CN105853386A - Dapagliflozin propanediol hydrate-contained tablet and method of manufacturing the same - Google Patents
Dapagliflozin propanediol hydrate-contained tablet and method of manufacturing the same Download PDFInfo
- Publication number
- CN105853386A CN105853386A CN201610198784.2A CN201610198784A CN105853386A CN 105853386 A CN105853386 A CN 105853386A CN 201610198784 A CN201610198784 A CN 201610198784A CN 105853386 A CN105853386 A CN 105853386A
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- Prior art keywords
- gelie
- tablet
- clean
- propylene glycol
- glycol hydrate
- 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.)
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- 238000004519 manufacturing process Methods 0.000 title claims description 15
- GOADIQFWSVMMRJ-UPGAGZFNSA-N dapagliflozin propanediol monohydrate Chemical compound O.C[C@H](O)CO.C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl GOADIQFWSVMMRJ-UPGAGZFNSA-N 0.000 title abstract 2
- 229960003700 dapagliflozin propanediol Drugs 0.000 title 1
- 239000003814 drug Substances 0.000 claims abstract description 26
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- 239000000243 solution Substances 0.000 claims description 50
- QMYDVDBERNLWKB-UHFFFAOYSA-N propane-1,2-diol;hydrate Chemical compound O.CC(O)CO QMYDVDBERNLWKB-UHFFFAOYSA-N 0.000 claims description 45
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Classifications
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- A—HUMAN NECESSITIES
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- 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
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
-
- 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
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Abstract
Dapagliflozin serves as a novel therapeutic drug for type II diabetes. The invention relates to a preparation process for a dapagliflozin-contained tablet. The preparation process is characterized as follows: firstly, the dapagliflozin propanediol hydrate is dissolved in a solvent to prepare a drug solution; secondly, the drug solution, a diluent, a binder, a disintegrating agent and a lubricant are subjected to the wet granulating and tabletting treatment to obtain a dapagliflozin-contained tablet. The prepared tablet is good in drug content uniformity, excellent in stability and rapid in dissolution effect. Meanwhile, the preparation process is simple and suitable for industrial production.
Description
Technical field
The present invention relates to a kind of tablet containing the clean propylene glycol hydrate of Da Gelie and manufacture method thereof, belong to formulation method
Field.
Background technology
Da Gelie is clean (dapagliflozin), chemistry entitled (2S, 3R, 4R, 5S, 6R)-2-[3-(4-ethoxyl phenenyl)-
4-chlorphenyl]-6-methylol tetrahydrochysene-2H-pyrans-3,4,5-triol.It is public by Bristol Myers Squibb and Astrazeneca AB
A kind of novel antidiabetic medicine developed jointly, listed in Europe in 2012, and it is 2 types that FDA also ratified it in 2014
Medicine for treating diabetes, its structure is as shown in the formula (I).
I
Along with socioeconomic development, the change of people life style and aged tendency of population, onset diabetes rate is in the world
In in increasing trend year by year, become after cardiovascular diseases and tumor, the 3rd threatens the non-infectious of health of people and life
Property disease.Along with the progress of type 2 diabetes mellitus conditions of patients, islet beta cell function gradually decays to exhaustion, and traditional treatment, no
The existence of islet beta cell function is all relied on by the blood sugar lowering curative effect being Insulin secretagogues or sensitizer.Therefore, more and more
Patient, especially in, the blood sugar level of patients with terminal is increasingly difficult to control to.For the 2 type sugar that these current treatments are not good enough
Urine patient, the hypoglycemic medicine not relying on insulin may provide significantly more efficient therapeutic choice, helps patient to realize more
Good glycemic control.Kidney has important function in maintaining human body metabolic balance and blood glucose regulation.The plasma glucose of 99% exists
Kidney is through glomerular filtration, then is weighed absorbed into serum again at renal tubules.In renal tubules, " sodium glucose is altogether to have one to be referred to as
Transport protein-2(SGLT-2) " material, its function is heavily to absorb the most of glucose through glomerular filtration.
Da Gelie is a kind of high selectivity SLGT-2 inhibitor only, the excretion of glucose in being urinated by enhancing and make blood plasma Portugal
Grape sugar level normalization, thus improve insulin sensitivity and postpone the progress of diabetic complication.The uniqueness that Da Gelie is clean
Mechanism of action to determine it be the orally-taken blood sugar reducing medicine for treating type 2 diabetes mellitus.Its oral absorption is good, through homaluria,
In body, blood drug level is stable, long half time, and the dosage of 1 times/day can maintain the effective blood drug concentration of 24 hours in body.
Additionally, in addition to effectively alleviating patient's sugar toxicity, Da Gelie the most also can loss of weight, blood pressure lowering, it is possible to reduce patient's cardiovascular disease
Sick occurrence risk.
The dissolubility of the clean monomer of Da Gelie is poor, thus is made into solvate on preparation to increase dissolubility, this
Bright selected solvate is the clean propylene glycol hydrate of Da Gelie, and wherein propylene glycol is S-propylene glycol, its structural formula such as Formula II
Shown in.
II
Research about the clean preparation of Da Gelie is few, some dosage forms that patent CN201210201489 Zhong Gong Kailiao Da Gelie is clean,
But the preparation method of preparation is not further elaborated by it.Da Gelie clean S-propylene glycol hydrate fusing point is relatively low, is a kind of heat
Quick property compound, needs more accurate temperature to control, further, since content clean for Da Gelie in tablet is relatively in production process
Low, therefore, the uniformity of dosage units of preparation and stability, determine the quality of the clean tablet of Da Gelie.For solving the problems referred to above, this
A kind of tablet containing the clean propylene glycol hydrate of Da Gelie of bright offer and manufacture method thereof, use obtained by this formula and method
Da Gelie clean tablet content good evenness, stability is high, and dissolution is rapid, and manufacturing process is simple, it is easy to industrialized production.
Summary of the invention
The present invention provides a kind of uniformity of dosage units good, and stability is high, and dissolution contains the clean aqueous polyethylene glycol of Da Gelie rapidly
The tablet of thing and manufacture method thereof, a kind of tablet containing the clean propylene glycol hydrate of Da Gelie, this tablet includes living
The property clean propylene glycol hydrate of composition Da Gelie, pharmaceutically acceptable pharmaceutic adjuvant, the manufacture method of this tablet is,
Weigh the clean propylene glycol hydrate of Da Gelie, be dissolved in solvent, then this drug solution is homogeneously dispersed in adjuvant
Prepare soft material, through pelletizing, being dried, after granulate with mix lubricant, tabletting, coating.
Solvent of the present invention can be any pharmaceutically acceptable solvent or their mixture, the most volatilizable
Solvent and mixture thereof, be selected from ethanol, water, methanol, acetone, isopropanol, ethyl acetate, acetonitrile, dichloromethane, just oneself
One or both in alkane, hexamethylene, one or both in preferred alcohol, water, methanol, acetone, isopropanol, more preferably second
Alcohol or the mixture of second alcohol and water, wherein, ethanol ratio in mixed solvent is 20% ~ 100%, preferably 50% ~ 100%.
Da Gelie of the present invention clean propylene glycol hydrate ratio in prescription is 3% ~ 8%.
Pharmaceutically acceptable pharmaceutic adjuvant of the present invention is the one in diluent, disintegrating agent, binding agent or several
Kind.
Diluent of the present invention can be saccharide, cellulose family, inorganic salts, it is also possible to is the mixed of two kinds of diluent
Compound, such as, can be lactose, starch, dextrin, sucrose, mannitol, sorbitol, pregelatinized Starch, calcium carbonate, calcium phosphate, phosphorus
Acid dihydride calcium, pregelatinized Starch, hydroxypropyl cellulose, methylcellulose, ethyl cellulose etc., preferably dextrin, mannitol, phosphorus
Acid dihydride calcium, pregelatinized Starch, hydroxypropyl cellulose, more preferably pregelatinized Starch, dalcium biphosphate.
Disintegrating agent of the present invention can be any pharmaceutically acceptable disintegrating agent, such as, can be dried starch, carboxylic
Methyl starch sodium, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, pregelatinized Starch, sodium alginate etc., preferably carboxymethyl form sediment
Powder sodium, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, more preferably cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone.
Binding agent of the present invention can be any pharmaceutically acceptable binding agent, such as, can be that pregelatinated forms sediment
Powder, methylcellulose, hydroxypropyl cellulose, polyvidone, glucose, polyvinyl alcohol etc., preferably methylcellulose, hydroxypropyl fibre
Dimension element, polyvidone, more preferably polyvidone.
Lubricant of the present invention can be any pharmaceutically acceptable lubricant, can be such as magnesium stearate,
Stearic acid, Palmic acid, zinc stearate etc., preferably magnesium stearate.
The clean propylene glycol hydrate of Da Gelie of the present invention, diluent, disintegrating agent, binding agent, lubricant are in prescription
Ratio be respectively 3wt% ~ 6wt%, 30 wt % ~ 90 wt %, 2wt % ~ 5 wt %, 1 wt % ~ 2 wt %, 0.5 wt % ~ 2wt
%；And the percentage ratio of all components is combined as 100%.
Baking temperature described in the manufacture method of the present invention can be 20 DEG C ~ 80 DEG C, preferably 40 DEG C ~ 60 DEG C.
Preferably, according to the preparation method of tablet of the present invention, comprise the steps:
Weigh the clean propylene glycol hydrate of Da Gelie, be dissolved in 100% ethanol；Weigh polyvidone and be configured to aqueous solution；Sieve will have been crossed
Pregelatinized Starch and polyvinylpolypyrrolidone join in mixer-granulator, mixing certain time after by medicament mixed solution add system
In grain pot, it is subsequently added polyvinylpolypyrrolidone aqueous solution, pelletizes through screen cloth after discharging；Wet granular is dried at a certain temperature, so
Rear granulate, and mix with magnesium stearate, tabletting, coating, wherein, the clean propylene glycol hydrate of described Da Gelie, pregelatinized Starch, friendship
Connection polyvidone, polyvidone, the ratio of magnesium stearate are respectively 4.92%, 87.2%, 4.8%, 1.08%, 2%.
Preferably, according to the preparation method of tablet of the present invention, comprise the steps:
Weigh the clean propylene glycol hydrate of Da Gelie, be dissolved in 50%(v/v) in the mixed solution of second alcohol and water；Weigh polyvidone to join
Make aqueous solution；The dalcium biphosphate and cross-linking sodium carboxymethyl cellulose of having crossed sieve are joined in mixer-granulator, mixes one
After fixing time, medicament mixed solution is added in granulation pot, be subsequently added polyvidone aqueous solution, pelletize through screen cloth after discharging；By wet
Granule is dried at a certain temperature, then granulate, and mixes with magnesium stearate, tabletting, coating, wherein, and described Da Gelie clean third
Glycol hydrate, dalcium biphosphate, cross-linking sodium carboxymethyl cellulose, polyvidone, the ratio of magnesium stearate be respectively 4.92%,
90%、2%、2.08%、1%。
More preferably, according to the preparation method of tablet of the present invention, comprise the steps:
Weigh the clean propylene glycol hydrate of Da Gelie, be dissolved in 60%(v/v) in the mixed solution of second alcohol and water；Weigh polyvidone to join
Make aqueous solution；Mixing granulation is joined by having crossed the dalcium biphosphate of sieve, pregelatinized Starch and cross-linking sodium carboxymethyl cellulose
In machine, after mixing certain time, medicament mixed solution is added in granulation pot, be subsequently added polyvidone aqueous solution, through sieve after discharging
Net is pelletized；Wet granular is dried at a certain temperature, then granulate, and mixes with magnesium stearate, tabletting, coating, wherein, described
The clean propylene glycol hydrate of Da Gelie, dalcium biphosphate, pregelatinized Starch, cross-linking sodium carboxymethyl cellulose, polyvidone, magnesium stearate
Ratio be respectively 4.92%, 50%, 39.48%, 3%, 1.6%, 1%.
Some specific embodiment of the manufacture method of the tablet according to the present invention is as described below, comparative example 1 and contrast
Embodiment 2 is the clean tablet of Da Gelie not using mixed solvent method to prepare, and below by experimental data, having of the present invention is described
Benefit effect.
Uniformity of dosage units detects
Respectively Example 1 ~ 4 and comparative example 1, each 10 of the clean tablet of Da Gelie of preparation in 2, commercially available former grinds control formulation
(Bristol Myers Squibb-Astrazeneca AB, FORXIGA) 10, every is placed in 100ml(10mg specification) or 50ml(5mg rule
Lattice) in measuring bottle, add flowing appropriate mutually, ultrasonic make medicine dissolution, add flowing phase dilution to scale, shake up, centrifugal, take supernatant filter
Crossing, precision measures subsequent filtrate 4ml, puts in 20ml measuring bottle, add flowing phase dilution to scale, shake up, as need testing solution, HPLC
Method measures content, according to " Chinese Pharmacopoeia " 2015 editions four calculating A+2.2S, investigates uniformity of dosage units.
Table 1 uniformity of dosage units testing result
| Sample | A+2.2S |
| Former triturate | 8.23 |
| Comparative example 1 | 14.85 |
| Comparative example 2 | 12.98 |
| Embodiment 1 | 6.30 |
| Embodiment 2 | 5.49 |
| Embodiment 3 | 5.55 |
| Embodiment 4 | 7.02 |
From result above, the Da Gelie clean tablet content uniformity using the method in the present invention to prepare is higher, and high
In former triturate, illustrate to use this method really can improve uniform content sex chromosome mosaicism clean for Da Gelie.
Dissolution detects
With the hydrochloric acid solution 900ml of pH1.2 as dissolution medium, use paddle method, 50 rpms carry out dissolution, respectively at 5,10,
15, within 30 minutes, taking solution 5ml, filter, take subsequent filtrate as need testing solution, HPLC sends out mensuration dissolution, evaluates embodiment 1-4
And clean for Da Gelie dissolved corrosion in comparative example 1-2, stripping curve is as shown in Figure 1.For evaluating self-control sample with commercially available
The former dissolved corrosion grinding control formulation (Bristol Myers Squibb-Astrazeneca AB, FORXIGA), selects water, pH1.2 salt respectively
Acid solution, pH4.5 acetate buffer, pH6.8 phosphate buffer are dissolution medium, investigate the Da Gelie in embodiment 1 clean
Sheet and former triturate dissolution concordance, stripping curve such as Fig. 2-Fig. 5.
As shown in Figure 1, the tablet dissolution using solvent method to prepare is rapid, and is provided without solvent method gained tablet dissolution rate
Relatively slow；From Fig. 2-Fig. 5, the clean tablet of Da Gelie in embodiment 1 with former grind control formulation compared with, Da Gelie is only four
Plant dissolution in dissolution medium consistent, all can reach Fast Stripping at 15min dissolution more than 90%.
Related substance is had to detect
Three batches of clean tablets of Da Gelie in Example 1 and commercially available former grind control formulation (Bristol Myers Squibb-AstraZeneca is public
Department, FORXIGA) each 20, grind in fine powder, take fine powder appropriate (being approximately equivalent to containing the clean 10mg of Da Gelie) accurately weighed, put
In 10ml measuring bottle, solubilizer (acetonitrile: water 40:60) is appropriate, and the ultrasonic Da Gelie of making only dissolves and is diluted to scale, shakes up, from
The heart, takes supernatant and filters, as need testing solution.Precision measures need testing solution 1ml, puts in 100ml measuring bottle, and solubilizer is dilute
Releasing to scale, shake up, precision measures above-mentioned solution 2ml and puts in 10ml measuring bottle, and solubilizer is diluted to scale, shakes up, as comparison
Solution.Another precision weighs impurity A and the clean reference substance of Da Gelie is appropriate, and solubilizer dissolves and dilutes to be made in every 1ml containing Da Gelie
Clean 1mg, impurity A about 2 mixed solution of μ g, as system suitability solution.Precision weighs that Da Gelie is clean and the clean impurity A of Da Gelie
In right amount, solubilizer dissolves and is configured in every 1ml and the mixed solution of impurity A about 0.5 μ g clean containing Da Gelie, molten as sensitivity
Liquid.Measure according to high performance liquid chromatography (Chinese Pharmacopoeia four general rules 0512 of version in 2015).Use octadecylsilane bonded silica
Glue is filler, with water as mobile phase A；Acetonitrile is Mobile phase B；Flow velocity is 1.0ml per minute；Carry out linear elution；Detection ripple
A length of 225nm.Precision measures system suitability solution 25 l, injects chromatograph of liquid, records chromatogram, the clean peak of Da Gelie and phase
The separating degree of adjacent impurity peaks should meet the requirements；Another precision measures sensitivity solution 25 l, injects chromatograph of liquid, records chromatograph
Figure, Da Gelie is clean and known impurities signal to noise ratio should be not less than 10；Precision measures contrast solution and need testing solution each 25 respectively
L, is injected separately into chromatograph of liquid, records chromatogram.If any impurity chromatographic peak in need testing solution chromatogram, its peak area must not
More than contrast solution main peak area (0.2%), impurity peak area and 10 times (2.0%) cannot be greater than contrast solution main peak area.
Concrete testing result is as shown in table 2.
Table 2 make by oneself the clean tablet of Da Gelie with former grind control formulation have related substance testing result
As shown in Table 2, that makes the clean tablet of Da Gelie by oneself has related substance basically identical or lower slightly with former control formulation of grinding, the most permissible
Illustrating, the quality of the clean tablet of Da Gelie prepared by the technique in the employing present invention is not inferior to former triturate.
Study on the stability
Take the clean tablet of Da Gelie of 3 batches of embodiments 1 respectively, transfer in long term test condition (25 DEG C, RH60%) and set to 0,3,6,9,
12 months, detection outward appearance, content, dissolution and have related substance, investigate the stability of the clean tablet of Da Gelie, concrete outcome such as table 3 ~
5。
3 20150313 batches of Da Gelie clean sheet long-term stable experiment results of table
4 20150406 batches of Da Gelie clean sheet long-term stable experiment results of table
5 20150408 batches of Da Gelie clean sheet long-term stable experiment results of table
Accompanying drawing explanation
Fig. 1 is embodiment 1-4 and comparative example 1-2 stripping curve in pH1.2 hydrochloric acid solution.
Fig. 2 is the self-control sample (embodiment 1) using preparation method gained of the present invention and the dissolution in water of the former triturate
Curve.
Fig. 3 uses the self-control sample (embodiment 1) of preparation method gained of the present invention with former triturate at pH1.2 hydrochloric acid solution
In stripping curve.
Fig. 4 is to use the self-control sample (embodiment 1) of preparation method gained of the present invention and former triturate at pH4.5 acetate
Stripping curve in buffer.
Fig. 5 is to use the self-control sample (embodiment 1) of preparation method gained of the present invention and former triturate at pH6.8 phosphate
Stripping curve in buffer.
Specific embodiment
The present invention is further illustrated below by specific embodiment.The present invention includes but not limited to these embodiments.At this
The simple modifications under the concept thereof of invention made product and the preparation method of the present invention broadly falls into claimed
Scope.Except as otherwise noted, " % " in the present invention is quality criteria.
The preparation of embodiment 1: Da Gelie clean propylene glycol hydrate tablet (10000, the every clean 5mg Han Da Gelie)
Take dalcium biphosphate, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch, cross 60 mesh sieves respectively, standby；Weigh 625.0g phosphorus
Acid dihydride calcium, 37.5g cross-linking sodium carboxymethyl cellulose, 493.5g pregelatinized Starch, standby；Weigh 20.0g PVP K30, molten
Yu Shuizhong, is made into 4% PVP K30 solution, standby；Weigh the clean propylene glycol hydrate of 61.5g Da Gelie, be dissolved in 60%(v/v) second
Alcohol-water solution, is made into the drug solution of about 20%, standby；By load weighted dalcium biphosphate, cross-linking sodium carboxymethyl cellulose, pre-
Gelling starch is added in wet mixing pelletizer, mixes 3 minutes；Drug solution is slowly added in granulation pot, open stirring and
Shears, is subsequently added PVP K30 solution soft material, pelletizes through 24 eye mesh screens after discharging；Wet granular is laid in pallet
Put in air dry oven, 40 DEG C of drying, control moisture 0～2%；Through 30 mesh sieve granulate；By whole good granule with
12.5g magnesium stearate mixes；The content of detection intermediate products, calculates the theoretical tablet weight, and uses rotary tablet machine to carry out tabletting, tablet weight
Difference controls ± 4%, and tablet hardness controls at 4-8kg；Label screens out fine powder be placed in coating pan, use 15% Opadry
Coating solution is coated, till weightening finish reaches 2-4%.The clean propylene glycol hydrate of Da Gelie, dalcium biphosphate, pregelatinated form sediment
Powder, polyvidone, cross-linking sodium carboxymethyl cellulose, the magnesium stearate ratio in prescription is respectively 4.92%, and 50%, 39.48%,
1.6%, 3%, 1%.
The preparation of embodiment 2: Da Gelie clean propylene glycol hydrate tablet (10000, the every clean 10mg Han Da Gelie)
Take dalcium biphosphate, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch, cross 60 mesh sieves respectively, standby；Weigh 1250.0g
Dalcium biphosphate, 75.0g cross-linking sodium carboxymethyl cellulose, 987.0g pregelatinized Starch, standby；Weigh 40.0g PVP K30,
Soluble in water, it is made into 4% PVP K30 solution, standby；Weigh the clean propylene glycol hydrate of Da Gelie of 123.0g, be dissolved in 60%(v/
V) ethanol water, is made into the drug solution of about 20%, standby；By load weighted dalcium biphosphate, cross-linked carboxymethyl cellulose
Sodium, pregelatinized Starch are added in wet mixing pelletizer, mix 3 minutes；Being slowly added to by drug solution in granulation pot, unlatching is stirred
Mix and stir shears, be subsequently added PVP K30 solution soft material, pelletize through 24 eye mesh screens after discharging；Wet granular is laid in torr
Dish is put in air dry oven, 40 DEG C of drying, control moisture 0～2%；Through 30 mesh sieve granulate；By whole good granule with
25.0g magnesium stearate mixes；The content of detection intermediate products, calculates the theoretical tablet weight, and uses rotary tablet machine to carry out tabletting, tablet weight
Difference controls ± 4%, and tablet hardness controls at 4-8kg；Label screens out fine powder be placed in coating pan, use 15% Opadry
Coating solution is coated, till weightening finish reaches 2-4%.The clean propylene glycol hydrate of Da Gelie, dalcium biphosphate, pregelatinated form sediment
Powder, PVP K30, cross-linking sodium carboxymethyl cellulose, the magnesium stearate ratio in prescription is respectively 4.92%, and 50%, 39.48%,
1.6%, 3%, 1%.
The preparation of embodiment 3: Da Gelie clean propylene glycol hydrate tablet (10000, the every clean 5mg Han Da Gelie)
Take polyvinylpolypyrrolidone, pregelatinized Starch, cross 60 mesh sieves respectively, standby；Weigh 60g polyvinylpolypyrrolidone, 1090g pregelatinated forms sediment
Powder, standby；Weigh 13.5g PVP K30, soluble in water, it is made into 4% PVP K30 solution, standby；Weigh 61.5g Da Gelie
Clean propylene glycol hydrate, is dissolved in 100% ethanol solution, is made into the drug solution of about 20%, standby；By load weighted biphosphate
Calcium, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch are added in wet mixing pelletizer, mix 3 minutes；Drug solution is slow
Add in granulation pot, open stirring and shears, be subsequently added PVP K30 solution soft material, through 24 eye mesh screen systems after discharging
Grain；Being laid in pallet by wet granular puts in air dry oven, 60 DEG C of drying, controls moisture 0～2%；Through 30 mesh sieves
Granulate；Whole good granule is mixed with 25g magnesium stearate；The content of detection intermediate products, calculates the theoretical tablet weight, and uses and rotates pressure
Sheet machine carries out tabletting, and tablet weight variation controls ± 4%, and tablet hardness controls at 4-8kg；Label is screened out fine powder and is placed on coating
In Guo, 15% Opadry coating solution is used to be coated, till weightening finish reaches 2-4%.The clean propylene glycol hydrate of Da Gelie, pre-
Gelling starch, polyvinylpolypyrrolidone, PVP K30, the ratio of magnesium stearate are respectively 4.92%, 87.2%, 4.8%, 1.08%, 2%.
The preparation of embodiment 4: Da Gelie clean propylene glycol hydrate tablet (10000, the every clean 5mg Han Da Gelie)
Take dalcium biphosphate, cross-linking sodium carboxymethyl cellulose and cross 60 mesh sieves respectively, standby；Weigh 1125g dalcium biphosphate, 25g
Cross-linking sodium carboxymethyl cellulose, standby；Weigh 52g PVP K30, soluble in water, it is made into 4% PVP K30 solution, standby；Claim
Take the clean propylene glycol hydrate of 61.5g Da Gelie, be dissolved in 50%(v/v) ethanol water, it is made into the drug solution of about 20%, standby；
Load weighted dalcium biphosphate, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch are added in wet mixing pelletizer, mix 3
Minute；Drug solution is slowly added in granulation pot, opens stirring and shears, be subsequently added PVP K30 solution soft material,
Pelletize through 24 eye mesh screens after discharging；Being laid in pallet by wet granular puts in air dry oven, 50 DEG C of drying, controls moisture and contains
Amount is 0～2%；Through 30 mesh sieve granulate；Whole good granule is mixed with 12.5g magnesium stearate；The content of detection intermediate products, meter
Calculating theoretical tablet weight, use rotary tablet machine to carry out tabletting, tablet weight variation controls ± 4%, and tablet hardness controls at 4-8kg；By sheet
Core screens out fine powder and is placed in coating pan, uses 15% Opadry coating solution to be coated, till weightening finish reaches 2-4%.Reach
Lattice arrange the ratio difference of clean propylene glycol hydrate, dalcium biphosphate, cross-linking sodium carboxymethyl cellulose, PVP K30, magnesium stearate
It is 4.92%, 90%, 2%, 2.08%, 1%.
Comparative example 1: (10000, every clean containing Da Gelie not to use the method for mixed solvent to prepare the clean sheet of Da Gelie
5mg)
Take the clean propylene glycol hydrate of Da Gelie, dalcium biphosphate, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch, cross 60 respectively
Mesh sieve, standby；Weigh the clean propylene glycol hydrate of 61.5g Da Gelie, 625.0g dalcium biphosphate, 37.5g cross-linked carboxymethyl fiber
Element sodium, 493.5g pregelatinized Starch, standby；Weigh 2.00g PVP K30, soluble in water, it is made into 4% PVP K30 solution, standby
With；Clean for load weighted Da Gelie propylene glycol hydrate, dalcium biphosphate, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch are added
In wet mixing pelletizer, mix 3 minutes；Open stirring and shears, be subsequently added PVP K30 solution soft material, go out
Pelletize through 24 eye mesh screens after material；Being laid in pallet by wet granular puts in air dry oven, 40 DEG C of drying, controls moisture
0～2%；Through 30 mesh sieve granulate；Whole good granule is mixed with 12.5g magnesium stearate；The content of detection intermediate products, calculates
Theoretical tablet weight, uses rotary tablet machine to carry out tabletting, and tablet weight variation controls ± 4%, and tablet hardness controls at 4-8kg；By label
Screen out fine powder to be placed in coating pan, use 15% Opadry coating solution to be coated, till weightening finish reaches 2-4%.Da Ge
Arrange clean propylene glycol hydrate, dalcium biphosphate, microcrystalline Cellulose, hydroxypropyl methyl cellulose sodium, cross-linking sodium carboxymethyl cellulose,
Magnesium stearate ratio in prescription is respectively 4.92%, and 50%, 39.48%, 1.6%, 3%, 1%.
Comparative example 2: (10000, every clean containing Da Gelie not to use the method for mixed solvent to prepare the clean sheet of Da Gelie
10mg)
Take the clean propylene glycol hydrate of Da Gelie, dalcium biphosphate, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch, cross 60 respectively
Mesh sieve, standby；Weigh the clean propylene glycol hydrate of 123.0g Da Gelie, 1250.0g dalcium biphosphate, 75.0g cross-linked carboxymethyl fibre
Dimension element sodium, 987.0g pregelatinized Starch, standby；Weigh 40.0g PVP K30, soluble in water, it is made into 4% PVP K30 solution,
Standby；By clean for load weighted Da Gelie propylene glycol hydrate, dalcium biphosphate, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch
It is added in wet mixing pelletizer, mixes 3 minutes；Open stirring and shears, be subsequently added PVP K30 solution soft material,
Pelletize through 24 eye mesh screens after discharging；Being laid in pallet by wet granular puts in air dry oven, 40 DEG C of drying, controls moisture and contains
Amount is 0～2%；Through 30 mesh sieve granulate；Whole good granule is mixed with 25.0g magnesium stearate；The content of detection intermediate products, meter
Calculating theoretical tablet weight, use rotary tablet machine to carry out tabletting, tablet weight variation controls ± 4%, and tablet hardness controls at 4-8kg；By sheet
Core screens out fine powder and is placed in coating pan, uses 15% Opadry coating solution to be coated, till weightening finish reaches 2-4%.Reach
Lattice row clean propylene glycol hydrate, dalcium biphosphate, microcrystalline Cellulose, hydroxypropyl methyl cellulose sodium, cross-linked carboxymethyl cellulose
Sodium, the magnesium stearate ratio in prescription is respectively 4.92%, and 50%, 39.48%, 1.6%, 3%, 1%.
Claims (10)
1. containing the tablet of the clean propylene glycol hydrate of Da Gelie of following formula (I), this tablet includes active component Da Gelie clean third
Glycol hydrate, pharmaceutically acceptable pharmaceutic adjuvant, it is characterised in that the manufacture method of described tablet is,
Weigh the clean propylene glycol hydrate of Da Gelie, be dissolved in solvent, then this drug solution is homogeneously dispersed in adjuvant,
Through prepare soft material, pelletize, be dried, after granulate with mix lubricant, tabletting, coating,
Wherein, described pharmaceutically acceptable pharmaceutic adjuvant is one or more in diluent, disintegrating agent, binding agent,
I。
2. profit requires the tablet described in 1, it is characterised in that described solvent is ethanol or the mixed solvent of second alcohol and water, Qi Zhongyi
The content of alcohol is 50% ~ 100%.
3. the tablet as described in any one of claim 1 ~ 2, it is characterised in that described diluent is selected from dalcium biphosphate, pre-
One or both mixture in gelling starch.
4. tablet as claimed in claim 3, it is characterised in that described diluent ratio in prescription is 30 wt % ~ 90
wt %。
5. the tablet as described in any one of claim 1 ~ 2, it is characterised in that described disintegrating agent is cross-linking sodium carboxymethyl cellulose
Or polyvinylpolypyrrolidone, described disintegrating agent ratio in prescription is 2wt % ~ 5 wt %.
6. the tablet as described in any one of claim 1 ~ 2, it is characterised in that described binding agent is polyvidone, wherein, described viscous
Mixture ratio in prescription is 1 wt % ~ 2 wt %.
7. the tablet as described in any one of claim 1 ~ 2, it is characterised in that described lubricant is magnesium stearate, wherein, described
Lubricant ratio in prescription is 0.5 wt % ~ 2wt %.
8. a manufacture method for the tablet containing the clean propylene glycol hydrate of Da Gelie according to claim 1, its feature
It is to comprise the steps；Weigh the clean propylene glycol hydrate of Da Gelie, be dissolved in 60%(v/v) in the mixed solution of second alcohol and water；
Weigh polyvidone and be configured to aqueous solution；Add having crossed the dalcium biphosphate of sieve, pregelatinized Starch and cross-linking sodium carboxymethyl cellulose
Enter in mixer-granulator, after mixing certain time, medicament mixed solution is added in granulation pot, be subsequently added polyvidone water-soluble
Liquid, pelletizes through screen cloth after discharging；Wet granular is dried at a certain temperature, then granulate, and mixes with magnesium stearate, tabletting,
Coating, wherein, the clean propylene glycol hydrate of described Da Gelie, dalcium biphosphate, pregelatinized Starch, cross-linking sodium carboxymethyl cellulose,
Polyvidone, the ratio of magnesium stearate are respectively 4.92%, 50%, 39.48%, 3%, 1.6%, 1%.
9. a manufacture method for the tablet containing the clean propylene glycol hydrate of Da Gelie according to claim 1, its feature
It is to comprise the steps；Weigh the clean propylene glycol hydrate of Da Gelie, be dissolved in 100% ethanol；Weigh polyvidone and be configured to water
Solution；The pregelatinized Starch and polyvinylpolypyrrolidone of having crossed sieve are joined in mixer-granulator, by medicine after mixing certain time
Mixed solution adds in granulation pot, is subsequently added polyvidone aqueous solution, pelletizes through screen cloth after discharging；By wet granular in uniform temperature
Lower dry, then granulate, and mix with magnesium stearate, tabletting, coating, wherein, the clean propylene glycol hydrate of described Da Gelie, pre-glue
Change starch, polyvinylpolypyrrolidone, polyvidone, the ratio of magnesium stearate are respectively 4.92%, 87.2%, 4.8%, 1.08%, 2%.
10. a manufacture method for the tablet containing the clean propylene glycol hydrate of Da Gelie according to claim 1, its feature
It is to comprise the steps；Weigh the clean propylene glycol hydrate of Da Gelie, be dissolved in 50%(v/v) in the mixed solution of second alcohol and water；
Weigh polyvidone and be configured to aqueous solution；The dalcium biphosphate and cross-linking sodium carboxymethyl cellulose of having crossed sieve are joined mixing granulation
In machine, after mixing certain time, medicament mixed solution is added in granulation pot, be subsequently added polyvidone aqueous solution, through sieve after discharging
Net is pelletized；Wet granular is dried at a certain temperature, then granulate, and mixes with magnesium stearate, tabletting, coating, wherein, described
The clean propylene glycol hydrate of Da Gelie, dalcium biphosphate, cross-linking sodium carboxymethyl cellulose, polyvidone, the ratio difference of magnesium stearate
It is 4.92%, 90%, 2%, 2.08%, 1%.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107714667A (en) * | 2017-11-20 | 2018-02-23 | 威海贯标信息科技有限公司 | A kind of Dapagliflozin agent composition |
| CN109705076A (en) * | 2019-01-21 | 2019-05-03 | 江苏苏中药业集团股份有限公司 | Dapagliflozin crystal form, preparation method and application thereof |
| CN111956622A (en) * | 2020-09-15 | 2020-11-20 | 北京福元医药股份有限公司 | Dagliflozin propylene glycol hydrate pharmaceutical preparation |
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| CN102743340A (en) * | 2007-03-22 | 2012-10-24 | 百时美施贵宝公司 | Pharmaceutical formulations containing dapagliflozin propylene glycol hydrate |
| CN104958338A (en) * | 2015-07-15 | 2015-10-07 | 江苏中兴药业有限公司 | Method for improving content uniformity of medicaments |
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| CN1706384A (en) * | 2004-06-11 | 2005-12-14 | 上海实业联合集团药业有限公司 | Prepn process of compound hydrocodone tablet |
| CN102743340A (en) * | 2007-03-22 | 2012-10-24 | 百时美施贵宝公司 | Pharmaceutical formulations containing dapagliflozin propylene glycol hydrate |
| WO2012041898A1 (en) * | 2010-09-29 | 2012-04-05 | Celon Pharma Sp. Z O.O. | Combination of sglt2 inhibitor and a sugar compound for the treatment of diabetes |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107714667A (en) * | 2017-11-20 | 2018-02-23 | 威海贯标信息科技有限公司 | A kind of Dapagliflozin agent composition |
| CN109705076A (en) * | 2019-01-21 | 2019-05-03 | 江苏苏中药业集团股份有限公司 | Dapagliflozin crystal form, preparation method and application thereof |
| CN109705076B (en) * | 2019-01-21 | 2023-03-24 | 苏中药业集团股份有限公司 | Dapagliflozin crystal form, preparation method and application thereof |
| CN111956622A (en) * | 2020-09-15 | 2020-11-20 | 北京福元医药股份有限公司 | Dagliflozin propylene glycol hydrate pharmaceutical preparation |
| CN111956622B (en) * | 2020-09-15 | 2022-11-15 | 北京福元医药股份有限公司 | Dapagliflozin propylene glycol hydrate pharmaceutical preparation |
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