lower floor；The charging quantity of intermediate 2 is set to 50.5mg, makees
For intermediate layer；The charging quantity of intermediate 3 is set to 75.7mg, is used as upper strata.
6th, the ethyl cellulose and hydroxypropyl cellulose of recipe quantity are dissolved by solvent of ethanol, the talcum powder of recipe quantity is added
Fully it is suspended, the tablet of above pastille is coated with above-mentioned suspension, it is 45 DEG C to control EAT, atomizing pressure is
0.6bar, intake is 39m3/ h, engine speed is 6 revs/min.Coating closes feed liquor and atomizing pressure after terminating, other ginsengs
Number is constant, dries 20 minutes.
The preparation of the tablet of embodiment 42
Prescription：
Preparation method：
1st, by citric acid (monohydrate), microcrystalline cellulose, mannitol and the hydroxypropyl methylcellulose of organic acid layer recipe quantity
Element mixing, plus purified water granulation, dry 2h at 50 DEG C in air dry oven, then cross 24 mesh sieve whole grains.
2nd, above particle is added in total blending bucket, weighs the magnesium stearate of recipe quantity, control hybrid parameter, with 15 turns/
Minute is total mixed 10 minutes.
3rd, above intermediate is subjected to tabletting, the scrobicula punching of selection 8mm prototypes controls tablet hardness in 70~100kN.
4th, the HPMC of separation layer recipe quantity is added in appropriate purified water and dissolved, be prepared into 5% hydroxypropyl
The aqueous solution of methylcellulose, adding the talcum powder of separation layer recipe quantity makes it be suspended.
5th, the label obtained by step 3 is coated with the suspension obtained by step 4, it is 75 DEG C, mist to control EAT
Change pressure is 0.8bar, and intake is 35m3/ h, engine speed is 6 revs/min, and control leaving air temp is between 38~45 DEG C；
Coating closes feed liquor and atomizing pressure after terminating, regulation EAT is 50 DEG C, is dried 20 minutes.
6th, the arginine and HPMC of compound layer recipe quantity are dissolved in appropriate purified water, are prepared into
The aqueous solution of 2.5% hydroxypropyl cellulose, adding the CT-383 and talcum powder of compound layer recipe quantity makes it be suspended.
7th, gained in step 5 is coated with the coated label of separation layer with the suspension obtained by step 6, control into
Air temperature is 75 DEG C, and atomizing pressure is 0.7bar, and intake is 35m3/ h, engine speed is 6 revs/min, controls leaving air temp
Between 38~42 DEG C；Coating closes feed liquor and atomizing pressure after terminating, regulation EAT is 50 DEG C, is dried 20 minutes.
8th, ethyl cellulose is dissolved in ethanol in proper amount, is prepared into the solution of 2.5% ethyl cellulose ethanol, added semi-transparent
The HPMC of film layer recipe quantity is fully swelled, and is added the talcum powder of semi-transparent film layer recipe quantity and it is suspended, is made half
Permeable membrane coating suspensions.
9th, the tablet obtained by step 7 is coated with above pellicle coating suspensions, it is 45 DEG C to control EAT,
Atomizing pressure is 0.6bar, and intake is 39m3/ h, engine speed is 6 revs/min；Coating closes feed liquor after terminating and atomization is pressed
Power, other specification is constant, dries 20 minutes.
The preparation of the CT-383 capsules of embodiment 43
Micropill 247.5mg in Example 32, is filled into No. 1 plant hollow capsule, obtains 5mg specification CT-383 capsules.
The preparation of the CT-383 capsules of embodiment 44
Micropill 112.5mg in Example 33, is filled into No. 1 plant hollow capsule, obtains 5mg specification CT-383 capsules.
The preparation of the CT-383 capsules of embodiment 45
Micropill 142mg in Example 34, is filled into No. 1 plant hollow capsule, obtains 5mg specification CT-383 capsules.
The preparation of the CT-383 capsules of embodiment 46
Micropill 87mg in Example 35, is filled into No. 3 plant hollow capsules, obtains 5mg specification CT-383 capsules.
The preparation of the CT-383 capsules of embodiment 47
Micropill 141.75mg in Example 36, is filled into No. 2 plant hollow capsules, obtains 5mg specification CT-383 capsules.
The preparation of the CT-383 capsules of embodiment 48
Micropill 283.5mg in Example 37, is filled into No. 1 plant hollow capsule, obtains 5mg specification CT-383 capsules.
The preparation of the CT-383 capsules of embodiment 49
Micropill 220mg in Example 38, is filled into No. 1 plant hollow capsule, obtains 5mg specification CT-383 capsules.
The preparation of the CT-383 capsules of embodiment 50
Micropill 144.75mg in Example 39, is filled into No. 1 plant hollow capsule, obtains 5mg specification CT-383 capsules.
The preparation of the CT-383 capsules of embodiment 51
Micropill 145.4mg in Example 40, is filled into No. 2 plant hollow capsules, obtains 5mg specification CT-383 capsules.
The Dissolution Rate Testing of embodiment 52
Example 13, embodiment 14, the sample of embodiment 15 and embodiment 16 respectively, according to dissolution method (in
The method of four general rules of state's pharmacopeia version in 2015 0931 second), plus dissolution medium 0.1M hydrochloric acid 500ml, rotating speed is 75 turns per minute, according to
Method is operated, respectively at 10,15,20,30 and 45 minutes when dissolution rate is measured by sampling.As a result it is as shown in table 1：
Table 1：Dissolution results
The Dissolution Rate Testing of embodiment 53
The sample of difference Example 43 and embodiment 48, according to dissolution method (Chinese Pharmacopoeia version two in 2010
The second methods of C of annex Ⅹ), solubilization goes out WATER AS FLOW MEDIUM 500ml, and rotating speed is 75 turns per minute, is operated in accordance with the law, respectively at 10,15,20,30,
Dissolution rate is measured by sampling at 45 and 60 minutes.As a result it is as shown in table 2：
Table 2：Dissolution results
The stability test of embodiment 54
The sample of Example 43, places at 25 DEG C and investigates stability, detected by below in connection with substance detecting method.
Relevant substance detecting method：
Instrument and reagent：Electronic analytical balance, volumetric flask, pipette, octadecylsilane chemically bonded silica post, efficient liquid phase
Chromatograph, ultrasonic cleaning instrument, centrifuge；Ammonium acetate, acetonitrile.
Chromatographic condition：Waters XBridge C18 (4.6 × 150mm, 5 μm) or performance suitable octadecyl silicon therewith
Alkane bonded silica gel chromatographic column；With 50mmol/L ammonium acetate solutions-acetonitrile (95：5) it is mobile phase A, 50mmol/L ammonium acetate solutions-
Acetonitrile (10：90) it is Mobile phase B, flow velocity is 1.2ml per minute, and according to the form below carries out linear gradient elution；Detection wavelength is
300nm；Column temperature is 40 DEG C.
Operating method：This product is taken, is shone《High performance liquid chromatography operation standard》Detection, using be not added with correction factor it is main into
Point Self-control method calculates acetylate, single impurity and the sum for calculating each impurity.Each impurity and refer to remove solvent peak, citron
Beyond sour peak and process contaminants amine isomer, bromo-derivative, condensation product, dimer peak, the peak area sum of each impurity peaks.As a result
As shown in table 3：
Table 3：25 DEG C of stability results
The stability test of embodiment 55
The sample of Example 43, places at 40 DEG C 6 months and investigates stability, by relevant material detection side in embodiment 54
Method detected, as a result as shown in table 4：
Table 4：40 DEG C of stability results
The bioavailability study of embodiment 56
From male machin, after the sample gavage of Example 43, whole blood sample is collected in different time points, using liquid
Phase chromatogram-tandem mass spectrometry determines the concentration of CT-383 in blood plasma, calculates pharmacokinetic parameter, and acquisition the results are shown in Table 5：
Table 5：Bioavilability result
| Group | Embodiment 43 |
| Tmax(h) | 1.50±0.55 |
| Cmax(ng/mL) | 978±459 |
| AUC0-t(ng·h/mL) | 4124±838 |
| AUC0-∞(ng·h/mL) | 4101±849 |
| MRT(h) | 8.06±3.71 |
| t1/2(h) | 26.2±12.9 |
Claims (18)
1. a kind of pharmaceutical composition for including the compound of formula 7, it is characterised in that the dosage of the compound of formula 7 is about 0.2-
20mg, preferably from about 0.5-10mg, even more preferably about 1-5mg.
2. pharmaceutical composition as claimed in claim 1, wherein the formulation is selected from granule, tablet, capsule, pill or micro-
Pill；It is preferred that capsule.
3. pharmaceutical composition as claimed in claim 2, wherein the capsule is made up of multiple micropills, the capsule Chinese style 7 is changed
The dosage of compound is about 0.2-20mg, even more preferably about preferably from about 0.5-10mg, 1-5mg.
4. pharmaceutical composition as claimed in claim 3, wherein the micropill includes from inside to outside：Capsule core and compound layer, its
Middle compound layer includes the compound of formula 7, and the weight ratio of wherein compound layer and capsule core is about 1:2-40, preferably from about 1:2-30,
Even more preferably about 1:4-25.
5. pharmaceutical composition as claimed in claim 4, wherein the compound layer also includes adhesive；Described adhesive is selected from
Hydroxypropyl cellulose, HPMC, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose
Sodium, PVP, copolyvidone, N- vinylpyrrolidones, Arabic gum or its mixture；It is preferred that hydroxypropyl cellulose, hydroxypropyl first
Base cellulose, sodium carboxymethylcellulose, PVP, copolyvidone or Arabic gum, more preferably hydroxypropyl cellulose or carboxymethyl
Sodium cellulosate.
6. pharmaceutical composition as claimed in claim 5, wherein the compound layer also includes filler, dispersant and/or pH
Conditioning agent；The filler is selected from microcrystalline cellulose, mannitol, lactose, pregelatinized starch or its mixture, and more preferably crystallite is fine
Dimension element or mannitol；The dispersant be selected from talcum powder, magnesium stearate, stearic acid, hydrogenated vegetable oil, Compritol 888 ATO or its
Mixture, preferably talc powder；The pH adjusting agent is selected from arginine, lysine, histidine, magnesium carbonate, dimeglumine, carbonic acid
Sodium, sodium acid carbonate or calcium carbonate.
7. the pharmaceutical composition as any one of claim 4-6, wherein the micropill includes separation layer and/or protection
Layer.
8. pharmaceutical composition, it includes organic acid and the compound of formula 7, wherein leading between the organic acid and the compound of the formula 7
Physics mode isolation is crossed, and semi-transparent film layer is scribbled on the surface of described pharmaceutical composition.
9. pharmaceutical composition as claimed in claim 8, wherein the organic acid is selected from citric acid, tartaric acid, vitamin C, apple
Tartaric acid, butanedioic acid, fumaric acid, maleic acid, glutamic acid, aspartic acid；Preferably citric acid, tartaric acid or malic acid；It is further excellent
Elect citric acid as.
10. the pharmaceutical composition as described in claim 8 or 9, wherein the compound of the formula 7 and the weight ratio of the organic acid
It is about 1:0.5~30；Preferably from about 1:1~15；Even more preferably about 1:2~10.
11. the pharmaceutical composition as any one of claim 8-10, wherein by weight, the semi-transparent film layer accounts for described
About the 1%~about 25% of pharmaceutical composition gross weight, preferably from about 2%~about 15%；More preferably from about 3%~about 10%.
12. the pharmaceutical composition as any one of claim 8-11, wherein pellicle layer includes water-soluble chemical combination
Thing and water-insoluble compound, and the weight ratio of the water soluble compound and the water-insoluble compound is about 1:0.05
~20；Preferably from about 1:0.1~10；Even more preferably about 1:0.2~4.
13. pharmaceutical composition as claimed in claim 12, wherein the water soluble compound is selected from methylcellulose, hydroxypropyl
Cellulose, HPMC, PVP, sodium carboxymethylcellulose, Hydroxypropyl Methylcellulose Phathalate, pectin,
Cyclodextrin, galactomannans, the polyethylene glycol of mean molecule quantity more than 4000, gelatin, water-soluble monose, water-soluble polysaccharide or
Its mixture；It is preferred that lactose, sucrose, methylcellulose, hydroxypropyl cellulose, HPMC, PEG6000, PVP
Or sodium carboxymethylcellulose；More preferably HPMC or hydroxypropyl cellulose.
14. the pharmaceutical composition as described in claim 12 or 13, wherein the water-insoluble compound be selected from ethyl cellulose,
HPMCAS, HPMCP, methacrylic acid copolymer or its mixture, preferred, ethyl, HPMCAS, Eudragit S100,
Eudragit L100 or HPMCP；More preferably ethyl cellulose.
15. the pharmaceutical composition as any one of claim 8-14, wherein pellicle layer also comprising antiplastering aid and/
Or plasticizer, wherein the antiplastering aid be selected from talcum powder, magnesium stearate, stearic acid, hydrogenated vegetable oil, Compritol 888 ATO or its
Mixture；Preferably talc powder, and the plasticizer be selected from triethyl citrate, it is ATBC, glycerol triacetate, poly-
Ethylene glycol or its mixture；It is preferred that polyethylene glycol.
16. the pharmaceutical composition as any one of claim 8-15, wherein physics mode isolation is with separation layer
Form provide.
17. the pharmaceutical composition as any one of claim 8-16, wherein the organic acid is in the form of organic acid layer
There is provided, and/or the compound of the formula 7 is provided in the form of compound layer.
18. the pharmaceutical composition any one of claim 1-17 is used to treat the suppression for benefiting from DPP-IV in preparation
Purposes in the medicine of disease；It is preferred that, the disease is selected from diabetes；It is furthermore preferred that the disease is selected from type ii diabetes.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110739923.9A CN113262227A (en) | 2016-01-29 | 2017-01-20 | Pharmaceutical compositions of DPP-IV inhibitors |
| CN202110739924.3A CN113262228A (en) | 2016-01-29 | 2017-01-20 | Pharmaceutical compositions of DPP-IV inhibitors |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2016100658566 | 2016-01-29 | ||
| CN201610065856 | 2016-01-29 |
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| CN202110739923.9A Division CN113262227A (en) | 2016-01-29 | 2017-01-20 | Pharmaceutical compositions of DPP-IV inhibitors |
| CN202110739924.3A Division CN113262228A (en) | 2016-01-29 | 2017-01-20 | Pharmaceutical compositions of DPP-IV inhibitors |
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| CN107019674B CN107019674B (en) | 2021-06-25 |
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| CN202110739924.3A Withdrawn CN113262228A (en) | 2016-01-29 | 2017-01-20 | Pharmaceutical compositions of DPP-IV inhibitors |
| CN202110739923.9A Withdrawn CN113262227A (en) | 2016-01-29 | 2017-01-20 | Pharmaceutical compositions of DPP-IV inhibitors |
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| CN202110739924.3A Withdrawn CN113262228A (en) | 2016-01-29 | 2017-01-20 | Pharmaceutical compositions of DPP-IV inhibitors |
| CN202110739923.9A Withdrawn CN113262227A (en) | 2016-01-29 | 2017-01-20 | Pharmaceutical compositions of DPP-IV inhibitors |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115487193A (en) * | 2022-11-09 | 2022-12-20 | 郑州德迈药业有限公司 | Ruuggolide tablet core and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102807568A (en) * | 2011-05-31 | 2012-12-05 | 江苏正大天晴药业股份有限公司 | Thiadiazole derivative DPP-IV (dipeptidyl peptidase IV) inhibitor |
| CN104644583A (en) * | 2014-12-25 | 2015-05-27 | 青岛黄海制药有限责任公司 | Dabigatran-containing multi-unit pellet tablet and preparation thereof |
-
2017
- 2017-01-20 CN CN201710052062.0A patent/CN107019674B/en not_active Expired - Fee Related
- 2017-01-20 CN CN202110739924.3A patent/CN113262228A/en not_active Withdrawn
- 2017-01-20 CN CN202110739923.9A patent/CN113262227A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102807568A (en) * | 2011-05-31 | 2012-12-05 | 江苏正大天晴药业股份有限公司 | Thiadiazole derivative DPP-IV (dipeptidyl peptidase IV) inhibitor |
| CN104644583A (en) * | 2014-12-25 | 2015-05-27 | 青岛黄海制药有限责任公司 | Dabigatran-containing multi-unit pellet tablet and preparation thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115487193A (en) * | 2022-11-09 | 2022-12-20 | 郑州德迈药业有限公司 | Ruuggolide tablet core and preparation method thereof |
| CN115487193B (en) * | 2022-11-09 | 2024-03-12 | 郑州德迈药业有限公司 | Preparation method of Rui Lu Geli tablet core and tablet |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107019674B (en) | 2021-06-25 |
| CN113262228A (en) | 2021-08-17 |
| CN113262227A (en) | 2021-08-17 |
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