WO2018097570A2 - Pharmaceutical formulation comprising dapagliflozin l-proline - Google Patents

Abstract

The present invention relates to a pharmaceutical formulation comprising dapagliflozin L-proline. The pharmaceutical formulation comprising dapagliflozin L-proline according to the present invention has excellent dissolution properties of active ingredients and exhibits high content uniformity. Therefore, the pharmaceutical formulation comprising dapagliflozin L-proline of the present invention can be used as a preventive or therapeutic agent, which has excellent quality and bioavailability, for diabetes, diabetes-related diseases, and diabetic complications.

Description

Pharmaceutical formulations comprising dapagliflozin L-proline

The present invention relates to a pharmaceutical formulation comprising dapagliflozin L-proline as an active ingredient exhibiting improved dissolution properties.

Diabetes is a disease that causes high blood sugar for a long time due to problems with insulin secretion, problems with insulin function, or a combination of both. Insulin is a hormone secreted by the pancreatic beta cells, which help send glucose into cells to convert nutrients such as glucose in the blood into energy. However, the lack of action of insulin, glucose does not enter the muscles or cells, accumulate in the blood, resulting in high blood sugar, and sugar in the urine. Long-term hyperglycemia causes many complications in the microvascular system. These complications can result in amputation of the lower extremities and loss of vision.

Diabetes is one of the leading causes of adult death worldwide, and the number of diabetics is increasing rapidly with the increase in the obese population.

Selective inhibition of SGLT-2 (SGLT-2) in diabetics can normalize plasma glucose by increasing glucose excretion in urine without significant gastrointestinal side effects, thereby improving insulin sensitivity and delaying the onset of diabetic complications. Therefore, SGLT-2 inhibitors are attracting attention as a prophylactic or therapeutic agent for diabetes, diabetes-related diseases and diabetic complications.

Dapagliflozin, (2S, 3R, 4R, 5S, 6R) -2- [4-chloro-3- (4-ethoxybenzyl) phenyl] -6- (hydr, one of the SGLT-2 inhibitors Oxymethyl) tetrahydro-2H-pyran-3,4,5-triol) is a compound of Formula 1, and is disclosed in US Pat. No. 6,515,117.

[Formula 1]

In addition, Korean Patent No. 1493102 discloses (S) -propylene glycol (PG), (R) -PG, EtOH, ethylene glycol (EG), 1: 2 L-proline, 1: 1 L-proline, 1: 1 Crystal structures of dapagliflozin, including L-proline hemihydrate, and 1: 1 L-phenylalanine, are disclosed.

Among these, dapagliflozin L-proline is excellent in efficacy, but there is a problem in pharmaceutical compatibility, such as elution. Therefore, in order to increase the bioavailability of dapagliflozin, it is necessary to improve the content uniformity and dissolution characteristics of the pharmaceutical preparation including dapagliflozin L-proline, but still exhibit satisfactory characteristics. There is no development of pharmaceutical formulations.

The present inventors studied a method for improving the dissolution characteristics and the content uniformity of a pharmaceutical preparation including dapagliflozin L-proline, and as a result, the present invention was completed.

It is therefore an object of the present invention to provide a pharmaceutical formulation comprising dapagliflozin L-proline which exhibits excellent dissolution properties and content uniformity.

The present invention to solve the above problems

Including dapagliflozin L-proline,

The d (0.9) particle size of the dapagliflozin L-proline provides a pharmaceutical formulation, characterized in that less than 60μm.

In this case, the d (0.9) particle size of the dapagliflozin L-proline may be 1μm or more and less than 30μm.

In this case, the dapagliflozin L-proline may be included in less than 20% by weight of the total weight of the composition.

In this case, the dapagliflozin L-proline may be included in 0.1 to 10% by weight of the total weight of the composition.

In this case, the preparation may be formulated in an oral dosage form, the oral dosage form may be a tablet.

In this case, the dissolution rate of dapagliflozin L-proline within 15 minutes when the dissolution test in the pH 4.5 test solution according to the second method of the U.S. Pharmacopeia dissolution test item, more preferably, Within 10 minutes, the dissolution rate of dapagliflozin L-proline can be at least 80%.

In addition, the pharmaceutical preparation may further include one or more drugs selected from the group consisting of diabetes treatment, diabetes complication treatment, hyperlipidemia treatment and hypertension treatment.

In this case, the medicament may be at least one diabetes treatment or diabetic complication.

In this case, the medicament may be at least one selected from the group consisting of metformin, citagliptin, bilagliptin, saxagliptin, linagliptin, anagliptin, allogliptin and gemigliptin.

The pharmaceutical preparation may be for the prevention or treatment of diabetes mellitus, diabetes related diseases and diabetic complications.

Pharmaceutical formulations containing dapagliflozin L-proline according to the present invention is excellent in the dissolution properties of the active ingredient, and exhibits high content uniformity. Therefore, the pharmaceutical preparations of the present invention can be used as a prophylactic or therapeutic agent for diabetes mellitus, diabetes-related diseases and diabetic complications having excellent quality and bioabsorption rate.

1 is a dissolution rate graph of the tablets of Examples 1-3 and Comparative Examples 1-2.

Figure 2 is a dissolution rate graph of the tablets of Examples 3, 4, Comparative Example 1, and 3.

Hereinafter, the present invention will be described in detail so that those skilled in the art can easily implement the present invention. As those skilled in the art would realize, the described embodiments may be modified in various different ways, all without departing from the spirit or scope of the present invention.

The present invention includes dapagliflozin L-proline,

The d (0.9) particle size of the dapagliflozin L-proline provides a pharmaceutical formulation, characterized in that less than 60μm.

Dapagliflozin L-proline that can be used in the present invention is a crystalline complex of formula (2).

[Formula 2]

(In Formula 2, x is 1 or 2, y is 0 to 1)

Preferably, the dapagliflozin L-proline of the invention may be a 1: 2 crystalline complex.

In the present invention, the particle size of the drug is expressed based on the particle size distribution. In the present invention, the d (0.9) particle size indicates the particle size distribution of the drug obtained by measuring the particle diameter of the drug by a cumulative curve. It means the particle diameter of 90%.

In this invention, the particle size of dapagliflozin L-proline can be performed using a commercially available apparatus based on the laser diffraction and scattering method based on Mie theory. For example, it can measure using a commercially available apparatus, such as HELOS (Helium-neon Laser for Optical Spectrometry, Sympatec company) laser diffraction apparatus. In this device, when a helium-neon laser beam is irradiated to particles, scattering occurs, a light scattering pattern appears in a detector, and the particle diameter distribution is obtained by analyzing the light scattering pattern according to Mie theory. Although the measuring method can be any of a dry method and a wet method, the following example showed the result measured using the dry method.

In the pharmaceutical formulation of the present invention, the d (0.9) particle size of the dapagliflozin L-proline is less than 60 μm, preferably less than 30 μm, and more preferably 1 to 20 μm.

As a result of the study by the present inventors, it has been found that when the d (0.9) particle size of dapagliflozin L-proline is micronized in the above range, the dissolution characteristics and content uniformity of the active ingredient can be improved.

This effect is better when the d (0.9) particle size of dapagliflozin L-proline is smaller, but when the d (0.9) particle size is extremely fine, less than 1 μm, it is difficult to recover during the micronization process and during the preparation of the complex preparation. Loss of active ingredient may occur and there is a problem of inferior fairness. Therefore, the particle size of dapagliflozin L-proline in the present invention preferably satisfies the above range.

In the present invention, the method for controlling the particle size of the dapagliflozin L-proline is not particularly limited, and a method known in the art may be appropriately selected. Specifically, the chlorthalidone is a conventional mill capable of micronizing particles such as a jet mill, a hammer mill, a ball mill, a fluid energy mill, and the like. Can be crushed. In addition, a size classification method such as a sieve method or air current classification performed using a sieve may be used to subdivide the particle size of the drug. In one embodiment of the present invention, the particle size of dapagliflozin L-proline was adjusted using a jet mill.

The dose of dapagliflozin L-proline may vary depending on the age, sex, weight, severity, and route of administration of the patient, but in general, dapagliflozin based on an adult (weight: 60 kg) As an amount of 5 to 10 mg per day.

The pharmaceutical formulation of the present invention comprises dapagliflozin L-proline up to 20% by weight of the total weight of the composition, more preferably from 0.1 to 10% by weight. When satisfying the above range, it is possible to ensure the uniformity of content and convenience in taking it can expect a certain pharmacological effect in the patient and obtain a high medication compliance.

The pharmaceutical preparation of the present invention contains dapagliflozin L-proline as an active ingredient, and is added to the conventional pharmaceutically acceptable carrier, additives, excipients, etc. For example, it may be formulated into oral or parenteral preparations such as tablets, capsules, beads, beadlets, granules, pills, troches, solutions, suspensions and the like.

Solid preparations for oral administration may be prepared by mixing at least one additive, such as excipients, disintegrants, binders, glidants and the like with dapagliflozin L-proline.

As the excipient, for example, lactose (lactose monohydrate), microcrystalline cellulose, mannitol, sodium citrate, calcium phosphate, glycine, starch or a combination thereof may be used.

Examples of the disintegrant include crospovidone, pregelatinized starch, corn starch, methylcellulose, hydroxypropylmethylcellulose, sodium starch glyconate, croscarmellose sodium, low-substituted hydroxypropylcellulose, starch, pregelatinized Starch, alginic acid or its sodium salt or combinations thereof can be used.

As the binder, for example, polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), copovidone, macrogol, hard silicic anhydride, synthetic aluminum silicate, calcium silicate, magnesium metasilicate Aluminate, calcium hydrogen phosphate, sucrose, gelatin, acacia gum or combinations thereof can be used.

As the lubricant, for example, silicon dioxide, palmitic acid, talc (talc), magnesium stearate, zinc stearate, calcium stearate or a combination thereof may be used.

As a liquid preparation for oral administration, suspending agents, liquid solutions, emulsions, syrups and the like are used. In addition to water and liquid paraffin, which are commonly used simple diluents, various additives such as wetting agents, sweeteners, fragrances, and preservatives may also be used.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like.

Examples of the non-aqueous solvent or suspension solvent include vegetable oils such as propylene glycol, polyethylene glycol and olive oil; Injectable esters such as ethyl oleate and the like can be used, and suppositories, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used for the suppository.

In addition, the pharmaceutical formulation of the present invention may further include a pH adjusting agent, suspending agent, preservative, flavoring agent, colorant, sweetening agent, adsorbent, solubilizer and the like as necessary. The content of such additives is not particularly limited in the present invention and may be appropriately adjusted as necessary.

Preferably, the pharmaceutical formulation of the present invention may be in oral dosage form, and the oral dosage form is not particularly limited in the present invention, but may be, for example, in the form of capsules, tablets, beads, beadlets, granules or pills. .

According to one preferred embodiment of the present invention, the oral dosage form may be a tablet.

When the pharmaceutical formulation comprising dapagliflozin L-proline of the present invention is a tablet, the tablet is dapagliflo within 15 minutes of the dissolution test in a pH 4.5 test solution according to the second method of the U.S. Pharmacopoeia Dissolution Test. The dissolution rate of gin L-proline may be 80% or more, and more preferably, the dissolution rate may be 80% or more within 10 minutes.

At this time, the second method of the US Pharmacopeia dissolution test item means a paddle method (Paddle), pH acetate test solution may be used as a sodium acetate (Sodium Acetate) solution.

The pharmaceutical formulation of the present invention can be adjusted to the d (0.9) particle size of dapagliflozin L-proline is less than 60μm, it can exhibit such excellent dissolution properties, according to the pharmaceutical formulation of the present invention is an excellent biological It can show the water absorption.

The pharmaceutical formulation of the present invention described above may be prepared by a manufacturing method comprising mixing dapagliflozin L-proline and a pharmaceutically acceptable additive.

When the pharmaceutical formulation of the present invention is a tablet, the tablet is prepared by mixing Dapagliflozin L-proline and a pharmaceutically acceptable additive to form granules and tableting the granules into tablets. It can be manufactured by the method. In this case, the granules may be prepared by conventional wet granulation or dry granulation methods known in the art. In addition, the tablet may be prepared by a direct tableting method.

For example, the tablet may be prepared by mixing dapagliflozin L-proline and excipients to prepare primary dry granules; Preparing a final granule by mixing the primary dry granules with a disintegrant and a lubricant; And it may be prepared by a manufacturing method comprising the step of tableting the final granules as a tablet. When the tablet is manufactured by such a manufacturing method, it is possible to improve the flowability of the raw material of dapagliflozin L-proline, and to provide uniformity of the tablet content. In addition, by increasing the efficiency of the tableting, it is desirable to secure a tablet tablet hardness and prevent defects such as capping and laminating to secure the effect of productivity improvement.

At this time, the excipient may preferably be a mixture of mannitol, microcrystalline cellulose and lactose, the content of the excipient may be included in 80 to 90% by weight of the total weight of the tablet.

In addition, crospovidone may be used as the disintegrant, and a mixture of silicon dioxide and magnesium stearate may be used as a lubricant. At this time, the disintegrant and lubricant may be included in 0.1 to 5% by weight of the total weight of the tablet.

The pharmaceutical formulation comprising the dapagliflozin L-proline of the present invention may be selected from sustained or immediate release. The sustained release means that the release of the active ingredient occurs slowly, including the base used for the purpose of sustained release in addition to the active ingredient, the immediate release means that the active ingredient is released immediately.

The pharmaceutical formulations of the present invention described above can be used for the prevention or treatment of diseases or conditions mediated by hyperglycemia such as diabetes, diabetes related diseases and diabetic complications by inhibiting SGLT activity.

Such diabetes includes insulin dependent diabetes mellitus (type I diabetes) and insulin independent diabetes mellitus (type II diabetes), and also includes other forms of diabetes due to certain causes.

Examples of the diabetes-related diseases include obesity, hyperinsulinemia, abnormal glucose metabolism, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism abnormality, hypertension, congestive heart failure, edema, hyperuricemia, gout and the like. However, it is not limited to these.

The diabetic complications include both acute and chronic complications.

Examples of the acute complications include hyperglycemia (ketoassissis and the like) and diabetic infections (skin infection, soft tissue infection, biliary tract infection, respiratory infection, urinary tract infection and the like).

The chronic complications include diabetic microangiopathy (nephropathy, renal failure, retinopathy, etc.), diabetic arteriosclerosis (atherosclerosis, myocardial infarction, cerebral infarction, lower limb artery occlusion), diabetic neuropathy (sensory neuropathy, motor nerve) Disorders, autonomic neuropathy), and diabetic foot ulcers.

Major diabetic complications include, but are not limited to, diabetic retinopathy, diabetic renal failure, diabetic neuropathy.

In addition, the dapagliflozin L-proline of the present invention may be used in combination with one or more therapeutic agents selected from anti-diabetic agents, diabetic complications, hyperlipidemia agents, hypertensive agents, etc., in addition to inhibitors of SGLT activity.

By combining the dapagliflozin L-proline of the present invention and other drugs, synergistic effects can be expected when used in combination with the effects obtained by a single agent in the above diseases, respectively.

First, as an antidiabetic agent or diabetic complication agent which can be used together, for example, an insulin sensitivity enhancer, an α-glucosidase inhibitor, a biguanide compound, an insulin secretagogue, an insulin preparation, a glucagon receptor antagonist, an insulin receptor kinase promoter , Tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase 1B inhibitors, glycogenphosphorylase inhibitors, glucose-6-phosphatase inhibitors, tetracycline inhibitors, fructose bisphosphatase inhibitors, pyruvic acid dehydro Genease inhibitors, glucokinase activators, D-chiroinositol, glycogen-like peptide-1 agonists, amilines, amiline flexibles, amiline agonists, glucocorticoid receptor antagonists, 11α-hydroxysteroid dehydrogenase inhibitors, Aldose reductase inhibitors, Protein kinase C inhibitors, α-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF-αB inhibitors, IKKα inhibitors, lipid peroxidase inhibitors, N-acetylation-α-binding-acid-dipeptidase inhibitors, insulin shape growth Factor-I, platelet-derived growth factor (PDGF), platelet-derived growth factor (PDGF) flexible body, epidermal growth factor (EGF), nerve growth factor, carnitine derivatives, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimochromol, a slowexide, Y-128, TAR-428, etc. are mentioned.

More specifically, the following drugs can be exemplified as the diabetes treatment agent and the diabetic complication treatment agent, but are not limited thereto.

Examples of the biguanide compound include metformin hydrochloride and phenformin.

Among the insulin secretagogues, sulfonylureas include, for example, glybide (glybenclamide), glyphidede, glyclazide, chloropropamide, and the like, and non-sulfonylurea compounds include nateglinide, repaglinide, Mitiglinide etc. are mentioned.

The insulin preparations include recombinant human insulin and animal derived insulin. It is classified into three types according to the time of action, specifically, the immediate effect type (human insulin, human neutral insulin), the intermediate type (insulin-human isopeninsulin aqueous suspension, human neutral insulin-human isopeninsulin aqueous suspension, human insulin zinc) Aqueous suspension, insulin zinc aqueous suspension), sustained form (human crystalline insulin zinc suspension).

Examples of the α-glucosidase inhibitor include acarbose, bogribose, migritol and the like.

Examples of the insulin sensitivity enhancer include triglitazone, pioglitazone, rosiglitazone, MK-767 (KRP-297), tesaglitazar, LM4156, LY510929, TY-51501, GW-501516, and the like.

UCL-139 etc. are mentioned as said tripeptidyl peptidase II inhibitor.

Examples of the dipeptidyl peptidase IV inhibitors include citagliptin, bildagliptin, saxagliptin, linagliptin, anagliptin, allogliptin, gemigliptin, and the like.

Examples of the aldose reductase inhibitor include ascorbic acid, ascorbyl, tolestart, epalestat, fidarestat, solvinyl, ponalestat, risarastat, and genarestat.

Topiramate etc. are mentioned as said (alpha)-aminobutyric-acid acceptor antagonist.

Examples of the sodium channel antagonists include mexyl hydrochloride and the like.

Dexlipotam etc. are mentioned as said transcription factor NF- (alpha) B inhibitor.

Examples of the lipid peroxidase inhibitors include mesylic acid tyrilazad.

GPI-5693 etc. are mentioned as said N-acetylation- (alpha) -binding-acid-dipeptidase inhibitor.

Examples of the carnitine derivatives include carnitine, levasecarnin hydrochloric acid, and the like.

Next, as an antihyperlipidemic agent and an antihypertensive agent which can be used together, it is a hydroxymethyl glutaryl coenzyme A reductase inhibitor, a fibrate type compound, the (alpha) 3- adrenergic receptor agonist, an AMPK activator, an acylcoenzyme A: Cholesterol acyl transferase inhibitors, probe calls, thyroid hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomtriglyceride transfer protein inhibitors, lipoxygenase inhibitors, carnitine palmitoyltransferase inhibitors, squalene synthetase inhibitors, low specific gravity lipo Protein receptor promoters, nicotinic acid derivatives, bile acid adsorbents, sodium conjugated bile acid transporter inhibitors, cholesterol ester transport protein inhibitors, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, endothelin converting enzyme inhibitors, endothelin receptor inners Natanists, diuretics, calcium antagonists, vasodilators, sympathetic blockers, central hypertensives, α2-adrenergic receptor agonists, antiplatelet drugs, uric acid production inhibitors, uric acid excretion promoters, urinary alkalizing agents, appetite suppressants, ACE inhibitors, adiponectin receptor agonists, GPR40 agonists, GPR40 antagonists and the like.

More specifically, the following drugs can be exemplified as the hyperlipidemia treatment agent and the hypertension treatment agent, but are not limited thereto.

Provastatin, lovastatin, pravastatin, cerivastatin, pitavastatin, etc. are mentioned as said hydroxymethyl glutaryl coenzyme A reductase inhibitor.

Examples of the fibrate-based compound include fenofibrate, bezafibrate, becrobrate, and vinifibrate.

Examples of the squalene synthetase inhibitor include TAK-475 and α-phosphonosulfonate derivatives (see US Patent No. 5712396).

Examples of the acylcoenzyme A: cholesterol acyl group transfer enzyme inhibitor include CI-1011, NTE-122, FCE-27677, RP-73163, MCC-147, and DPU-129.

As said low specific gravity lipoprotein receptor promoter, MD-700, LY-295427, etc. are mentioned.

Examples of the microsomtriglyceride transfer protein inhibitors (MTP inhibitors) include compounds disclosed in US Pat. No. 5,39,135, US Pat. No. 5,572,279, US Pat.

Examples of the appetite suppressant include adrenergic-noradrenergic agonists (margindol, ephedrine, etc.), serotonin agonists (selective serotonin reinhibitor inhibitors, e.g. fluvoxamine, etc.), adrenergic-serotonin agonists (sibutramine, etc.), melano Cortin 4 receptor (MC4R) agonists, α-melanosite stimulating hormone (α-MSH), leptin, cocaine and amphetamine-regulated transcripts (CART), and the like.

Examples of the thyroid hormone receptor agonists include lyothyronine sodium, repotyroxine sodium, and the like.

Ezetimibe etc. are mentioned as said cholesterol absorption inhibitor.

Orlistat etc. are mentioned as said lipase inhibitor.

Examples of the carnitine palmitoyl transferase inhibitor include etmokysyl and the like.

Examples of the nicotinic acid derivatives include nicotinic acid, nicotinic acid amide, nicomol, and nicorandil.

Examples of the angiotensin-converting enzyme inhibitor include capryl, maleic acid enalapril, alacepril, silazapril, and the like.

Examples of the anziontensin II receptor antagonist include candesaltanexetyl, potassium losaltan, mesyl acid eprosaltan and the like.

CGS-31447, CGS-35066, etc. are mentioned as said endothelin conversion enzyme inhibitor.

For example, in the treatment of diabetes and the like, the dapagliflozin L-proline of the present invention, an insulin sensitivity enhancer, an α-glucosidase inhibitor, a biguanide compound, an insulin secretagogue, an insulin preparation, and a dipeptidyl peptidida Combination with at least one drug selected from the group consisting of the IV inhibitors is preferred. In one example, the dapagliflozin L-proline of the present invention is selected from the group consisting of metformin, citagliptin, bildagliptin, saxagliptin, linagliptin, anagliptin, allogliptin and gemigliptin It may be used in combination with at least one agent.

Or dapagliflozin L-proline and hydroxymethylglutarylcoenzyme A reductase inhibitor, fibrate compound, squalene synthetase inhibitor, acylcoenzyme A in the treatment of hyperlipidemia, hypertension, etc. The combination with at least 1 type of agent chosen from the group which consists of a real transfer enzyme inhibitor, a low specific gravity lipoprotein receptor promoter, a microsomtriglyceride transfer protein inhibitor, and an appetite suppressant is preferable.

The present invention provides a method of preventing or treating diabetes mellitus, diabetes related diseases and diabetic complications of a mammal comprising administering to the mammal the above-described pharmaceutical agent in an effective amount.

Hereinafter, preferred examples are provided to help the understanding of the present invention, but the following examples are merely for exemplifying the present invention, and various changes and modifications within the scope and spirit of the present invention are apparent to those skilled in the art. It goes without saying that changes and modifications belong to the appended claims.

EXAMPLE

Examples 1-4: Preparation of Dapagliflozin Tablets

To prepare a tablet comprising a dapagliflozin L-proline 1: 2 crystalline complex (Hanmi Precision, Korea) with different particle sizes in the composition of Table 1. In Table 1, the particle size unit of dapagliflozin L-proline is μm.

After mixing dapagliflozin L-proline with mannitol, lactose and microcrystalline cellulose, compacting with a roller compactor (TF-1-A60, Freund vector, USA) Was prepared.

Crospovidone, silicon dioxide and magnesium stearate were added to the prepared primary granules and mixed to prepare final granules.

The final granules were compressed using a rotary tablet press (GRC-18, Sejong Machinery, Korea) to contain 15.6 mg (10 mg as dapagliflozin) as dapagliflozin L-proline in one tablet. Tablets containing pagliflozin L-proline were prepared.

Composition			Content (mg)
			Example 1	Example 2	Example 3	Example 4
Raw materials including 1st dry granule	Dapagliflozin L-Proline	0.1≤d (0.1) <1	15.6	-	-	-
		1≤d (0.5) <10
		5≤d (0.9) <10
		0.1≤d (0.1) <1	-	15.6	-	-
		1≤d (0.5) <10
		10≤d (0.9) <30
		0.1≤d (0.1) <1	-	-	15.6	-
		1≤d (0.5) <10
		30≤d (0.9) <60
		0.1≤d (0.1) <1	-	-	-	15.6
		10≤d (0.5) <30
		30≤d (0.9) <60
	Mannitol		100.0	100.0	100.0	100.0
	Microcrystalline cellulose		50.0	50.0	50.0	50.0
	Lactose		50.0	50.0	50.0	50.0
Raw granules included	Crospovidone		10.0	10.0	10.0	10.0
	Silicon dioxide		3.4	3.4	3.4	3.4
	Magnesium stearate		2.0	2.0	2.0	2.0
Total weight (mg)			231.0	231.0	231.0	231.0

Comparative Examples 1 to 3: Preparation of Dapagliflozin Tablets

Dapagliflozin tablets were prepared in the same manner as in Table 2 and Example 1 using dapagliflozin L-proline having a d (0.9) particle size of 60 μm or more. In Table 2, the particle size unit of dapagliflozin L-proline is μm.

Composition			Content (mg)
			Comparative Example 1	Comparative Example 2	Comparative Example 3
Raw materials including 1st dry granule	Dapagliflozin L-Proline	0.1≤d (0.1) <1	15.6	-	-
		1≤d (0.5) <10
		60≤d (0.9) <90
		0.1≤d (0.1) <1	-	15.6	-
		1≤d (0.5) <10
		90≤d (0.9) <120
		0.1≤d (0.1) <1	-	-	15.6
		10≤d (0.5) <30
		60≤d (0.9) <90
	Mannitol		100.0	100.0	100.0
	Microcrystalline cellulose		50.0	50.0	50.0
	Lactose		50.0	50.0	50.0
Raw granules included	Crospovidone		10.0	10.0	10.0
	Silicon dioxide		3.4	3.4	3.4
	Magnesium stearate		2.0	2.0	2.0
Total weight (mg)			231.0	231.0	231.0

Test Example 1: Comparative Evaluation of Dissolution Rate

According to the USP dissolution test item 2 method (Paddle) using 1000 ml of pH 4.5 acetate solution at dissolution temperature 37 ℃, rotation speed 60 rpm Examples 1 to 4 and Comparative Examples 1 to A dissolution test for three tablets was performed.

Elution test solution samples were taken at 0, 5, 10, 15, 20, and 30 minutes after the start of the test, subjected to liquid chromatography under the following conditions. Shown in

<Liquid chromatography conditions>

Column: A column filled with octadecylsilylated silica gel for liquid chromatograph with a particle diameter of 4.2 μm in a stainless tube about 4.6 mm in diameter and 15 cm in length (Zorbax SB-C8, Agilent Zorbax)

Column temperature: 25 ° C.

Sample injection volume: 10 μL

Mobile phase: pH 7.2 phosphate / acetonitrile = 60/40 (v / v)

Flow rate: 1.0 mL / min

Detector: ultraviolet absorbance photometer (wavelength 240 nm)

		Dissolution time (minutes)
		0	5	10	15	20	30
Dissolution rate (%)	Example 1	0	63	91	97	100	100
	Example 2	0	56	86	94	98	100
	Example 3	0	49	79	89	95	99
	Example 4	0	48	80	91	94	97
	Comparative Example 1	0	35	58	78	88	94
	Comparative Example 2	0	29	54	70	79	88
	Comparative Example 3	0	32	59	76	85	91

Referring to Table 3, it can be seen that in Examples 1 to 4 having a d (0.9) particle size of dapagliflozin L-proline of less than 60 μm, the dissolution rate in 15 minutes was 85% or more, indicating excellent dissolution properties. . On the other hand, all of Comparative Examples 1 to 3 having a d (0.9) particle size of 60 μm or more showed a dissolution rate of less than 60% within 15 minutes, which showed a significantly lower dissolution rate than the Example.

Referring to FIG. 1, it can be seen that the smaller the d (0.9) particle size of dapagliflozin L-proline, the faster the dissolution rate. In particular, Examples 1 and 2 having a d (0.9) particle size of dapagliflozin L-proline of less than 30 μm showed a dissolution rate of 85% or more in 10 minutes, showing very excellent dissolution properties.

On the other hand, the d (0.5) particle size of dapagliflozin L-proline did not appear to affect the dissolution properties. As a result of comparing the elution characteristics of Examples 3 and 4 and Comparative Examples 1 and 3 with the same d (0.9) particle size but different d (0.5) particle sizes of dapagliflozin L-proline, d ( 0.9) There was a difference in dissolution characteristics between Examples and Comparative Examples with different particle sizes, but there was no clear difference between Examples 3 and 4 and d.

From the above experimental results, it was confirmed that the d (0.9) particle size of dapagliflozin L-proline affects the dissolution properties of the pharmaceutical formulation. In addition, it was confirmed that the pharmaceutical formulation of the present invention having a d (0.9) particle size of dapagliflozin L-proline exhibiting excellent dissolution properties.

As described above, the pharmaceutical formulation of the present invention having a controlled particle size can improve the dissolution properties and increase the in vivo absorption rate of dapagliflozin, and exhibits high content uniformity. It can be used as a preventive or therapeutic agent for complications.

Claims (12)

1. Including dapagliflozin L-proline,

   Pharmaceutical formulation, characterized in that the d (0.9) particle size of the dapagliflozin L-proline is less than 60μm.
2. The method of claim 1,

   Pharmaceutical formulation, characterized in that the d (0.9) particle size of the dapagliflozin L-proline is 1 μm or more and less than 30 μm.
3. The method of claim 1,

   The dapagliflozin L-proline is a pharmaceutical formulation, characterized in that it comprises less than 20% by weight of the total weight of the composition.
4. The method of claim 1,

   The dapagliflozin L-proline is a pharmaceutical formulation, characterized in that it comprises 0.1 to 10% by weight of the total weight of the composition.
5. The method of claim 1,

   Pharmaceutical composition, characterized in that the formulation is formulated in oral administration form.
6. The method of claim 5,

   The oral dosage form is a pharmaceutical preparation, characterized in that the tablet.
7. The method of claim 1,

   The pharmaceutical formulation is a pharmaceutical formulation, characterized in that the dissolution rate of dapagliflozin L-proline within 80 minutes when the dissolution test in pH 4.5 test solution according to the second method of the U.S. pharmaceutical dissolution test item 80% or more.
8. The method of claim 7, wherein

   The pharmaceutical formulation is a pharmaceutical formulation, characterized in that the dissolution rate of dapagliflozin L-proline within 10 minutes when the dissolution test in pH 4.5 test solution according to the second method of the U.S. pharmaceutical dissolution test item 80% or more.
9. The method of claim 1,

   A pharmaceutical formulation further comprising at least one medicament selected from the group consisting of: antidiabetic agents, diabetic complications, hyperlipidemia agents, and hypertension agents.
10. The method of claim 9,

    The agent is a pharmaceutical agent, characterized in that one or more anti-diabetic agents or diabetic complications.
11. The method of claim 10,

    The drug is a pharmaceutical agent, characterized in that at least one member selected from the group consisting of metformin, citagliptin, bilagliptin, saxagliptin, linagliptin, anagliptin, allogliptin and gemigliptin.
12. The method according to any one of claims 1 to 11,

    The pharmaceutical formulation is a pharmaceutical formulation, characterized in that for the prevention or treatment of diabetes mellitus, diabetes-related diseases and diabetic complications.

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