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WO2024162731A1 - Formulation pharmaceutique composite comprenant de la lobeglitazone et de la sitagliptine - Google Patents

Formulation pharmaceutique composite comprenant de la lobeglitazone et de la sitagliptine Download PDF

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Publication number
WO2024162731A1
WO2024162731A1 PCT/KR2024/001378 KR2024001378W WO2024162731A1 WO 2024162731 A1 WO2024162731 A1 WO 2024162731A1 KR 2024001378 W KR2024001378 W KR 2024001378W WO 2024162731 A1 WO2024162731 A1 WO 2024162731A1
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Prior art keywords
composite formulation
sitagliptin
formulation
lobeglitazone
pharmaceutical
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Min Young Kim
Min Kwan Cho
Shin Jung Park
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Chong Kun Dang Corp
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Chong Kun Dang Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a pharmaceutical formulation comprising lobeglitazone and sitagliptin.
  • Diabetes is a disease in which metabolic abnormalities, including hyperglycemia, persist due to insufficient action of insulin, and also chronic disease with a high possibility of vascular complications, which can be largely divided into type 1 diabetes and type 2 diabetes.
  • type 2 diabetes is a disease associated with both insulin resistance (i.e., a state in which the responsiveness of cells or tissues to insulin is reduced than normal at a given insulin concentration) and insulin secretion disorders due to decreased pancreatic ⁇ -cell function, and that more than 85% of diabetic patients have adult type 2 diabetes, and the prevalence of type 2 diabetes continues to increase as modern people's westernized lifestyle and obesity increase.
  • Oral hypoglycemic agents used for the treatment of diabetes may be divided into 1) insulin secretion stimulants (sulfonylureas, non-sulfonylureas), 2) biguanide-based drugs, 3) alpha-glucosidase inhibitors, 4) glitazone-based drugs, 5) DPPIV inhibitors, and 6) SGLT-2 inhibitors, and the like, depending on the mechanism of action.
  • Sitagliptin a drug in the class of DPPIV (dipeptidyl peptidase-4) inhibitors, is able to effectively control the decrease in secretion or the decrease in action of glucagon like peptide-1 (GLP-1).
  • DPPIV is an aminopeptidase present in various tissues, including the intestinal mucosa, and degrades GLP-1 and GIP.
  • DPPIV inhibitors degrade the DPPIV to increase the concentration of GLP-1, thereby stimulating insulin secretion and suppressing glucagon secretion.
  • sitagliptin is widely used recently because of low risk of weight gain and hypoglycemia.
  • glitazone-based drugs are peroxisome proliferator activated receptor gamma agonist (PPAR ⁇ agonists), which are expressed in adipocytes to stimulate PPAR ⁇ that promotes adipogenesis and glucose uptake, thereby improving the sensitivity to insulin in the body.
  • PPAR ⁇ agonists peroxisome proliferator activated receptor gamma agonist
  • the glitazone-based drugs do not have a mechanism to promote insulin secretion, which is advantageous for protecting ⁇ -cells of the pancreas and improve insulin resistance, which is particularly effective for diabetic patients with insulin resistance.
  • these drugs are known to maintain blood glucose for a long time, slow down the progression of type 2 diabetes, and exhibit a stronger therapeutic effect on early diabetes.
  • glitazone-based drugs drugs having a thiazolidinedione (TZD) structure are currently the mainstream of the market.
  • ZTD thiazolidinedione
  • glitazone-based drugs do not have high antidiabetic efficacy when used alone, and thus there is a limit to treatment with a single drug, and side effects such as edema or weight gain may occur depending on the person.
  • Lobeglitazone one of these glitazone-based drugs, is a domestic novel drug for diabetes developed by the present applicant, which is a drug not only having a stable molecular dynamic energy structure, but also having a structural feature that best matches the active site pocket of PPAR ⁇ , thereby exhibiting high pharmacological activity, and enhancing the weak blood lipid-lowering effect, which was pointed out as a disadvantage of existing glitazone-based drugs.
  • Diabetes has a very complex etiology, and each antidiabetic drug has distinct advantages and disadvantages.
  • dual combination therapy using antidiabetic agents having different mechanisms of action to simultaneously act on multiple targets is frequently prescribed clinically.
  • This combination therapy may result in improvement in blood sugar control compared to monotherapy and may reduce the possibility of various side effects that may occur due to administration of a high dose of a single active ingredient.
  • administering two or more types of drugs separately has the problem of poor patient medication convenience, and therefore, composite formulations for the treatment of diabetes that is able to administer two or more types of drugs in one formulation are being developed.
  • a composite formulation is a formulation comprising two or more active ingredients in one dosage form, in which two or more active ingredients are capable of being administered at once, thereby increasing the patient medication convenience.
  • the composite formulations have limitations in that medication compliance may be reduced due to greatly increased size of the formulation, and as the total weight increases, it is difficult to manufacture high-content formulations.
  • composite formulations encounter many difficulties in the formulation process since problems such as a decrease in stability and uniformity, and changes in dissolution patterns, etc., may occur due to the interaction of each active ingredient.
  • An object of the present invention is to provide a composite formulation comprising lobeglitazone and sitagliptin.
  • a pharmaceutical composite formulation in the form of a single layer tablet comprising: lobeglitazone or a pharmaceutically acceptable salt thereof; and sitagliptin or a pharmaceutically acceptable salt thereof.
  • lobeglitazone is a glitazone-based drug, which is a compound represented by the following Chemical Formula 1:
  • sitagliptin is a drug in the class of DPPIV inhibitors, which is a compound represented by the following Chemical Formula 2:
  • the term "pharmaceutically acceptable salt” refers to any organic or inorganic addition salt of which concentration has effective action that is relatively non-toxic and harmless to patients in which side effects caused by these salts do not degrade the beneficial efficacy of pharmacologically active ingredients.
  • the pharmaceutically acceptable salt includes salts derived from pharmaceutically acceptable acids or bases.
  • the acid usable for the preparation of the pharmaceutically acceptable salt may be an inorganic acid or an organic acid.
  • Examples of the inorganic acid may include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, and the like
  • examples of the organic acid may include acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, benzoic acid, pamoic acid, aspartic acid, glutamic acid, and the like, but the inorganic acid and the organic acid are not limited thereto.
  • the pharmaceutically acceptable salt in the present invention may also comprise hydrates and solvates of each active ingredient.
  • the hydrate or solvate may be formed by dissolving active ingredients in a water-miscible solvent such as methanol, acetone, or 1,4-dioxane and then adding a free acid or free base, followed by crystallization or recrystallization, but the method of forming the hydrate or solvate is not limited thereto.
  • lobeglitazone may be used as the pharmaceutically acceptable salt in various forms, and according to an embodiment of the present invention, lobeglitazone may be lobeglitazone sulfate.
  • sitagliptin may be used as the pharmaceutically acceptable salt in various forms, and according to an embodiment of the present invention, sitagliptin may be sitagliptin phosphate hydrate.
  • the composite formulation of the present invention may comprise the lobeglitazone and sitagliptin which are active ingredients, in a content of 20 wt% to 40 wt%, specifically 25 wt% to 35 wt%, based on the total weight of the formulation.
  • the content thereof may be 0.1 wt% to 0.5 wt%, specifically 0.1 wt% to 0.3 wt%, based on the total weight of the formulation, and may be 0.12 wt% according to an embodiment of the present invention. Further, the lobeglitazone sulfate may have a content of 0.4 to 2 mg per unit dosage form.
  • a composite formulation containing 0.5 mg of lobeglitazone sulfate is exemplified, but the content of lobeglitazone sulfate capable of being contained in the composite formulation of the present invention is not limited thereto.
  • the above range will be a value converted by considering the molecular weight of lobeglitazone itself or another lobeglitazone salt compared to the molecular weight of lobeglitazone sulfate.
  • sitagliptin phosphate hydrate when sitagliptin phosphate hydrate is used as the active ingredient, sitagliptin, in the composite formulation of the present invention, the content thereof may be 7 wt% to 35 wt%, specifically 10 wt% to 33 wt%, based on the total weight of the formulation, and may be 31 wt% according to an embodiment of the present invention. Further, the sitagliptin phosphate hydrate may have a content of 30 to 130 mg per unit dosage form. In an embodiment of the present invention, a composite formulation containing 128.5 mg of sitagliptin phosphate hydrate is exemplified, but the content of sitagliptin phosphate hydrate capable of being contained in the composite formulation of the present invention is not limited thereto.
  • sitagliptin itself or a sitagliptin salt other than sitagliptin phosphate hydrate is used as the active ingredient, the above range will be a value converted by considering the molecular weight of sitagliptin itself or another sitagliptin salt compared to the molecular weight of sitagliptin phosphate hydrate.
  • the composite formulation of the present invention may be manufactured in the form of a single layer tablet, and the release pattern of each active ingredient may be improved through the formulation in the form of a single layer tablet as described above.
  • the composite formulation of the present invention formulated in the form of a single layer tablet had improved release patterns of each active ingredient compared to the composite formulation in the form of a bi-layer tablet, and furthermore, exhibited an equivalent or similar level of release patterns as those of the reference drugs for each single formulation.
  • the composite formulation in the form of a single layer tablet of the present invention may exhibit the equivalent or similar dissolution rates as the reference drugs, which are single formulations for each active ingredient.
  • the equivalent dissolution rate may indicate that the dissolution rate of the test drug is within ⁇ 15% of the dissolution rate of the reference drug at a specific time (e.g., within 15 minutes).
  • the pharmaceutical composite formulation of the present invention may have a dissolution rate of lobeglitazone of 80% or more or equivalent thereto within 30 minutes in a dissolution test according to the Korean Pharmacopoeia Method 2 (paddle method, 37 ⁇ 0.5 °C, pH 1.2, 900 mL, and 50 rpm).
  • the pharmaceutical composite formulation of the present invention may have a dissolution rate of lobeglitazone of less than 85% or equivalent thereto within 10 minutes in a dissolution test according to the Korean Pharmacopoeia Method 2 (paddle method, 37 ⁇ 0.5 °C, pH 1.2, 900 mL, and 50 rpm).
  • the pharmaceutical composite formulation of the present invention may have a dissolution rate of lobeglitazone of less than 80% or equivalent thereto within 5 minutes in a dissolution test according to the Korean Pharmacopoeia Method 2 (paddle method, 37 ⁇ 0.5 °C, pH 1.2, 900 mL, and 50 rpm).
  • the pharmaceutical composite formulation of the present invention may have a dissolution rate of sitagliptin of 90% or more or equivalent thereto within 15 minutes in a dissolution test according to the Korean Pharmacopoeia Method 2 (paddle method, 37 ⁇ 0.5 °C, pH 1.2, 900 mL, and 50 rpm).
  • the pharmaceutical composite formulation of the present invention may have a dissolution rate of sitagliptin of 85% or more or equivalent thereto within 10 minutes in a dissolution test according to the Korean Pharmacopoeia Method 2 (paddle method, 37 ⁇ 0.5 °C, pH 1.2, 900 mL, and 50 rpm).
  • the pharmaceutical composite formulation of the present invention may have a dissolution rate of sitagliptin of 60% or more or equivalent thereto within 5 minutes in a dissolution test according to the Korean Pharmacopoeia Method 2 (paddle method, 37 ⁇ 0.5 °C, pH 1.2, 900 mL, and 50 rpm).
  • the pharmaceutical composite formulation of the present invention is characterized in that the dissolution rates of lobeglitazone and sitagliptin are equivalent to the dissolution rates of lobeglitazone of Duvie tablet and sitagliptin of Januvia tablet having the same active ingredient dose.
  • the dissolution rate and pattern of lobeglitazone in the composite formulation of the present invention are similar or equivalent to the dissolution rate and pattern of lobeglitazone of Duvie tablet, the reference drug with the same dose.
  • the dissolution rate and pattern of sitagliptin in the composite formulation of the present invention are similar or equivalent to the dissolution rate and pattern of sitagliptin of Januvia tablet, the reference drug with the same dose.
  • the composite formulation of the present invention may exhibit blood concentration patterns that are equivalent or bioequivalent to the reference drugs, which are single formulations for each active ingredient.
  • the composite formulation of the present invention is characterized by showing equivalent or bioequivalent levels of area under the blood concentration-time curve (AUC) and peak blood concentration (C max ) compared to Duvie tablet and Januvia tablet having the same active ingredient dose.
  • AUC blood concentration-time curve
  • C max peak blood concentration
  • the composite formulation of the present invention had bioequivalent levels of area under the blood concentration-time curve (AUC) and peak blood concentration (C max ) compared to those of the above reference drugs.
  • the composite formulation of the present invention may further comprise at least one additive selected from the group consisting of binders, disintegrants, excipients, lubricants, and coating agents.
  • the binder, disintegrant, excipient, lubricant, and coating agent may be any binder, disintegrant, excipient, lubricant, and coating agent known in the art, respectively, and they are not particularly limited as long as the composite formulation of the present invention does not inhibit the desired effect.
  • the composite formulation of the present invention may comprise the above additives in a content of 50 wt% to 80 wt%, specifically 55 wt% to 75 wt%, based on the total weight of the formulation.
  • the binder may be any binder known in the art as long as it is possible to improve the content uniformity and the release pattern for each active ingredient, but may specifically be povidone, hydroxypropylcellulose, or a mixture thereof, and more specifically, may be povidone, and may not include copovidone.
  • the binder may have a content of 1 to 8 wt%, specifically 2 to 6 wt%, based on the total weight of the formulation.
  • the disintegrant may be at least one selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, calcium carboxymethyl cellulose, alginic acid, low-substituted hydroxypropyl cellulose, and pregelatinized starch, and specifically, may be croscarmellose sodium.
  • the disintegrant may have a content of 1 to 15 wt%, specifically 1 to 12 wt%, and more specifically 8 to 12 wt%, based on the total weight of the formulation.
  • the excipient may be at least one selected from the group consisting of sugars such as lactose, glucose, sucrose, fructose, and maltose; sugar alcohols such as mannitol, sorbitol, erythritol, xylitol, lactitol, and maltitol; cellulose such as microcrystalline cellulose, Ludipress, and cellactose; starches such as wheat starch, rice starch, corn starch, and potato starch; and ⁇ -starch, partial ⁇ -starch, and hydroxypropyl starch, and specifically, may be microcrystalline cellulose.
  • sugars such as lactose, glucose, sucrose, fructose, and maltose
  • sugar alcohols such as mannitol, sorbitol, erythritol, xylitol, lactitol, and maltitol
  • cellulose such as microcrystalline cellulose, Ludipress, and cellactose
  • the lubricant may be at least one selected from the group consisting of sodium stearyl fumarate, magnesium stearate, silica oxide, colloidal silicon dioxide, and talc, and specifically, magnesium stearate, colloidal silicon dioxide, or a mixture thereof.
  • the coating agent may be hydroxypropyl methylcellulose, ethyl cellulose, polyvinyl acetate, polyethylene glycol, titanium dioxide, iron oxide, etc., or Opadry®, or a mixture thereof, and specifically may be Opadry®.
  • the formulation in the form of a bi-layer tablet having the same composition as that of the present invention did not satisfy the above dissolution characteristics, and from this confirmation, it was found that the composition of the composite formulation of the present invention was suitable for a single layer tablet.
  • the composite formulation of the present invention may be manufactured in the form of a single layer tablet by any tablet manufacturing method known in the art, for example, by the direct compression method (mixed tablet compression), the slugging method (dry granulation), or the wet granulation method. Specifically, the composite formulation of the present invention may be manufactured by the wet granulation method.
  • the wet granulation method may be performed by applying a high shear granulation or fluid-bed granulation process.
  • the composite formulation of the present invention may be manufactured by granulating lobeglitazone and sitagliptin with a binder, mixing excipients, disintegrants, and lubricants, and then compressing the mixture into tablets, but the manufacturing method thereof is not limited thereto. According to an experimental example of the present invention, it was confirmed that the composite formulation manufactured by the wet granulation method showed particularly excellent content uniformity.
  • the composite formulation of the present invention may further comprise a coating layer on the outside.
  • the coating layer may be formed on a surface of an uncoated tablet according to a film coating layer formation method commonly used in the art.
  • the composite formulation of the present invention may be administered once a day.
  • the composite formulation of the present invention may be provided for oral administration.
  • the composite formulation of the present invention may be usefully employed in all cases requiring simultaneous, sequential or combination use of lobeglitazone and sitagliptin. Specifically, the composite formulation of the present invention may be used to prevent or treat type 2 diabetes, such as by reducing blood sugar, etc.
  • the pharmaceutical composite formulation of the present invention comprises two pharmacologically active ingredients, lobeglitazone and sitagliptin together, in one formulation, thereby being useful in the treatment or prevention of diabetes, eliminating the inconvenience of having to take the two formulations separately, and significantly improving the patient medication convenience.
  • the pharmaceutical composite formulation of the present invention may have reduced total weight and size, thereby improving medication compliance.
  • the composite formulation of the present invention may have a total weight of 500 mg or less, which is characterized by improved medication compliance by reducing the total weight compared to the sum of the weights of the reference drugs for each active ingredient.
  • the total weight of the composite formulation of the present invention may be smaller than the sum of the weights of the reference drugs comprising the same dose for each active ingredient, i.e., Duvie tablet (125 mg) and Januvia tablet (416.1 mg).
  • the formulation of the present invention may have a weight smaller than the reference drug, which is a sitagliptin single layer tablet, thereby improving the patient's medication compliance.
  • the composite formulation of the present invention may reduce the number of administrations of the existing lobeglitazone and sitagliptin single formulations, improve medication compliance, and achieve equivalent or better therapeutic effects.
  • the composite formulation comprising lobeglitazone and sitagliptin of the present invention ensures content uniformity for each active ingredient while simultaneously exhibiting dissolution patterns equivalent to those of the reference drugs, and is in the form of a single layer tablet, thereby making it easier to manufacture and providing improved medication convenience and compliance compared to bi-layer tablets.
  • FIG. 1 is a graph showing the results of a dissolution test using the paddle method in the pH 1.2 eluates of Examples 1 to 3.
  • FIG. 2 is a graph showing the results of a dissolution test using the flow-through cell (FTC) method in the pH 1.2 eluates of Examples 7 and 8.
  • FTC flow-through cell
  • FIG. 3 is a graph showing the blood concentration of each active ingredient of Examples 7 and 8.
  • the drug for Comparative Example 1 was 'Duvie Tablet 0.5 mg', a single layer tablet containing 0.5 mg of lobeglitazone sulfate and sold commercially by the present applicant, and the drug for Comparative Example 2 was 'Januvia Tablet 100 mg' from MSD Korea, Co., Ltd., a single layer tablet containing 128.5 mg of sitagliptin phosphate hydrate (100 mg as sitagliptin).
  • a composite formulation in the form of a bi-layer tablet containing lobeglitazone and sitagliptin as active ingredients was prepared by a wet granule manufacturing method using a high speed mixer (HSM).
  • HSM high speed mixer
  • the granules of the lobeglitazone layer and sitagliptin layer were manufactured in the following orders: weighing raw materials, preparing binder, dispersing, mixing and combining using HSM, granulating (co-mill), drying (cabinet dryer), sizing (co-mill), post-mixing, and lubrication.
  • the granules of each main ingredient layer as prepared above were tableted using a multi-layer tablet press, and then the tablets were coated to manufacture a composite formulation in the form of a bi-layer tablet.
  • the specific compositions of Examples 1 to 3 are shown in Table 1 below.
  • the raw materials were weighed, then the main ingredients were dispersed, mixed, and lubricated, and the thus-obtained granules were tableted and coated to be manufactured into a single layer tablet using the direct compression method.
  • Example 5 Single layer tablet by slugging method
  • Example 4 The same amount of raw materials as in Example 4 were weighed, and then the main ingredients were dispersed and mixed, and the obtained mixture was slugged with a slugging machine, then sized using a co-mill, and then the post-mixed and lubricated granules were tableted and coated to manufacture tablets in a single layer tablet form.
  • the raw materials were weighed, then the main ingredients were dispersed and added to HSM with other additives, mixed, and then the prepared binding solution was added thereto and combined for 2 minutes. Next, the combined product was granulated using a co-mill and then dried in a cabinet dryer. Then, the dried product was sized using a co-mill, post-mixed, and lubricated, and the obtained final mixture was tableted and coated to manufacture tablets in a single layer tablet form.
  • Examples 1 to 3 in the form of bi-layer tablets had different dissolution patterns of each active ingredient compared to the reference drugs, and in particular, showed a slower initial release rate of sitagliptin compared to the reference drug.
  • Example 4 using the direct compression method and Example 5 using the slugging method showed that the uniformity of lobeglitazone was unsuitable, but Examples 6 and 9 using the wet granulation method were confirmed to have excellent uniformity of both lobeglitazone and sitagliptin.
  • Examples 6 and 9 in the form of single layer tablets showed the dissolution rates and patterns of each active ingredient equivalent to the reference drugs, and in particular, showed that the dissolution rate of sitagliptin was 85% or more within 10 minutes, indicating that the initial release pattern was similar to that of the reference drug.
  • Example 7 showed that the initial dissolution pattern of lobeglitazone was similar to that of the reference drug, and that sitagliptin had a fast initial release rate as shown in the reference drug.
  • Example 8 it was confirmed in Example 8 that both lobeglitazone and sitagliptin had different release patterns compared to the reference drugs, and in particular, the initial release rates thereof were slow.
  • Blood collection points Pre-dose, at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours (14 time points)
  • Blood concentrations of lobeglitazone and sitagliptin were respectively quantified using LC-MS/MS, then the geometric means were obtained from the log-transformed AUC and C max values, and the 90% confidence interval for the ratio of the geometric means was calculated.
  • the 90% confidence interval of 0.8 to 1.25 indicates that two agents are bioequivalent, and a case where the T/R ratio (geometric mean of test drug / geometric mean of reference drug) is close to 1 means that two agents are bioequivalent.
  • Example 8 had a 90% confidence interval outside the range of 0.8 to 1.25 for both lobeglitazone and sitagliptin, but Example 7 showed that both lobeglitazone and sitagliptin were within the range of the above confidence interval, showing bioavailability that was bioequivalent to those of the reference drugs for each single agent.
  • Example 9 a single oral administration of the composite formulation of Example 9 or a combination of the single formulations of Comparative Examples 1 and 2 was administered to 30 healthy adult volunteers, and blood samples were collected therefrom.
  • the blood concentrations of lobeglitazone and sitagliptin were quantified using LC-MS/MS, respectively, and statistically processed in the same manner as in Experimental Example 5. Results thereof are shown in Table 7 below.

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  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une formulation pharmaceutique composite comprenant de la lobeglitazone et de la sitagliptine, garantissant l'uniformité du contenu de chaque principe actif tout en présentant simultanément des schémas de dissolution équivalents à ceux des médicaments de référence, et se présentant sous la forme d'un comprimé monocouche, ce qui facilite la fabrication et offre une commodité et une observance du traitement améliorées par rapport aux comprimés bicouches.
PCT/KR2024/001378 2023-01-31 2024-01-30 Formulation pharmaceutique composite comprenant de la lobeglitazone et de la sitagliptine Ceased WO2024162731A1 (fr)

Applications Claiming Priority (2)

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KR1020230013161A KR20240120463A (ko) 2023-01-31 2023-01-31 로베글리타존 및 시타글립틴을 포함하는 약제학적 복합제제
KR10-2023-0013161 2023-01-31

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WO2024162731A1 true WO2024162731A1 (fr) 2024-08-08

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KR (1) KR20240120463A (fr)
WO (1) WO2024162731A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20170049129A (ko) * 2015-10-28 2017-05-10 주식회사 종근당 메트포르민 및 로베글리타존을 포함하는 약제학적 조성물
KR20200078353A (ko) * 2018-12-21 2020-07-01 (주)휴온스 엠파글리플로진 및 시타글립틴을 포함하는 약학적 조성물

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20170049129A (ko) * 2015-10-28 2017-05-10 주식회사 종근당 메트포르민 및 로베글리타존을 포함하는 약제학적 조성물
KR20200078353A (ko) * 2018-12-21 2020-07-01 (주)휴온스 엠파글리플로진 및 시타글립틴을 포함하는 약학적 조성물

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Title
ANONYMOUS: "A Clinical Study to Evaluate the Pharmacokinetics and Safety of CKD-396", CLINICALTRIALS.GOV NCT04246190, 5 February 2020 (2020-02-05), XP093197101, Retrieved from the Internet <URL:https://clinicaltrials.gov/study/NCT04246190> *
ANONYMOUS: "CKD-396 Drug-drug Interaction Study(B) (CKD-396 DDI(B) P1)", CLINICALTRIALS.GOV NCT02827890, 9 August 2017 (2017-08-09), XP093197094, Retrieved from the Internet <URL:https://clinicaltrials.gov/study/NCT02827890> *
LIM SOO, KU EU JEONG, LEE SEO YOUNG, LEE JI HYUN, LEE JIE-EUN, KIM KYOUNG MIN, DAVIES MELANIE J: "Therapeutic efficacy and safety of initial triple combination of metformin, sitagliptin, and lobeglitazone in drug-naïve patients with type 2 diabetes: initial triple study", BMJ OPEN DIABETES RESEARCH & CARE, BMJ PUBLISHING GROUP, BMA HOUSE, TAVISTOCK SQUARE, LONDON, WC1H 9JR, vol. 8, no. 1, 1 January 2020 (2020-01-01), BMA House, Tavistock Square, London, WC1H 9JR, pages e000807, XP093149799, ISSN: 2052-4897, DOI: 10.1136/bmjdrc-2019-000807 *
MOON, S. J. ET AL.: "An assessment of pharmacokinetic interaction between lobeglitazone and sitagliptin after multiple oral administrations in healthy men", CLINICAL THERAPEUTICS, vol. 42, no. 6, 2020, pages 1047 - 1057, XP086196200, DOI: 10.1016/j.clinthera.2020.04.005 *

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