EP3445350A1 - Compositions liquides à libération prolongée de guanfacine - Google Patents

Compositions liquides à libération prolongée de guanfacine

Info

Publication number
EP3445350A1
EP3445350A1 EP16899321.0A EP16899321A EP3445350A1 EP 3445350 A1 EP3445350 A1 EP 3445350A1 EP 16899321 A EP16899321 A EP 16899321A EP 3445350 A1 EP3445350 A1 EP 3445350A1
Authority
EP
European Patent Office
Prior art keywords
extended release
guanfacine
liquid composition
composition
release liquid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP16899321.0A
Other languages
German (de)
English (en)
Other versions
EP3445350A4 (fr
Inventor
Romi Barat Singh
Kalaiselvan Ramaraju
Balaram Mondal
Ashish Kumar
Suchitra Kaushik
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sun Pharmaceutical Industries Ltd
Original Assignee
Sun Pharmaceutical Industries Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US15/133,826 external-priority patent/US20160228379A1/en
Application filed by Sun Pharmaceutical Industries Ltd filed Critical Sun Pharmaceutical Industries Ltd
Priority claimed from PCT/IB2016/052607 external-priority patent/WO2017182852A1/fr
Publication of EP3445350A1 publication Critical patent/EP3445350A1/fr
Publication of EP3445350A4 publication Critical patent/EP3445350A4/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14—Details; Accessories therefor
    • A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
    • A61J1/2093—Containers having several compartments for products to be mixed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14—Details; Accessories therefor
    • A61J1/1412—Containers with closing means, e.g. caps
    • A61J1/1418—Threaded type
    • A—HUMAN NECESSITIES
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    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14—Details; Accessories therefor
    • A61J1/18—Arrangements for indicating condition of container contents, e.g. sterile condition
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
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    • A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
    • A61J1/2003—Accessories used in combination with means for transfer or mixing of fluids, e.g. for activating fluid flow, separating fluids, filtering fluid or venting
    • A61J1/2006—Piercing means
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    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
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    • A61J1/2003—Accessories used in combination with means for transfer or mixing of fluids, e.g. for activating fluid flow, separating fluids, filtering fluid or venting
    • A61J1/202—Separating means
    • A61J1/2027—Separating means having frangible parts
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    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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    • 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
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    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
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    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
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    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D51/00—Closures not otherwise provided for
    • B65D51/24—Closures not otherwise provided for combined or co-operating with auxiliary devices for non-closing purposes
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    • B65D51/2807—Closures not otherwise provided for combined or co-operating with auxiliary devices for non-closing purposes with auxiliary containers for additional articles or materials the closure presenting means for placing the additional articles or materials in contact with the main contents by acting on a part of the closure without removing the closure, e.g. by pushing down, pulling up, rotating or turning a part of the closure, or upon initial opening of the container
    • B65D51/2814—Closures not otherwise provided for combined or co-operating with auxiliary devices for non-closing purposes with auxiliary containers for additional articles or materials the closure presenting means for placing the additional articles or materials in contact with the main contents by acting on a part of the closure without removing the closure, e.g. by pushing down, pulling up, rotating or turning a part of the closure, or upon initial opening of the container the additional article or materials being released by piercing, cutting or tearing an element enclosing it
    • B65D51/2828—Closures not otherwise provided for combined or co-operating with auxiliary devices for non-closing purposes with auxiliary containers for additional articles or materials the closure presenting means for placing the additional articles or materials in contact with the main contents by acting on a part of the closure without removing the closure, e.g. by pushing down, pulling up, rotating or turning a part of the closure, or upon initial opening of the container the additional article or materials being released by piercing, cutting or tearing an element enclosing it said element being a film or a foil
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    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B65D81/00—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents
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Definitions

  • the present invention relates to extended release liquid compositions of guanfacine.
  • the extended release liquid compositions of the present invention are bioequivalent to marketed extended release tablet compositions of guanfacine.
  • Said extended release liquid compositions provide substantially similar in-vitro dissolution release profile upon storage for at least seven days. Further, the extended release liquid compositions are stable.
  • the extended release liquid compositions are in the form of ready-to-use liquid compositions or reconstituted liquid compositions. It also relates to processes for the preparation of said extended release liquid compositions.
  • Guanfacine is a central alpha2A-adrenergic receptor agonist indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as a monotherapy and as an adjunctive therapy to stimulant medications.
  • ADHD Attention Deficit Hyperactivity Disorder
  • guanfacine hydrochloride N-amidino-2-(2, 6- dichlorophenyl)-acetamide monohydrochloride.
  • the chemical structure is:
  • U.S. Patent No. 5,854,290 discloses the method of treating a behavioral disinhibition ⁇ e.g. Attention-Deficit Hyperactivity Disorder) in a primate with minimal sedative side effects by administering thereto a therapeutically effective amount of guanfacine.
  • U.S. Patent No.'s. 6,287,599 and 6,811,794 describe sustained release tablet compositions of guanfacine, comprising at least one non-pH dependent sustained release agent, and at least one pH dependent agent that increases the rate of release of guanfacine from the tablet at a pH in excess of 5.5.
  • Guanfacine is presently marketed only in solid dosage forms i.e. immediate release and extended release tablets for oral administration. However, these solid dosage forms are not suited for patients who have difficulty in swallowing. Further, solid dosage forms may not be convenient, when chronic therapy is needed.
  • liquid compositions of guanfacine for better patient compliance, convenience and dose flexibility.
  • extended release liquid compositions that can provide effective plasma levels over a prolonged period of time.
  • extended release liquid compositions are clearly advantageous over the presently available solid dosage forms.
  • the inventors of the present invention have addressed all these challenges and have for the first time developed extended release liquid compositions of guanfacine.
  • the compositions described herein are capable of providing consistent in-vitro extended release of guanfacine which further ensures steady plasma concentrations throughout the shelf life of the compositions.
  • said extended release liquid compositions provide desired in-vivo release of guanfacine and are bioequivalent to a reference composition.
  • the extended release liquid compositions are stable both during
  • the present invention is a significant advance over the available solid dosage forms of guanfacine and fulfills the long felt need to improve patient compliance by providing an extended release liquid composition of guanfacine with consistent release and acceptable stability.
  • the extended release liquid compositions of guanfacine offer additional advantages as they are easy to manufacture with functional reproducibility.
  • the extended release liquid compositions described herein are provided with a pleasant mouth feel thereby further enhancing patient compliance and ease of administration.
  • the present invention relates to extended release liquid compositions of guanfacine.
  • the extended release liquid compositions of the present invention are bioequivalent to a marketed extended release tablet of guanfacine. Said compositions provide substantially similar in-vitro dissolution release profile upon storage for at least seven days. Further, the extended release liquid compositions of the present invention are stable.
  • the extended release liquid compositions are in the form of ready-to-use liquid compositions or reconstituted liquid compositions.
  • the extended release liquid compositions offer better patient compliance and dosing flexibility based on age and body weight of the patients. It further relates to processes for the preparation of said extended release liquid compositions.
  • a first aspect of the present invention provides an extended release liquid composition comprising guanfacine in a pharmaceutically acceptable carrier.
  • a second aspect of the present invention provides an extended release liquid composition
  • guanfacine in a pharmaceutically acceptable carrier, wherein the composition comprises guanfacine in a concentration from about 0.1 mg/mL to about 12.0 mg/mL of the composition.
  • the composition comprises guanfacine in a concentration from about 1.0 mg/mL to about 7.0 mg/mL of the composition.
  • a third aspect of the present invention provides an extended release liquid composition comprising guanfacine in a pharmaceutically acceptable carrier, wherein the extended release liquid composition is bioequivalent to a marketed extended release tablet composition.
  • the composition exhibits an AUCo ⁇ ranging from about 34000 hr*pg/mL to about 220000 hr*pg/mL upon administration of a 4 mg dose of guanfacine under fasting state.
  • the composition exhibits an AUCo ⁇ ranging from about 34000 hr*pg/mL to about 160000 hr*pg/mL upon administration of a 4 mg dose of guanfacine under fasting state.
  • the composition exhibits an AUCi as t ranging from about 32000 hr*pg/mL to about 180000 hr*pg/mL upon administration of a 4 mg dose of guanfacine under fasting state.
  • the composition exhibits an AUCi as t ranging from about 32000 hr*pg/mL to about 150000 hr*pg/mL upon administration of a 4 mg dose of guanfacine under fasting state.
  • the composition exhibits a C max from about 1800 pg/mL to about 9000 pg/mL upon administration of a 4 mg dose of guanfacine under fasting state.
  • the composition exhibits 3 ⁇ Cmax from about 1800 pg/mL to about 4000 pg/mL upon administration of a 4 mg dose of guanfacine under fasting state.
  • the composition exhibits a Tmax from about 2 hours to about 10 hours upon administration of a 4 mg dose of guanfacine under fasting state.
  • the composition exhibits a Ti ag of less than about 2 hours, upon administration of a 4 mg dose of guanfacine under fasting state.
  • a fourth aspect of the present invention provides an extended release liquid composition
  • guanfacine in a pharmaceutically acceptable carrier
  • the composition is characterized by having an in-vitro dissolution release profile when determined for a 4 mg dose of 1 mg/mL concentration using USP type II apparatus at 75 rpm, in 900 mL of hydrochloric acid buffer with a pH 2.2 at 37°C as follows:
  • the in-vitro dissolution release profile of the composition upon storage for at least seven days remains substantially similar to the initial in-vitro dissolution release profile.
  • a fifth aspect of the present invention provides an extended release liquid composition comprising guanfacine in a pharmaceutically acceptable carrier, wherein the composition is a stable composition.
  • the composition is stable for at least seven days. More particularly, the composition is stable for at least one month, or further, to the extent necessary for the sale and use of the composition.
  • the composition comprises less than about 1.0% w/w of 2, 6-dichlorophenyl acetic acid. Particularly, the composition comprises less than about 0.7% w/w of 2, 6-dichlorophenyl acetic acid.
  • the composition comprises less than about 3.0% w/w of total related substances. Particularly, the composition comprises less than about 2.0% w/w of total related substances.
  • a sixth aspect of the present invention provides an extended release liquid composition
  • guanfacine in a pharmaceutically acceptable carrier, wherein the composition has a pH of less than about 6.8.
  • a seventh aspect of the present invention provides an extended release liquid composition comprising guanfacine in a pharmaceutically acceptable carrier, wherein the composition is a ready-to-use liquid composition or a reconstituted liquid composition.
  • the ready-to-use liquid composition comprises a suspension, a syrup, a concentrate, an elixir or an emulsion.
  • the reconstituted liquid composition comprises a suspension reconstituted from dry powder comprising granules, pellets, or beads.
  • the composition is a taste- masked composition.
  • An eighth aspect of the present invention provides an extended release liquid composition comprising guanfacine in a pharmaceutically acceptable carrier, wherein the composition comprises:
  • guanfacine may be present in the core or layered over an inert particle to form a core.
  • the core is in the form of a bead, a pellet, a granule, a spheroid, or the like.
  • the inert particle is selected from a group comprising a non-pareil seed, a microcrystalline cellulose sphere, a dibasic calcium phosphate bead, a mannitol bead, a silica bead, a tartaric acid pellet, or a wax based pellet.
  • the release-controlling agent may be present in the core or coated over the guanfacine core or both.
  • the release-controlling agent is selected from the group comprising a pH-dependent release controlling agent, a pH-independent release controlling agent, or mixtures thereof.
  • the core further comprises other
  • pharmaceutically acceptable excipients selected from the group comprising acids, osmogents, binders, glidants, or combinations thereof.
  • the pharmaceutically acceptable carrier comprises one or more of liquid adjuvants and other pharmaceutically acceptable excipients.
  • the other pharmaceutically acceptable excipients in the carrier are selected from the group comprising acids, osmogents, buffering agents, suspending agents, glidants, sweetening agents, flavors, colorants, anti- caking agents, wetting agents, preservatives, antioxidants, chelating agents, binders, viscosity modifiers, and combinations thereof.
  • the cores comprising guanfacine and a release -controlling agent have a particle size dgo value of less than about 1.5 mm.
  • the extended release liquid composition is characterized by having an osmolality ratio of at least about 1.
  • the pharmaceutically acceptable carrier has an osmolality of about 1 osmol/kg or more than about 1 osmol/kg of the carrier.
  • the composition further comprises guanfacine in an immediate release form.
  • a ninth aspect of the present invention provides a method of treating Attention Deficit Hyperactivity Disorder by administering an extended release liquid composition comprising guanfacine in a pharmaceutically acceptable carrier.
  • the extended release liquid composition is administered once daily.
  • guanfacine refers to guanfacine, as well as its pharmaceutically acceptable salts, polymorphs, hydrates, solvates, prodrugs, chelates, and complexes.
  • exemplary salts include salts of inorganic or organic acids such as hydrochloride, hydrobromide, sulphate, sulfamate, nitrate, phosphate, formate, mesylate, citrate, benzoate, fumarate, maleate, tartrate, and succinate.
  • a particularly preferred salt of guanfacine is guanfacine hydrochloride.
  • the extended release liquid composition comprises guanfacine in a concentration from about 0.1 mg/mL to about 12 mg/mL of the composition.
  • the extended release liquid composition comprises guanfacine in a concentration from about 1.0 mg/mL to about 7.0 mg/mL of the composition.
  • extended release is used to define a release profile to effect delivery of guanfacine over an extended period of time, as being between about 60 minutes to about 2, 4, 6, 8, 12 or 24 hours.
  • the extended release includes sustained release, controlled release, multiphase release, delayed release, pulsatile release, chrono release and the like.
  • the extended release liquid composition of the present invention is bioequivalent to a reference product.
  • the reference product is an extended release tablet of guanfacine available in strengths of 1 mg, 2 mg, 3 mg and 4 mg marketed under the brand name Intuniv ® by Shire.
  • bioequivalent is a term of art and is defined to mean the term used by the drug approval agencies, such as the US Food and Drug
  • Bioequivalence of different formulations of the same drug substance involves equivalence with respect to the rate and extent of drug absorption. Two formulations whose rate and extent of absorption differ by -20%/+25% or less are generally considered to be bioequivalent. Detailed guidelines for establishing the bioequivalence of a formulation with a reference formulation have been published by the FDA Office of Generic Drugs, Division of Bioequivalence. Pharmacokinetic parameters such as Cma X , T m ax, AUCi as t and AUCo ⁇ are used to establish bioequivalency.
  • AUCo ⁇ refers to the area under the plasma concentration-time curve extrapolated to infinity.
  • AUCi as t refers to the area under the plasma concentration-time curve from time 0 up to the time corresponding to the last quantifiable concentration.
  • C max refers to the maximum plasma concentration of guanfacine.
  • Tmax refers to the time to reach maximum plasma guanfacine concentration of guanfacine.
  • composition administration of the composition and the first quantifiable plasma level concentration of guanfacine in the plasma concentration versus time curve.
  • the pharmacokinetic parameters are calculated as mean values taken from a population of individuals participating in the study.
  • the extended release liquid compositions also provide the consistent in-vivo release which ensures steady and predictable guanfacine release with minimal inter and intra subject variation throughout the shelf life of the composition.
  • the in-vitro dissolution release profile of the extended release liquid compositions upon storage for at least seven days remains substantially similar to the initial in-vitro dissolution release profile obtained as soon as practicable after preparation of the extended release liquid compositions.
  • the in-vitro dissolution release profile of the extended release liquid compositions upon storage at room temperature for at least one month remains substantially similar to the initial in-vitro dissolution release profile obtained as soon as practicable after preparation of the extended release liquid compositions.
  • the in-vitro dissolution release profile of the extended release liquid compositions upon storage at room temperature for at least three months remains substantially similar to the initial in-vitro dissolution release profile obtained as soon as practicable after preparation of the extended release liquid compositions.
  • the in- vitro dissolution release profile is measured by using any known dissolution methods, in particular the in-vitro dissolution release is measured at 37°C using a USP type II apparatus at 75 rpm, in 900 mL of hydrochloric acid buffer with a pH 2.2.
  • Guanfacine particularly guanfacine hydrochloride, is found to degrade at high pH values. Solution state stability studies have indicated that at 16 hours, assay values of guanfacine have dropped down to 86.3% and 84% at pH 6.8 and 7.5 respectively and even further reduced at 24 hours.
  • One of the major impurity of guanfacine is 2, 6- dichlorophenyl acetic acid.
  • the pH of the reconstituted liquid composition or ready-to-use liquid composition implies pH values measured for the pharmaceutically acceptable carrier, for the coated cores, or in the microenvironment of guanfacine, or combination of these that is sufficient to prevent degradation of guanfacine.
  • stable refers to chemical stability, wherein the amount of impurity 2, 6- dichlorophenyl acetic acid in the composition remains less than about 1.0% w/w, particularly less than about 0.7% w/w upon storage of the composition for a period of at least seven days, more particularly, for a period of at least one month, or further, to the extent necessary for the sale and use of the composition.
  • the extended release liquid composition is in the form of a ready-to-use liquid composition or a reconstituted liquid composition.
  • the ready-to-use liquid composition comprises a suspension, a syrup, a concentrate, an elixir or an emulsion or like.
  • the reconstituted liquid composition comprises a suspension reconstituted in the carrier from dry powder comprising pellets, granules, beads, or the like.
  • the present invention provides extended release liquid composition comprising:
  • a pharmaceutically acceptable carrier acts as a suspension base used to suspend the guanfacine cores.
  • This pharmaceutically acceptable carrier comprises one or more of liquid adjuvants and other pharmaceutically acceptable excipients.
  • one or more of other pharmaceutically acceptable excipients may be mixed with the cores of guanfacine which may then be reconstituted with a liquid adjuvant.
  • the pharmaceutically acceptable carrier may be pre-formed or formed at the time of reconstitution.
  • the pharmaceutically acceptable carrier may play a role in creating a hypertonic environment.
  • hypertonic environment means that the pharmaceutically acceptable carrier has higher solute concentration which helps to generate high osmotic pressure such that there is no leaching of guanfacine from the extended release coated cores into the carrier.
  • osmolality means the number of moles of any water- soluble compound per kg of the carrier.
  • the osmolality may be measured according to known methods, such as using a Vapor pressure Osmometer, a Colloid Osmometer, or a Freezing Point Depression Osmometer such as Osmomat® 030-D or Osmomat® 3000, in particular by a Freezing Point Depression Osmometer.
  • pharmaceutically acceptable carrier has an osmolality of about 1 osmol/kg or more than about 1 osmol/kg of the pharmaceutically acceptable carrier.
  • osmolality ratio means the ratio of osmolality of the external phase to the osmolality of the internal phase.
  • the external phase herein means the carrier without the coated cores of guanfacine.
  • the internal phase herein means the coated cores of guanfacine.
  • the osmolality of the internal phase is represented as the osmolality of a solution which prevents significant leaching of guanfacine from the coated cores into the solution.
  • the leaching of guanfacine from the coated cores is determined by the difference in the osmolalities across the coating layer and the absence of any significant leaching from the coated cores directs that the osmolality of the solution has become equal to the osmolality of the coated cores.
  • the osmolality ratio of the extended release liquid compositions of present invention is at least about 1.0.
  • the osmolality of the carrier remains equivalent upon storage for at least seven days.
  • the osmolality of the carrier measured after one month remains equivalent to the osmolality of the carrier measured as soon as practicable after preparation of the extended release liquid compositions.
  • the osmolality of the carrier measured after three months remains equivalent to the osmolality of the carrier measured as soon as practicable after preparation of the extended release suspension compositions.
  • the osmolality of the carrier measured after three months remains substantially similar to the osmolality of the carrier measured as soon as practicable after preparation of the extended release liquid compositions.
  • the equivalent osmolality of the carrier ensures that there is no leaching of the guanfacine from the coated cores into carrier.
  • the pharmaceutically acceptable carrier in the present invention comprises one or more of liquid adjuvants and other pharmaceutically acceptable excipients.
  • Suitable liquid adjuvants comprise water. It may optionally comprise a co-solvent, for example, propylene glycol, glycerol, sorbitol, and the like, to assist solubilization and incorporation of various water-insoluble ingredients, such as flavoring oils and the like, into the composition.
  • a co-solvent for example, propylene glycol, glycerol, sorbitol, and the like, to assist solubilization and incorporation of various water-insoluble ingredients, such as flavoring oils and the like, into the composition.
  • other pharmaceutically acceptable excipients in the carrier are selected from the group comprising acids, osmogents, buffering agents, suspending agents, glidants, sweetening agents, flavors, colorants, anti-caking agents, wetting agents, preservatives, antioxidants, chelating agents, binders, viscosity modifiers, and
  • Suitable acids are selected from the group comprising organic acids, inorganic acids or mixtures thereof.
  • Organic acids are selected from the group comprising citric acid, fumaric acid, tartaric acid, oxalic acid, succinic acid, adipic acid, phthalic acid, acetic acid, alginic acid, ascorbic acid, aspartic acid, benzoic acid, cyclamic acid, erythorbic acid, glutamic acid hydrochloride, lactic acid, maleic acid, methacrylic acid, oleic acid, palmitic acid, sorbic acid, stearic acid, and combinations thereof.
  • Inorganic acids are selected from the group comprising hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid, boric acid, perchloric acid, and combinations thereof.
  • Citric acid, fumaric acid, tartaric acid, ascorbic acid, benzoic acid, and hydrochloric acid are preferably used.
  • osmogents refers to all pharmaceutically acceptable inert water-soluble compounds that can imbibe or dissolve in water and/or aqueous biological fluids.
  • Suitable examples of osmogents or pharmaceutically acceptable inert water-soluble compounds are selected from the group comprising carbohydrates such as xylitol, mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose, maltose, lactose, dextrose and raffinose; water-soluble salts of inorganic acids such as magnesium chloride, magnesium sulfate, potassium sulfate, lithium chloride, sodium chloride, potassium chloride, lithium hydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and sodium phosphate tribasic; water-soluble salts of organic acids
  • Suitable buffering agents are selected from the group comprising hydrochloric acid, citric acid, sodium citrate, potassium citrate, acetate, sodium acetate trihydrate, potassium dihydrogen orthophosphate, trisodium hydrogen orthophosphate, sodium dihydrogen orthophosphate, disodium hydrogen orthophosphate, and mixtures thereof.
  • Suitable suspending agents are selected from the group comprising cellulose derivatives such as co-processed spray dried forms of microcrystalline cellulose and carboxymethyl cellulose sodium, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, carboxymethyl cellulose and its salts/derivatives, and microcrystalline cellulose; carbomers; gums such as locust bean gum, xanthan gum, tragacanth gum, arabinogalactan gum, agar gum, gellan gum, guar gum, apricot gum, karaya gum, sterculia gum, acacia gum, gum arabic, and carrageenan; pectin; dextran; gelatin; polyethylene glycols; polyvinyl compounds such as polyvinyl acetate, polyvinyl alcohol, and polyvinyl pyrrolidone; sugar alcohols such as xylitol and mannitol; colloidal silica; and mixtures thereof.
  • Suitable glidants are selected from the group comprising silica, calcium silicate, magnesium silicate, colloidal silicon dioxide, corn starch, talc, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, hydrogenated vegetable, and mixtures thereof.
  • Suitable sweetening agents are selected from the group comprising saccharine or its salts such as sodium, potassium, or calcium, cyclamate or its salt, aspartame, alitame, acesulfame or its salt, stevioside, glycyrrhizin or its derivatives, sucralose, and mixtures thereof.
  • Suitable flavors are selected from the group comprising peppermint, grapefruit, orange, lime, lemon, mandarin, pineapple, strawberry, raspberry, mango, passion fruit, kiwi, apple, pear, peach, apricot, cherry, grape, banana, cranberry, blueberry, black currant, red currant, gooseberry, lingon berries, cumin, thyme, basil, camille, valerian, fennel, parsley, chamomile, tarragon, lavender, dill, bargamot, salvia, aloe vera balsam, spearmint, eucalyptus, and combinations thereof.
  • Suitable coloring agents are selected from the group comprising dyes, natural coloring agents or pigments, approved for use under Federal Food, Drug and Cosmetic Act.
  • Suitable anti-caking agents are selected from the group comprising colloidal silicon dioxide, tribasic calcium phosphate, powdered cellulose, magnesium trisilicate, starch, and mixtures thereof.
  • Suitable wetting agents are selected from the group comprising anionic, cationic, nonionic, or zwitterionic surfactants, and combinations thereof.
  • Suitable examples of wetting agents are sodium lauryl sulphate; cetrimide; polyethylene glycols;
  • polyoxyethylene-polyoxypropylene block copolymers such as poloxamers; polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate; sorbitan fatty acid esters such as sorbitan monostearate; polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene sorbitan monooleate; polyethylene glycol fatty acid ester such as polyoxyethylene monostearate; polyoxyethylene alkyl ether such as polyoxyethylene lauryl ether; polyoxyethylene castor oil; and mixtures thereof.
  • Suitable preservatives are selected from the group comprising parabens such as methyl, ethyl, propyl, and butyl p-hydroxybenzoic acid esters, alkyl hydroxybenzoates, sorbic acid or a salt thereof, benzoic acid or a salt thereof, salts of edetate (also known as salts of ethylenediaminetetraacetic acid or EDTA, such as disodium edetate),
  • Suitable antioxidants are selected from the group comprising butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium metabisulfite, ascorbic acid, propyl gallate, thiourea, tocopherols, beta-carotene, and mixtures thereof.
  • BHT butylated hydroxytoluene
  • BHA butylated hydroxyanisole
  • sodium metabisulfite sodium metabisulfite
  • ascorbic acid propyl gallate
  • thiourea thiourea
  • tocopherols beta-carotene, and mixtures thereof.
  • Suitable chelating agents are selected from the group comprising ethylenediamine tetraacetic acid (EDTA) and its salts, such as, for example, dipotassium ethylenediamine tetraacetate, calcium disodium ethylenediamine tetraacetate, tetrasodium ethylenediamine tetraacetate, and mixtures thereof.
  • EDTA ethylenediamine tetraacetic acid
  • salts such as, for example, dipotassium ethylenediamine tetraacetate, calcium disodium ethylenediamine tetraacetate, tetrasodium ethylenediamine tetraacetate, and mixtures thereof.
  • Suitable binders are selected from the group comprising polyvinyl pyrrolidone, starch, pregelatinized starch, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, gums, acrylate polymers, and mixtures thereof.
  • Suitable viscosity modifiers are selected from the group comprising chitosan, acacia, alginic acid bentonite, carbomers, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, glycerin, gelatin guar gum, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, any other suitable cellulose-based component, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, starch, sodium starch glycolate, starch tragacanth, and xanthan gum, and mixtures thereof.
  • the extended release liquid composition may additionally include an immediate release component of guanfacine that can help in providing a biphasic or pulsatile type release.
  • Immediate release component may help in providing an immediate therapeutic effect which could be subsequently followed by an extended therapeutic effect over a longer duration of time.
  • the immediate release guanfacine may be present in the carrier in an amount that is less than the saturation amount. Alternatively, the amount of immediate release guanfacine may be more than the amount needed to form the saturated solution either initially or during storage of the extended release composition.
  • This immediate release component may be present in the form of powder, pellets, beads, spheroids or granules of guanfacine.
  • the immediate release component may be present in the form of an immediate release coating of guanfacine over the extended release cores of guanfacine.
  • the immediate release component of guanfacine may be present in form of guanfacine-resin complexes.
  • Cation- and anion-exchange resins are well-known in the art. Few exemplary resins that can be used according to the invention include, but are not limited to, Dowex ® resins and others made by Dow Chemical; Amberlite ® , Amberlyst ® and other resins made by Rohm and Haas; Indion ® resins made by Ion Exchange, Ltd.
  • hydrophilic colloids such as, e.g., alginate, chitsoan, carboxymethylcellulose,
  • croscarmellose microcrystalline cellulose
  • xanthan gum carboxy vinyl polymers such as carbomer 94, polylysine, gelatin
  • resins having polymer backbones comprising styrene-divinyl benzene copolymers and having pendant ammonium or tetraalkyl ammonium functional groups, available from Rohm and Haas, and sold under the tradename DUOLITETM API 43; or any combinations thereof.
  • the viscosity of the pharmaceutically acceptable carrier ranges from about 300 cps to about 15,000 cps. Preferably, the viscosity of the carrier ranges from about 500 cps to about 10,000 cps. More preferably, the viscosity of the carrier ranges from about 500 cps to about 7,000 cps.
  • the viscosity of the carrier of the present invention is measured by using a Brookfield Viscometer having a # 3 spindle rotating at 20 rpm at 25°C.
  • the cores may comprise guanfacine in the form of powder, granules, and pellets.
  • guanfacine may be layered over an inert particle to form a core.
  • guanfacine may be in the form of complex with a suitable complexing agent such as cyclodextrin or ion-exchange resins.
  • the core is in the form of a bead, a pellet, a granule, a spheroid, or the like.
  • inert particle refers to a particle made from a sugar sphere also known as a non-pareil seed, a microcrystalline cellulose sphere, a dibasic calcium phosphate bead, a mannitol bead, a silica bead, a tartaric acid pellet, a wax based pellet, and the like.
  • Release-controlling agent may be mixed with guanfacine in the core. Alternatively, release-controlling agent may be coated over the guanfacine core. Alternatively, release- controlling agent may be present both in the core and as coating over guanfacine cores.
  • the release-controlling agent present in the core and/or as coating over the core is selected from the group comprising a pH-dependent release-controlling agent, a pH- independent release-controlling agent, or mixtures thereof.
  • pH-dependent release-controlling agents are selected from the group comprising acrylic copolymers such as methacrylic acid and methyl methacrylate copolymers, e.g., Eudragit ® L 100 and Eudragit ® S 100, methacrylic acid and ethyl acrylate copolymers, e.g.
  • Eudragit ® L 100-55 and Eudragit ® L 30 D-55 dimethylaminoethyl methacrylate and butyl methacrylate and methyl methacrylate copolymers e.g., Eudragit ® E 100, Eudragit ® E PO, methyl acrylate and methacrylic acid and octyl acrylate copolymers, styrene and acrylic acid copolymers, butyl acrylate and styrene and acrylic acid copolymers, and ethylacrylate-methacrylic acid copolymer;
  • cellulose acetate phthalate cellulose acetate succinates
  • hydroxyalkyl cellulose phthalates such as hydroxypropylmethyl cellulose phthalate
  • hydroxyalkyl cellulose acetate succinates such as hydroxypropylmethyl cellulose acetate succinate
  • vinyl acetate phthalates vinyl acetate succinate
  • cellulose acetate trimelliate polyvinyl derivatives such as polyvinyl acetate phthalate, polyvinyl alcohol phthalate, polyvinyl butylate phthalate, and polyvinyl acetoacetal phthalate
  • zein shellac
  • mixtures thereof such as polyvinyl acetate phthalate, polyvinyl alcohol phthalate, polyvinyl butylate phthalate, and polyvinyl acetoacetal phthalate
  • pH-independent release-controlling agents are selected from the group comprising cellulosic polymers such as ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose, cellulose acetate, and carboxy methylcellulose; acrylic copolymers such as methacrylic acid copolymers, e.g., Eudragit ® RS, Eudragit ® RL,
  • Eudragit ® NE 30 D polyethylene derivatives e.g., polyethylene glycol and polyethylene oxide; polyvinyl alcohol; polyvinyl acetate; gums e.g. , guar gum, locust bean gum, tragacanth, carrageenan, alginic acid, gum acacia, gum arabic, gellan gum, and xanthan gum; triglycerides; waxes, e.g.
  • the cores of the present invention may additionally comprise one or more of other pharmaceutically acceptable excipients selected from the group comprising acids, osmogents, binders, glidants, or combinations thereof. These have been defined above in the specification.
  • the diameter of the cores comprising guanfacine and a release-controlling agent has a dgo value of less than about 1.5 mm. More particularly, the dgo value is less than about 1.2 mm. It is desirable to keep the diameter of the cores within the specified size so as to avoid sedimentation of the cores, grittiness in the mouth and thereby rendering the composition more acceptable.
  • the diameter of the cores is measured according to known methods, such as using Camsizer®.
  • the term '3 ⁇ 4 ⁇ value means at least 90% of the cores have volume diameter in the specified range when measured by a suitable method, for example, Camsizer®.
  • the coating additives used in the present invention are selected from the group comprising plasticizers, opacifiers, anti-tacking agents, coloring agents, or combinations thereof.
  • Suitable plasticizers are selected from the group comprising triethyl citrate, dibutylsebacate, triacetin, acetylated triacetin, tributyl citrate, glyceryl tributyrate, diacetylated monoglyceride, rapeseed oil, olive oil, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, glycerin, sorbitol, diethyl oxalate, diethyl phthalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, and mixtures thereof.
  • Suitable opacifiers are selected from the group comprising titanium dioxide, manganese dioxide, iron oxide, silicon dioxide, and combinations thereof.
  • Suitable anti-tacking agents are selected from the group comprising talc, magnesium stearate, calcium stearate, stearic acid, silica, glyceryl monostearate, and mixtures thereof.
  • Suitable coloring agents are selected from the group consisting of FD&C (Federal Food, Drug and Cosmetic Act) approved coloring agents; natural coloring agents; natural juice concentrates; pigments such as iron oxide, titanium dioxide, and zinc oxide; and mixtures thereof.
  • Suitable solvents used for granulation or for forming a solution or dispersion for coating are selected from the group comprising water, ethanol, methylene chloride, isopropyl alcohol, acetone, methanol, and combinations thereof.
  • equivalent refers to any value which lies within the range defined by a variation of up to ⁇ 30% of the value.
  • significant leaching means more than 20% of the guanfacine is leached out from the coated cores into the carrier.
  • the extended release liquid compositions of the present invention are homogenous and delivers the desired dose of guanfacine in every use without any risk of overdosing or under dosing.
  • the invention also provides for methods of making the compositions described herein by usual methods well known in the art.
  • the cores of the present invention comprising guanfacine can be prepared by any method known in the art, e.g., extrusion-spheronization, wet granulation, dry granulation, hot-melt extrusion granulation, spray drying, and spray congealing.
  • guanfacine can be layered over an inert particle to form the core by conventional coating processes.
  • guanfacine can be directly coated with a release-controlling agent to form the microparticles or microcapsules.
  • the microparticles or microcapsules can be prepared by a process of homogenization, solvent evaporation, coacervation, phase separation, spray drying, spray congealing, polymer precipitation, or supercritical fluid extraction.
  • Coating may be performed by applying the coating composition as a solution/ suspension/ blend using any conventional coating technique known in the art, such as spray coating in a conventional coating pan, fluidized bed processor, dip coating, or compression coating.
  • the percentage of the coating build-up shall be varied depending on the required extended release.
  • the process also includes forming complexes of guanfacine with ion-exchange resins, comprising loading a plurality of resin particles with guanfacine to form drug-resin particles. These particles may optionally be further coated with immediate release or extended release coating using conventional techniques. Methods of loading drugs onto resin particles are generally known in the art.
  • the ready-to-use extended release liquid compositions of the present invention may be packaged in a suitable package such as a bottle.
  • the dry powder for reconstitution may be packaged in a suitable package such as a bottle or a sachet.
  • the sachet can be filled as a unit dose or a multi dose sachet.
  • the present invention further includes a co- package or a kit comprising two components, wherein one package or one component comprises a dry powder and another package or another component comprises the pharmaceutically acceptable carrier.
  • a twin chamber pack with two chambers can be used. In this case, one chamber comprises a powder for suspension and another chamber comprises the carrier.
  • the invention also provides for various methods of treatment using the compositions described herein.
  • the invention provides for methods of treating ADHD comprising administering an effective amount of any of the composition described herein.
  • Examples 1-2 Comparative compositions of guanfacine
  • compositions prepared as per Example 1 and Example 2 were stored at room temperature and the samples were analyzed after 3 days and 7 days. Stability results are represented in Table 2 below.
  • Guanfacine hydrochloride suitable acid (fumaric/tartaric/citric acids) were mixed in water to form liquid compositions.
  • compositions prepared as per Examples 3-5 were stored at room temperature and the samples were analyzed after 30 days. Stability results are represented in Table 3 below.
  • Citric acid, mannitol, hydroxypropylmethyl cellulose, guanfacine hydrochloride were dissolved in purified water.
  • Ethyl cellulose and dibutyl sebacate were dispersed in a mixture of acetone and purified water.
  • step 4 The drug layered cores of step 2 were coated with the coating dispersion of step 3 to form extended release powder for suspension.
  • Microcrystalline cellulose - sodium carboxymethyl cellulose, xanthan gum, colloidal silicon dioxide, sucralose, xylitol, strawberry flavor, citric acid, methyl/ propyl paraben (if present) were mixed in purified water to form the pharmaceutically acceptable carrier.
  • the extended release powder for suspension compositions prepared as per Examples 7 and 8 were stored at 40°C/ 75%RH for 3 months and 1 month respectively. Thereafter, the powder for suspension was reconstituted with the carrier and the amounts of impurity 2, 6-dichlorophenyl acetic acid and total related substances was determined. The initial levels of impurities/ related substances and levels after 3 months/ 1 month are represented in Table 4 below.
  • the extended release powder for suspension prepared as per Examples 6 and 8 was reconstituted with the carrier and the in-vitro dissolution was determined for 4 mg dose at day 0 using USP type II apparatus at 75 rpm, in 900 mL of hydrochloric acid buffer with pH 2.2 at 37°C.
  • the results of the release studies are represented in Table 5.
  • step 4 The drug layered cores of step 2 were coated with the coating dispersion of step 3 to form extended release powder for suspension.
  • Xylitol and citric acid were mixed in purified water to form the pharmaceutically acceptable carrier.
  • compositions prepared as per Examples 9-12 were stored at room temperature for 30 days. After 30 days, the amounts of impurity 2, 6-dichlorophenyl acetic acid and total related substances was determined. The results are represented in Table 6 below.
  • the powder for suspension compositions prepared as per Examples 9-11 was stored for 10 days/ 30 days. After 10 days/ 30 days, the in-vitro dissolution was determined for 4 mg dose using USP type II apparatus at 75 rpm, in 900 mL of hydrochloric acid buffer with pH 2.2 at 37°C. The results of the release studies are represented in Table 7 below. Table 7- Percentage (%) of guanfacine release from reconstituted liquid compositions prepared as per Examples 9-11 in hydrochloric acid buffer pH 2.2, USP type II, 75
  • Citric acid, mannitol, hydroxypropyl methylcellulose, guanfacine hydrochloride were dissolved in purified water.
  • Ethyl cellulose and dibutyl sebacate were dispersed in a mixture of acetone and purified water.
  • step 4 The drug layered cores of step 2 were coated with the coating dispersion of step 3 to form extended release powder for suspension.
  • Microcrystalline cellulose - sodium carboxymethyl cellulose, xylitol, citric acid, xanthan gum, colloidal silicon dioxide, sucralose, strawberry flavor, methyl paraben and propyl paraben were mixed in purified water to form the pharmaceutically acceptable carrier.
  • the extended release powder for suspension composition prepared as per Example 14 was stored at 40°C/75%RH for one month. After one month, the powder for suspension was reconstituted with the carrier and the amounts of impurity 2, 6-dichlorophenyl acetic acid and total related substances was determined. The initial levels of impurities/ related substances and levels after 1 month are represented in Table 8 below.
  • the extended release powder for suspension prepared as per Example 14 was stored at 40°C/75%RH for one month. After one month, the in-vitro dissolution was determined for 4 mg dose using USP type II apparatus at 75 rpm, in 900 mL of hydrochloric acid buffer with pH 2.2 at 37°C. The results of the initial release studies and after 1 month are represented in Table 9 below.
  • Viscosity of the carrier prepared as per Example 14 was measured by Brookfield viscometer. The values are provided in the Table 11 below. Table 11 - Viscosity measurements
  • Example 13 Xylitol, microcrystalline cellulose - sodium carboxymethyl cellulose, xanthan gum, strawberry flavor, sucralose, citric acid, methyl paraben, propyl paraben and colloidal silicon dioxide, purified water were mixed as per Example 13. This suspension was then filtered and diluted with purified water, and the osmolality of the external phase was measured using Osmomat 030-D.
  • Osmolality of the external phase/ carrier was determined to be 4.105 osmol/ kg of the carrier.
  • the coated cores for osmolality measurement of internal phase were prepared as provided in above Table 13. These cores were dispersed in different solutions as per Examples A- D. These suspensions were kept for seven days at room temperature. After seven days, each suspension was filtered and diluted with purified water. These were then analyzed by using HPLC for guanfacine content. The results are represented in Table 14.
  • Osmolality ratio is calculated to be 1.149.
  • Example 15 Guanfacine extended release powder for suspension compositions
  • Citric acid, Eudragit ® L 100-55, triethyl citrate, talc, guanfacine hydrochloride were dispersed in a mixture of acetone and purified water.
  • Microcrystalline cellulose spheres were coated with the dispersion of step 1.
  • Ethyl cellulose and dibutyl sebacate were dispersed in a mixture of acetone and purified water.
  • step 4 The drug layered cores of step 2 were coated with the coating dispersion of step 3 to form extended release powder for suspension. 5.
  • Microcrystalline cellulose - sodium carboxymethyl cellulose, xylitol, citric acid, xanthan gum, colloidal silicon dioxide, sucralose, strawberry flavor, methyl paraben and propyl paraben were mixed in purified water to form the pharmaceutically acceptable carrier.
  • Example 14 The extended release liquid composition of Example 14 having a concentration of 1 mg/mL was dosed in an amount equivalent to 4 mg of guanfacine (Test product). This composition was compared with the commercially available extended release tablet composition of guanfacine (Intuniv® 4mg tablets) (Reference product).
  • Tables 15 and 16 indicate the results of the study. It was observed that the extended release composition of the present invention is bioequivalent to marketed extended release tablet composition.

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Abstract

La présente invention concerne des compositions liquides à libération prolongée de guanfacine. Les compositions liquides à libération prolongée de la présente invention sont bioéquivalentes aux compositions commercialisées de guanfacine de type comprimés à libération prolongée. Lesdites compositions liquides à libération prolongée offrent un profil de libération de dissolution in vitro sensiblement similaire lors d'un stockage d'au moins sept jours. De plus, les compositions liquides à libération prolongée sont stables. Les compositions liquides à libération prolongée se présentent sous la forme de compositions liquides prêtes à l'emploi ou de compositions liquides reconstituées. La présente invention concerne également des procédés de préparation desdites compositions liquides à libération prolongée.
EP16899321.0A 2016-04-20 2016-05-06 Compositions liquides à libération prolongée de guanfacine Pending EP3445350A4 (fr)

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US15/133,826 US20160228379A1 (en) 2014-05-01 2016-04-20 Extended release suspension compositions
PCT/IB2016/052607 WO2017182852A1 (fr) 2016-04-20 2016-05-06 Compositions liquides à libération prolongée de guanfacine

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US5854290A (en) * 1995-09-21 1998-12-29 Amy F. T. Arnsten Use of guanfacine in the treatment of behavioral disorders
US7838032B2 (en) * 2000-04-28 2010-11-23 Reckitt Benckiser Inc. Sustained release of guaifenesin
US6811794B2 (en) * 2001-12-20 2004-11-02 Shire Laboratories, Inc. Sustained release pharmaceutical dosage forms with minimized pH dependent dissolution profiles
US8318210B2 (en) * 2005-02-28 2012-11-27 Neos Therapeutics, Lp Compositions and methods of making sustained release liquid formulations
US20130149383A1 (en) * 2011-12-12 2013-06-13 Cory Berkland Sustained release particle formulations of guaifenesin
EP2796133A1 (fr) * 2013-04-26 2014-10-29 Salmon Pharma GmbH Formulation contenant hydrochloride de guanfacine à libération prolongée
JP2017514903A (ja) * 2014-05-01 2017-06-08 サン ファーマシューティカル インダストリーズ リミテッドＳｕｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｉｎｄｕｓｔｒｉｅｓ Ｌｔｄ． 徐放性懸濁組成物

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