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WO2016016770A1 - Nouvelle composition pharmaceutique à libération modifiée de la sitagliptine ou d'un sel pharmaceutiquement acceptable correspondant - Google Patents

Nouvelle composition pharmaceutique à libération modifiée de la sitagliptine ou d'un sel pharmaceutiquement acceptable correspondant Download PDF

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Publication number
WO2016016770A1
WO2016016770A1 PCT/IB2015/055554 IB2015055554W WO2016016770A1 WO 2016016770 A1 WO2016016770 A1 WO 2016016770A1 IB 2015055554 W IB2015055554 W IB 2015055554W WO 2016016770 A1 WO2016016770 A1 WO 2016016770A1
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Prior art keywords
sitagliptin
composition
pharmaceutically acceptable
acceptable salt
modified release
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Inventor
Mandar Madhukar KODGULE
Amit Bansal
Manohar LALGE
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Wockhardt Ltd
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Wockhardt Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates

Definitions

  • the present invention relates to a novel modified release pharmaceutical composition
  • a novel modified release pharmaceutical composition comprising sitagliptin or pharmaceutically acceptable salt thereof.
  • sitagliptin or pharmaceutically acceptable salt thereof By providing a novel modified release composition of sitagliptin or pharmaceutically acceptable salt thereof, it is possible to achieve desired minimum effective plasma concentration of sitagliptin that is sufficient for effective glycemic control in patients with type 2 diabetes mellitus.
  • the invention further provides a method of improving glycemic control in adults with type 2 diabetes mellitus and reducing or eliminating fluctuations in plasma concentration of sitagliptin by using such composition. A method for the preparation of such composition is also described.
  • Type 2 diabetes is the most common form of diabetes and it is one of the most prevalent chronic diseases.
  • Treatment of type 2 diabetes mellitus (T2DM) initially starts with diet and exercise, followed by oral antidiabetic monotherapy. During long-term treatment these regimens do not sufficiently control hyperglycemia in many patients, leading to a requirement for combination therapy within several years following diagnosis.
  • T2DM type 2 diabetes mellitus
  • Drugs of choice for combination therapy include biguanides, DPP-IV inhibitors, sulfonylurea, thiazolidinedione, alphaglucosidase inhibitor, amylin analog, glucagon-like peptide-1 (GLP-1 ) or incretin mimetic, meglitinide and insulin.
  • biguanides and DPP-IV inhibitors are preferred choices for management of type 2 diabetes in the recent past.
  • the DPP-IV inhibitors are specific to reduction of post-prandial elevated glucose level as opposed to the lack of effect on the resting glucose level, combining them with biguanide is preferred.
  • Dipeptidyl peptidase IV (DPP-IV) inhibitors act by inhibiting dipeptidyl peptidase IV (DPP-IV) enzyme, a multifunctional transmembrane glycoprotein enzyme that cleaves N-terminal dipeptides from polypeptides with L-proline or L-alanine at the penultimate position.
  • DPP-IV dipeptidyl peptidase IV
  • the selectivity of DPP-IV inhibitors against other closely- related proline-specific dipeptidyl peptidases, particularly DPP-8 and DPP-9 has been a potential for adverse events associated with non-selective DPP-IV inhibitors.
  • the inhibition of DPP-8 and DPP-9 has been found to be associated with toxicities in rat and dog (Lankas, G. R., et al. Diabetes, 2005; 54:2988- 2994). Therefore, it is important to demonstrate that DPP-IV inhibitors do not appreciably inhibit these closely related enzymes.
  • Sitagliptin is an orally-active DPP-IV enzyme inhibitor, available as monohydrate of its phosphate salt. Chemically, monohydrate of sitagliptin phosphate is 7-[(3R)- 3-amino-1 -oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8tetrahydro-3- (trifluoromethyl) -1 ,2,4-triazolo [4,3-a] pyrazine phosphate (1 : 1 ) monohydrate with the following structure:
  • U.S. Patent number US 6,099,862 discloses controlled release tablet containing metformin and glipizide.
  • U.S. Patent RE44,186 discloses a method of treatment for T2DM using DPP-IV inhibitor and one or more other antidiabetic agents such as metformin, glyburide, troglitazone, pioglitazone and rosiglitazone.
  • U.S. Patent 8,414,921 discloses pharmaceutical compositions comprising fixed- dose combinations of a DPP-IV inhibitor and metformin.
  • U.S. Publication number 20070172525 and 20080064701 discloses pharmaceutical compositions comprising an immediate-release DPP-IV inhibitor and a slow-release form of metformin.
  • U.S. Patent 8,329,217 discloses a controlled release osmotic device containing a bi-layered core of at least two different active agents which provides therapeutically effective levels of both the actives for an extended period of time following oral administration.
  • U.S. Publication number 20130059002 discloses a pharmaceutical composition comprising metformin and sitagliptin or pharmaceutically acceptable salt thereof in two separate compartments.
  • the document also discloses a combination composition comprising an extended release metformin HCI and an extended release sitagliptin.
  • European patent publication number EP 1 ,537,880 A1 relates to a sustained release formulation of DPP-IV inhibitor comprising a hydrophilic polymer. Even though antidiabetic combinations have been proven effective for diabetes management, existing once daily formulations still may fall short by exhibiting sub-therapeutic plasma concentrations or expose to undesired higher plasma concentrations of antidiabetic agents than that required for safe glycemic control and may ultimately failing to provide round the clock diabetes management. This variation in plasma levels of the antidiabetic agents may be attributed to their varying solubilities, different physiological targets and pharmacokinetic (PK) profiles.
  • PK pharmacokinetic
  • DPP-IV activity potentiates the vasodilating action of substance P.
  • DPP-IV activity of nasal mucosa and the density of inflammatory cells in nasal mucosa of patients with chronic rhinosinusitis are in a reverse correlation and DPP-IV activity increases when chronic rhinosinusitis was cured (FASEB, 2002; 16:1 132-1 134). Therefore, strong inhibition of DPP-IV activity in diabetic patients with concurrent chronic inflammation is not considered preferable as it may cause aggravation of the inflammation.
  • the plasma concentration of below 100 nM achieved by 24 hours post administration of 100 mg dose of Januvia ® is sub-therapeutic, which may lead to loss of glycemic control for about last 4 hours with current once daily dosage regimen.
  • Such inadequate glycemic control of about 4 hours after each dose administration may be seen until the steady state plasma concentration is achieved on 10 th day of the once daily dosage regimen.
  • Such inadequate glycemic control should be avoided for effective management of T2DM.
  • the 100 mg immediate release dosage form leads to essentially non required maximum plasma concentration of about 950 nM within 1 .3 hours post administration, since the maximal DPP-IV inhibition occurs at about 125 nM.
  • Such higher plasma concentration achieved by the 100 mg immediate release dosage may aggravate inflammation or lead to depression and anxiety which are not desirable for the diabetic patient as mentioned above.
  • Sitagliptin has average renal clearance of 350 ml/min and volume of distribution of about 198 liters. As sitagliptin is cleared off body mainly through kidney, its dose adjustment prior to initiation of therapy and periodically thereafter is essential in renal function compromised patients and becomes even more essential due to role of renal function in diabetic patients. Specifically patient with renal insufficiency is prescribed lesser dose of sitagliptin than that to normal patient. Thus, as a result, the existing sitagliptin products may suffer from three issues, firstly causing hyperglycemia in last few hours (e.g. last eight hours) of the day post administration causing hyperglycemia, secondly exposing the patient for several initial hours to essentially non required maximum plasma concentration following administration, and thirdly require renal function monitoring before and during treatment.
  • a modified release composition comprising sitagliptin or pharmaceutically acceptable salt thereof and optionally, at least one antidiabetic agent, wherein sitagliptin in the composition inhibits activity of DPP-IV enzyme by 80% or more over a period of at least 24 hours after oral administration of single dose of the composition to a subject.
  • a modified release composition comprising sitagliptin or pharmaceutically acceptable salt thereof; one or more rate controlling excipients and optionally, at least one antidiabetic agent, wherein sitagliptin in the composition inhibits activity of DPP-IV enzyme by 80% or more over a period of at least 24 hours after oral administration of single dose of the composition to a subject.
  • a modified release composition comprising sitagliptin or pharmaceutically acceptable salt thereof and optionally, at least one antidiabetic agent, wherein once daily administration of said composition to a subject achieves mean steady state plasma concentration (C ss ) of sitagliptin on or before 7 days.
  • sitagliptin in the composition exhibit modified release so as to inhibit activity of DPP-IV enzyme by 80% or more over a period of at least 24 hours after oral administration of single dose of the composition to a subject.
  • a modified release composition comprising about 25mg to about " l OOmg sitagliptin or pharmaceutically acceptable salt thereof and optionally, at least one antidiabetic agents, wherein once daily administration of said composition to a subject inhibit activity of DPP- IV enzyme by 80% or more over a period of at least 24 hours.
  • a modified release composition comprising sitagliptin or pharmaceutically acceptable salt thereof and optionally, at least one antidiabetic agent wherein a substantial dose of sitagliptin in the composition exhibit zero order release over a period of at least 24 hours after oral administration of single dose of the composition.
  • antidiabetic agent in the modified release composition exhibit immediate and/or extended release from said composition.
  • total dose of the sitagliptin in modified release composition is divided into an immediate release part and an extended release part.
  • the extended release part of sitagliptin in the modified release composition exhibits zero order release.
  • the modified release composition of sitagliptin further comprises two antidiabetic agents.
  • a modified release composition comprising:
  • a substantial dose of sitagliptin in the composition exhibit zero order release over at least 24 hours after oral administration of single dose of the composition to a subject.
  • a modified release composition comprising:
  • Additional antidiabetic agents may be selected from DPP-IV inhibitors, insulin sensitizers, ⁇ -glucosidase inhibitors, biguanides, insulin secretagogues, sodium- glucose co-transporter-2 (SGLT-2) inhibitors, ⁇ 3 agonists, GPR40 agonists, GLP- 1 receptor agonists, amylin agonists, phosphotyrosine phosphatase inhibitors, gluconeogenesis inhibitors, 1 1 ⁇ -hydroxysteroid dehydrogenase inhibitors, adiponectin or agonist thereof, IKK inhibitors, leptin resistance improving drugs, somatostatin receptor agonists, and glucokinase activators.
  • DPP-IV inhibitors insulin sensitizers, ⁇ -glucosidase inhibitors, biguanides, insulin secretagogues, sodium- glucose co-transporter-2 (SGLT-2) inhibitors, ⁇ 3 agonists, GPR40 agonists, GLP- 1 receptor agonist
  • Suitable biguanides may be selected from metformin, buformin, phenformin or pharmaceutically acceptable salt thereof.
  • Suitable insulin secretagogues may be selected from acetohexamide, chlorpropamide, tolbutamide, tolazamide, glipizide, glybuzole, gliclazide, glibenclamide, gliquidone, glyclopyramide, glimepiride, neteglinide, repaglinide, mitiglinide or pharmaceutically acceptable salt thereof.
  • Suitable sodium-glucose co-transporter-2 (SGLT-2) inhibitors may be selected from dapagliflozin, canagliflozin, ipragliflozin, tofoglif lozin, empagliflozin, sergliflozin, remogliflozin, ertugliflozin, luseogliflozin, atigliflozin or pharmaceutically acceptable salt thereof.
  • Suitable a-glucosidase inhibitors may be selected from voglibose, acarbose, miglitol, emiglitate or pharmaceutically acceptable salt thereof.
  • Suitable GPR40 agonists may be selected from AMG 837, TAK-875 or pharmaceutically acceptable salt thereof.
  • Suitable GLP-1 receptor agonists may be selected from AMG 837, TAK-875, NN- 221 1 , exendin-4, BIM-51077, CJC-1 131 or pharmaceutically acceptable salt thereof.
  • Suitable gluconeogenesis inhibitors may be selected from glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, glucagon antagonist or pharmaceutically acceptable salt thereof.
  • amylin agonist is pramlintide
  • phosphotyrosine phosphatase inhibitor is sodium vanadate
  • 11 ⁇ -hydroxysteroid dehydrogenase inhibitor is BVT-3498
  • glucokinase activators is Ro-28-1675 or pharmaceutically acceptable salt thereof.
  • a modified release composition comprising sitagliptin or pharmaceutically acceptable salt thereof and optionally, at least one antidiabetic agents, wherein the composition maintains mean plasma concentration of sitagliptin in the range of about 100 nM to about 850 nM over a period of at least 24 hours after oral administration of single dose of the composition to a subject.
  • a modified release composition comprising sitagliptin or pharmaceutically acceptable salt thereof and optionally, at least one antidiabetic agents, wherein the composition provides mean plasma concentration of sitagliptin in the range of about 100 nM to about 850 nM over a period of at least 24 hours after oral administration of single dose of the composition to a subject.
  • a modified release composition comprising:
  • composition provides mean plasma concentration of sitagliptin or pharmaceutically acceptable salt thereof in the range of about 100 nM to about 850 nM over a period of at least 24 hours after oral administration of single dose of the composition.
  • a modified release composition comprising:
  • sitagliptin or pharmaceutically acceptable salt thereof (b) one or more rate controlling excipients and
  • composition provides mean plasma concentration of sitagliptin or pharmaceutically acceptable salt thereof in the range of about 100 nM to about 850 nM over a period of at least 24 hours after oral administration of single dose of the composition.
  • a modified release composition comprising:
  • composition provides mean plasma concentration of sitagliptin or pharmaceutically acceptable salt thereof in the range of about 100 nM to about 850 nM over a period of at least 24 hours after oral administration of single dose of the composition to a subject.
  • the modified release composition comprises about 25mg to about 100mg sitagliptin or equivalent amount of its pharmaceutically acceptable salt.
  • the dose of sitagliptin or equivalent amount of its pharmaceutically acceptable salt administered through the modified release composition for treatment of type 2 diabetes mellitus in the renal function compromised patient is about 25 mg or 50 mg.
  • the individual dose can be adjusted based on the renal function assessment.
  • a modified release composition comprising about 25mg to about 100mg sitagliptin or pharmaceutically acceptable salt thereof and optionally, at least one antidiabetic agents, wherein once daily administration of said composition to a subject provides a mean steady state maximum plasma concentration (C SS (max)) of sitagliptin in the range of about 350 nM to about 750 nM after oral administration of single dose of the composition to a subject.
  • C SS (max) mean steady state maximum plasma concentration
  • a modified release composition comprising 100 mg sitagliptin or pharmaceutically acceptable salt thereof and optionally, at least one antidiabetic agents, wherein the composition exhibit a mean steady state minimum plasma concentration (C ss (mm)) of sitagliptin in the range of about 200 nM to about 500 nM after oral administration of single dose of the composition to a subject.
  • C ss steady state minimum plasma concentration
  • a modified release composition comprising sitagliptin or pharmaceutically acceptable salt thereof and optionally, at least one antidiabetic agent, wherein said composition exhibit an in vitro release profile such that about 30% to about 70% of sitagliptin is dissolved within 8 hour and/or about 50% to about 90% of sitagliptin is dissolved within 16 hour after placement of the composition in a dissolution test conducted according to USP, using USP Apparatus I at 100 rpm and a dissolution medium of water at about 37°C.
  • the modified release composition comprises 100 mg sitagliptin or pharmaceutically acceptable salt thereof wherein the composition comprises 10mg to 50mg of sitagliptin in immediate release part and 50 mg to 90 mg of sitagliptin in extended release part.
  • the modified release composition comprises 100 mg sitagliptin or pharmaceutically acceptable salt thereof and provides mean plasma concentration in the range of about 100 nM to about 400 nM, after 4 hours of oral administration of single-dose of the composition to a subject.
  • the modified release composition comprises 100 mg sitagliptin or pharmaceutically acceptable salt thereof and provides a mean plasma concentration of sitagliptin or pharmaceutically acceptable salt thereof in the range of about 150 nM to about 350 nM after 8 hours of single dose administration of said composition to a subject.
  • the modified release composition comprises 100 mg sitagliptin or pharmaceutically acceptable salt thereof and provides a mean plasma concentration of sitagliptin or pharmaceutically acceptable salt thereof in the range of about 200 nM to about 320 nM after 12 hours of single dose administration of said composition to a subject.
  • the modified release composition comprises 100 mg sitagliptin or pharmaceutically acceptable salt thereof and provides a mean plasma concentration of sitagliptin or pharmaceutically acceptable salt thereof in the range of about 180 nM to about 370 nM after 20 hours of single dose administration of said composition to a subject.
  • a modified release composition comprising:
  • composition maintains mean plasma concentration of sitagliptin or pharmaceutically acceptable salt thereof in the range of about 100 nM to about 850 nM over a period of at least 24 hours after oral administration of single dose of said composition to a subject.
  • the minimum therapeutically effective plasma concentration of sitagliptin and optionally, at least one antidiabetic agent in the modified release composition is achieved by their osmotically controlled release from the composition.
  • the modified release composition is in the form of an osmotic dosage form.
  • the modified release composition comprises: (i) a semipermeable wall provided around an osmotic formulation comprising sitagliptin or pharmaceutically acceptable salt thereof, optionally at least one antidiabetic agent or pharmaceutically acceptable salt thereof, an osmotic agent, and an osmopolymer; and (ii) a passageway.
  • a method of reducing side effects associated with increased plasma concentration of sitagliptin in a patient undergoing T2DM treatment comprises of orally administering single dose of a modified release composition comprising sitagliptin or pharmaceutically acceptable salt thereof and optionally, at least one antidiabetic agent or pharmaceutically acceptable salt thereof, wherein a substantial dose of sitagliptin in the composition exhibit zero order release over a period of at least 24 hours.
  • a method of treating type 2 diabetes mellitus comprising administration of the modified release composition to a subject in need thereof as substantially described herein before.
  • FIGURE 1 is a graph showing plasma concentration profile of Januvia ® , 100 mg tablet in fasting conditions.
  • FIGURE 2 is a graph showing plasma concentration profile of Januvia , 100 mg tablet in fed conditions.
  • FIGURE 3 is a graph showing comparative plasma concentration profile of Januvia ® , 100 mg tablet (Innovator) and 3 different modified release compositions of the invention (Test, viz. 10 mg + 90 mg ER, 25 mg + 75 mg ER and 50 mg IR + 50 mg ER).
  • FIGURE 4 is a graph showing simulated plasma concentration profile of modified release 100 mg sitagliptin composition with 10 mg of immediate release part and 90 mg of extended release part.
  • FIGURE 5 is a graph showing simulated plasma concentration profile of modified release 100 mg sitagliptin composition with 25 mg of immediate release part and 75 mg of extended release part.
  • FIGURE 6 is a graph showing simulated plasma concentration profile of modified release 100 mg sitagliptin composition with 50 mg of immediate release part and 50 mg of extended release part.
  • novel modified release composition of sitagliptin maintains the therapeutically effective plasma concentration of sitagliptin and does not allow it to surpass the optimal level, therefore avoids side effects or problems associated with administration of sitagliptin.
  • novel modified release composition according to the present invention provides sufficient plasma concentration of sitagliptin over 24 hours after single dose oral administration. Additionally, such compositions achieve steady state concentration of sitagliptin relatively earlier than that achieved by conventional dosage forms.
  • the inventors have surprisingly found that the desired DPP-IV inhibition can be achieved with a once daily dose of sitagliptin using the novel modified release composition.
  • the composition achieves more than 80% of DPP-IV enzyme inhibition over a period of over at least 24 hours after single dose oral administration.
  • the novel modified release composition of sitagliptin in accordance with the present invention achieves optimal plasma concentration, thus avoiding undesirable side effects such as aggravation of inflammation in diabetic patients with concurrent inflammation and depression/anxiety.
  • T2DM can be done by providing modified release composition comprising sitagliptin.
  • modified release composition comprising sitagliptin.
  • sitagliptin For providing better glycemic control over at least 24 hours after single dose administration and reducing the side-effects due to undesirably higher C ma x and strong inhibition of DPP-IV activity by sitagliptin is, however, not always required for effective type 2 diabetes therapy.
  • the novel modified release composition of the present invention is capable of appropriately inhibiting DPP-IV activity and that can be administered once daily. It is also possible to achieve a desired effect by maintaining a minimum effective plasma concentration of sitagliptin by administering the composition of the present invention. Particularly, the modified release composition avoids peaks and valleys (fluctuations) in plasma concentration of sitagliptin alone or in combination with other antidiabetic agent.
  • Figure 3 shows the comparative plasma concentration profile of Januvia ® tablet and modified release composition of the present invention containing equal doses of sitagliptin.
  • pharmaceutically acceptable salt are meant those salts in which the anion does not contribute significantly to the toxicity or pharmacological activity of the salt, and, as such, they are the pharmacological equivalents of the bases of the drug compound.
  • DPP-IV inhibitor refers to compounds that are intended to potentiate the endogenous incretin response by preventing the proteolysis of GLP 1 or GIP through the inhibition of one or more of the DPP-IV isoforms in the body (Mcintosh, C. H. S., et al., Regulatory Peptides, 2005; 128:159-65). A number of such agents have been approved, under review at the FDA or in clinical development (Hunziker, D., et al., Curr. Top. Med. Chem., 2005; 5:1623-37; Kim, D., et al., J. Med. Chem., 2005; 48:141 -51 ).
  • modified release as used herein in relation to the composition according to the invention or used in any other context means release, which is not completely immediate release and is taken to encompass controlled release, sustained release, prolonged release, timed release, retarded release, extended release and delayed release.
  • modified release composition as used herein can be described as compositions whose drug-release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as a solution or an immediate release dosage form.
  • the modified release composition may exhibit combination of at least two types of releases of the drug.
  • the composition comprising an immediate release part and an extended release part of sitagliptin may, overall, exhibit modified release of sitagliptin from such dosage form.
  • extended release is used in its conventional sense to refer to a composition that makes the drug available over an extended period after ingestion, and preferably, although not necessarily, results in substantially constant blood levels of the drug over an extended time period.
  • extended release used in context of the present invention includes, but not limited to, zero order release of the drug.
  • rate controlling excipients is used to refer to excipients which modify release of active agent from compositions whose drug-release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as a solution or an immediate release dosage form.
  • zero order release includes a zero order release as well as pseudo- zero order release profiles of the drug.
  • a zero order release profile characterizes the release profile of a dosage form that releases a constant amount of drug per unit time.
  • a pseudo-zero order release profile is one that approximates a zero- order release profile.
  • steady state or 'C S s' is meant a pattern of plasma concentration versus time following continuous administration of a constant dose, where the plasma concentration peaks and plasma concentration troughs are essentially identical within each dosing interval.
  • the upper (peak) and lower (trough) values of the steady state concentration are termed as 'steady state maximum concentration' or 'Css (max)' and 'steady state minimum concentration' or 'C SS (min)' respectively.
  • subject or alternatively “individual” includes mammals.
  • mammals include humans, preferably human suffering from diabetes and particularly type 2 diabetes.
  • substantially amount of sitagliptin refers to at least 5% and more preferably at least 10% of the total amount of sitagliptin in the composition or any amount of sitagliptin that is released at least 1 hour post oral administration of the composition.
  • Substantial release of sitagliptin from the composition may be achieved, for example, by providing a composition releasing sitagliptin in at least two separate pulses.
  • Such formulation includes a composition with an immediate release part and an extended release part of sitagliptin.
  • the release profiles of the modified release compositions containing sitagliptin have several potential advantages over its conventional immediate release (IR) formulations. Mainly the gradual release of sitagliptin into the gastrointestinal (Gl) tract provides lower maximum effective concentrations, thus reducing or avoiding unwanted side effects.
  • IR immediate release
  • the novel modified release composition of the present invention exhibits release of sitagliptin in such a way that it achieves and maintains minimum effective concentration of sitagliptin for at least 24 hours after oral administration.
  • the composition maintains about 80% or more inhibition of sitagliptin for at least 24 hours after oral administration of single dose of the composition.
  • the DPP-IV enzyme activity in plasma can be measured by, for example, a method utilizing the "method of Raymond et al., Diabetes, vol. 47, pp. 1253-1258 (1998)".
  • the decrease rate of the DPP-IV enzyme activity in plasma may be different from the determined values as long as it is within the general error range.
  • the decrease rate of the DPP-IV enzyme activity in plasma may be different from the determined values depending on the measurement method of the DPP-IV enzyme activity in plasma.
  • the decrease rate of the DPP-IV enzyme activity in plasma may be greater than the determined values and, for example, 90% may be a value not less than 95%.
  • a bioluminescent assay for determining DPP-IV enzyme activity by means of detecting the Gly-Pro cleaving activity is provided by Martha O'Brien et al. (Cell Notes, lssue-16, 2006).
  • antidiabetic agents may be selected from the group comprising insulin sensitizers (e.g. pioglitazone, rosiglitazone, tesaglitazar, ragaglitazar, muraglitazar, edaglitazone, metaglidasen, naveglitazar), a-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglitate), biguanides (e.g., metformin, buformin), insulin secretagogues [sulfonylurea e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybuzole;, repaglinide, nateglinide, mitiglinide), sodium- glucose co-transporter-2 (SGLT
  • gluconeogenesis inhibitors e.g., glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, glucagon antagonist
  • sodium-glucose cotransporter (SGLUT) inhibitors e.g., T-1095
  • 1 1 ⁇ -hydroxysteroid dehydrogenase inhibitors e.g., BVT-3498
  • adiponectin or agonist thereof IKK inhibitors (e.g., AS-2868), leptin resistance improving drugs, somatostatin receptor agonists, glucokinase activators (e.g., Ro-28-1675), GIP (Glucose-dependent insulinotropic peptide) and the like or one or more pharmaceutically acceptable salt, ester, solvates and derivatives thereof.
  • DPP-IV inhibitors may be selected from the group comprising alogliptin, linagliptin, vildagliptin, saxagliptin, dutogliptin, gemigliptin, denagliptin, evogliptin, gosogliptin, omarigliptin, teneligliptin, trelagliptin and melogliptin or pharmaceutically acceptable salt thereof.
  • a preferred salt of sitagliptin is the phosphate salt, most preferably in the form of its monohydrate.
  • a preferred salt of saxagliptin is the hydrochloride salt.
  • a preferred salt of alogliptin is the benzoate salt.
  • a pharmaceutically acceptable salt of sitagliptin and/or antidiabetic agents especially a salt exhibiting moderate to high solubility in water.
  • Illustrative salts include those prepared using the following acids: hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, methanesulfonic acid, ethanesulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, p-hydroxybenzoic, toluenesulfonic, formic, acetic, propionic, benzoic, anthranilic, tartaric, maleic, malic, citric, isocitric, succinic, ascorbic, lactic, glycolic, gluconic, glucuronic, pyruvic, oxaloacetic, fumaric, aspartic, glutamic, stearic, salicylic, phenylacetic, mandelic, pamoic, pantothenic, sulfanilic,
  • Rate controlling excipients are chosen to modify release of active agent from compositions and may be selected from but not limited to osmopolymers, hydrogels, osmogents, hydrophilic, hydrophobic, amphiphilic polymers or copolymers or inert materials or derivatives and or combinations thereof.
  • mean steady state plasma concentration (C ss ) of sitagliptin is achieved on or before 7 days on once daily administration of the modified release composition in accordance with the present invention.
  • the modified release composition comprising sitagliptin or pharmaceutically acceptable salt thereof and optionally maintains mean plasma concentration of sitagliptin in the range of about 100 nM to about 850 nM after oral administration of single dose of said composition.
  • the modified release composition comprising sitagliptin or pharmaceutically acceptable salt thereof and optionally provides mean plasma concentration of sitagliptin in the range of about 100 nM to about 850 nM after oral administration of single dose of said composition to a subject.
  • the modified release composition maintains mean plasma concentration of sitagliptin in the range of about 100 nM to about 700 nM and more preferably in the range of 100 nM to about 500 nM after oral administration of single dose of the said composition to a subject.
  • the modified release composition comprising sitagliptin or pharmaceutically acceptable salt thereof exhibits a mean steady state maximum plasma concentration (C SS (max)) of sitagliptin in the range of about 350 nM to about 750 nM after oral administration of single dose of the said composition to a subject.
  • C SS (max) mean steady state maximum plasma concentration
  • the modified release composition comprising sitagliptin or pharmaceutically acceptable salt thereof provides a mean steady state minimum plasma concentration (C ss (min)) of sitagliptin in the range of about 200 nM to about 500 nM after oral administration of single dose of the composition to a subject.
  • C ss (min) mean steady state minimum plasma concentration
  • the modified release composition comprising sitagliptin or pharmaceutically acceptable salt thereof have maximum plasma concentration (Cmax) and exhibits a mean steady state minimum plasma concentration (C ss (min)) of sitagliptin in the range given below after oral administration of single dose of said composition to a subject.
  • Day 3 300-500 450-650 600-800 Day 4 (Steady State achieved by Day 3)
  • the amount of sitagliptin present in modified release composition is sufficient to provide a daily dose in one to a small plurality, for example one to about 4, of dosage units to be administered at one time.
  • the full daily dose is delivered in a single dosage unit.
  • the amount of sitagliptin may be calculated on the basis of its base or salt.
  • an amount of about 25 mg to about 100 mg sitagliptin per dosage unit is present.
  • Specific amounts per tablet contemplated herein include 25, 50, and 100 mg sitagliptin base, however overages may be added as and when required according to composition and release profile requirements.
  • total dose of sitagliptin in the composition is divided in to an immediate release part and an extended release part.
  • the extended release part in the composition exhibits zero order release of sitagliptin.
  • the antidiabetic agent in the composition exhibits immediate and/or extended release.
  • the particular release and/or PK profile as defined herein can be achieved using one or more release-modifying means, for example, providing the composition in the form of matrix or sitagliptin with various rate controlling substances known in the art or by providing coating of rate controlling substances over the sitagliptin containing core.
  • dose of sitagliptin can be adjusted considering progression of disease and patient's physiology.
  • dose of sitagliptin in the modified release composition can be adjusted (from 100 mg to 50 mg or 25 mg) in case of renal function compromised patients.
  • the modified release composition comprises " l OOmg sitagliptin or pharmaceutically acceptable salt thereof in which total dose of sitagliptin or pharmaceutically acceptable salt thereof is divided in to about 10 mg to about 50 mg of immediate release part and about 50 mg to about 90 mg of extended release part.
  • Figure 4 to 6 shows the plasma concentration profile of sitagliptin 100 mg composition with immediate and extended release parts in said ranges.
  • the modified release composition may take any form suitable for oral administration, but is typically formulated as a discrete solid dosage unit such as a tablet or capsule, wherein sitagliptin or pharmaceutically acceptable salt thereof is present as solid particles, and is formulated together with one or more pharmaceutically acceptable excipients.
  • the excipients are selected in part to provide a release profile and/or PK profile consistent with those defined above.
  • the modified release composition in the form of a tablet can be of any suitable size and shape, for example round, oval, polygonal or pillow-shaped, and optionally bear nonfunctional surface markings. Especially in the case of coated tablets they are preferably designed to be swallowed whole and are therefore typically not provided with a breaking score.
  • Dosage unit compositions of the invention can be packaged in a container, accompanied by a package insert providing pertinent information such as, for example, dosage and administration information, contraindications, precautions, drug interactions and adverse reactions.
  • the modified release composition may comprises an active core comprised of one or more inert particles, each in the form of a bead, pellet, pill, granular particle, microcapsule, microsphere, microgranule, nanocapsule, or nanosphere coated on its surfaces with sitagliptin in the form of e.g., a sitagliptin -containing coating or film-forming composition using, for example, fluid bed techniques or other methodologies known to those of skill in the art.
  • the inert particle can be of various sizes, so long as it is large enough to remain poorly dissolved.
  • the active core may be prepared by granulating and milling and/or by extrusion and spheronization of a polymer composition containing sitagliptin.
  • release-modifying means suitable for use in a composition of the invention include a polymer matrix wherein the sitagliptin is dispersed; a release- controlling layer or coating surrounding the whole dosage unit or sitagliptin- containing particles, granules, beads or zones within the dosage unit; and an osmotic pump.
  • the modified release composition is provided in the form of an osmotic pump.
  • the hydrophilic polymer matrix may further include an ionic polymer, a non-ionic polymer, or water-insoluble hydrophobic polymer to provide a stronger gel layer and/or reduce pore quantity and dimensions in the matrix so as to slow diffusion and erosion rates and concomitant release of sitagliptin. This may additionally produce a more steady, zero order release of the sitagliptin.
  • an ionic polymer, a non-ionic polymer, or water-insoluble hydrophobic polymer known in the art may be used.
  • the modified release composition comprises-
  • a substantial dose of sitagliptin in the composition exhibits zero order release over a period of at least 24 hours after oral administration of single dose of the composition.
  • the modified release composition comprising sitagliptin or pharmaceutically acceptable salt thereof and optionally, at least one antidiabetic agent, exhibit an in vitro release profile such that about 30% to about 70% of sitagliptin is dissolved within 8 hour and/or about 50% to about 90% of sitagliptin is dissolved within 16 hour after placement of the composition in a dissolution test conducted according to USP, using USP Apparatus I at 100 rpm and a dissolution medium of water at about 37°C.
  • the modified release composition may comprise pH modifying agent and or suitable pharmaceutically acceptable buffer.
  • both the antidiabetic agent and a substantial dose of sitagliptin in the composition exhibit zero order release from said composition.
  • a substantial dose of sitagliptin in the modified release composition exhibits zero order release over at least 24 hours after oral administration of single dose of the composition.
  • the minimum therapeutically effective plasma concentration of sitagliptin and optionally, at least one antidiabetic agent from the modified release composition is achieved by their osmotically controlled release from the composition.
  • the osmotic dosage form comprises: (i) a semipermeable wall provided around an osmotic formulation comprising sitagliptin or pharmaceutically acceptable salt thereof, an osmotic agent, and an osmopolymer; and (ii) a passageway.
  • a capsule based on osmotic release mechanism may be formulated with a single osmotic unit or it may incorporate 2, 3, 4, 5, or 6 push- pull units encapsulated within a hard gelatin capsule, whereby each bilayer push pull unit contains an osmotic push layer and sitagliptin layer, both surrounded by a semi-permeable membrane. One or more orifices are drilled through the membrane next to the sitagliptin layer. This membrane may be additionally covered with a ph-dependent enteric coating to prevent release until after gastric emptying. The gelatin capsule dissolves immediately after ingestion.
  • the enteric coating breaks down, which then allows fluid to flow through the semi-permeable membrane, swelling the osmotic push compartment to force sitagliptin out through the orifice(s) at a rate precisely controlled by the rate of water transport through the semi-permeable membrane. Release of sitagliptin can occur over a constant rate for at least up to 24 hours.
  • the osmotic push layer comprises one or more osmotic agents creating the driving force for transport of water through the semi-permeable membrane into the core of the delivery vehicle.
  • osmotic agents include water- swellable hydrophilic polymers, also referred to as “osmopolymers” and “hydrogels,” including, but not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, sodium croscarmellose
  • osmotic agents include osmogents, which are capable of imbiging water to affect an osmotic pressure gradient across the semi-permeable membrane.
  • exemplary osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, gluta
  • Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water-permeable and water-insoluble at physiologically relevant pHs, or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking.
  • Suitable osmotic dosage form may be provided in the form of a mono-layer, bi- layer or tri-layer dosage form.
  • the bi-layer oral osmotic dosage forms include a first component layer, comprising at least one drug, one of which is sitagliptin and excipients for forming a deliverable drug composition when hydrated, and a second push layer, comprising a fluid-expandable osmopolymer and excipients, contained within a compartment formed by a semipermeable membrane and having exit means for drug release from the compartment.
  • the two layers are compressed into bi-layer tablet cores before the semipermeable membrane is applied and a suitable orifice for drug release there through is formed.
  • the bi-layer tablet cores are formed when two component layers are compressed together to provide a longitudinally compressed tablet core having a 'capsule-shaped' configuration with a different layer at each narrow end.
  • Bi-layer oral osmotic dosage forms and methods of making and using such dosage forms are known in the art, for example, as described and claimed in the following US Patents, owned by Alza Corporation: U.S. Pat. Nos. 4,327,725; 4,612,008; 4,783,337; and 5,082,668, each of which is incorporated in its entirety by reference herein.
  • the suitable pH modifying agent include malic acid, fumaric acid, adipic acid, succinic acid, lactic acid, acetic acid, oxalic acid, maleic acid, ammonium chloride, preferably tartaric acid, and more preferably citric acid, or a combination of such acids.
  • weak acids such as colloidal silica
  • a particulate carrier material such as colloidal silica
  • the suitable buffer system include materials that, when provided in a composition of the invention, provide a weakly acidic buffer system and are present in a sufficient amount to enable the maintenance of pH buffer forming materials thus include combinations of weak acid and salt of weak acid, such as combinations of the aforementioned acids with alkaline salts of those acids, including sodium citrate, potassium citrate, sodium tartrate, potassium tartrate and the like.
  • Preferred buffer forming materials are citric acid and sodium citrate.
  • materials may be adsorbed into a particulate carrier material (such as colloidal silica) in order to provide particles comprising the weakly-acidic buffer forming materials.
  • the combination of features including the osmotic properties of the component layers, the fluid flux properties of the semipermeable membrane and the configuration of the tablet core ensures that sitagliptin is released at a desired rate over an extended time period, preferably over at least 24 hours.
  • the tri-layer oral osmotic dosage forms include a novel tri-layer tablet core surrounded by a semipermeable membrane and having suitable exit means for releasing at least one drug, one of which is sitagliptin through the semipermeable membrane.
  • the tri-layer tablet core has a first drug-containing layer, a second drug-containing layer and a third push layer.
  • drug is successively released from the first drug-containing layer and then from the second drug- containing layer.
  • Excipients in the drug-containing layers may be varied and adjusted for other purposes such as manufacturing convenience and pharmaceutical elegance. In this manner, dosage forms that exhibit reliable drug release having the desired profile over an extended time period, preferably over at least 24 hours, can be reliably and efficiently manufactured.
  • a method of reducing side effects associated with increased plasma concentration of sitagliptin in a patient undergoing T2DM treatment comprises of orally administering single dose of a modified release composition comprising sitagliptin or pharmaceutically acceptable salt thereof and optionally, at least one antidiabetic agent or pharmaceutically acceptable salt thereof, wherein a substantial dose of sitagliptin in the composition exhibits zero order release over a period of at least 24 hours.
  • a method of treatment of a subject having a condition or disorder for which sitagliptin is indicated comprising orally administering to the subject, not more than once daily, a modified release composition as substantially described herein before throughout the specification.
  • Example 1 Modified release tablet containing 25, 50 and 100mg Sitagliptin or pharmaceutically acceptable salt thereof
  • Sitagliptin phosphate anhydrous, Lactose, Microcrystalline cellulose, Hypromellose (HPMC K4M) and Hypromellose (HPMC K100M) were co-sifted together using vibro-sifter fitted with 40# ASTM sieve.
  • the mixture was granulated in a rapid mixer granulator for 5-10 min by spraying aqueous/hydro- alcoholic medium.
  • Wet granules were dried in fluidized bed dryer at 60 ⁇ 5°C. The dried granules were then screened through #30 mesh and milled using a multimill. Dried granules were blended in a double cone blender for 3 min with colloidal silicon dioxide and magnesium stearate, both previously sifted through #60 mesh. Finally, the lubricated blend was compressed using a rotary compress tablet machine.
  • Example 2 Modified release tablet containing 25, 50 and 100mg Sitagliptin or pharmaceutically acceptable salt thereof Table 2
  • Sitagliptin phosphate anhydrous, Microcrystalline cellulose, Hypromellose (HPMC K4M) and Hypromellose (HPMC K100M) were co-sifted together using vibro-sifter fitted with 40# ASTM sieve.
  • the mixture was granulated in a rapid mixer granulator for 5-10 min by spraying aqueous/hydro-alcoholic medium.
  • Wet granules were dried in fluidized bed dryer at 60 ⁇ 5°C. The dried granules were then screened through #30 mesh and milled using a multimill. Dried granules were blended in a double cone blender for 3 min with colloidal silicon dioxide and magnesium stearate, both previously sifted through #60 mesh.
  • the lubricated blend then compressed using a rotary compress tablet machine.
  • Aqueous dispersion of Eudragit with Triethyl citrate and Silicon dioxide was prepared and coated on the tablets in a perforated pan coater while keeping the temperature between 50-60° C.
  • the extended release coated tablet was dried in coating pan at 45 ⁇ 5° C to remove coating solvent.
  • Aqueous solution of Sitagliptin phosphate anhydrous and Opadry clear in purified water was then sprayed over previously drilled tablets in coater till the desired drug is loaded.
  • Example 3 Modified release tablet containing 25, 50 and 100mg Sitagliptin or pharmaceutically acceptable salt thereof
  • Sitagliptin phosphate anhydrous, Microcrystalline cellulose, Hypromellose (HPMC K4M) and Hypromellose (HPMC K100M) were co-sifted together using vibro-sifter fitted with 40# ASTM sieve.
  • the mixture was granulated in a rapid mixer granulator for 5-10 min by spraying aqueous/hydro-alcoholic medium.
  • Wet granules were dried in fluidized bed dryer at 60 ⁇ 5°C. The dried granules were then screened through #30 mesh and milled using a multimill. Dried granules were blended in a double cone blender for 3 min with colloidal silicon dioxide and magnesium stearate, both previously sifted through #60 mesh.
  • the lubricated blend then compressed using a rotary compress tablet machine.
  • Aqueous dispersion of Polymethyl acrylic acid polymer with Triethyl citrate, HPMC E5/Povidone K30 and Silicon dioxide was prepared and coated on the tablets in a perforated pan coater while keeping the temperature between 50-60° C.
  • the extended release coated tablet was dried in coating pan at 45 ⁇ 5° C to remove coating solvent.
  • Example 4 Modified release tablet containing 25, 50 and 100mg Sitagliptin or pharmaceutically acceptable salt thereof
  • Sitagliptin phosphate anhydrous, Microcrystalline cellulose, Hypromellose (HPMC K4M) and Hypromellose (HPMC K100M) were co-sifted together using vibro-sifter fitted with 40# ASTM sieve.
  • the mixture was granulated in a rapid mixer granulator for 5-10 min by spraying aqueous/hydro-alcoholic solution of Povidone.
  • Wet granules were dried in fluidized bed dryer at 60 ⁇ 5°C. The dried granules were then screened through #30 mesh and milled using a multimill.
  • Dried granules were blended in a double cone blender for 3 min with Glyceryl Behenate, colloidal silicon dioxide and magnesium stearate, both previously sifted through #60 mesh.
  • the lubricated blend then compressed using a rotary compress tablet machine.
  • Organic dispersion of ethylcellulose with PEG and Poviodne was prepared using methylene chloride and iso-propyl alcohol or ethanol and iso-propyl alcohol and coated on the tablets in a perforated pan coater while keeping the temperature between 50 ⁇ 5° C.
  • the extended release coated tablet was dried in coating pan at 45 ⁇ 5° C to remove coating solvent.
  • Aqueous dispersion of Eudragit with Triethyl citrate, Polyethylene glycol and Silicon dioxide was prepared and coated on the tablets in a perforated pan coater while keeping the temperature between 50-60° C.
  • the extended release coated tablet was dried in coating pan at 45 ⁇ 5° C to remove coating solvent.
  • Example 5 Modified release tablet containing 25, 50 and 100mg Sitagliptin or pharmaceutically acceptable salt thereof
  • Sitagliptin phosphate anhydrous, Mannitol, Povidone K 90 and Microcrystalline cellulose were co-sifted using vibro-sifter fitted with 40# ASTM sieve. The mixture was again mixed in a rapid mixer granulator for 5 minutes and then granulated using aqueous/hydro-alcoholic solution of polyethylene glycol 6000. Wet granules were then dried in fluidized bed dryer at about 40-55 ° C. Dried granules were then screened through #20 mesh sieve and the retained granules were milled in a multimill.
  • the milled granules were then blended in a double cone blender for 3 min with a previously sifted [through #60 mesh] mixture of colloidal silicon dioxide and magnesium stearate.
  • the lubricated blend was then compressed using rotary compress tablet machine.
  • Aqueous solution of Polyethylene Glycol (PEG) 400 was prepared in purified water.
  • Cellulose acetate (CA-320S) followed by cellulose acetate (CA-398-10) were added in acetone slowly under continuous stirring.
  • Aqueous solution of PEG 400 was then added in the cellulose acetate-acetone mixture.
  • the solution was then stirred at slow speed for about 1 h to get a clear/transparent solution.
  • the core tablets as obtained above were coated with extended release coating solution using a perforated pan coater while keeping the temperature between 30-45°C.
  • the extended release coated tablets were dried in coating pan at 45 ⁇ 5°C to remove coating solvent.
  • the extended release coated tablets were drilled mechanically or by means of laser drilling system with orifice size of about 0.5-0.8 mm.
  • Example 6 Modified release tablet containing 25, 50 and 100mg Sitagliptin or pharmaceutically acceptable salt thereof
  • Sitagliptin phosphate Anhydrous was mixed with Polyethylene oxide (Sentry Polyox WSR N80) and then and sifted through #20 ASTM.
  • Hypromellose 2910 (METHOCELTM E5 Premium LV) was and sifted through #30 ASTM.
  • Pre-sifted iron oxide red was added to the drug layer composition for identification.
  • the above mixture was granulated for 10 minutes using isopropyl alcohol.
  • Wet granules were dried in fluidized bed dryer and sifted through #20ASTM followed by blending with pre-sifted magnesium stearate [through #60 ASTM] for 3 min in double cone blender.
  • the above mixture was granulated in rapid mixer granulator for 5 min using isopropyl alcohol. Wet granules then dried in fluidised bed dryer and sifted through #20ASTM followed by blending with pre-sifted magnesium stearate [through #60 ASTM] for 3 min in double cone blender.
  • the blend of drug layer and push layer was compressed to form bi-layer tablets using a bi-layer tabletting machine.
  • the core tablets as prepared above were coated with extended release coating solution of cellulose acetate and polyethylene glycol 3350 in perforated pan coater.
  • the drug layer side of extended release coated tablets were then drilled by using tablet drilling laser system with one preformed passageway (orifice) of 0.7 ⁇ 0.1 mm diameter.
  • Aqueous solution of sitagliptin phosphate anhydrous and Opadry system in purified water was prepared. The solution was sprayed over previously drilled tablets in pan coater till the desired drug is loaded.
  • Example 7 Modified release tablet containing 25, 50 and 100mg Sitagliptin or pharmaceutically acceptable salt thereof
  • Sitagliptin phosphate anhydrous, Lactose and Microcrystalline cellulose were co- sifted using vibro-sifter fitted with 40# ASTM sieve. The mixture was again mixed in a rapid mixer granulator for 5 minutes and then granulated using aqueous/hydro-alcoholic solution of povidone K30. Wet granules were then dried in fluidized bed dryer at about 50-60 ° C. Dried granules were then screened through #20 mesh sieve and the retained granules were milled in a multimill. The milled granules were then blended in a double cone blender for 3 min with a previously sifted [through #60 mesh] mixture of colloidal silicon dioxide and magnesium stearate. The lubricated blend was then compressed using rotary compress tablet machine.
  • Aqueous solution of Polyethylene Glycol (PEG) 400 was prepared in purified water.
  • Cellulose acetate (CA-320S) followed by cellulose acetate (CA-398-10) were added in acetone slowly under continuous stirring.
  • Aqueous solution of PEG 400 was then added in the cellulose acetate-acetone mixture.
  • the solution was then stirred at slow speed for about 1 h to get a clear/transparent solution.
  • the core tablets as obtained above were coated with extended release coating solution using a perforated pan coater while keeping the temperature between 30-45°C.
  • the extended release coated tablets were dried in coating pan at 45 ⁇ 5°C to remove coating solvent.
  • Aqueous solution of sitagliptin phosphate anhydrous in hypromellose E3 and purified water was prepared. The solution was sprayed over previously coated tablets in pan coater till the desired drug is loaded.
  • Example 8 Modified release tablet containing 25, 50 and 100mg Sitagliptin
  • Example 3 The tablets were prepared according to Example 3 in which the extended release coating composition was prepared by making a solution of polyacrylic resin, Ethyl cellulose, Hydroxylpropyl cellulose and tri-ethyl citrate in alcohol. The solution was then applied on to core tablets as per Example 3.
  • Example 9 Modified release tablet containing Sitagliptin or Pharmaceutically acceptable salt thereof
  • Example 10 Modified release tablet containing Sitagliptin or Pharmaceutically acceptable salt thereof
  • Example 6 Tablets obtained from example 9 and 10 were subjected to dissolution studies. The results of dissolution studies performed are provided in Table 1 1 and 12 respectively.
  • Example 11 Modified release tablet containing Sitagliptin or pharmaceutically acceptable salt thereof
  • Example 12 Modified release tablet containing Sitagliptin or pharmaceutically acceptable salt thereof

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Abstract

La présente invention concerne une nouvelle composition pharmaceutique à libération modifiée de sitagliptine ou d'un sel pharmaceutiquement acceptable correspondant. En particulier, la présente invention concerne une nouvelle composition à libération modifiée de la sitagliptine ou d'un sel pharmaceutiquement acceptable correspondant, qui atteint une concentration plasmatique efficace minimale souhaitée en sitagliptine, suffisante pour une régulation glycémique efficace chez des patients atteints d'un diabète sucré de type 2. L'invention concerne également un procédé d'amélioration de la régulation glycémique chez des adultes atteints d'un diabète sucré de type 2 et de réduction ou de suppression de fluctuations de la concentration plasmatique en sitagliptine.
PCT/IB2015/055554 2014-07-26 2015-07-22 Nouvelle composition pharmaceutique à libération modifiée de la sitagliptine ou d'un sel pharmaceutiquement acceptable correspondant Ceased WO2016016770A1 (fr)

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US9902751B2 (en) 2013-12-30 2018-02-27 Mylan Laboratories Limited Process for the preparation of empagliflozin
WO2020026273A1 (fr) * 2018-07-31 2020-02-06 Msn Laboratories Private Limited, R&D Center Formes solides de base libre d'ertugliflozine et dispersions à l'état solide comprenant de l'acide ertugliflozin l-pyroglutamique
IT201800011119A1 (it) 2018-12-14 2020-06-14 Dpl Pharma S P A Composizioni farmaceutiche orali solide per la somministrazione cronotropica di sitagliptin
WO2021076066A1 (fr) 2019-10-14 2021-04-22 Santa Farma İlaç Sanayi̇ A.Ş. Formulations orales comprenant du monohydrate de hci de sitagliptine présentant des caractéristiques pharmaceutiques améliorées
EP3813801A4 (fr) * 2018-05-25 2022-03-30 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Forme posologique de comprimé osmotique à libération prolongée comprenant de la metformine et de la sitagliptine
US20230225979A1 (en) * 2020-05-14 2023-07-20 Mogon Pharmaceuticals Sagl Solid oral compositions comprising composite monolithic matrices for chronotropic administration of active ingredients in the gastrointestinal tract

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WO2020026273A1 (fr) * 2018-07-31 2020-02-06 Msn Laboratories Private Limited, R&D Center Formes solides de base libre d'ertugliflozine et dispersions à l'état solide comprenant de l'acide ertugliflozin l-pyroglutamique
IT201800011119A1 (it) 2018-12-14 2020-06-14 Dpl Pharma S P A Composizioni farmaceutiche orali solide per la somministrazione cronotropica di sitagliptin
WO2020121231A1 (fr) * 2018-12-14 2020-06-18 Dpl Pharma S.P.A. Compositions pharmaceutiques orales solides pour l'administration chronotrope d'inhibiteurs de la dipeptidyl-peptidase iv
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US20230225979A1 (en) * 2020-05-14 2023-07-20 Mogon Pharmaceuticals Sagl Solid oral compositions comprising composite monolithic matrices for chronotropic administration of active ingredients in the gastrointestinal tract

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