Classifications

• • 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
  • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/426—1,3-Thiazoles
• • 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
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
  • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

• the present invention relates to a pharmaceutical composition, particularly a modified release tablet composition comprising mirabegron or a pharmaceutically acceptable salt thereof and to a process for preparing such a composition.
• a mirabegron containing pharmaceutical product is approved in many countries all over the world under the brand name Betmiga® in the EU, Myrbetriq® in the US US and Betanis® in Japan as modified release tablets comprising 25 and 50 mg of mirabegron.
• Mirabegron is the generic name of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2- phenylethyl)amino]ethyl]acetic acid anilide,
• overactive bladder such as overactive bladder accompanied by prostatic hyperplasia, or overactive bladder accompanied by urinary urgency, urinary incontinence, and urinary frequency.
• Mirabegron is considered to be a Class III compound according to the
• Biopharmaceutical Classification System that means that it has high solubility and low permeability.
• Betmiga® published by the European Medicines Agency, mirabegron is soluble in water between neutral to acidic pH.
• mirabegron is affected by the presence of food in the GI tract.
• the commercially available pharmaceutical formulation of mirabegron is in the form of a modified-release (MR) tablet formulation based on an orally controlled absorption system (OCAS®) tablet formulation.
• MR modified-release
• OCAS® orally controlled absorption system
• WO9406414 (Al) describes a hydrogel-type sustained-release preparation comprising (1) at least one drug (tamsulosine as one of the examples), (2) an additive which insures penetration of water into the core of the preparation and (3) a hydrogel-forming polymer, wherein said preparation is capable of undergoing substantially complete gelation during its stay in the upper digestive tract including stomach and small intestine and is capable of releasing the drug in the lower digestive tract including colon.
• the preparation undergoes a substantially complete gelation in the upper part of the GI tract, namely stomach and small intestine.
• the formed gel matrix is then maintained in the hydrated state during the passage through the GI tract for 4 hours or more maintaining a constant release and thus reducing the effects by food, because the drug release from the formulation becomes the rate-limiting step for absorption.
• the 4 hours release period has been selected to simply avoid the effect of food since on the basis of the elimination half-life (Tl/2) of mirabegron, which is known to be approximately 18 to 24 hours, a sustained release per se is not needed.
• the present invention relates to a modified release tablet composition
• a modified release tablet composition comprising:
• polyethylene oxide (PEO) having an average molecular weight of approximately 7,000,000 or a viscosity of 7500 to 10000 cps at a 1% aqueous solution at 25° C and polyethylene glycol (PEG) having an average molecular weight of approximately 6000 to 10000, preferably 8000,
• the present invention also relates to a dry granulation process to prepare such a modified release composition and to a multilayer tablet comprising such a modified release tablet composition.
• the present invention relates to a modified release tablet composition
• a modified release tablet composition comprising:
• polyethylene oxide (PEO) having an average molecular weight of approximately 7,000,000 or a viscosity of 7500 to 10000 cps at a 1% aqueous solution at 25° C and polyethylene glycol (PEG) having an average molecular weight of approximately 6000 to 10000, preferably 8000,
• weight ratio PEO to PEG ranges from 1:3 to 1:4.5.
• the modified release tablet compositions of the present invention are stable and show an in vitro dissolution profile wherein mirabegron is released 15-35% within 1 hour, at least 50% within 2 hours and at least 90% within 3 hours when the composition is subjected to a dissolution study in 250 ml phosphate buffer (pH 6.8) using a USP apparatus 3 at 20 rpm at 37°C.
• stable means that tablets comply with the dissolution specification when subjected to a 6 months stability study at the accelerated stability conditions of 40°C and 75% RH.
• total weight refers to the total weight of the uncoated tablet.
• Modified release hydrogel tablets based on polyethylene oxide tend to suffer changes in their dissolution release profile when exposed to oxygen or UV light not complying with the dissolution specifications during the stability study. This is relevant since it may cause loss of the desired therapeutic control of the modified release tablets.
• the weight ratio of polyethylene oxide in the tablet and the average molecular weight of the polyethylene oxide may affect the stability of the tablets and their dissolution profile when exposed to a 6 months stability study at the accelerated stability conditions of 40°C and 75% RH.
• the pharmaceutical tablet composition of the present invention is stabilized by an oxygen and UV light barrier like for example a primary packaging material like Aluminium/ Aluminium blister foil or a light resistant HDPE container.
• an oxygen and UV light barrier like for example a primary packaging material like Aluminium/ Aluminium blister foil or a light resistant HDPE container.
• modified release tablet composition of the present invention is described in further detail hereinafter.
• a therapeutically effective dose of mirabegron or a pharmaceutically acceptable salt thereof is present at a weight ratio of 5 to 25% in the tablet with respect to the total weight of the uncoated tablet.
• mirabegron or a pharmaceutically acceptable salt thereof has a particle size distribution of D90 between 5 and 150 ⁇ .
• the D90 is between 10 and 60 ⁇ .
• the modified release tablet composition of the present invention further comprises PEO having an average molecular weight of approximately 7,000,000 or a viscosity of 7500 to 10000 cps at a 1% aqueous solution at 25° C and PEG having an average molecular weight of approximately 6000 to 10000, preferably 8000.
• Polyethylene oxide is a nonionic homopolymer of ethylene oxide, represented by the formula [(OCH 2 CH 2 )n], in which n represents the average number of oxyethylene groups and varies from about 2,000 to 160,000; the molecular weights range from about 100,000 to 7 million. Polyethylene oxide occurs as a white to off-white, free-flowing powder. It is available in different grades that vary in viscosity profiles in aqueous isopropyl alcohol solutions. Polyethylene oxide may degrade by oxidation and commercially available polyethylene oxide may therefore contain a suitable antioxidant.
• Polyethylene oxide is a very hydrophilic polymer. Upon contact with an aqueous medium, it hydrates rapidly to form a gel layer to support the release of the active. Typically the drug release occurs by combination of two mechanisms; diffusion and erosion. For a water soluble drug substance as mirabegron, diffusion of the active through the gel layer is the dominant mechanism but gradual erosion of the gel, exposing fresh surfaces containing drug to the dissolution media, may also take place.
• Figure 1 shows the dissolution profile of a formulation with a weight ratio PEO having an average molecular weight of approximately 7,000,000 and PEG having an average molecular weight of approximately 8000, with respect to the total weight of the uncoated tablet in comparison to the reference product Mirbetriq®.
• Polyethylene oxide having an average molecular weight of 7,000,000 forms a high viscosity matrix typically leading to a decrease in the diffusion of the drug, slowing excessively the dissolution rate.
• PEO with an average molecular weight of 7,000,000 can be used minimising this behaviour by using it in combination with PEG having an average molecular weight of approximately 6000 to 10000 in the specific weight ratio of the invention.
• the weight ratio PEO to PEG ranges from 1:3 to 1:4.5, preferably from 1:3 to 1:4, more preferably from 1:3.2 to 1:3.8, it decreases the gel viscosity on the surface of the tablet which accelerates the diffusion of the drug from the gel layer.
• using the weight ratio of the invention results in less stability problems, when compared with the examples provided in WO2010038690 (Al).
• the PEO 7M has a tendency to oxidise. When the PEO oxidises, it becomes less viscous, accelerating the dissolution.
• the modified release tablet of the present invention can additionally comprise an antioxidant.
• a preferred antioxidant is butylated hydroxytoluene (BHT).
• the present invention may comprise other pharmaceutically acceptable excipients, for example, binders, diluents, lubricants, and glidants.
• Binders which are suitable for use in accordance with the present invention include hydroxypropyl cellulose, povidone, dihydroxy propylcellulose, and sodium carboxyl methylcellulose. Binders are preferably used in an amount of from 1 to 5 wt with respect to the total weight of the uncoated tablet. A preferred binder is hydroxypropylcellulose.
• Diluents are fillers which are used to increase the bulk volume of a tablet or capsule. Generally, by combining a diluent with the active pharmaceutical ingredient, the final product is given adequate weight and size to assist in production and handling. Diluents give volume to low active dose tablets.
• the present invention may comprise one or more diluents. Suitable examples of diluents to be used in accordance with the present invention include starch, pregelatinized starch, microcrystalline cellulose (MCC), calcium phosphate, lactose, sorbitol, mannitol. In a preferred embodiment one of the diluents is MCC. In a more preferred embodiment the amount of MCC is 5 to 25% with respect to the total weight of the uncoated tablet. Most preferably, the amount of MCC is 8 to 20% with respect to the total weight of the uncoated tablet.
• the tablet composition of the invention may also contain a lubricant.
• Lubricants are generally used in order to reduce sliding friction. In particular, to decrease friction at the interface between a tablet's surface and the die wall during ejection, and reduce wear on punches and dies.
• Suitable lubricants to be used in accordance with the present invention include magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, hydrogenated vegetable oil, and glycerine fumarate.
• the tablet composition of the invention may also contain a glidant. Glidants enhance product flow by reducing interp articulate friction.
• a suitable example is colloidal silicon dioxide.
• Lubricants and glidants preferably are used in a total amount of from 0.05 to 5 wt% with respect to the total weight of the uncoated tablet.
• the tablet composition of the present invention comprises the following ingredients, based on the total weight of the composition:
• polyethylene oxide (PEO) having an average molecular weight of approximately 7,000,000 or a viscosity of 7500 to 10000 cps at a 1% aqueous solution at 25° C and polyethylene glycol (PEG) having an average molecular weight of approximately 6000 to 10000, preferably 8000,
• weight ratio PEO to PEG ranges from 1:3 to 1:4.5;
• a binder in an amount of from 1% to 5wt% with respect to the total weight of the uncoated tablet; 4.
• a lubricant in an amount from 0.05% to 5wt% with respect to the total weight of the uncoated tablet;
• MCC preferably in an amount 5 to 25% with respect to the total weight of the uncoated tablet.
• the therapeutically effective dose of mirabegron is 25 mg or 50 mg.
• the pharmaceutical composition of the present invention can be used in combination with another API to form a multilayer tablet.
• a preferred API to be used in combination with mirabegron is solifenacin or an acceptable salt thereof.
• the present invention further relates to a tablet composition as described hereinabove, prepared by a dry- granulation process by slugging or roller compaction.
• Said process comprises the steps of:
• the granules of the present invention typically have a particle size distribution D90 equal or less than 1 mm.
• the pharmaceutical compositions described herein can be made using conventional methods and equipment well-known in the art.
• the modified release tablet compositions of the present invention are stable and show an in vitro dissolution profile wherein mirabegron is released 15-35% within 1 hour, at least 50% within 2 hours and at least 90% within 3 hours when the composition is subjected to a dissolution study in 250 ml phosphate buffer (pH 6.8) using a USP apparatus 3 at 20 rpm at 37°C.
• Figure 1 shows the in vitro dissolution profile of tablet composition in accordance with the present invention compared to commercially available tablets.
• the present invention is illustrated by the following Examples.
• Figure 1 shows the in vitro dissolution profiles of 50 mg mirabegron modified release tablets prepared following example 1 in accordance with the present invention as compared to commercially available Myrbetriq® 50 mg tablets.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (3)

Publications (1)

Family

ID=60702778

Family Applications (1)

Country Status (3)

Families Citing this family (1)

Family Cites Families (6)

• 2017
  • 2017-12-14 WO PCT/EP2017/082896 patent/WO2019072404A1/en unknown
  • 2017-12-14 EP EP17816802.7A patent/EP3694492A1/de not_active Withdrawn
  • 2017-12-14 CA CA3078568A patent/CA3078568A1/en not_active Abandoned

Also Published As

Similar Documents

Legal Events