CN108078945A - Canagliflozin pharmaceutical composition - Google Patents
Canagliflozin pharmaceutical composition Download PDFInfo
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- CN108078945A CN108078945A CN201810029933.1A CN201810029933A CN108078945A CN 108078945 A CN108078945 A CN 108078945A CN 201810029933 A CN201810029933 A CN 201810029933A CN 108078945 A CN108078945 A CN 108078945A
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- canagliflozin
- weight
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- tablet
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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
- A61K9/20—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
-
- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Abstract
The present invention relates to canagliflozin pharmaceutical compositions.Specifically, canagliflozin pharmaceutical composition of the present invention includes：Active medicine canagliflozin or its hydrate, diluent, disintegrant, adhesive, lubricant, the hydrate of the canagliflozin is canagliflozin semihydrate.The invention further relates to the preparation methods and their pharmaceutical applications of the troche medical composition.Pharmaceutical composition of the present invention as a kind of using SGLT2 inhibitor as the small molecule oral hypoglycemic agents of active ingredient, with excellent pharmaceutical properties as described in the present invention for example with excellent stability and dissolving out capability.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are related to a kind of pharmaceutical composition of small molecule oral hypoglycemic agents, particularly relate to
It is and a kind of using SGLT2 inhibitor canagliflozin as the pharmaceutical composition of active medicine.The invention further relates to such pharmaceutical compositions
Preparation method.Excellent pharmaceutical properties as described in the present invention are presented in canagliflozin tablet medicament composition of the present invention.
Background technology
The most hot small molecule oral hypoglycemic agents of last decade research mainly has two classes, i.e. DPP-IV inhibitor (Ge Lieting class medicines
Object) and SGLT2 inhibitor (lattice arrange net class drug).The recent studies on of Decision Resource Decision Resources companies shows, with
The sales volume for the treatment of diabetes B key agents increases, and will promote this market (including the U.S., France, Germany, Italy, west
Class's tooth, Britain and Japan) increase to from 19,000,000,000 dollars of 2009 2019 36000000000 dollars.Since 2013 list, card
Lattice row as the first SGLT-2 inhibitor in the U.S., are listed less than 4 years, in the market share that 2016 create 1,900,000,000 dollars only.
Canagliflozin is first drug being approved in sodium-glucose co-transporters body 2 (SGLT2) inhibitor, suitable for II
Patients with type Ⅰ DM adult patient combination diet control and physical training control blood glucose.It acts in kidney the suction again for helping glucose
The SGLT2 albumen of receipts makes more sugar be excluded by the urine of patient, declines blood glucose level.
Canagliflozin ground by Tian Bian Mitsubishis pharmacy original, and the Janssen Pharmaceutica under Johnson ＆ Johnson obtained USA and EU in 2012
The mandate in area.Obtain the listing approval of U.S. FDA, the listing for obtaining European EMA on November 15 in 2013 batch on March 29th, 2013
Standard, the approval for obtaining Japanese PMDA on July 14 in 2014.The medicine logs in American market with trade name Invokana.Japan Area by
The production and sales of Tian Bian Mitsubishis are promoted jointly by Sankyo Co..According to tPharma data statistics, canagliflozin in 2014
7.2 hundred million dollars of global marketing volume, 2015 1400000000 dollars, reach within 2016 19.6 hundred million dollars, sell API needed for preparation up to 46
Ton.
Canagliflozin (Invokana) is the first SGLT-2 inhibitor of FDA approvals, and first enters market.With Mo Shadong
Xi Gelieting has forcibly occupied oral hypoglycemic agents eldest child position for many years to represent DPP-4 inhibitor, 2015 of Januvia/Janumet
Sales volume adds up to 60.14 hundred million dollars, presses on towards antidiabetic drug star actor Lantus.And SGLT-2 inhibitor is up-and-coming youngster, is listed less than 4
Year, the market share for creating 1,900,000,000 dollars in 2016.
If current antidiabetic drug is arranged from high to low by world market share, be successively insulin, DPP-IV inhibitor,
GLP-1 receptor stimulating agents and SGLT-2 inhibitor.Evaluate Pharma are pre- to the market share of all kinds of antidiabetic drugs in 2022
It surveys, wherein insulin was still one kind of market share maximum in all diabetes medicaments in 2022；GLP-1 receptor stimulating agents expand
Hold rapidly, share is only second to insulin；SGLT-2 inhibitor then squeezes out DPP-4 inhibitor, becomes best-selling oral hypoglycemic agents.
Canagliflozin, also known as canagliflozin, English name Canagliflozin, film coating tablet is by Belgium
Janssen-Cilag International NV companies are pacified or INVOKANA imports are to Chinese market so that trade name is happy, every
100mg (H20170375) and 300mg (H20170374) are calculated as with anhydride comprising canagliflozin.
The happy active ingredient pacified in Discussion on Chinese Listed is canagliflozin semihydrate, wherein cultural scientific name：(2S,3R,
4R, 5S, 6R) -2- { 3- [5- (4- fluoro-phenyls)-thiophene -2- ylmethyls] -4- methylphenyls } -6- methylol-ttetrahydro-pyrans -
3,4,5- triol semihydrates, English language Chemical entitled (2S, 3R, 4R, 5S, 6R) -2- 3- [5- (4-Fluoro-phenyl) -
thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-
Triol hemihydrates, molecular formula C24H25FO5S1/2H2O, molecular weight 453.53, chemical structural formula are：
Canagliflozin is practically insoluble in the water-bearing media of pH1.1 to 12.9.Commercially available INVOKANA every contains canagliflozin
Semihydrate 102mg and 306mg are respectively equivalent to anhydride 100mg and 300mg.The INVOKANA pieces are thin membrane coated tablet,
Following auxiliary material is further included in label in addition to active ingredient：Croscarmellose sodium, hydroxypropyl cellulose, Lactis Anhydrous,
Magnesium stearate, microcrystalline cellulose；Tablet is coated with commercial thin film coating material, and the auxiliary material included in thin film coating material has：It is poly-
Vinyl alcohol, titanium dioxide, polyethylene glycol, talcum powder and pigment oxidation iron oxide yellow.
The preparation manufacture of canagliflozin has many document reports at present.For example, CN106606489A (Chinese patent applications
Number 201510686747.1) disclose a kind of canagliflozin pharmaceutical composition and its preparation process, the canagliflozin drug
Composition contains canagliflozin and carrier material, and wherein carrier material is povidone.It is believed that the canagliflozin piece of the invention has
The characteristics of dissolution is fast, preparation process is simple.
CN103655539A (Chinese Patent Application No. 201310675536.9) discloses a kind of canagliflozin oral administration solid
Pharmaceutical composition and preparation method thereof, said composition contain canagliflozin and pharmaceutic adjuvant, and wherein canagliflozin is unformed shape
State, mean particle size are 2.5~30um.It is believed that said composition efficiently solves the canagliflozin of unformed form in solid
The brilliant technical barrier with poor compressibility of formulation process transfer.
CN104586795A (Chinese Patent Application No. 201410840598.5) discloses a kind of canagliflozin piece and its system
Preparation Method, which is characterized in that containing hydroxypropyl cellulose, diatomite in preparation, prepared by following technique：(1) it is hydroxypropyl is fine
Dimension element is added in ethyl alcohol, and stirring adds in canagliflozin and stir to dissolving to being completely dissolved, spare；(2) diatomite is added in (1)
It in the solution of preparation, stirs evenly, volatilizes solvent, obtain canagliflozin solid dispersions；(3) solid dispersions for preparing (2)
It is mixed with other pharmaceutically acceptable auxiliary materials, tabletting.
CN106474484A (Chinese Patent Application No. 201510553788.3) disclose a kind of canagliflozin with it is medicinal auxiliary
The composition and its manufacturing method of material, it includes canagliflozin and two or more pharmaceutic adjuvant, canagliflozin with it is complete
The weight ratio of portion's pharmaceutic adjuvant is 1:0.1~100, wherein, the canagliflozin in composition is unformed shape, the composition
Characteristic peak without canagliflozin crystal after the background peaks of deduction pharmaceutic adjuvant in X-ray powder diffraction spectrum.It is believed that the invention
The composition stability and favorable dispersibility of canagliflozin and pharmaceutic adjuvant, add the dissolution rate of canagliflozin, are more advantageous to
The absorption of the bioavilability and body of pharmaceutical preparation to drug is improved, under the conditions of accelerated test, good physics can be kept
Stability and chemical stability.The preparation method of the unformed composition of the present invention is easy to operate, of low cost, favorable reproducibility,
It is easily achieved, is suitble to industrialized production.
CN104523573A (Chinese Patent Application No. 201410836189.8) discloses a kind of canagliflozin quick release
Tablet, its piece hardness are 50N-80N, and in parts by weight, its constituent is 100-300 parts of canagliflozins, 35-110 parts
Pharmaceutical filler, 70-190 portion disintegrant, its preparation method comprise the following steps：In parts by weight, 100-300 parts of cards are taken respectively
Lattice row are net, 35-110 parts of pharmaceutical fillers, 70-190 portions of disintegrants sieve, then obtained powder are uniformly mixed, then directly
Tabletting, control sheet hardness are 50N-80N to get to the canagliflozin immediate-release tablet；Compared with prior art, it is believed that
Canagliflozin immediate-release tablet can be completely disintegrated in 1min or so in the invention, greatly speeded up the absorption of drug, increased
Added drug reaches peak kurtosis, shortens the peak time of drug, has on clinical efficacy and have great advantage；It is prepared in the present invention
Method uses direct powder compression, simple for process, is easy to industrialized production.
CN105769803A (Chinese Patent Application No. 201410773880.6) discloses one kind for treating diabetes B
Pharmaceutical composition and preparation method thereof, which is by active ingredient canagliflozin
And the pharmaceutic adjuvants such as water-soluble solid dispersible carrier, disintegrant, lubricant composition, it is believed that be used to treat obtained by the invention
To the grain size of active ingredient, without particular/special requirement, ultramicro grinding is not required, low energy consumption, dissolution rate in the pharmaceutical composition of diabetes B
Reaching more than 90%, bioavilability is high, solves the defects of active ingredient solubility is poor, bioavilability is low, stable quality,
Reliably, the great prospect of marketing.
CN102883726A (Chinese Patent Application No. 201180023642.8) discloses a kind of comprising 1- (β-D- pyrans Portugals
Grape glycosyl) the pharmaceutical preparation of -2- thienyl-methyls benzene derivative as SGLT inhibitor, the drug system of this orally available application
Agent includes at least one diluent or filler, optionally at least one disintegrant, optionally at least one adhesive, optional
At least one lubricant, wherein formula (I) reactive compound in the range of about 1% to about 80 weight % amount exist, diluent or
Filler exists with the amount in the range of about 10% to about 95 weight %, disintegrant, if it exists, with about 0.1% to about 20
Amount in the range of weight % exists, adhesive, if it exists, exist with the amount in the range of about 0.1% to about 20 weight %,
Lubricant, if it exists, exist with the amount in the range of about 0.1% to about 5 weight %, it is micro- to include in this application file
Crystalline cellulose (diluent), Lactis Anhydrous (diluent), hydroxypropyl cellulose (wet granulation adhesive), cross-linked carboxymethyl fiber
Plain sodium (disintegrant), magnesium stearate prepare tablet with classical wet granulation mode, and are coated material with commercialization as label auxiliary material
Expect Opadry II to label wrap film clothing to tablet weightening 3~4%.It is believed that tablet made from the invention is with good internal
Behavior.It is well known that since the internal behavior of drug can be carried out by the dissolving out capability in a variety of different dissolution mediums
Simulation, by vitro Drug behavior it is this it is simple in a manner of speculate the internal behavior of drug, such as by molten with commercially available reference substance
It goes on a journey to be compared, shows that drug obtained has and the same or similar body of commercially available reference substance if dissolved corrosion is similar
Interior behavior.
For this purpose, this field still expects have new method to be particularly its tablet to prepare canagliflozin pharmaceutical composition, and
And expect that canagliflozin tablet made from this method has excellent property, such as with going with the comparable release of commercially available product
For.
The content of the invention
It is an object of the invention to provide a kind of method for preparing canagliflozin pharmaceutical composition and being particularly its tablet, and
Expect canagliflozin tablet made from this method have excellent property, such as with commercially available product it is comparable release go
For.Another object of the present invention is to provide a kind of canagliflozin pharmaceutical composition as made from the above method to be particularly its piece
Agent.Have discovered that by the realization one or more advantageous effect that inventive formulation and preparation method can be beneficial.
In a first aspect, the present invention provides a kind of canagliflozin pharmaceutical composition in tablet form, including：Active drug
Object canagliflozin or its hydrate, diluent, disintegrant, adhesive, lubricant.
Canagliflozin pharmaceutical composition according to the present invention, wherein the hydrate of the canagliflozin is half water of canagliflozin
Close object.
Canagliflozin pharmaceutical composition according to the present invention, wherein in the tablet the every active medicine included amount with
Canagliflozin anhydride is calculated as 50~300mg, such as 100~300mg, for example, the every active medicine included amount with Ka Gelie
Net anhydride is calculated as 50mg, 100mg, 200mg or 300mg.
Canagliflozin pharmaceutical composition according to the present invention, wherein the diluent is selected from：Starch, microcrystalline cellulose, silicon
Change microcrystalline cellulose, lactose (Lactis Anhydrous or a Lactose hydrate), sucrose, dextrin and combinations thereof.In one embodiment, institute
State the combination that diluent is microcrystalline cellulose and lactose (Lactis Anhydrous or a Lactose hydrate).In one embodiment, it is described
Diluent is both microcrystalline cellulose and lactose (Lactis Anhydrous or a Lactose hydrate) with weight ratio 1：0.75~1.25 combination.
Canagliflozin pharmaceutical composition according to the present invention, wherein in terms of the canagliflozin anhydride of every 100 parts by weight, institute
The amount of diluent is stated as 60~100 parts by weight, such as 70~90 parts by weight.
Canagliflozin pharmaceutical composition according to the present invention, wherein the disintegrant is selected from：Croscarmellose sodium,
Crosslinked polyvinylpyrrolidone, sodium carboxymethyl starch etc..
Canagliflozin pharmaceutical composition according to the present invention, wherein in terms of the canagliflozin anhydride of every 100 parts by weight, institute
The amount of disintegrant is stated as 10~15 parts by weight, such as 11~13 parts by weight.
Canagliflozin pharmaceutical composition according to the present invention, wherein described adhesive are selected from：Hypromellose, hydroxypropyl
Base cellulose, polyethylene glycol, polyvinylpyrrolidone (such as PVP K15, PVP K30), starch.
Canagliflozin pharmaceutical composition according to the present invention, wherein in terms of the canagliflozin anhydride of every 100 parts by weight, institute
The amount of adhesive is stated as 4~8 parts by weight, such as 5~7 parts by weight.In one embodiment, described adhesive is with dry method system
The technique of grain tabletting is added in the tablet.
Canagliflozin pharmaceutical composition according to the present invention, wherein the lubricant is selected from：It is magnesium stearate, stearic acid, hard
Resin acid calcium, talcum powder, colloidal silicon dioxide etc..Preferred lubricant is magnesium stearate.
Canagliflozin pharmaceutical composition according to the present invention, wherein in terms of the canagliflozin anhydride of every 100 parts by weight, institute
The amount of lubricant is stated as 1~2 parts by weight, such as 1.2~1.8 parts by weight.
Canagliflozin pharmaceutical composition according to the present invention, wherein the active medicine with the diluent, disintegrant,
Before adhesive, mix lubricant, micronization processes are carried out in advance.
Canagliflozin pharmaceutical composition according to the present invention, wherein particle of the active medicine after micronization processes is put down
Equal grain size is 5~20 μm.
Canagliflozin pharmaceutical composition according to the present invention, wherein the active medicine is also adding together through micronization processes
Add selected from following phosphate：Calcium phosphate or calcium monohydrogen phosphate (such as calcium phosphate dibasic anhydrous).In one embodiment, with every
The canagliflozin anhydride meter of 100 parts by weight, the phosphatic amount are 5~15 parts by weight, such as 8~12 parts by weight.
Canagliflozin pharmaceutical composition according to the present invention, wherein the active medicine is also adding together through micronization processes
Adding inorganic salts, it is, for example, sodium chloride or potassium chloride.In one embodiment, with the canagliflozin anhydride of every 100 parts by weight
Meter, the amounts of the inorganic salts are 1~3 parts by weight, such as 1~2 parts by weight.Unexpected discovery, when active medicine with
When two kinds of substances of above-mentioned phosphate and inorganic salts carry out micronization processes together, can make drug smoothly realize granularity drop to 5~
20 μm of desired size, and these micronizing substances can on the one hand be easily uniformly mixed with materials such as diluents, it is another
Aspect can be respectively provided in the dissolution medium in the range of wide pH value using tablet made from this micronizing bulk pharmaceutical chemicals excellent
Good dissolving out capability.
Canagliflozin pharmaceutical composition according to the present invention in tablet form is the method by including the following steps
It is prepared：
(1) active medicine is made to carry out micronization processes together with phosphate and inorganic salts, until gained particle average grain diameter
For 5~20 μm, micronizing mixed powder is obtained；
(2) micronizing mixed powder is made to be uniformly mixed with diluent, part or all of disintegrant, adhesive, adds in dry method system
Dry granulation is carried out in grain machine, obtains particle；
(3) make gained particle and the disintegrant and mix lubricant of optional surplus uniform, obtain mixed mixture eventually；
(4) mixed mixture eventually is pressed into the tablet of plain piece form.
Canagliflozin pharmaceutical composition according to the present invention, in preparation process (2), the partial disintegration agent is disintegrant
The 30~80% of total amount, such as 50~80%.
Canagliflozin pharmaceutical composition according to the present invention in tablet form, the wherein plain piece obtained by step (4) are also
Further it is wrapped film-coating.
Canagliflozin pharmaceutical composition according to the present invention, the film-coating are using hydroxypropyl methyl cellulose as coating base
The coating material of material is either using polyvinyl alcohol as the coating material of coating base material.In one embodiment, the bag and material
Auxiliary agents such as plasticizer such as glyceryl triacetate, polyethylene glycol are further included in material, opacifier is such as titanium dioxide.One
In a embodiment, auxiliary agents such as polyethylene glycol, opacifier such as titanium dioxide, suspending agent are further included in the bag and material
Such as talcum powder and optional pigment.The additive amount of these adjuvants is well known to those skilled in the art, and this bag
Clothing material pre-composition can directly be bought from city, such as directly be bought from the happy Kanggong department of card, such as buy Europe from the happy Kanggong department of card
Bar for II be coated premixing flour.
Canagliflozin pharmaceutical composition according to the present invention, the film-coating account for the 1~5% of tablet label total weight, example
Such as account for the 2~4% of tablet label total weight.
Second aspect, the present invention provides the canagliflozin pharmaceutical composition such as present invention first prepared in tablet form
It is in the method for the canagliflozin pharmaceutical composition of tablet form described in aspect, this method comprises the following steps：
(1) active medicine is made to carry out micronization processes together with phosphate and inorganic salts, until gained particle average grain diameter
For 5~20 μm, micronizing mixed powder is obtained；
(2) micronizing mixed powder is made to be uniformly mixed with diluent, part or all of disintegrant, adhesive, adds in dry method system
Dry granulation is carried out in grain machine, obtains particle；
(3) make gained particle and the disintegrant and mix lubricant of optional surplus uniform, obtain mixed mixture eventually；
(4) mixed mixture eventually is pressed into the tablet of plain piece form.
The method according to the invention, in preparation process (2), the partial disintegration agent be disintegrant total amount 30~
80%, such as 50~80%.
The method according to the invention, wherein described include in the canagliflozin pharmaceutical composition of tablet form：Active medicine
Canagliflozin or its hydrate, diluent, disintegrant, adhesive, lubricant.
The method according to the invention, wherein the hydrate of the canagliflozin is canagliflozin semihydrate.
The method according to the invention, wherein the amount of the every active medicine included is with canagliflozin anhydride in the tablet
50~300mg, such as 100~300mg are calculated as, such as the amount of the every active medicine included is calculated as with canagliflozin anhydride
50mg, 100mg, 200mg or 300mg.
The method according to the invention, wherein the diluent is selected from：Starch, microcrystalline cellulose, silicified microcrystalline cellulose, breast
Sugared (Lactis Anhydrous or a Lactose hydrate), sucrose, dextrin and combinations thereof.In one embodiment, the diluent is crystallite
The combination of cellulose and lactose (Lactis Anhydrous or a Lactose hydrate).In one embodiment, the diluent is crystallite fibre
Both dimension element and lactose (Lactis Anhydrous or a Lactose hydrate) are with weight ratio 1：0.75~1.25 combination.
The method according to the invention, wherein in terms of the canagliflozin anhydride of every 100 parts by weight, the amount of the diluent is
60~100 parts by weight, such as 70~90 parts by weight.
The method according to the invention, wherein the disintegrant is selected from：Croscarmellose sodium, crosslinked polyethylene pyrroles
Alkanone, sodium carboxymethyl starch etc..
The method according to the invention, wherein in terms of the canagliflozin anhydride of every 100 parts by weight, the amount of the disintegrant is
10~15 parts by weight, such as 11~13 parts by weight.
The method according to the invention, wherein described adhesive are selected from：Hypromellose, hydroxypropyl cellulose, poly- second
Glycol, polyvinylpyrrolidone (such as PVP K15, PVP K30), starch.
The method according to the invention, wherein in terms of the canagliflozin anhydride of every 100 parts by weight, the amount of described adhesive is
4~8 parts by weight, such as 5~7 parts by weight.In one embodiment, described adhesive is added with the technique of dry granulation tabletting
Enter into the tablet.
The method according to the invention, wherein the lubricant is selected from：Magnesium stearate, stearic acid, calcium stearate, talcum powder,
Colloidal silicon dioxide etc..Preferred lubricant is magnesium stearate.
The method according to the invention, wherein in terms of the canagliflozin anhydride of every 100 parts by weight, the amount of the lubricant is
1~2 parts by weight, such as 1.2~1.8 parts by weight.
The method according to the invention, wherein the active medicine with the diluent, disintegrant, adhesive, lubricant
Before mixing, micronization processes are carried out in advance.
The method according to the invention, wherein particle average grain diameter of the active medicine after micronization processes is 5~20 μ
m。
The method according to the invention, wherein the phosphate is selected from：Calcium phosphate or calcium monohydrogen phosphate (such as anhydrous phosphoric acid hydrogen
Calcium).In one embodiment, in terms of the canagliflozin anhydride of every 100 parts by weight, the phosphatic amount is 5~15 weights
Measure part, such as 8~12 parts by weight.
The method according to the invention, wherein the inorganic salts are selected from sodium chloride or potassium chloride.In one embodiment, with
The canagliflozin anhydride meter of every 100 parts by weight, the amounts of the inorganic salts are 1~3 parts by weight, such as 1~2 parts by weight.
Plain piece obtained by the method according to the invention, wherein step (4) is also further wrapped film-coating.
The method according to the invention, the film-coating be using hydroxypropyl methyl cellulose as coating base material coating material or
Person is the coating material using polyvinyl alcohol as coating base material.In one embodiment, auxiliary is further included in the bag and material
Agent such as plasticizer such as glyceryl triacetate, polyethylene glycol, opacifier is such as titanium dioxide.In one embodiment,
It is described bag and material in further include auxiliary agents such as polyethylene glycol, opacifier such as titanium dioxide, suspending agents such as talcum powder with
And optional pigment.The additive amount of these adjuvants is well known to those skilled in the art, and this coating material pre-composition
It can directly buy from city, such as directly be bought from the happy Kanggong department of card, such as Opadry II coatings are bought in advance from the happy Kanggong department of card
Mixed powder.
The method according to the invention, the film-coating account for the 1~5% of tablet label total weight, such as to account for tablet label total
The 2~4% of weight.
The third aspect, the present invention provides canagliflozin pharmaceutical composition described in first aspect present invention or the present invention the
Use of the canagliflozin pharmaceutical composition made from two aspect the methods in the drug for preparing the illness related with SGLT2 activity
On the way.
The present invention also provides canagliflozin pharmaceutical composition or second aspect of the present invention described in first aspect present invention
Canagliflozin pharmaceutical composition made from the method is being prepared as antidiabetic, antihyperglycemic agents, lipid-lowering agent or fat
Purposes in matter depressant, antiobesity agent, rescinnamine and appetite inhibitor drug.
The present invention also provides canagliflozin pharmaceutical composition or second aspect of the present invention described in first aspect present invention
Purposes of the canagliflozin pharmaceutical composition made from the method in the drug for preparing treatment type-2 diabetes mellitus.
Any embodiment of either side according to the present invention, wherein the canagliflozin pharmaceutical composition has such as this hair
Formula any one of bright any embodiment.
Any embodiment of either side according to the present invention, wherein the canagliflozin pharmaceutical composition has such as this hair
Formula and preparation method any one of bright any embodiment.
In the step of above-mentioned preparation method of the invention, although the specific steps of its description are in some details or language
The step of in description with described in the preparation example of following detailed description part, is otherwise varied, however, people in the art
The detailed disclosure of member's full text according to the present invention can summarize approach described above step completely.
Any embodiment of the either side of the present invention, can be combined with other embodiments, as long as they are not
It is present with contradiction.In addition, in any embodiment of either side of the present invention, any technical characteristic can be adapted for other realities
The technical characteristic in scheme is applied, as long as they are not in contradiction.The invention will be further described below.
All documents recited in the present invention, their full content are incorporated herein by reference, and if these are literary
When offering expressed meaning and the inconsistent present invention, the statement of the present invention is subject to.In addition, the various terms that use of the present invention and
Phrase has well known to a person skilled in the art general sense, nonetheless, the present invention remain desirable at this to these terms and
Phrase is described in more detail and explains, the term and phrase referred to is if any inconsistent with common art-recognized meanings, with institute's table of the present invention
Subject to the meaning stated.
Canagliflozin is first drug being approved in sodium-glucose co-transporters body 2 (SGLT2) inhibitor, suitable for II
Patients with type Ⅰ DM adult patient combination diet control and physical training control blood glucose.It acts in kidney the suction again for helping glucose
The SGLT2 albumen of receipts makes more sugar be excluded by the urine of patient, declines blood glucose level.
The present invention provides a kind of beneficial method, and obtained canagliflozin medicine for the preparation production of canagliflozin
Compositions are particularly the technique effect that one or more aspects are presented in its tablet.
Specific embodiment
The present invention can be further described by the following examples, however, the scope of the present invention and unlimited
In following embodiments.One of skill in the art, can be with it is understood that on the premise of without departing substantially from the spirit and scope of the present invention
Various change and modification are carried out to the present invention.The present invention carries out the material and test method that are arrived used in experiment general
And/or specific description.Although to realize the present invention many materials used in purpose and operating method be it is known in the art that
But the present invention is still described in detail as far as possible herein.
It is also found in various experiments herein, for the material of same a collection of pharmaceutical composition, when they are pressed into every
It is same during tablet comprising active ingredient (in terms of canagliflozin anhydride) 50mg, 100mg, 200mg, 300mg/ piece equal-specification
The stripping curve criticized between the preparation of the different size obtained by pharmaceutical composition material is identical；Therefore, various examples below
In, if not otherwise indicated, as typical preparation specification, when preparing tablet, active ingredient in every (with canagliflozin without
Water object meter) it measures as 100mg.In following example, when preparing composition, recorded when listing prescription with the amount of every middle material,
But when actually feeding intake, fed intake with being not less than the material ratio of 50,000 scales of preparation.In following various examples, such as not
In addition illustrate, canagliflozin used is its semihydrate.
A, embodiment part is prepared
Embodiment 1：Prepare canagliflozin piece
Formula：
Canagliflozin semihydrate：(in terms of anhydride) 100mg,
Phosphate：10mg、
Inorganic salts：1.5mg、
Diluent (microcrystalline cellulose/lactose (anhydrous)=1:1)：80mg、
Disintegrant (croscarmellose sodium)：12mg、
Adhesive (PVP K15)：6mg、
Lubricant (magnesium stearate)：1.5mg.
Preparation method：
(1) active medicine is made to carry out micronization processes together with phosphate (calcium phosphate) and inorganic salts (sodium chloride), until
Gained particle average grain diameter is 5~20 μm (actual measurement average grain diameter is 16 μm), obtains micronizing mixed powder；
(2) micronizing mixed powder is made to be uniformly mixed with diluent, partial disintegration agent (70%), adhesive, adds in dry method system
Dry granulation is carried out in grain machine, obtains particle；
(3) make gained particle and surplus disintegrant and mix lubricant uniform, obtain mixed mixture eventually；
(4) mixed mixture eventually is pressed into the tablet of plain piece form.
The present embodiment and the other embodiments for preparing canagliflozin piece herein, make in step (2) micronizing mixed powder with
Diluent, disintegrant, adhesive are mixed in efficient mixed granulation machine when mixing and (often mix batch at least 5kg powders
Material) 30min, surface of material in mixer is taken to be mixed for totally ten parts adjacent to corner and centre adjacent to corner and centre, material bottom
Powder sample measures their active component content, and the active ingredient proceeded to operation in mixed material obtained by this step is theoretical
On the basis of content, with reference to 2015 version Chinese Pharmacopoeia four " 0941 Content uniformity test " method, ask calculate A+2.2S values,
This value preferably should be less than 15 and the smaller the better.A+2.2S=1.7 in this example,
The A+2.2S values of embodiment 2-9 show that step (2) can be in short-term in these experiments in the range of 1.1~2.3
It is interior to obtain excellent mixed effect.
Further, it has been found that in the above-mentioned steps (1) of 1-5 of the embodiment of the present invention, it is micronized to active medicine and is advised
Phosphate is not added about the time required to fixed particle average grain diameter degree, does not add inorganic salts or does not add phosphate/inorganic
23~37% the time required to during both salt, show that adding both phosphate/inorganic salts simultaneously can greatly improve at micronizing
The efficiency of reason.Further, it has been found that the selection of phosphate and inorganic salts is unique, because the present inventor is in other supplement
Found in experiment, when with reference to above-described embodiment 1-5 steps (1) when, by the phosphate replace with equivalent potassium dihydrogen phosphate or
The inorganic salts are replaced with equivalent calcium chloride or phosphate simultaneously are replaced with equivalent potassium dihydrogen phosphate and will be inorganic by person
Salt replaces with equivalent calcium chloride, is taken the particle average grain diameter degree that active medicine is micronized to defined under three kinds of situations
Between about described in embodiment 1-5 using 3.8~5.1 times the time required to during both phosphate/inorganic salts, show to use other kinds instead
The effect for improving micronization processes efficiency cannot be obtained when the phosphate and inorganic salts of class.
Embodiment 2：Prepare canagliflozin piece
Formula：
Canagliflozin semihydrate：(in terms of anhydride) 100mg,
Phosphate：8mg、
Inorganic salts：2mg、
Diluent (microcrystalline cellulose/lactose (anhydrous)=1:1.25)：70mg、
Disintegrant (croscarmellose sodium)：11mg、
Adhesive (PVP K30)：5mg、
Lubricant (magnesium stearate)：1.2mg.
Preparation method：
(1) active medicine is made to be carried out together with phosphate (calcium phosphate dibasic anhydrous) and inorganic salts (sodium chloride) at micronizing
Reason until gained particle average grain diameter is 5~20 μm (actual measurement average grain diameter is 11 μm), obtains micronizing mixed powder；
(2) micronizing mixed powder is made to be uniformly mixed with diluent, partial disintegration agent (50%), adhesive, adds in dry method system
Dry granulation is carried out in grain machine, obtains particle；
(3) make gained particle and surplus disintegrant and mix lubricant uniform, obtain mixed mixture eventually；
(4) mixed mixture eventually is pressed into the tablet of plain piece form.
Embodiment 3：Prepare canagliflozin piece
Formula：
Canagliflozin semihydrate：(in terms of anhydride) 100mg,
Phosphate：12mg、
Inorganic salts：1mg、
Diluent (microcrystalline cellulose/lactose (monohydrate)=1:0.75)：70mg、
Disintegrant (sodium carboxymethyl starch)：13mg、
Adhesive (PVP K15)：7mg、
Lubricant (magnesium stearate)：1.8mg.
Preparation method：
(1) active medicine is made to carry out micronization processes together with phosphate (calcium phosphate) and inorganic salts (sodium chloride), until
Gained particle average grain diameter is 5~20 μm (actual measurement average grain diameter is 19 μm), obtains micronizing mixed powder；
(2) micronizing mixed powder is made to be uniformly mixed with diluent, partial disintegration agent (80%), adhesive, adds in dry method system
Dry granulation is carried out in grain machine, obtains particle；
(3) make gained particle and surplus disintegrant and mix lubricant uniform, obtain mixed mixture eventually；
(4) mixed mixture eventually is pressed into the tablet of plain piece form.
Embodiment 4：Prepare canagliflozin piece
Formula：
Canagliflozin anhydride：100mg、
Phosphate：5mg、
Inorganic salts：3mg、
Diluent (microcrystalline cellulose/lactose (anhydrous)=1:0.9)：100mg、
Disintegrant (crosslinked polyvinylpyrrolidone)：10mg、
Adhesive (PVP K30)：4mg、
Lubricant (magnesium stearate)：2mg.
Preparation method：
(1) active medicine is made to carry out micronization processes together with phosphate (calcium phosphate) and inorganic salts (potassium chloride), until
Gained particle average grain diameter is 5~20 μm (actual measurement average grain diameter is 5 μm), obtains micronizing mixed powder；
(2) micronizing mixed powder is made to be uniformly mixed with diluent, disintegrant, adhesive, adds in dry granulating machine and carries out
Dry granulation obtains particle；
(3) make gained particle uniform with mix lubricant, obtain mixed mixture eventually；
(4) mixed mixture eventually is pressed into the tablet of plain piece form.
Embodiment 5：Prepare canagliflozin piece
Formula：
Canagliflozin semihydrate：(in terms of anhydride) 100mg,
Phosphate：15mg、
Inorganic salts：1mg、
Diluent (microcrystalline cellulose/lactose (anhydrous)=1:1.2)：60mg、
Disintegrant (croscarmellose sodium)：15mg、
Adhesive (PVP K15)：8mg、
Lubricant (magnesium stearate)：1mg.
Preparation method：
(1) active medicine is made to be carried out together with phosphate (calcium phosphate dibasic anhydrous) and inorganic salts (potassium chloride) at micronizing
Reason until gained particle average grain diameter is 5~20 μm (actual measurement average grain diameter is 8 μm), obtains micronizing mixed powder；
(2) micronizing mixed powder is made to be uniformly mixed with diluent, partial disintegration agent (60%), adhesive, adds in dry method system
Dry granulation is carried out in grain machine, obtains particle；
(3) make gained particle and surplus disintegrant and mix lubricant uniform, obtain mixed mixture eventually；
(4) mixed mixture eventually is pressed into the tablet of plain piece form.
Embodiment 6：Prepare canagliflozin piece
Formula：
Canagliflozin anhydride：100mg、
Phosphate：9mg、
Inorganic salts：1.2mg、
Diluent (microcrystalline cellulose/lactose (monohydrate)=1:0.8)：85mg、
Disintegrant (sodium carboxymethyl starch)：12mg、
Adhesive (PVP K30)：6mg、
Lubricant (magnesium stearate)：1.5mg.
Preparation method：
(1) active medicine is made to be carried out together with phosphate (calcium phosphate dibasic anhydrous) and inorganic salts (potassium chloride) at micronizing
Reason until gained particle average grain diameter is 5~20 μm (actual measurement average grain diameter is 14 μm), obtains micronizing mixed powder；
(2) micronizing mixed powder is made to be uniformly mixed with diluent, partial disintegration agent (60%), adhesive, adds in dry method system
Dry granulation is carried out in grain machine, obtains particle；
(3) make gained particle and surplus disintegrant and mix lubricant uniform, obtain mixed mixture eventually；
(4) mixed mixture eventually is pressed into the tablet of plain piece form.
Embodiment 7：Prepare canagliflozin piece
Formula：
Canagliflozin semihydrate：(in terms of anhydride) 100mg,
Phosphate：10mg、
Inorganic salts：1.5mg、
Diluent (microcrystalline cellulose/lactose (anhydrous)=1:0.9)：80mg、
Disintegrant (crosslinked polyvinylpyrrolidone)：12mg、
Adhesive (PVP K15)：7mg、
Lubricant (magnesium stearate)：1.5mg.
Preparation method：
(1) active medicine is made to carry out micronization processes together with phosphate (calcium phosphate) and inorganic salts (sodium chloride), until
Gained particle average grain diameter is 5~20 μm (actual measurement average grain diameter is 13 μm), obtains micronizing mixed powder；
(2) micronizing mixed powder is made to be uniformly mixed with diluent, partial disintegration agent (60%), adhesive, adds in dry method system
Dry granulation is carried out in grain machine, obtains particle；
(3) make gained particle and surplus disintegrant and mix lubricant uniform, obtain mixed mixture eventually；
(4) mixed mixture eventually is pressed into the tablet of plain piece form.
Embodiment 8：Prepare canagliflozin piece
Formula：
Canagliflozin semihydrate：(in terms of anhydride) 100mg,
Phosphate：11mg、
Inorganic salts：2mg、
Diluent (microcrystalline cellulose/lactose (anhydrous)=1:1.1)：80mg、
Disintegrant (croscarmellose sodium)：11mg、
Adhesive (PVP K15)：5mg、
Lubricant (magnesium stearate)：2mg.
Preparation method：
(1) active medicine is made to be carried out together with phosphate (calcium phosphate dibasic anhydrous) and inorganic salts (sodium chloride) at micronizing
Reason until gained particle average grain diameter is 5~20 μm (actual measurement average grain diameter is 15 μm), obtains micronizing mixed powder；
(2) micronizing mixed powder is made to be uniformly mixed with diluent, partial disintegration agent (70%), adhesive, adds in dry method system
Dry granulation is carried out in grain machine, obtains particle；
(3) make gained particle and surplus disintegrant and mix lubricant uniform, obtain mixed mixture eventually；
(4) mixed mixture eventually is pressed into the tablet of plain piece form.
Embodiment 9：Prepare canagliflozin piece
Formula：
Canagliflozin semihydrate：(in terms of anhydride) 100mg,
Phosphate：7mg、
Inorganic salts：1mg、
Diluent (microcrystalline cellulose/lactose (anhydrous)=1:1)：100mg、
Disintegrant (croscarmellose sodium)：102mg、
Adhesive (PVP K30)：6mg、
Lubricant (magnesium stearate)：1mg.
Preparation method：
(1) active medicine is made to carry out micronization processes together with phosphate (calcium phosphate) and inorganic salts (potassium chloride), until
Gained particle average grain diameter is 5~20 μm (actual measurement average grain diameter is 12 μm), obtains micronizing mixed powder；
(2) micronizing mixed powder is made to be uniformly mixed with diluent, disintegrant, adhesive, adds in dry granulating machine and carries out
Dry granulation obtains particle；
(3) make gained particle uniform with mix lubricant, obtain mixed mixture eventually；
(4) mixed mixture eventually is pressed into the tablet of plain piece form.
Embodiment 11：Prepare canagliflozin piece
The formula and preparation method of Examples 1 to 5 are respectively referred to, different is only not add phosphate, and 5 batches of tablets are made.
In the step of prepared by these tablets (2), the A+2.2S of material mixing 30min, 60min, 120min is respectively 14.7~18.1,
12.4~14.6,10.7~13.1, this shows that mixing difficulty of these materials mixing difficulty significantly than embodiment 1-5 is big, A+
2.2S values are unacceptable or close to unacceptable.
Embodiment 12：Prepare canagliflozin piece
The formula and preparation method of Examples 1 to 5 are respectively referred to, different is only not add inorganic salts, and 5 batches of tablets are made.
In the step of prepared by these tablets (2), the A+2.2S of material mixing 30min, 60min, 120min is respectively 13.9~18.5,
12.1~15.4,10.2~13.5, this shows that mixing difficulty of these materials mixing difficulty significantly than embodiment 1-5 is big, A+
2.2S values are unacceptable or close to unacceptable.
Embodiment 13：Prepare canagliflozin piece
The formula and preparation method of Examples 1 to 5 are respectively referred to, different is only not add phosphate and inorganic salts, is made 5 batches
Tablet.Prepared by these tablets the step of in (2), the A+2.2S of material mixing 30min, 60min, 120min is respectively 15.4~
19.3rd, 13.3~15.9,11.7~13.4, this shows mixing difficulty of these materials mixing difficulty significantly than embodiment 1-5
Greatly, A+2.2S values are unacceptable or close to unacceptable.
Embodiment 14：Prepare canagliflozin piece
It (suppresses every with reference to formula and preparation method the preparation plain piece of the embodiment 4 of CN103655539A and includes anhydrous Ka Gelie
The piece of net 100mg)；The formula and preparation method of the embodiment 1 of reference CN104523573A prepare plain piece, and (bulk pharmaceutical chemicals are through crushing and mistake
200 mesh sieves (usual bulk pharmaceutical chemicals, which are crushed to, in production can cross 120 mesh sieves), compacting every includes anhydrous canagliflozin 100mg
Piece)；With reference to CN104586795A embodiments 1 formula and preparation method prepare plain piece (bulk pharmaceutical chemicals through crush and cross 200 mesh sieves, pressure
Make the every piece for including anhydrous canagliflozin 100mg)；Plain piece is prepared with reference to the formula and preparation method of CN106606489A embodiments 1
(bulk pharmaceutical chemicals suppress the every piece for including anhydrous canagliflozin 100mg through crushing and crossing 200 mesh sieves)；With reference to CN106243097A
The formula and preparation method of embodiment 2 prepare plain piece, and (bulk pharmaceutical chemicals include anhydrous canagliflozin through crushing and crossing 200 mesh sieves, compacting every
The piece of 100mg).
Embodiment 21：Friability test
According to 2015 version Chinese Pharmacopoeia four " 0923 tablet friability inspection technique " method, measure embodiment 1-9 and
(compression force of these tablets in tabletting is 15KN to plain piece obtained by 11~14 each embodiment of embodiment, and obtained sheet
The hardness of agent is in the range of 17~21kg) friability.The results show that the tablet of whole batches does not occur being broken, be cracked
And the situation crushed, and less loss weight is averaged in the range of 0.22~0.34%, it is excellent crisp to show that these tablets have
Broken degree.
Embodiment 22：Dissolution Rate Testing
With《Normal oral solid pharmaceutical preparation Dissolution Rate Testing technological guidance's principle》(State Food and Drug Administration,
On February 05th, 2015) defined method, reference preparation is ground so that commercially available canagliflozin piece is (happy to pacify) for original, to implementing above
The dissolution rate of plain piece obtained by example 11~14 each embodiment of 1-9 and embodiment is tested, and with 900ML dissolution mediums, is shone
The method of the second method (paddle method, 50rpm) of version Chinese Pharmacopoeia four in 2015 " 0931 dissolution rate and drug release determination method ", warp
5min, 15min, 30min, 45min, 60min are separately sampled, measure stripping quantity at 254nm with spectrophotometry and calculate molten
Out-degree, and calculate respective film-making agent and it is happy pacify between stripping curve similar factors f2 values, which shows closer to 100
Product is ground with more similar dissolving out capability to original from film-making.It is respectively (a) pH1.5 hydrochloric acid solutions using four kinds of dissolution mediums
(3.73ml hydrochloric acid->1000mL), (b) pH3.8 acetate buffers (0.67g sodium acetates->1000mL is molten with 2mol/L acetic acid
Liquid adjust pH value), (c) pH5.5 phosphate buffers (0.05mol/L potassium dihydrogen phosphates with sodium hydroxide solution adjust pH
Value), (d) pH6.8 phosphate buffers (0.05mol/L potassium dihydrogen phosphates with sodium hydroxide solution adjust pH value), four kinds
0.25% lauryl sodium sulfate is respectively added in dissolution medium.As a result：It is real with the happy f2 values pacified under the conditions of pH6.8
Apply whole plain pieces obtained by 1-9 they in the range of 91~96, the whole plain pieces of 11~14 gained of embodiment they 87~
In the range of 93；With the happy f2 values pacified under the conditions of pH5.5, whole plain pieces obtained by embodiment 1-9 they in 86~94 scopes
It is interior, the whole plain pieces of the gained of embodiment 11~14 they in the range of 73~81；Under the conditions of pH3.8 with the happy f2 values pacified,
Whole plain pieces obtained by embodiment 1-9 they in the range of 88~96, the whole plain pieces of 11~14 gained of embodiment they 33
In the range of~39；With the happy f2 values pacified under the conditions of pH1.5, whole plain pieces obtained by embodiment 1-9 they in 85~91 models
In enclosing, the whole plain pieces of 11~14 gained of embodiment they in the range of 21~27；The above result shows that obtained by embodiment 1-9
Whole plain pieces grind commercially available product under the conditions of whole pH with height dissolution similitude with original, and 11~14 gained of embodiment is all plain
Piece grinds commercially available product with original has height dissolution similitude in neutral conditions, but the smaller similitudes of pH are poorer or even in pH value
Similitude is unacceptable under conditions of less than 4.
In addition, after measured, whole tablets dissolution rate when under the conditions of pH6.8 in 60min reaches more than 85%, such as this
Inventive embodiments 1-9 wholes tablet when under the conditions of pH6.8 in 60min dissolution rate in the range of 91~96%.
Embodiment 23：Tablet is coated
Premixing flour is coated with commercially available Opadry II, respectively to embodiment 1-9 and the whole batches of 11~14 gained of embodiment
Plain piece be coated, coating weight gain 2~5% (Examples 1 to 4 plain piece coating weight gain is respectively 2%, 3%, 4%, 5%,
3.5%) remaining embodiment plain piece coating weight gain is.These coated tablets are with reference to the Dissolution Rate Testing side of the embodiment of the present invention 22
Method, the results show coating tablet is substantially similar to the f2 values of its corresponding plain piece (related to be no more than 5 quantitative values), shows the present invention
Tablet does not influence dissolution rate whether coating.
Embodiment 24：Tablet stability is tested
Whole tablets obtained by 1-9 of the embodiment of the present invention are placed in the state of simulation listing packaging at 40 DEG C of temperature and are placed
6 months, measure the content of tablet, dissolution rate, related substance at 0 month and June.The results show that these tablets are at June
Content, dissolution rate, related substance during compared with its 0 month there is no variation, such as 1 tablet content in June phase of embodiment
When in the 99.2% of 0 month content.These are the result shows that Tablets have excellent stability.
Claims (10)
1. it is in the canagliflozin pharmaceutical composition of tablet form, including：Active medicine canagliflozin or its hydrate, dilution
Agent, disintegrant, adhesive, lubricant.
2. canagliflozin pharmaceutical composition according to claim 1, wherein the hydrate of the canagliflozin is canagliflozin half
Hydrate；And/or the amount of the every active medicine included is calculated as 50~300mg, example with canagliflozin anhydride in the tablet
Such as 100~300mg, for example, the amount of the every active medicine included with canagliflozin anhydride be calculated as 50mg, 100mg, 200mg,
Or 300mg.
3. canagliflozin pharmaceutical composition according to claim 1, wherein the diluent is selected from：Starch, microcrystalline cellulose, silicon
Change microcrystalline cellulose, lactose (Lactis Anhydrous or a Lactose hydrate), sucrose, dextrin and combinations thereof；For example, with every 100 parts by weight
Canagliflozin anhydride meter, the amount of the diluent is 60~100 parts by weight, such as 70~90 parts by weight.
4. canagliflozin pharmaceutical composition according to claim 1, wherein the disintegrant is selected from：Cross-linked carboxymethyl cellulose
Sodium, crosslinked polyvinylpyrrolidone, sodium carboxymethyl starch etc.；For example, in terms of the canagliflozin anhydride of every 100 parts by weight, institute
The amount of disintegrant is stated as 10~15 parts by weight, such as 11~13 parts by weight.
5. canagliflozin pharmaceutical composition according to claim 1, wherein described adhesive are selected from：Hypromellose, hydroxyl
Propyl cellulose, polyethylene glycol, polyvinylpyrrolidone (such as PVP K15, PVP K30), starch；For example, with every 100 weight
Part canagliflozin anhydride meter, the amount of described adhesive is 4~8 parts by weight, such as 5~7 parts by weight；For example, the bonding
Agent is to be added to the technique of dry granulation tabletting in the tablet；And/or the lubricant is selected from：Magnesium stearate, tristearin
Acid, calcium stearate, talcum powder, colloidal silicon dioxide etc.；Preferred lubricant is magnesium stearate；For example, with every 100 parts by weight
Canagliflozin anhydride meter, the amount of the lubricant are 1~2 parts by weight, such as 1.2~1.8 parts by weight.
6. canagliflozin pharmaceutical composition according to claim 1, the active medicine with the diluent, disintegrant, viscous
Before mixture, mix lubricant, micronization processes are carried out in advance；For example, particle of the active medicine after micronization processes
Average grain diameter is 5~20 μm；For example, the active medicine is also adding phosphate and/or inorganic salts together through micronization processes.
7. canagliflozin pharmaceutical composition according to claim 1, is prepared by a method comprising the following steps to obtain：
(1) active medicine is made to carry out micronization processes together with phosphate and inorganic salts, until gained particle average grain diameter for 5~
20 μm, obtain micronizing mixed powder；
(2) micronizing mixed powder is made to be uniformly mixed with diluent, part or all of disintegrant, adhesive, adds in dry granulating machine
Middle carry out dry granulation, obtains particle；
(3) make gained particle and the disintegrant and mix lubricant of optional surplus uniform, obtain mixed mixture eventually；
(4) mixed mixture eventually is pressed into the tablet of plain piece form.
8. canagliflozin pharmaceutical composition according to claim 7, in preparation process (2), the partial disintegration agent is disintegration
The 30~80% of agent total amount, such as 50~80%；Alternatively, the plain piece wherein obtained by step (4) is also further wrapped film
Clothing；For example, the film-coating be using hydroxypropyl methyl cellulose as be coated base material coating material either using polyvinyl alcohol as
It is coated the coating material of base material；For example, the film-coating accounts for the 1~5% of tablet label total weight, such as account for tablet label gross weight
The 2~4% of amount.
9. prepare the method for the canagliflozin pharmaceutical composition described in claim any one of 1-8 in tablet form, this method bag
Include following steps：
(1) active medicine is made to carry out micronization processes together with phosphate and inorganic salts, until gained particle average grain diameter for 5~
20 μm, obtain micronizing mixed powder；
(2) micronizing mixed powder is made to be uniformly mixed with diluent, part or all of disintegrant, adhesive, adds in dry granulating machine
Middle carry out dry granulation, obtains particle；
(3) make gained particle and the disintegrant and mix lubricant of optional surplus uniform, obtain mixed mixture eventually；
(4) mixed mixture eventually is pressed into the tablet of plain piece form.
10. card lattice made from any one of the claim 1-8 canagliflozin pharmaceutical compositions or claim the method
Arrange purposes of the net pharmaceutical composition in the drug for preparing the illness related with SGLT2 activity；For example, it is used as anti-glycosuria preparing
In sick agent, antihyperglycemic agents, lipid-lowering agent or lipid lowering agent, antiobesity agent, rescinnamine and appetite inhibitor drug
Purposes；For example, the purposes in the drug for preparing treatment type-2 diabetes mellitus.
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| CN111773194A (en) * | 2019-04-04 | 2020-10-16 | 常州恒邦药业有限公司 | Canagliflozin tablet and preparation method thereof |
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|---|---|---|---|---|
| CN111773194A (en) * | 2019-04-04 | 2020-10-16 | 常州恒邦药业有限公司 | Canagliflozin tablet and preparation method thereof |
| CN111773194B (en) * | 2019-04-04 | 2023-06-30 | 常州恒邦药业有限公司 | Canagliflozin tablet and preparation method thereof |
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| CN108078945B (en) | 2020-09-11 |
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Application publication date: 20180529 Assignee: HUADONG MEDICINE Co.,Ltd. Assignor: HANGZHOU ZHONGMEI HUADONG PHARMACEUTICAL Co.,Ltd. Contract record no.: X2023330000031 Denomination of invention: Cargliptin pharmaceutical composition Granted publication date: 20200911 License type: Common License Record date: 20230131 |
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