CN108078945B - Canagliflozin pharmaceutical composition - Google Patents
Canagliflozin pharmaceutical composition Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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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- 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
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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Abstract
The invention relates to a canagliflozin pharmaceutical composition. Specifically, the canagliflozin pharmaceutical composition comprises: an active drug canagliflozin or a hydrate thereof, a diluent, a disintegrant, a binder, a lubricant, the hydrate of canagliflozin being canagliflozin hemihydrate. The invention also relates to a preparation method of the tablet pharmaceutical composition and pharmaceutical application thereof. The pharmaceutical composition of the invention is used as a small-molecule oral hypoglycemic drug taking an SGLT2 inhibitor as an active ingredient, and has excellent pharmaceutical properties such as excellent stability and dissolution performance.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to a pharmaceutical composition of a small-molecule oral hypoglycemic drug, and particularly relates to a pharmaceutical composition taking SGLT2 inhibitor canagliflozin as an active drug. The invention also relates to a preparation method of the pharmaceutical composition. The canagliflozin tablet pharmaceutical composition of the invention exhibits excellent pharmaceutical properties as described herein.
Background
The hottest small molecule oral hypoglycemic agents studied in the last decade are mainly classified into two groups, namely DPP-IV inhibitors (gliptin drugs) and SGLT2 inhibitors (gliflozin drugs). Decision Resources new research by Decision Resources corporation shows that as the sales of major drugs for the treatment of type 2 diabetes increase, this market (including us, france, germany, italy, spain, uk and japan) will be driven from $ 190 billion in 2009 to $ 360 billion in 2019. Since 2013, canagliflozin was marketed as the first SGLT-2 inhibitor in the united states for less than 4 years, and a market share of $ 19 billion was created in 2016.
Canagliflozin is the first approved drug in sodium-glucose co-transporter 2(SGLT2) inhibitors and is suitable for controlling blood glucose in type II diabetic adult patients in combination with dietary control and physical exercise. It acts on the SGLT2 protein in the kidney to help reabsorb glucose, removing more sugar from the patient's urine, and lowering blood glucose levels.
Canagliflozin is originally developed by mitsubishi, a minister of dynasty that receives authorization from the united states and the european union in 2012 by the seng. Us FDA marketing approval was obtained at 29/3/2013, european EMA marketing approval at 15/11/2013, and japanese PMDA approval at 14/7/2014. The drug is marketed under the trade name Invokana in the United states. The Japanese area is produced and sold by Mitsubishi on Tianbian, and is promoted by the first Sanshui Co. According to tPharma data statistics, Kagelet net global sales in 2014 is 7.2 billion dollars, 14 billion dollars in 2015, 19.6 billion dollars in 2016, and the API required for formulation sales is 46 tons.
Canagliflozin (invitana) is the first SGLT-2 inhibitor approved by the FDA and first entered the market. Taking the visalazigliptin as a representative DPP-4 inhibitor, the DPP-4 inhibitor accounts for many years in the old position of oral hypoglycemic drugs, and the annual sale amount of Januvia/Janumet in 2015 is 60.14 hundred million dollars, which is a direct trend of hypoglycemic drug head brand Lantus. While the SGLT-2 inhibitor is well-developed and has been on the market for less than 4 years, a market share of $ 19 billion is created in 2016.
Current hypoglycemic agents, which range in global market share from high to low, are, in turn, insulin, a DPP-IV inhibitor, a GLP-1 receptor agonist, and an SGLT-2 inhibitor. Evaluate Pharma forecasts the market share of various hypoglycemic agents in 2022, wherein insulin remains the largest market share of all diabetic drugs in 2022; GLP-1 receptor agonists expand rapidly, second in share to insulin; the SGLT-2 inhibitor squeezes out the DPP-4 inhibitor, and becomes the best oral hypoglycemic agent.
Canagliflozin, also known as Canagliflozin, having the english name Canagliflozin, film-coated tablets which have been imported by Janssen-Cilag International NV corporation, belgium under the trade name either joyakan or INVOKANA to the chinese market, each tablet containing 100mg (H20170375) and 300mg (H20170374) Canagliflozin calculated as anhydrate.
The active ingredient of canagliflozin marketed in china is canagliflozin hemihydrate, wherein the chemical name: (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 hemihydrate, known as English chemistry (2S,3R,4R,5S,6R) -2- {3- [5- (4-Fluoro-phenyl) -thiophen-2-ylmethyi ] -4-methyl-phenyl } -6-hydroxymethy l-tetrahydro-pyran-3,4,5-triol hemihydrates, having the formula C24H25FO 5S. 1/2H2O, molecular weight 453.53, chemical formula:
canagliflozin is practically insoluble in aqueous media at ph1.1 to 12.9. Commercially available INVokana contained 102mg and 306mg of canagliflozin hemihydrate per tablet, corresponding to 100mg and 300mg of anhydride, respectively. The INVOKANA tablet is a film-coated tablet, and the tablet core of the INVOKANA tablet comprises the following auxiliary materials besides active ingredients: croscarmellose sodium, hydroxypropyl cellulose, anhydrous lactose, magnesium stearate, microcrystalline cellulose; tablets are coated with a commercial film coating material containing the following auxiliary materials: polyvinyl alcohol, titanium dioxide, polyethylene glycol, talcum powder and pigment iron oxide yellow.
At present, the preparation development of canagliflozin has been reported in various documents. For example, CN106606489A (chinese patent application No. 201510686747.1) discloses a canagliflozin pharmaceutical composition and a preparation process thereof, the canagliflozin pharmaceutical composition contains canagliflozin and a carrier material, wherein the carrier material is povidone. The canagliflozin tablet provided by the invention is believed to have the characteristics of fast dissolution and simple preparation process.
CN103655539A (Chinese patent application No. 201310675536.9) discloses a canagliflozin oral solid pharmaceutical composition and a preparation method thereof, the composition contains canagliflozin and pharmaceutic adjuvant, wherein the canagliflozin is in an amorphous form, and the average particle size of particles of the canagliflozin is 2.5-30 um. The composition is believed to effectively solve the technical problems of crystal transformation and poor compressibility of amorphous canagliflozin in the preparation process of solid preparations.
CN104586795A (chinese patent application No. 201410840598.5) discloses a canagliflozin tablet and a preparation method thereof, which is characterized in that the preparation contains hydroxypropyl cellulose and diatomite and is prepared by the following processes: (1) adding hydroxypropyl cellulose into ethanol, stirring until the hydroxypropyl cellulose is completely dissolved, adding canagliflozin, and stirring until the canagliflozin is dissolved for later use; (2) adding diatomite into the solution prepared in the step (1), uniformly stirring, and volatilizing the solvent to obtain a canagliflozin solid dispersion; (3) mixing the solid dispersion prepared in the step (2) with other pharmaceutically acceptable auxiliary materials, and tabletting.
CN106474484A (Chinese patent application No. 201510553788.3) discloses a composition of canagliflozin and pharmaceutic adjuvant and a preparation method thereof, wherein the composition comprises the canagliflozin and two or more pharmaceutic adjuvants, the weight ratio of the canagliflozin to all the pharmaceutic adjuvants is 1: 0.1-100, the canagliflozin in the composition is in an amorphous state, and characteristic peaks of canagliflozin crystals are absent in an X-ray powder diffraction spectrum of the composition after background peaks of the pharmaceutic adjuvants are deducted. The composition of canagliflozin and pharmaceutic adjuvant disclosed by the invention is good in stability and dispersibility, the dissolution rate of the canagliflozin is increased, the bioavailability of a pharmaceutical preparation and the absorption of a drug by an organism are facilitated to be improved, and good physical stability and chemical stability can be maintained under an accelerated test condition. The preparation method of the amorphous composition has the advantages of simple operation, low cost, good reproducibility and easy realization, and is suitable for industrial production.
CN104523573A (Chinese patent application No. 201410836189.8) discloses a canagliflozin fast-release tablet, the tablet hardness of which is 50N-80N, and the components of the tablet in parts by weight are 100-300 parts of canagliflozin, 35-110 parts of drug filler and 70-190 parts of disintegrant, and the preparation method comprises the following steps: respectively sieving 100-300 parts of canagliflozin, 35-110 parts of a drug filler and 70-190 parts of a disintegrating agent by weight, uniformly mixing the obtained powder, and then directly tabletting to control the tablet hardness to be 50N-80N so as to obtain the canagliflozin fast-release tablet; compared with the prior art, the canagliflozin fast-release tablet can be completely disintegrated within about 1min, so that the absorption of the medicine is greatly accelerated, the peak reaching degree of the medicine is increased, the peak reaching time of the medicine is shortened, and the canagliflozin fast-release tablet has great advantages in clinical curative effect; the preparation method of the invention adopts direct powder tabletting, has simple process and is easy for industrial production.
CN105769803A (Chinese patent application No. 201410773880.6) discloses a pharmaceutical composition for treating type 2 diabetes and a preparation method thereof, the pharmaceutical composition for treating type 2 diabetes consists of an active ingredient canagliflozin and pharmaceutic adjuvants such as a water-soluble solid dispersion carrier, a disintegrating agent, a lubricant and the like, and the pharmaceutical composition for treating type 2 diabetes, which is prepared by the invention, has no special requirements on the particle size of the active ingredient, does not need superfine grinding, has low energy consumption, high bioavailability and high dissolution rate of more than 90 percent, solves the defects of poor solubility and low bioavailability of the active ingredient, and has stable and reliable quality and great market development prospect.
CN102883726A (chinese patent application No. 201180023642.8) discloses a pharmaceutical formulation comprising a 1- (β -D-glucopyranosyl) -2-thienyl-methylbenzene derivative as SGLT inhibitor, such an orally administrable pharmaceutical formulation comprising at least one diluent or filler, optionally at least one disintegrant, optionally at least one binder, optionally at least one lubricant, wherein the active compound of formula (I) is present in an amount ranging from about 1% to about 80% by weight, the diluent or filler is present in an amount ranging from about 10% to about 95% by weight, the disintegrant, if present, is present in an amount ranging from about 0.1% to about 20% by weight, the binder, if present, is present in an amount ranging from about 0.1% to about 20% by weight, the lubricant, if present, is present in an amount ranging from about 0.1% to about 5% by weight, in the application document, microcrystalline cellulose (diluent), anhydrous lactose (diluent), hydroxypropyl cellulose (wet granulation binder), croscarmellose sodium (disintegrant) and magnesium stearate are used as auxiliary materials of a tablet core to prepare the tablet in a classical wet granulation mode, and a commercial coating material Opadry II is used for coating the tablet core with a film coating until the weight of the tablet is increased by 3-4%. The tablets prepared by the invention are believed to have good in vivo behavior. It is well known that since the in vivo behavior of a drug can be simulated by dissolution behavior in a variety of different dissolution media, the in vivo behavior of a drug can be inferred in a simple manner from the in vitro behavior of the drug, for example by comparison with the dissolution behavior of a commercially available control, and if the dissolution behavior is similar, it indicates that the resulting drug has the same or similar in vivo behavior as the commercially available control.
For this reason, there is still a need in the art for new processes for preparing pharmaceutical compositions of canagliflozin, in particular tablets thereof, and for canagliflozin tablets prepared by such processes to have excellent properties, for example a release behaviour comparable to that of the commercial products.
Disclosure of Invention
The object of the present invention is to provide a process for the preparation of a pharmaceutical composition of canagliflozin, in particular a tablet thereof, and the canagliflozin tablet prepared by this process is expected to have excellent properties, for example a release behaviour comparable to that of the commercially available product. Another object of the present invention is to provide a pharmaceutical composition of canagliflozin, in particular a tablet thereof, prepared by the above process. It has been found that one or more benefits may be beneficially achieved by the formulations and methods of the present invention.
In a first aspect, the present invention provides a pharmaceutical composition of canagliflozin in the form of a tablet comprising: active medicine canagliflozin or hydrate thereof, diluent, disintegrant, adhesive and lubricant.
The canagliflozin pharmaceutical composition according to the invention, wherein the hydrate of canagliflozin is canagliflozin hemihydrate.
The canagliflozin pharmaceutical composition according to the invention, wherein each tablet comprises the active drug in an amount of 50 to 300mg, such as 100 to 300mg, based on the canagliflozin anhydrate, such as 50mg, 100mg, 200mg, or 300mg, based on the canagliflozin anhydrate.
The canagliflozin pharmaceutical composition according to the invention, wherein the diluent is selected from: starch, microcrystalline cellulose, silicified microcrystalline cellulose, lactose (anhydrous or monohydrate), sucrose, dextrin, and combinations thereof. In one embodiment, the diluent is a combination of microcrystalline cellulose and lactose (anhydrous lactose or lactose monohydrate). In one embodiment, the diluent is microcrystalline cellulose and lactose (anhydrous lactose or lactose monohydrate) both in a weight ratio of 1:0.75 to 1.25 in combination.
The canagliflozin pharmaceutical composition according to the invention, wherein the diluent is in an amount of 60 to 100 parts by weight, for example 70 to 90 parts by weight, per 100 parts by weight of canagliflozin anhydrate.
The canagliflozin pharmaceutical composition according to the invention, wherein the disintegrant is selected from: croscarmellose sodium, crospovidone, sodium carboxymethyl starch, and the like.
The canagliflozin pharmaceutical composition according to the invention, wherein the disintegrant is in an amount of 10 to 15 parts by weight, for example 11 to 13 parts by weight, per 100 parts by weight of canagliflozin anhydrate.
The canagliflozin pharmaceutical composition according to the invention, wherein the binder is selected from: hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyethylene glycol, polyvinylpyrrolidone (e.g., PVP K15, PVP K30), starch.
The canagliflozin pharmaceutical composition according to the invention, wherein the amount of the binder is 4 to 8 parts by weight, for example 5 to 7 parts by weight, per 100 parts by weight of canagliflozin anhydrate. In one embodiment, the binder is added to the tablet in a dry granulation tableting process.
The canagliflozin pharmaceutical composition according to the invention, wherein the lubricant is selected from: magnesium stearate, stearic acid, calcium stearate, talc, colloidal silicon dioxide, and the like. A preferred lubricant is magnesium stearate.
The canagliflozin pharmaceutical composition according to the invention, wherein the lubricant is present in an amount of 1 to 2 parts by weight, for example 1.2 to 1.8 parts by weight, per 100 parts by weight of canagliflozin anhydrate.
The canagliflozin pharmaceutical composition according to the invention, wherein the active drug is previously micronized before being mixed with the diluent, disintegrant, binder, lubricant.
According to the canagliflozin pharmaceutical composition, the average particle size of the micronized active drug particles is 5-20 microns.
The canagliflozin pharmaceutical composition according to the invention, wherein the active pharmaceutical substance is further added together with a phosphate salt selected from the group consisting of: calcium phosphate or dibasic calcium phosphate (e.g., anhydrous dibasic calcium phosphate). In one embodiment, the phosphate is present in an amount of 5 to 15 parts by weight, for example 8 to 12 parts by weight, per 100 parts by weight of canagliflozin anhydrate.
The canagliflozin pharmaceutical composition according to the invention, wherein the active drug is also added together with an inorganic salt, such as sodium chloride or potassium chloride, after being micronized. In one embodiment, the inorganic salt is present in an amount of 1 to 3 parts by weight, for example 1 to 2 parts by weight, per 100 parts by weight of canagliflozin anhydrate. It has been found that when the active drug is micronized together with the phosphate and the inorganic salt, the desired size of the drug can be smoothly reduced to 5-20 μm, and the micronized material can be mixed with diluent easily, and the tablet prepared from the micronized material has excellent dissolution performance in dissolution medium with wide pH range.
The canagliflozin pharmaceutical composition in the form of a tablet according to the invention is prepared by a process comprising the following steps:
(1) micronizing the active drug, phosphate and inorganic salt until the average particle size of the obtained particles is 5-20 μm to obtain micronized mixed powder;
(2) uniformly mixing the micronized mixed powder with a diluent, part or all of a disintegrating agent and an adhesive, and adding the mixture into a dry granulation machine for dry granulation to obtain granules;
(3) uniformly mixing the obtained granules with optional rest of disintegrating agent and lubricant to obtain a final mixed mixture;
(4) the final blend is compressed into tablets in the form of plain tablets.
According to the canagliflozin pharmaceutical composition disclosed by the invention, in the preparation step (2), the part of the disintegrant is 30-80%, such as 50-80% of the total amount of the disintegrant.
The pharmaceutical composition of canagliflozin in the form of a tablet according to the invention, wherein the plain tablet prepared in step (4) is further coated with a film coat.
According to the canagliflozin pharmaceutical composition, the film coating is a coating material taking hydroxypropyl methylcellulose as a coating base material or a coating material taking polyvinyl alcohol as a coating base material. In one embodiment, adjuvants such as plasticizers, e.g., triacetin, polyethylene glycol, opacifiers, e.g., titanium dioxide, and the like, are also included in the package and material. In one embodiment, the package and material further includes adjuvants such as polyethylene glycol, opacifiers such as titanium dioxide, suspending agents such as talc and optionally pigments. The amounts of these adjuvants added are well known to those skilled in the art, and such coating material premixes are available directly from the market, e.g. directly from carrousel, e.g. opadry II coating premix powder from carrousel.
According to the canagliflozin pharmaceutical composition, the film coating accounts for 1-5% of the total weight of the tablet core, for example, 2-4% of the total weight of the tablet core.
In a second aspect, the present invention provides a process for the preparation of a canagliflozin pharmaceutical composition in the form of a tablet, for example a canagliflozin pharmaceutical composition in the form of a tablet as described in the first aspect of the invention, the process comprising the steps of:
(1) micronizing the active drug, phosphate and inorganic salt until the average particle size of the obtained particles is 5-20 μm to obtain micronized mixed powder;
(2) uniformly mixing the micronized mixed powder with a diluent, part or all of a disintegrating agent and an adhesive, and adding the mixture into a dry granulation machine for dry granulation to obtain granules;
(3) uniformly mixing the obtained granules with optional rest of disintegrating agent and lubricant to obtain a final mixed mixture;
(4) the final blend is compressed into tablets in the form of plain tablets.
According to the method of the present invention, in the preparation step (2), the part of the disintegrant is 30 to 80%, for example, 50 to 80% of the total amount of the disintegrant.
The method according to the invention, wherein the pharmaceutical composition of canagliflozin in tablet form comprises: active medicine canagliflozin or hydrate thereof, diluent, disintegrant, adhesive and lubricant.
The process according to the invention, wherein the hydrate of canagliflozin is canagliflozin hemihydrate.
The method according to the invention, wherein each tablet of the tablet comprises 50 to 300mg, such as 100 to 300mg, of active drug in canagliflozin anhydrate, such as 50mg, 100mg, 200mg, or 300mg, of active drug in each tablet in canagliflozin anhydrate.
The process according to the invention, wherein the diluent is selected from: starch, microcrystalline cellulose, silicified microcrystalline cellulose, lactose (anhydrous or monohydrate), sucrose, dextrin, and combinations thereof. In one embodiment, the diluent is a combination of microcrystalline cellulose and lactose (anhydrous lactose or lactose monohydrate). In one embodiment, the diluent is microcrystalline cellulose and lactose (anhydrous lactose or lactose monohydrate) both in a weight ratio of 1:0.75 to 1.25 in combination.
The process according to the invention wherein the diluent is present in an amount of from 60 to 100 parts by weight, for example from 70 to 90 parts by weight, per 100 parts by weight of canagliflozin anhydrate.
The method according to the invention, wherein the disintegrant is selected from the group consisting of: croscarmellose sodium, crospovidone, sodium carboxymethyl starch, and the like.
The process according to the invention, wherein the amount of the disintegrant is 10 to 15 parts by weight, for example 11 to 13 parts by weight, per 100 parts by weight of canagliflozin anhydrate.
The method according to the invention, wherein the binder is selected from: hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyethylene glycol, polyvinylpyrrolidone (e.g., PVP K15, PVP K30), starch.
The process according to the invention wherein the amount of binder is from 4 to 8 parts by weight, for example from 5 to 7 parts by weight, per 100 parts by weight of canagliflozin anhydrate. In one embodiment, the binder is added to the tablet in a dry granulation tableting process.
The method according to the invention, wherein the lubricant is selected from: magnesium stearate, stearic acid, calcium stearate, talc, colloidal silicon dioxide, and the like. A preferred lubricant is magnesium stearate.
The process according to the invention, wherein the lubricant is present in an amount of 1 to 2 parts by weight, for example 1.2 to 1.8 parts by weight, per 100 parts by weight of canagliflozin anhydrate.
The process according to the invention, wherein the active drug is previously micronized before being mixed with the diluent, disintegrant, binder, lubricant.
According to the method, the average particle size of the micronized active drug particles is 5-20 μm.
The process according to the invention, wherein the phosphate is selected from: calcium phosphate or dibasic calcium phosphate (e.g., anhydrous dibasic calcium phosphate). In one embodiment, the phosphate is present in an amount of 5 to 15 parts by weight, for example 8 to 12 parts by weight, per 100 parts by weight of canagliflozin anhydrate.
The process according to the invention, wherein the inorganic salt is selected from sodium chloride or potassium chloride. In one embodiment, the inorganic salt is present in an amount of 1 to 3 parts by weight, for example 1 to 2 parts by weight, per 100 parts by weight of canagliflozin anhydrate.
The method of the invention, wherein the plain tablet prepared in the step (4) is further coated with a film coat.
According to the method of the invention, the film coating is a coating material which takes hydroxypropyl methylcellulose as a coating base material or a coating material which takes polyvinyl alcohol as a coating base material. In one embodiment, adjuvants such as plasticizers, e.g., triacetin, polyethylene glycol, opacifiers, e.g., titanium dioxide, and the like, are also included in the package and material. In one embodiment, the package and material further includes adjuvants such as polyethylene glycol, opacifiers such as titanium dioxide, suspending agents such as talc and optionally pigments. The amounts of these adjuvants added are well known to those skilled in the art, and such coating material premixes are available directly from the market, e.g. directly from carrousel, e.g. opadry II coating premix powder from carrousel.
According to the method of the invention, the film coat is present in an amount of 1 to 5% by weight, for example 2 to 4% by weight, based on the total weight of the tablet core.
In a third aspect, the present invention provides the use of a canagliflozin pharmaceutical composition according to the first aspect of the invention or a canagliflozin pharmaceutical composition prepared by the method according to the second aspect of the invention in the preparation of a medicament for a condition associated with SGLT2 activity.
The invention also provides the use of a canagliflozin pharmaceutical composition according to the first aspect of the invention or a canagliflozin pharmaceutical composition produced by the process according to the second aspect of the invention in the manufacture of a medicament for use as an antidiabetic agent, an antihyperglycemic agent, a hypolipidemic or lipid-lowering agent, an antiobesity agent, an antihypertensive agent and an appetite suppressant.
The invention also provides the use of a canagliflozin pharmaceutical composition according to the first aspect of the invention or a canagliflozin pharmaceutical composition prepared by the method according to the second aspect of the invention in the preparation of a medicament for treating type II diabetes.
Any embodiment according to any aspect of the invention, wherein the canagliflozin pharmaceutical composition has a formulation as described in any one of the embodiments of the invention.
According to any of the embodiments of any of the aspects of the invention, wherein the canagliflozin pharmaceutical composition has the formulation and the preparation method as described in any of the embodiments of the invention.
In the above-described steps of the preparation method of the present invention, although the specific steps described therein are distinguished in some detail or in language description from the steps described in the preparation examples of the detailed embodiments below, those skilled in the art can fully summarize the above-described method steps in light of the detailed disclosure throughout the present disclosure.
Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict. The invention is further described below.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.
Canagliflozin is the first approved drug in sodium-glucose co-transporter 2(SGLT2) inhibitors and is suitable for controlling blood glucose in type II diabetic adult patients in combination with dietary control and physical exercise. It acts on the SGLT2 protein in the kidney to help reabsorb glucose, removing more sugar from the patient's urine, and lowering blood glucose levels.
The invention provides an advantageous method for producing the preparation of canagliflozin, and the prepared canagliflozin pharmaceutical composition, particularly the tablet thereof, has one or more technical effects.
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible.
It has also been found in various tests herein that for the same batch of pharmaceutical composition material, when they are compressed into tablets of specifications comprising 50mg, 100mg, 200mg, 300mg, etc. of active ingredient (calculated as canagliflozin anhydrate) per tablet, the dissolution profiles between the different specifications of the formulations obtained for the same batch of pharmaceutical composition material are the same; thus, in the following examples, as a typical formulation specification, the amount of active ingredient (in canagliflozin anhydrate) in each tablet is 100mg when preparing tablets, unless otherwise specified. In each of the following examples, the compositions were prepared by the prescription described as the amount of material per tablet, but in the actual dosing, the compositions were dosed at a ratio of material not less than the scale at which 5 ten thousand tablets were prepared. In the various examples below, canagliflozin used was its hemihydrate, as not otherwise specified.
A. Preparation examples section
Example 1: preparation of Canagliflozin tablets
The formula is as follows:
canagliflozin hemihydrate: (calculated as anhydride) 100mg,
Phosphate salt: 10mg of,
Inorganic salts: 1.5mg of,
Diluent (microcrystalline cellulose/lactose (anhydrous) ═ 1: 1): 80mg of,
Disintegrant (croscarmellose sodium): 12mg of,
Binder (PVP K15): 6mg of,
Lubricant (magnesium stearate): 1.5 mg.
The preparation method comprises the following steps:
(1) micronizing the active drug, phosphate (calcium phosphate) and inorganic salt (sodium chloride) until the average particle size of the obtained particles is 5-20 μm (the actual average particle size is 16 μm) to obtain micronized mixed powder;
(2) uniformly mixing the micronized mixed powder with a diluent, part of disintegrant (70%) and an adhesive, and adding the mixture into a dry granulating machine for dry granulation to obtain granules;
(3) uniformly mixing the obtained granules with the rest of disintegrant and lubricant to obtain a final mixed mixture;
(4) the final blend is compressed into tablets in the form of plain tablets.
In this example and other examples of the preparation of canagliflozin tablets herein, when the micronized mixed powder is mixed with diluent, disintegrant, binder, etc. in step (2), mixing is carried out in a high-efficiency mixing granulator for 30min (at least 5kg of powder material per mixing batch), ten mixed powder samples of which the surfaces of the materials in the mixer are adjacent to four corners and the middle and the bottom of the materials is adjacent to four corners and the middle are taken, the content of active ingredients is measured, and the value of a +2.2S is calculated by referring to the method of "0941 content uniformity inspection method" in the four parts of the chinese pharmacopoeia 2015 edition based on the theoretical content of active ingredients in the mixed material obtained by the operation to this step, and this value should ideally be less than 15 and the smaller is the better. In this example a +2.2S is 1.7,
the A +2.2S values of examples 2 to 9 were all in the range of 1.1 to 2.3, indicating that the excellent mixing effect can be obtained in a short time in step (2) in these tests.
In addition, it has been found that in step (1) above of inventive examples 1-5, the time required to micronize the active drug to the specified average particle size level of the microparticles is about 23-37% of the time required without the addition of phosphate, without the addition of inorganic salts, or without the addition of both phosphate/inorganic salts, indicating that the simultaneous addition of both phosphate/inorganic salts greatly increases the efficiency of the micronization process. In addition, it has been found that the selection of phosphate and inorganic salt is unique because the present inventors found in additional supplementary experiments that, when the phosphate is replaced with an equal amount of monopotassium phosphate, or the inorganic salt is replaced with an equal amount of calcium chloride, or the phosphate is replaced with an equal amount of monopotassium phosphate and the inorganic salt is replaced with an equal amount of calcium chloride in the case of step (1) referred to in examples 1-5 above, the time required to micronize the active drug to the specified average particle size of the microparticles is about 3.8 to 5.1 times the time required when both phosphate/inorganic salt are used as described in examples 1-5, indicating that the effect of improving the efficiency of the micronization process cannot be obtained when other kinds of phosphate and inorganic salt are used instead.
Example 2: preparation of Canagliflozin tablets
The formula is as follows:
canagliflozin hemihydrate: (calculated as anhydride) 100mg,
Phosphate salt: 8mg of,
Inorganic salts: 2mg of,
Diluent (microcrystalline cellulose/lactose (anhydrous) ═ 1: 1.25): 70mg of,
Disintegrant (croscarmellose sodium): 11mg of,
Binder (PVP K30): 5mg of,
Lubricant (magnesium stearate): 1.2 mg.
The preparation method comprises the following steps:
(1) micronizing the active drug, phosphate (anhydrous calcium hydrogen phosphate) and inorganic salt (sodium chloride) until the average particle size of the obtained particles is 5-20 μm (the actual average particle size is 11 μm) to obtain micronized mixed powder;
(2) uniformly mixing the micronized mixed powder with a diluent, part of disintegrant (50%) and an adhesive, and adding the mixture into a dry granulating machine for dry granulation to obtain granules;
(3) uniformly mixing the obtained granules with the rest of disintegrant and lubricant to obtain a final mixed mixture;
(4) the final blend is compressed into tablets in the form of plain tablets.
Example 3: preparation of Canagliflozin tablets
The formula is as follows:
canagliflozin hemihydrate: (calculated as anhydride) 100mg,
Phosphate salt: 12mg of,
Inorganic salts: 1mg of,
Diluent (microcrystalline cellulose/lactose (monohydrate) ═ 1: 0.75): 70mg of,
Disintegrant (sodium carboxymethyl starch): 13mg of,
Binder (PVP K15): 7mg of,
Lubricant (magnesium stearate): 1.8 mg.
The preparation method comprises the following steps:
(1) micronizing the active drug, phosphate (calcium phosphate) and inorganic salt (sodium chloride) until the average particle size of the obtained particles is 5-20 μm (the actual average particle size is 19 μm) to obtain micronized mixed powder;
(2) uniformly mixing the micronized mixed powder with a diluent, part of disintegrant (80%) and an adhesive, and adding the mixture into a dry granulating machine for dry granulation to obtain granules;
(3) uniformly mixing the obtained granules with the rest of disintegrant and lubricant to obtain a final mixed mixture;
(4) the final blend is compressed into tablets in the form of plain tablets.
Example 4: preparation of Canagliflozin tablets
The formula is as follows:
canagliflozin anhydrate: 100mg of,
Phosphate salt: 5mg of,
Inorganic salts: 3mg of,
Diluent (microcrystalline cellulose/lactose (anhydrous) ═ 1: 0.9): 100mg of,
Disintegrant (crosslinked polyvinylpyrrolidone): 10mg of,
Binder (PVP K30): 4mg of,
Lubricant (magnesium stearate): 2 mg.
The preparation method comprises the following steps:
(1) micronizing the active drug, phosphate (calcium phosphate) and inorganic salt (potassium chloride) until the average particle size of the obtained particles is 5-20 μm (the actual average particle size is 5 μm) to obtain micronized mixed powder;
(2) uniformly mixing the micronized mixed powder with a diluent, a disintegrating agent and an adhesive, and adding the mixture into a dry granulation machine for dry granulation to obtain granules;
(3) uniformly mixing the obtained particles with a lubricant to obtain a final mixed mixture;
(4) the final blend is compressed into tablets in the form of plain tablets.
Example 5: preparation of Canagliflozin tablets
The formula is as follows:
canagliflozin hemihydrate: (calculated as anhydride) 100mg,
Phosphate salt: 15mg of,
Inorganic salts: 1mg of,
Diluent (microcrystalline cellulose/lactose (anhydrous) ═ 1: 1.2): 60mg of,
Disintegrant (croscarmellose sodium): 15mg of,
Binder (PVP K15): 8mg of,
Lubricant (magnesium stearate): 1 mg.
The preparation method comprises the following steps:
(1) micronizing the active drug, phosphate (anhydrous calcium hydrogen phosphate) and inorganic salt (potassium chloride) until the average particle size of the obtained particles is 5-20 μm (the actual average particle size is 8 μm), to obtain micronized mixed powder;
(2) uniformly mixing the micronized mixed powder with a diluent, part of disintegrant (60%) and an adhesive, and adding the mixture into a dry granulating machine for dry granulation to obtain granules;
(3) uniformly mixing the obtained granules with the rest of disintegrant and lubricant to obtain a final mixed mixture;
(4) the final blend is compressed into tablets in the form of plain tablets.
Example 6: preparation of Canagliflozin tablets
The formula is as follows:
canagliflozin anhydrate: 100mg of,
Phosphate salt: 9mg of,
Inorganic salts: 1.2mg of,
Diluent (microcrystalline cellulose/lactose (monohydrate) ═ 1: 0.8): 85mg of,
Disintegrant (sodium carboxymethyl starch): 12mg of,
Binder (PVP K30): 6mg of,
Lubricant (magnesium stearate): 1.5 mg.
The preparation method comprises the following steps:
(1) micronizing the active drug, phosphate (anhydrous calcium hydrogen phosphate) and inorganic salt (potassium chloride) until the average particle size of the obtained particles is 5-20 μm (the actual average particle size is 14 μm), to obtain micronized mixed powder;
(2) uniformly mixing the micronized mixed powder with a diluent, part of disintegrant (60%) and an adhesive, and adding the mixture into a dry granulating machine for dry granulation to obtain granules;
(3) uniformly mixing the obtained granules with the rest of disintegrant and lubricant to obtain a final mixed mixture;
(4) the final blend is compressed into tablets in the form of plain tablets.
Example 7: preparation of Canagliflozin tablets
The formula is as follows:
canagliflozin hemihydrate: (calculated as anhydride) 100mg,
Phosphate salt: 10mg of,
Inorganic salts: 1.5mg of,
Diluent (microcrystalline cellulose/lactose (anhydrous) ═ 1: 0.9): 80mg of,
Disintegrant (crosslinked polyvinylpyrrolidone): 12mg of,
Binder (PVP K15): 7mg of,
Lubricant (magnesium stearate): 1.5 mg.
The preparation method comprises the following steps:
(1) micronizing the active drug, phosphate (calcium phosphate) and inorganic salt (sodium chloride) until the average particle size of the obtained particles is 5-20 μm (the actual average particle size is 13 μm) to obtain micronized mixed powder;
(2) uniformly mixing the micronized mixed powder with a diluent, part of disintegrant (60%) and an adhesive, and adding the mixture into a dry granulating machine for dry granulation to obtain granules;
(3) uniformly mixing the obtained granules with the rest of disintegrant and lubricant to obtain a final mixed mixture;
(4) the final blend is compressed into tablets in the form of plain tablets.
Example 8: preparation of Canagliflozin tablets
The formula is as follows:
canagliflozin hemihydrate: (calculated as anhydride) 100mg,
Phosphate salt: 11mg of,
Inorganic salts: 2mg of,
Diluent (microcrystalline cellulose/lactose (anhydrous) ═ 1: 1.1): 80mg of,
Disintegrant (croscarmellose sodium): 11mg of,
Binder (PVP K15): 5mg of,
Lubricant (magnesium stearate): 2 mg.
The preparation method comprises the following steps:
(1) micronizing the active drug, phosphate (anhydrous calcium hydrogen phosphate) and inorganic salt (sodium chloride) until the average particle size of the obtained particles is 5-20 μm (the actual average particle size is 15 μm) to obtain micronized mixed powder;
(2) uniformly mixing the micronized mixed powder with a diluent, part of disintegrant (70%) and an adhesive, and adding the mixture into a dry granulating machine for dry granulation to obtain granules;
(3) uniformly mixing the obtained granules with the rest of disintegrant and lubricant to obtain a final mixed mixture;
(4) the final blend is compressed into tablets in the form of plain tablets.
Example 9: preparation of Canagliflozin tablets
The formula is as follows:
canagliflozin hemihydrate: (calculated as anhydride) 100mg,
Phosphate salt: 7mg of,
Inorganic salts: 1mg of,
Diluent (microcrystalline cellulose/lactose (anhydrous) ═ 1: 1): 100mg of,
Disintegrant (croscarmellose sodium): 102mg of,
Binder (PVP K30): 6mg of,
Lubricant (magnesium stearate): 1 mg.
The preparation method comprises the following steps:
(1) micronizing the active drug, phosphate (calcium phosphate) and inorganic salt (potassium chloride) until the average particle size of the obtained particles is 5-20 μm (the actual average particle size is 12 μm), and obtaining micronized mixed powder;
(2) uniformly mixing the micronized mixed powder with a diluent, a disintegrating agent and an adhesive, and adding the mixture into a dry granulation machine for dry granulation to obtain granules;
(3) uniformly mixing the obtained particles with a lubricant to obtain a final mixed mixture;
(4) the final blend is compressed into tablets in the form of plain tablets.
Example 11: preparation of Canagliflozin tablets
5 batches of tablets were prepared with reference to the formulations and methods of examples 1-5, respectively, except that no phosphate was added. In the step (2) of preparing the tablets, A +2.2S of the materials mixed for 30min, 60min and 120min are respectively 14.7-18.1, 12.4-14.6 and 10.7-13.1, which shows that the mixing difficulty of the materials is obviously higher than that of the examples 1-5, and the value of A +2.2S is unacceptable or nearly unacceptable.
Example 12: preparation of Canagliflozin tablets
5 batches of tablets were prepared with reference to the formulations and methods of examples 1-5, respectively, except that no inorganic salt was added. In the step (2) of preparing the tablets, A +2.2S of the materials mixed for 30min, 60min and 120min are respectively 13.9-18.5, 12.1-15.4 and 10.2-13.5, which shows that the mixing difficulty of the materials is obviously higher than that of the examples 1-5, and the value of A +2.2S is unacceptable or close to unacceptable.
Example 13: preparation of Canagliflozin tablets
5 batches of tablets were prepared with reference to the formulations and methods of examples 1-5, respectively, except that no phosphate or inorganic salt was added. In the step (2) of preparing the tablets, A +2.2S of the materials mixed for 30min, 60min and 120min are respectively 15.4-19.3, 13.3-15.9 and 11.7-13.4, which shows that the mixing difficulty of the materials is obviously higher than that of the examples 1-5, and the value of A +2.2S is unacceptable or nearly unacceptable.
Example 14: preparation of Canagliflozin tablets
Preparing plain tablets (compressing tablets containing 100mg of anhydrous canagliflozin per tablet) with reference to the formulation and preparation of example 4 of CN 103655539A; preparing plain tablets by referring to the formula and the preparation method of example 1 of CN104523573A (raw material medicines are crushed and sieved by a 200-mesh sieve (raw material medicines are crushed to be sieved by a 120-mesh sieve in production), and pressing each tablet containing 100mg of anhydrous canagliflozin; preparing plain tablets by referring to the formula and preparation method of CN104586795A example 1 (raw material is crushed and sieved by a 200-mesh sieve, and each tablet containing 100mg of anhydrous canagliflozin is pressed); preparing plain tablets by referring to the formula and preparation method of CN106606489A example 1 (raw material is crushed and sieved by a 200-mesh sieve, and each tablet containing 100mg of anhydrous canagliflozin is pressed); plain tablets were prepared according to the formulation and preparation method of CN106243097A example 2 (crude drug substance was crushed and sieved through 200 mesh sieve, and each tablet was compressed to contain 100mg of anhydrous canagliflozin).
Example 21: friability test
The friability of the plain tablets obtained in examples 1 to 9 and examples 11 to 14 (the tablet compression force during compression was 15KN, and the hardness of the obtained tablets was in the range of 17 to 21 kg) was measured by the method of "0923 tablet friability test method" in the fourth pharmacopoeia of China, edition 2015. The results show that all batches of tablets did not break, crack or pulverize, and the average weight loss was in the range of 0.22-0.34%, indicating that these tablets had excellent friability.
Example 22: dissolution test
The dissolution rates of the tablets prepared in the above examples 1-9 and examples 11-14 were tested by using a method specified in the general guidelines for dissolution testing of oral solid preparations (national food and drug administration, day 05 02/2015) and commercial canagliflozin tablets (yikean) as a reference preparation in the original research, using 900ML dissolution medium and a method of a second method (paddle method, 50rpm) of the dissolution and release determination method "0931, four parts of the pharmacopoeia of the 2015 edition, and sampling at 5min, 15min, 30min, 45min and 60min respectively, measuring the dissolution rate at 254nm by spectrophotometry and calculating the dissolution rate, and calculating a similar factor f2 value of a dissolution curve between each homemade tablet and yikean, wherein the closer to 100 the f2 value indicates the dissolution performance similar to the original research product. Four dissolution media, namely (a) a hydrochloric acid solution with pH of 1.5 (3.73mL hydrochloric acid- >1000mL), (b) an acetate buffer solution with pH of 3.8 (0.67g sodium acetate- >1000mL, pH value of which is adjusted by 2mol/L acetic acid solution), (c) a phosphate buffer solution with pH of 5.5 (pH value of which is adjusted by 0.05mol/L potassium dihydrogen phosphate solution by sodium hydroxide solution), (d) a phosphate buffer solution with pH of 6.8 (pH value of which is adjusted by 0.05mol/L potassium dihydrogen phosphate solution by sodium hydroxide solution), are respectively added with 0.25% of lauryl sodium sulfate. As a result: under the condition of pH6.8 and the f2 value of Perkean, all the plain films obtained in examples 1-9 are within the range of 91-96, and all the plain films obtained in examples 11-14 are within the range of 87-93; under the condition of pH5.5 and the f2 value of Perkean, all the plain films obtained in examples 1-9 are in the range of 86-94, and all the plain films obtained in examples 11-14 are in the range of 73-81; under the condition of pH3.8 and the f2 value of Perkean, all the plain films obtained in examples 1-9 are in the range of 88-96, and all the plain films obtained in examples 11-14 are in the range of 33-39; under the condition of pH1.5 and the f2 value of Perkean, all the plain films obtained in examples 1-9 are in the range of 85-91, and all the plain films obtained in examples 11-14 are in the range of 21-27; the above results show that all the plain tablets obtained in examples 1 to 9 have high dissolution similarity with the original ground product under all pH conditions, while all the plain tablets obtained in examples 11 to 14 have high dissolution similarity with the original ground product under neutral conditions, but the lower the pH, the worse the similarity, and even at pH values lower than 4, the similarity is not acceptable.
In addition, the dissolution rate of all tablets reaches more than 85% at 60min under the condition of pH6.8 through measurement, for example, the dissolution rates of all tablets of examples 1 to 9 of the invention are within the range of 91 to 96% at 60min under the condition of pH 6.8.
Example 23: tablet coating
The coating weight of the tablets obtained in examples 1-9 and examples 11-14 was increased by 2-5% by coating the whole batch of tablets with a commercially available opadry II coating premix powder (2%, 3%, 4%, 5% for the coating weight of the tablets in examples 1-4, and 3.5% for the coating weight of the tablets in the remaining examples). The coated tablets were tested according to the dissolution test method of example 22 of the present invention and the results showed that the f2 values of the coated tablets and their corresponding plain tablets were substantially similar (none of the related values exceeded 5 numerical values), indicating that whether the tablets of the present invention were coated or not did not affect dissolution.
Example 24: tablet stability test
All tablets obtained in examples 1 to 9 of the present invention were placed at a temperature of 40 ℃ for 6 months in a state of a pseudo-marketed package, and the content, dissolution rate, and related substances of the tablets at 0 month and 6 months were measured. The results show that the content, dissolution rate and related substances of the tablets at 6 months are basically unchanged relative to the content at 0 month, for example, the content at 6 months of the tablets in example 1 is equal to 99.2 percent of the content at 0 month. These results indicate that the tablets of the present invention have excellent stability.
Claims (22)
1. A canagliflozin pharmaceutical composition in tablet form comprising: the active drug canagliflozin or the hydrate thereof comprises, by weight, 100 parts of canagliflozin anhydrate, 60-100 parts of diluent, 10-15 parts of disintegrating agent, 4-8 parts of adhesive, 1-2 parts of lubricant, 5-15 parts of phosphate and 1-3 parts of inorganic salt; the diluent is selected from: starch, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, dextrin, and combinations thereof; the disintegrant is selected from: croscarmellose sodium, crospovidone, sodium carboxymethyl starch; the adhesive is selected from: hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, polyvinylpyrrolidone, starch; the lubricant is selected from: magnesium stearate, stearic acid, calcium stearate, talc, colloidal silicon dioxide; the phosphate is calcium phosphate or calcium hydrogen phosphate; the inorganic salt is sodium chloride or potassium chloride; the pharmaceutical composition is prepared by a method comprising the following steps:
(1) micronizing the active drug, phosphate and inorganic salt until the average particle size of the obtained particles is 5-20 μm to obtain micronized mixed powder;
(2) uniformly mixing the micronized mixed powder with a diluent, part or all of a disintegrating agent and an adhesive, and adding the mixture into a dry granulation machine for dry granulation to obtain granules;
(3) uniformly mixing the obtained granules with optional rest of disintegrating agent and lubricant to obtain a final mixed mixture;
(4) the final blend is compressed into tablets in the form of plain tablets.
2. The canagliflozin pharmaceutical composition according to claim 1, wherein the hydrate of canagliflozin is canagliflozin hemihydrate.
3. The canagliflozin pharmaceutical composition according to claim 1, each tablet comprising an active drug in an amount of 50 to 300mg based on the canagliflozin anhydrate.
4. The canagliflozin pharmaceutical composition according to claim 1, each tablet comprising the active drug in an amount of 100 to 300mg based on the canagliflozin anhydrate.
5. The canagliflozin pharmaceutical composition according to claim 1, each tablet comprising an amount of active drug that is 50mg, 100mg, 200mg, or 300mg, based on the canagliflozin anhydrate.
6. The canagliflozin pharmaceutical composition according to claim 1, wherein the diluent is in an amount of 70 to 90 parts by weight per 100 parts by weight of the canagliflozin anhydrate.
7. The canagliflozin pharmaceutical composition according to claim 1, the disintegrant is in an amount of 11 to 13 parts by weight per 100 parts by weight of the canagliflozin anhydrate.
8. The canagliflozin pharmaceutical composition according to claim 1, the amount of the binder is 5 to 7 parts by weight per 100 parts by weight of the canagliflozin anhydrate.
9. The canagliflozin pharmaceutical composition according to claim 1, the lubricant being magnesium stearate.
10. The canagliflozin pharmaceutical composition according to claim 1, the lubricant being in an amount of 1.2 to 1.8 parts by weight per 100 parts by weight of the canagliflozin anhydrate.
11. The canagliflozin pharmaceutical composition according to claim 1, wherein the phosphate is in an amount of 8 to 12 parts by weight per 100 parts by weight of the canagliflozin anhydrate.
12. The canagliflozin pharmaceutical composition according to claim 1, wherein the inorganic salt is in an amount of 1 to 2 parts by weight per 100 parts by weight of the canagliflozin anhydrate.
13. The canagliflozin pharmaceutical composition according to claim 1, wherein in the preparation step (2), the partial disintegrant is 30 to 80% of the total amount of the disintegrant.
14. The canagliflozin pharmaceutical composition according to claim 1, wherein in the preparation step (2), the partial disintegrant is 50 to 80% of the total amount of the disintegrant.
15. The canagliflozin pharmaceutical composition according to claim 1, wherein the plain tablet produced in step (4) is further coated with a film coat.
16. The canagliflozin pharmaceutical composition according to claim 15, wherein the film coat is a coating material with hydroxypropyl methylcellulose as a coating base or a coating material with polyvinyl alcohol as a coating base.
17. The canagliflozin pharmaceutical composition according to claim 15, the film coat comprising 1 to 5% of the total weight of the tablet core.
18. The canagliflozin pharmaceutical composition according to claim 15, the film coat comprising 2 to 4% of the total weight of the tablet core.
19. A process for the preparation of a pharmaceutical composition of canagliflozin in tablet form according to any one of claims 1 to 18, comprising the steps of: (1) micronizing the active drug, phosphate and inorganic salt until the average particle size of the obtained particles is 5-20 μm to obtain micronized mixed powder; (2) uniformly mixing the micronized mixed powder with a diluent, part or all of a disintegrating agent and an adhesive, and adding the mixture into a dry granulation machine for dry granulation to obtain granules; (3) uniformly mixing the obtained granules with optional rest of disintegrating agent and lubricant to obtain a final mixed mixture; (4) the final blend is compressed into tablets in the form of plain tablets.
20. Use of a canagliflozin pharmaceutical composition according to any one of claims 1 to 18 or produced by the process according to claim 19 in the manufacture of a medicament for a condition associated with SGLT2 activity.
21. Use of a canagliflozin pharmaceutical composition according to any one of claims 1 to 18 or produced by the process according to claim 19 in the manufacture of a medicament for use as an antidiabetic agent, an antihyperglycemic agent, a hypolipidemic or lipid-lowering agent, an antiobesity agent, an antihypertensive agent and an appetite suppressant.
22. Use of a canagliflozin pharmaceutical composition according to any one of claims 1 to 18 or a canagliflozin pharmaceutical composition produced according to the method of claim 19 in the manufacture of a medicament for the treatment of type II diabetes.
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