US20160128979A1 - Modified release formulation - Google Patents

Modified release formulation Download PDF

Info

Publication number
US20160128979A1
US20160128979A1 US14/897,439 US201414897439A US2016128979A1 US 20160128979 A1 US20160128979 A1 US 20160128979A1 US 201414897439 A US201414897439 A US 201414897439A US 2016128979 A1 US2016128979 A1 US 2016128979A1
Authority
US
United States
Prior art keywords
modified release
afq056
release formulation
formulation according
minutes
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.)
Abandoned
Application number
US14/897,439
Other languages
English (en)
Inventor
Hubert Thoma
Bruno Galli
Dirk Spickermann
Karsten PUTZBACH
Klaus-Peter MOLL
Mike UFER
Arnaud Grandeury
Jean-Marie GLANTZMANN
Martin MUELLER-ZSIGMONDY
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.)
Novartis AG
Novartis Pharma AG
Original Assignee
Individual
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=51211272&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20160128979(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Individual filed Critical Individual
Priority to US14/897,439 priority Critical patent/US20160128979A1/en
Publication of US20160128979A1 publication Critical patent/US20160128979A1/en
Assigned to NOVARTIS PHARMA STEIN AG reassignment NOVARTIS PHARMA STEIN AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SPICKERMANN, DIRK
Assigned to NOVARTIS AG reassignment NOVARTIS AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NOVARTIS PHARMA AG
Assigned to NOVARTIS PHARMA AG reassignment NOVARTIS PHARMA AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: UFER, Mike, THOMA, HUBERT, GALLI, BRUNO, GLANTZMANN, Jean-Marie, GRANDEURY, ARNAUD, MOLL, Klaus-Peter, MUELLER-ZSIGMONDY, Martin, PUTZBACH, Karsten
Assigned to NOVARTIS AG reassignment NOVARTIS AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NOVARTIS PHARMA STEIN AG
Abandoned legal-status Critical Current

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404Indoles, e.g. pindolol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61JCONTAINERS 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
    • A61J3/00Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/02Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of powders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61JCONTAINERS 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
    • A61J3/00Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/10Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of compressed tablets
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404Indoles, e.g. pindolol
    • A61K31/4045Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38Cellulose; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1652Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682Processes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5089Processes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/04Centrally acting analgesics, e.g. opioids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16Anti-Parkinson drugs
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/24Antidepressants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/30Drugs for disorders of the nervous system for treating abuse or dependence
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/30Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32Alcohol-abuse
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/30Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34Tobacco-abuse
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/30Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36Opioid-abuse

Definitions

  • the drug substance AFQ056 is a subtype-selective, non-competitive antagonist at the metabotropic glutamate receptor 5 (mGluR5).
  • Glutamate is the main excitatory neurotransmitter in the nervous system and as such is involved in a variety of physiological and pathophysiological functions. Excessive glutamatergic transmission has been shown to play a role in both movement disorders and psychiatric conditions and the pharmacological use of glutamate receptor antagonists has shown efficacy in these indications.
  • AFQ056 has the molecular formula C 19 H 23 NO 3 and the following structural formula:
  • AFQ056 is a chiral molecule with 3 asymmetric carbon atoms and has a melting point of about 115° C. One single polymorph has been identified.
  • WO 03/047581 describes the preparation of AFQ056 and its use as a pharmaceutical, especially in the treatment of nervous system disorders including Parkinson's disease.
  • Parkinson's disease PD
  • L-dopa a precursor of dopamine
  • LIDs dyskinesias
  • AFQ056 has previously been formulated as a hard gelatin capsule and as a powder for oral suspension, both with immediate release (IR) properties.
  • Results in Parkinson's disease patients administered AFQ056 demonstrate a reduction in L-dopa induced dyskinesias without inducing any clinically or statistically significant worsening of the underlying Parkinsonian motor symptoms.
  • the most frequent adverse events observed in patients are in the nervous system and psychiatric system organ class, including dizziness, dyskinesia, nausea, fatigue, and hallucinations. Results also revealed that a significant proportion of patients did not achieve and maintain the target dose throughout the study, presumably due to tolerability issues such as dizziness.
  • the IR formulation used in these studies required twice-daily dosing.
  • modified release formulations are the prolonged blood plasma levels of drug compared to an immediate release formulation.
  • Modified release formulations usually contain more of the drug than the single dose administered in an immediate release dose form. If the formulation releases the drug at a rate that is faster than the intended controlled release rate (often referred to as dose dumping), there is a risk of overdosing with potential severe consequences for the patient.
  • U.S. 2003/0118641 relates to abuse-resistant sustained release opioid formulations using an ionic exchange resin.
  • WO 2008/086804 describes the preparation of pharmaceutical compositions comprising polyglycols that mitigate the risk of alcohol induced dose dumping and that reduce the risk of drug abuse.
  • U.S. 2008/0085305 refers to robust sustained release formulations based on hydrophilic gums that resist dose dumping when ingested with alcohol.
  • Roberts et al. (Int. Journal of Pharmaceutics 2007, 332, p. 31-37) describe the influence of ethanol on an oral dosage form comprising hypromellose matrices and aspirin.
  • no modified release formulation has been developed that takes into account the specificities of AFQ056 and at the same time eliminates the risk for alcohol induced does dumping after co-ingestion.
  • a safe modified release formulation preferably a once daily dose, with a lowered Cmax/AUC ratio relevant for tolerability, efficacy and compliance, thus allowing more patients to be treated with clinically efficacious doses of AFQ056.
  • a pharmaceutical formulation that prevents drug abuse, in particular regarding a concomitant consumption of alcoholic beverages.
  • the present invention provides drug products comprising AFQ056 having modified drug substance release properties.
  • a modified release formulation comprising (-)-(3aR,4S,7aR)-4-Hydroxy-4m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester in free base form, and a modified release agent, preferably hydroxy propyl methylcellulose (also known as hypromellose), together with one or more pharmaceutically acceptable excipients.
  • a modified release formulation comprising (-)-(3aR,4S,7aR)-4-Hydroxy-4m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester in free base form as active pharmaceutical ingredient and a modified release agent, preferably hydroxyl propyl methylcellulose, such that the active pharmaceutical ingredient is released from the formulation in a controlled fashion over a period of 6 hours, or over a period of 7 hours, so that at least 80% of the active pharmaceutical ingredient has been released at the end of this period.
  • a modified release agent preferably hydroxyl propyl methylcellulose
  • the drug products in the form of modified release formulations of the present invention release AFQ056 in a range of from about 14% to about 20% after 60 minutes; about 51% to about 61% after 180 minutes; about 67% to about 77% after 240 minutes; about 90% to about 95% after 360 minutes; and about 95% to about 99% after 420 minutes.
  • a modified release formulation comprising (—)-(3aR,4S,7aR)-4-Hydroxy-4m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester in free base form that exhibits a similar or decreased release rate in ethanol containing media as compared to a purely aqueous media.
  • the drug substance has a particle size distribution of x10 ⁇ 50 ⁇ m, x50 ⁇ 100 ⁇ m and x90 ⁇ 200 ⁇ m.
  • the drug products of the present invention are single unit dosage forms with AFQ056 present in an amount of about 25 mg to about 250 mg.
  • AFQ056 is present in an amount of about 50 to about 200 mg, more preferably in an amount of about 75 to 150 mg, more preferably in an amount of about 100 mg.
  • the pharmaceutical composition comprises a coating.
  • a single unit dosage form comprising about 25 mg to about 250 mg AFQ056, about 69 mg to about 135 mg hypromellose (type 2208 characterized by viscosities between about 80 to about 120 cP (2% in water at 20° C.)) about 20 mg to about 160 mg lactose monohydrate, about 3 mg to about 38 mg sodium starch glycolate, about 2 mg to about 4.5 mg Magnesium stearate and about 1 mg to about 2.2 mg colloidal silicon dioxide.
  • the drug product is a pharmaceutical composition comprising (—)-(3aR,4S,7aR)-4-Hydroxy-4m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester in the form of a single unit dosage form comprising equal to or less than 100 mg AFQ056 compressed to round tablets with a diameter of about 8 mm.
  • the drug product comprising AFQ056 is in the form of a single unit dosage form comprising more than 100 mg AFQ056 compressed to round tablets with a diameter of about 11 mm.
  • a process for the production of a composition comprising AFQ056 and having modified release properties.
  • the process comprises
  • step (viii) final mixing the mixture from step (vii) in a diffusion mixer.
  • a modified release formulation in the manufacture of a medicament for the treatment of Parkinson's disease L-dopa induced dyskinesia, Fragile X syndrome (Martin-Bell syndrome), dyskinesia in Fragile X syndrome, obsessive compulsory disorders, autism, cystitis, and for the treatment, prevention or delay of progression of acute, traumatic and chronic degenerative processes of the nervous system, such as Parkinson's disease, senile dementia, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, diseases such as schizophrenia and anxiety, depression, pain, itch and drug abuse such as alcohol and nicotine abuse and cocaine use disorders.
  • a method of treating a patient with Parkinson's disease and exhibiting L-dopa induced dyskinesia which comprises administering to said patient an effective amount of the drug product comprising AFQ056 with a modified release profile of Cmax/AUC of about, 0.08 to about 0.18 and a Tmax of about 4 hours to about 6 hours.
  • FIG. 1 shows the dissolution profiles and the in vivo-in vitro correlation (IVIVC) of two modified release formulations and of a formulation for a capsule (immediate release form 50 mg).
  • the calculated profiles are in line with the measured human plasma concentrations.
  • FIG. 1 shows the validity of the used prediction model.
  • the measured in-vitro profiles together with the model (not shown) allow to predict the human profiles derived from the in-vitro modified release and immediate release-formulation dissolution data.
  • FIG. 2 graphically depicts the solubility of AFQ056 at 37° C. in different aqueous media.
  • FIG. 2 shows that raising ethanol levels in the pure aqueous solution lead to a steadily increasing solubility of AFQ056.
  • the LDAO Liauryldimethylamine N-oxide
  • the water-ethanol solution show a different solubility pattern of AFQ056.
  • both the LDAO in water solution and the water-ethanol solution show a similar solubility for AFQ056.
  • FIG. 3 shows the dissolution rate of the modified release form. All modified release dosage strengths show consistently a lower dissolution rate in the presence of 20% ethanol.
  • FIG. 4 graphically depicts the dissolution rates of the modified release form and of the immediate release form in the presence of ethanol, the latter consistently showing a trend to faster dissolution rate in the presence of 20% and 40% Ethanol which is expected from solubility at the respective ethanolic concetrations.
  • FIG. 5 shows the dissolution profile of the immediate release form (capsule) comprising 50 mg AFQ056. After about 30 minutes in the 0.5% LDAO in water solution containing 40% ethanol, a dissolution of 100% is achieved.
  • FIG. 5 shows also that in the simulation of human PK parameters (simulation of human PK applying the in-vitro in-vivo correlation model) the Tmax value in the ethanol containing solution is achieved faster and the Cmax and the AUC 48h are both higher compared to the observed plasma concentrations in study X2101.
  • FIG. 6 graphically depicts the dissolution profile of the immediate release form (capsule) comprising 400 mg AFQ. After about 30 minutes in the LDAO in water solution containing 40% ethanol, a dissolution of almost 100% is achieved.
  • human PK parameters simulation of human PK applying the in-vitro in-vivo correlation model
  • the Tmax value in the ethanol containing solution is achieved faster and the Cmax and the AUC 48h are both higher compared to the observed plasma concentrations in study X2101.
  • FIG. 7 graphically depicts the dissolution profile of the modified release form comprising 200 mg AFQ056. After 8 hours in the LDAO in water solution containing 40% ethanol, a dissolution of less than 80% was observed.
  • human PK parameters simulation of human PK applying the in-vitro in-vivo correlation model
  • the Tmax value in the ethanol containing solution is almost identical and the Cmax and the AUC 48h are both almost equal to the observed plasma concentrations in study X2101.
  • FIG. 8 provides a comparative dissolution profile of AFQ056 modified release film-coated tablets studied in a human experiment. It is shown that the modified release tablets release the active pharmaceutical ingredient in a controlled fashion almost linearly during several hours. At the end of a period of 6 hours, or at the end of a period of 7 hours, at least 80% of the active pharmaceutical ingredient has been released.
  • FIG. 9 graphically depicts mean (SD) plasma concentration-time profiles of modified release forms compared with a capsule immediate release form, under fasted and fed conditions.
  • FIG. 10 graphically depicts mean (SD) plasma concentration-time profile of a selected modified release formulation B under fasted versus fed conditions.
  • FIG. 11 graphically depicts percent AFQ056 drug substance dissolved after 45 minutes versus AFQ056 drug substance particle size x90 value (90% of the particles are smaller or equal).
  • the present invention provides drug products in the form of modified-release formulations of AFQ056, which alter the pharmacokinetic profile of AFQ056, resulting in effective and sustained drug concentration over a longer period of time, reducing the peak to trough ratio.
  • the modified release formulations of the present invention have a positive food effect with increased Cmax compared to the fasted state.
  • a modified release form is a solid oral dosage form that permits the release of the active ingredient over an extended period of time to maintain therapeutically effective plasma levels.
  • the modified release formulation may be a controlled release formulation, one that exhibits substantially zero order release kinetics. It may also be a sustained release formulation, which exhibits first order kinetics.
  • An immediate release form is a solid oral dosage form that permits the release of most or all of the active ingredient over a short period of time, such as 60 minutes or less, and make rapid absorption of the drug possible.
  • Dose dumping is an unintended, rapid drug release in a short period of time of the entire amount or of a significant fraction of the active drug substance retained in a release dosage form.
  • AFQ056 The solubility pattern of AFQ056 was examined ( FIG. 1 ). AFQ056 is hardly soluble in water but soluble in organic solvents such as ethanol. In pure aqueous solutions the solubility of AFQ056 steadily increases with raising ethanol concentrations. The solubility pattern of AFQ056 in a LDAO water-ethanol solution is distinct from the solubility pattern of AFQ056 in a pure aqueous solution only up to an amount of 20% ethanol present in the solution. It was observed that the increase in solubility of AFQ056 by raising the presence of ethanol is even steeper than the solubility of a comparable drug such as aspirin (Roberts et al.; Int.
  • Solubilities of AFQ056 are about 0.02 mg/ml in water and raise up to about 53 mg/ml (factor 2500x solubility increase) in ethanol at room temperature. This is in contrast to 8.4 mg/ml for Aspirin in water raising up to about 237 mg/ml in ethanol (factor 28x solubility increase). It was observed that high concentrations of ethanol significantly raise the dissolution rate and thus have an impact on the pharmacokinetic parameters.
  • FIGS. 5 and 6 show that the predicted pharmacokinetic parameters of AFQ056 immediate release forms (50 mg AFQ056 capsule and 400 mg AFQ056 capsule) change dramatically in the presence of ethanol.
  • Tmax is reached faster and both Cmax and AUC 48h are higher for an immediate relase form in the presence of ethanol.
  • Immediate release forms of AFQ056 have therefore the inherent risk of dose dumping and can create severe consequences for the patient if ethanol-containing beverages are consumed in parallel.
  • Particle size distribution is also an important factor influencing the dissolution of a drug substance and is known to influence the drug release from matrix tablets.
  • FIG. 3 and FIG. 4 illustrate the release pattern of the present formulations in ethanol containing solutions. It is speculated that the combination of several factors such as the presence of hypromellose, the particle size and the size distribution of the drug substance result in the observed release pattern of the AFQ056 modified release formulations. Surprisingly the predicted pharmacokinetic parameters of the modified release formulation remain almost equal in the presence of ethanol ( FIG. 7 ). It is therefore shown that the modified release form is dose dumping resistant in the presence of ethanol.
  • AFQ056 may be prepared as described in WO 03/047581, the contents of which are incorporated by reference. In the modified release formulations of the present invention, AFQ056 is present as free base.
  • Excipients that may be used in the formulations of the present invention are standard excipients commonly used for tablet dosage forms and include but are not limited to fillers, modified release agents, disintegrants, lubricants, glidants, solvents, viscosity agents, emulsifiers, binding agents, buffers, bulking agents, coloring agents, taste-improving agents, flow agents, fillers, absorbents and water soluble coatings.
  • fillers which may be used in the formulations of the present invention include but are not limited to lactose monohydrate, dibasic calcium phosphate, calcium carbonate, sugar alcohols (e.g. mannitol), microcrystalline cellulose and starch.
  • lactose monohydrate is used as a filler.
  • modified release agents which may be used in the formulations of the present invention without being resistant to dose dumping in the presence of ethanol include but are not limited to hydroxy propyl methylcellulose (HPMC), also known as hypromellose, (a) hydrophilic carbohydrate macromolecules (acacia, agar, alginic acid, carboxymethylcellulose, carrageenans, dextrin, gellan gum, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, maltodextrin, methylcellulose, pectin, propylene glycol alginate, sodium alginate, starch, tragacanth, and xanthan gum) and (b) noncarbohydrate hydrophilic macromolecules, including gelatin, povidone carbomers, polyethylene oxide, and polyvinyl alcohol.
  • HPMC hydroxy propyl methylcellulose
  • hydrophilic carbohydrate macromolecules acacia, agar, alginic acid, carboxymethyl
  • Modified release agents which may be used in formulations of the present invention that are dose dumping resistant in the presence of ethanol are preferably, hypromellose such as hypromellose type 2208 and type 2910 is used. More preferably, Methocel K100 Premium LV CR, Methocel K4M Premium CR, Methocel K15M Premium CR, Methocel K100M Premium CR, Methocel E4M Premium CR, and Methocel E10M Premium CR is used, in sum characterized by viscosities between about 80 to about 120000 cP (20° C.).
  • binders which may be used in the formulations of the present invention include but are not limited to cellulose derivatives (e.g. hypromellose, hydroxypropylcellulose, methylcellulose), gelatin, polyvinylpyrrolidone, copovidone, starch, sucrose and polyethylene glycol.
  • cellulose derivatives e.g. hypromellose, hydroxypropylcellulose, methylcellulose
  • gelatin e.g. hypromellose, hydroxypropylcellulose, methylcellulose
  • polyvinylpyrrolidone e.g. hypromellose, hydroxypropylcellulose, methylcellulose
  • copovidone e.g. hypromellose, type 2910, is used.
  • glidants may be used in the formulations of the present invention and include e.g. silicon dioxide asprecipitated silica and as colloidal silica, colloidal silicon dioxide.
  • silicon dioxide asprecipitated silica and as colloidal silica, colloidal silicon dioxide.
  • colloidal silicon dioxide e.g., Aerosil® is used.
  • disintegrants may be used in the formulations of the present invention, including, but not limited to, sodium starch glycolate, carboxymethylcellulose sodium /croscarmellose Sodium, crospovidone/ cross-linked polyvinylpyrrolidone, starches, celluloses and pullulan.
  • sodium starch glycolate is used.
  • lubricants which may be used in the formulations of the present invention, include but are not limited to magnesium stearate, calcium stearate, zinc stearate, stearic acid, sodium benzoate, sodium stearyl fumarate, sodium lauryl sulfate, hydrogenated vegetable oil, glycerides (glyceryl behenate and distearate).
  • magnesium stearate is used as lubricant.
  • Coatings which may be used in the formulations of the present invention include but are not limited to hypromellose, hydroxypropyl cellulose, methylcellulose, povidone, polyvinyl alcohol, Macrogol poly(vinyl alcohol) grafted copolymer and starches.
  • hypromellose macrogol 4000/polyethylene glycol 4000, talc, iron oxide (red, yellow, black), and titanium dioxide is used.
  • modified release formulations of the present invention may be made by mixing, aqueous granulation, screening, drying, tablet compression and film-coating steps, all of which are well known in the art.
  • the modified release formulations are made by mixing AFQ056, filler, binder and disintegrant in a high shear granulator for approximately 5 minutes. Purified water is added under mixing and the mixture kneaded in a high shear granulator. The granulate is then passed through a screen using a screening mill and dried in a fluid bed dryer.
  • the granulate After drying, the granulate is mixed with filler, modified release agent and glidant, followed by consecutive sieving using a screening mill and mixing in a diffusion mixer (tumble). A lubricant is sieved and then added to the mixture from the diffusion mixer. The composition is then formed by final mixing.
  • the resulting granules of the composition may have a diameter from a few microns to a few hundred microns; e.g., diameters of at most about 450 microns, e.g., 20 to 450 microns, preferably 50-200 ⁇ m, most preferably, 100-200 ⁇ m.
  • a narrow particle size distribution is preferred.
  • a preferred particle size distribution is x10 ⁇ 50 ⁇ m, x50 ⁇ 100-150 ⁇ m and x90 ⁇ 200-450 ⁇ m, i.e., 10% of particles are smaller than 50 ⁇ m, 50% of particles are smaller than 150 ⁇ m, and 90% of particles are smaller than 450 ⁇ m.
  • the blend is then compressed into tablet cores using a rotary tablet press.
  • a coating mixture in purified water is dispersed and the tablet cores are film coated in a pan coater with perforated coating system.
  • the modified release formulations are made by mixing AFQ056, lactose monohydrate, hypromellose (type 2208) and sodium starch glycolate in a high shear granulator for approximately 5 minutes. Purified water is added under mixing and the mixture kneaded in a high shear granulator. The granulate is then passed through a screen using a screening mill and dried in a fluid bed dyer.
  • the granulate is mixed with hypromellose (type 2208), lactose monohydrate and colloidal silicon dioxide followed by consecutive sieving using a screening mill and mixing in a diffusion mixer (tumble).
  • the magnesium stearate is sieved and then added to the mixture from the diffusion mixer.
  • the composition is formed by final mixing.
  • the blend is then compressed into tablet cores using a rotary tablet press.
  • a coating mixture in purified water is dispersed and the tablet cores are film coated in a pan coater with perforated coating system.
  • the modified release formulations of the present invention are useful in treating Parkinson's disease (PD) and effective amounts of such formulations are administered to such patients.
  • PD Parkinson's disease
  • phrases “effective amount”, “amount effective” or “amounts effective” describe concentrations or amounts of the drug substance according to the present invention, which may be used to produce a favorable change in L-dopa induced motor complications such as dyskinesias (LIDs).
  • the total daily effective amount(s) can be administered in divided doses (e.g., multiple capsules or tablets).
  • the total daily effective amount is delivered in a single dosage form (e.g., one tablet), which in total, delivers an effective amount of AFQ056.
  • a single dosage form e.g., one tablet
  • the drug products of the present invention may be administered multiple times a day, twice a day (b.i.d.) or once a day (o.d.). A once a day dose is preferable since it may lead to increased patient compliance.
  • a single dosage form of the modified release formulation of the present invention provides AFQ056 in an amount of about 25 mg to about 250 mg.
  • a single dosage form of the modified release formulation of the present invention provides AFQ056 in an amount of about 50 to about 200 mg.
  • the drug products of the present invention may be used to treat nervous system disorders mediated in full or in part by mGluR5.
  • Such disorders include Parkinson's disease L-dopa induced dyskinesia, Fragile X syndrome (Martin-Bell syndrome), dyskinesia in Fragile X syndrome, obsessive compulsory disorders, autism, cystitis, acute, traumatic and chronic degenerative diseases of the nervous system such as Parkinson's disease, senile dementia, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychiatric diseases such as schizophrenia and anxiety, depression, pain, itch and drug abuse, e.g. alcohol and nicotine abuse and cocaine use disorders.
  • the drug products of the present invention may be used in the manufacture of a medicament for the treatment of Parkinson's disease L-dopa induced dyskinesia, Fragile X syndrome (Martin-Bell syndrome), dyskinesia in Fragile X syndrome, obsessive compulsory disorders, autism, cystitis, and for the treatment, prevention or delay of progression of acute, traumatic and chronic degenerative processes of the nervous system, such as Parkinson's disease, senile dementia, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychiatric diseases such as schizophrenia and anxiety, depression, pain, itch and drug abuse such as alcohol and nicotine abuse and cocaine use disorders.
  • Parkinson's disease L-dopa induced dyskinesia Fragile X syndrome (Martin-Bell syndrome)
  • dyskinesia in Fragile X syndrome obsessive compulsory disorders
  • autism cystitis
  • psychiatric diseases such as schizophrenia and anxiety, depression, pain,
  • the drug products of the present invention are used to treat Parkinson's Disease-Levodopa Induced Dyskinesia (PD-LID).
  • PD-LID Parkinson's Disease-Levodopa Induced Dyskinesia
  • An open-label, randomized, five periods, seven treatments cross-over study in healthy subjects is conducted.
  • a total of forty five (45) subjects are enrolled to obtain data on at least 30 completers.
  • Each subject receives a total of 5 single doses of AFQ056; three doses under fasted conditions and two doses under fed conditions.
  • the study consists of a screening period (up to 27 days), 5 baseline periods, 4 wash out periods of 7-2 days inclusive. 5 treatment periods followed by a Study Completion Evaluation 5-10 days (inclusive) after the last drug administration.
  • Subjects who meet the eligibility criteria at screening are admitted to baseline evaluations for treatment period 1. Subjects are admitted to the study site at least 12 hours prior to dosing in each period for baseline evaluations. All baseline safety evaluation results must be available prior to dosing. After an overnight fast, subjects are randomized to one of the treatment sequence (Table 2).
  • Treatment 1 AFQ056 100 mg Form-A. fasted
  • Treatment 2 AFQ056 100 mg Form-A, fed
  • Treatment 4 AFQ056 100 mg Form-B. fed
  • pharmacokinetic assessments are made up to 72 h post dose.
  • a wash-out period of 7 ⁇ 2 days inclusive separates each treatment period. The washout period is calculated between dose to dose and baseline of subsequent period can overlap with the 5 th day after dosing.
  • the total study duration for each subject lasts a minimum of 53 days and a maximum of 70 days from screening to study completion. Subject are domiciled for approximately 20 days in total (4 days for each period) for all sequences.
  • the study has a 3-Latin, 5-sequences ⁇ 5-period open-label design that is suitable for comparing the pharmacokinetics including relative bioavailability of three modified release formulations of AFQ056.
  • the immediate release capsule formulation size O, IR
  • This study design allows the comparison of pharmacokinetic profile of AFQ056 from three modified release (MR) formulations relative to the IR formulation under fasted conditions, and to assess the food effect on the pharmacokinetics of the three MR forms.
  • Latin-square design is selected as it offers maximum precision of comparison across different treatments with minimum number of study subjects.
  • the cross-over design permits investigation of all five treatment conditions within each subject and is used to account for interindividual variability.
  • a wash out period of at least 5 days ensures complete washout of AFQ056 based on a half life of 7 to 17 hours for 50 mg and for 100 mg doses. Sampling for 72 hours post dose is considered sufficient for characterizing the PK profiles of all formulations, including the MR forms.
  • Mean (SD) plasma concentration-time profile of selected modified release formulation form B, fasted versus fed, is depicted in FIG. 10 .
  • the tablet core is formulated using common excipients for such pharmaceutical dosage forms. Release of the drug substance from the tablet core occurs through an erosion and diffusion mechanism, and is controlled by the hypromellose (type 2208) content of the formulated product. A pharmacokinetic study is performed using different 100 mg modified release tablet formulations in order to evaluate the impact of delaying release of the active ingredient.
  • the same ratio of excipients in the 100 mg tablet core is used to create the additional dosage strengths.
  • the lower dosage strengths e.g. 25 mg, 50 mg and 75 mg use lactose monohydrate as compensation for drug substance in order to maintain the tablet weight and size.
  • the tablet cores of dosage strengths less than or equal to 100 mg are compressed to round tablets possessing a diameter of 8 mm.
  • the tablet weight and size are increased.
  • the same formulation principle is applied i.e. using lactose monohydrate as compensation for drug substance.
  • the tablet cores of dosage strengths more than 100 mg are compressed to round tablets possessing a diameter of 11 mm.
  • Table 4 summarizes the tablet core composition of the different dosage strengths.
  • Dissolution of AFQ056 modified release film-coated tablets occurs through an erosion and diffusion mechanism, with a target release time of approximately 6 to 7 hours for >80% of the active ingredient (Table 5).
  • the dissolution method uses dissolution apparatus 2 (paddle) at 100 rpm with 900 ml of Water+0.5% LDAO. Comparative dissolution profiles for AFQ056 modified release film-coated tablets are provided in FIG. 8 .
  • Particle size distribution is an important factor in dissolution of the modified release forms of the present invention.
  • the following experiments are performed to in order to determine how particle size effects dissolution at various time points.
  • FIG. 11 graphically depicts the percentage of AFQ056 dissolved after 45 minutes versus particle size at x90. As can be discerned from the figure, particle size distribution is a key factor in dissolution rate and thus the performance of the MR Form.
  • the drug substance has a particle size distribution of x10 ⁇ 50 ⁇ m, x50 ⁇ 100 ⁇ m and x90 ⁇ 200 ⁇ m.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Addiction (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Pain & Pain Management (AREA)
  • Inorganic Chemistry (AREA)
  • Hospice & Palliative Care (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US14/897,439 2013-06-12 2014-06-11 Modified release formulation Abandoned US20160128979A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US14/897,439 US20160128979A1 (en) 2013-06-12 2014-06-11 Modified release formulation

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201361834104P 2013-06-12 2013-06-12
PCT/IB2014/062136 WO2014199316A1 (en) 2013-06-12 2014-06-11 Modified release formulation
US14/897,439 US20160128979A1 (en) 2013-06-12 2014-06-11 Modified release formulation

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2014/062136 A-371-Of-International WO2014199316A1 (en) 2013-06-12 2014-06-11 Modified release formulation

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US16/898,071 Continuation US20210069150A1 (en) 2013-06-12 2020-06-10 Modified release formulation

Publications (1)

Publication Number Publication Date
US20160128979A1 true US20160128979A1 (en) 2016-05-12

Family

ID=51211272

Family Applications (3)

Application Number Title Priority Date Filing Date
US14/897,439 Abandoned US20160128979A1 (en) 2013-06-12 2014-06-11 Modified release formulation
US16/898,071 Pending US20210069150A1 (en) 2013-06-12 2020-06-10 Modified release formulation
US18/355,618 Pending US20230355582A1 (en) 2013-06-12 2023-07-20 Modified release formulation

Family Applications After (2)

Application Number Title Priority Date Filing Date
US16/898,071 Pending US20210069150A1 (en) 2013-06-12 2020-06-10 Modified release formulation
US18/355,618 Pending US20230355582A1 (en) 2013-06-12 2023-07-20 Modified release formulation

Country Status (22)

Country Link
US (3) US20160128979A1 (pt)
EP (1) EP3007682B1 (pt)
JP (1) JP6444996B2 (pt)
KR (1) KR102290249B1 (pt)
CN (2) CN105263479A (pt)
AU (1) AU2014279743B2 (pt)
BR (1) BR112015030431B1 (pt)
CA (1) CA2911486C (pt)
CL (1) CL2015003596A1 (pt)
EA (1) EA031395B1 (pt)
ES (1) ES2644698T3 (pt)
HK (1) HK1216839A1 (pt)
MA (1) MA38646B1 (pt)
MX (1) MX369742B (pt)
PE (1) PE20160183A1 (pt)
PH (1) PH12015502556A1 (pt)
PL (1) PL3007682T3 (pt)
PT (1) PT3007682T (pt)
SG (1) SG11201509178TA (pt)
TN (1) TN2015000498A1 (pt)
WO (1) WO2014199316A1 (pt)
ZA (1) ZA201508228B (pt)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019025931A1 (en) * 2017-07-31 2019-02-07 Novartis Ag USE OF A MUSSEL FOR REDUCING THE USE OF COCAINE OR FOR PREVENTING A RECHUTE IN THE USE OF COCAINE
WO2019025932A1 (en) * 2017-07-31 2019-02-07 Novartis Ag USE OF MUSSELUROUS IN REDUCING THE USE OF ALCOHOL OR IN THE PREVENTION OF RECHUTE IN THE USE OF ALCOHOL
RU2804834C2 (ru) * 2017-07-31 2023-10-06 Новартис Аг Применение мавоглуранта при снижении употребления кокаина или при предупреждении рецидива употребления кокаина

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2016328150B2 (en) 2015-09-23 2020-10-01 Xw Laboratories Inc. Prodrugs of gamma-hydroxybutyric acid, compositions and uses thereof
MX2021008827A (es) 2019-01-29 2021-09-08 Novartis Ag Uso de un antagonista de mglur5 para el tratamiento de la tolerancia a los analgesicos opioides.
EP4181918A2 (en) 2020-07-17 2023-05-24 Novartis AG Mavoglurant, a mglur5 antagonist, for use in the treatment in the reduction of opioid use
US20240050408A1 (en) 2020-12-11 2024-02-15 Novartis Ag Use of mglur5 antagonists for treating amphetamine addiction
WO2022130136A1 (en) 2020-12-14 2022-06-23 Novartis Ag Use of mglur5 antagonists for treating gambling disorder

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060216347A1 (en) * 2003-08-25 2006-09-28 Federico Stroppolo Tablet punches and methods for tableting
US7348353B2 (en) * 2001-12-04 2008-03-25 Novartis Ag Acetylene derivatives having mGluR 5 antagonistic activity
US20080207749A1 (en) * 2005-07-12 2008-08-28 Novartis Ag Use of Mglur5 (Esp. Afq056) in Gi (Esp.Gerd)
US20090215744A1 (en) * 2005-11-18 2009-08-27 Astrazeneca Ab Solid Formulations
US20120040008A1 (en) * 2010-08-11 2012-02-16 Ashish Chatterji Pharmaceutical compositions of metabotropic glutamate 5 receptor (mglu5) antagonists

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030118641A1 (en) 2000-07-27 2003-06-26 Roxane Laboratories, Inc. Abuse-resistant sustained-release opioid formulation
US20070141148A1 (en) * 2005-11-30 2007-06-21 Merz Pharma Gmbh & Co. Kgaa Neramexane MR matrix tablet
US20080085305A1 (en) 2006-10-10 2008-04-10 Penwest Pharmaceuticals Co. Robust sustained release formulations of oxymorphone
EP2104493A2 (en) 2007-01-16 2009-09-30 Egalet A/S Use of i) a polyglycol and n) an active drug substance for the preparation of a pharmaceutical composition for i) mitigating the risk of alcohol induced dose dumping and/or ii) reducing the risk of drug abuse
WO2010048095A2 (en) 2008-10-22 2010-04-29 House Ear Institute Treatment and/or prevention of inner ear conditions by modulation of a metabotropic glutamate receptor
US20120039999A1 (en) * 2010-08-11 2012-02-16 Ashish Chatterji Pharmaceutical compositions of metabotropic glutamate 5 receptor (mglu5) antagonists
WO2012085167A1 (en) * 2010-12-22 2012-06-28 Merz Pharma Gmbh & Co. Kgaa Metabotropic glutamate receptor modulators
WO2012139876A1 (en) * 2011-04-14 2012-10-18 Merz Pharma Gmbh & Co. Kgaa Enteric formulations of metabotropic glutamate receptor modulators

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7348353B2 (en) * 2001-12-04 2008-03-25 Novartis Ag Acetylene derivatives having mGluR 5 antagonistic activity
US20060216347A1 (en) * 2003-08-25 2006-09-28 Federico Stroppolo Tablet punches and methods for tableting
US20080207749A1 (en) * 2005-07-12 2008-08-28 Novartis Ag Use of Mglur5 (Esp. Afq056) in Gi (Esp.Gerd)
US20090215744A1 (en) * 2005-11-18 2009-08-27 Astrazeneca Ab Solid Formulations
US20120040008A1 (en) * 2010-08-11 2012-02-16 Ashish Chatterji Pharmaceutical compositions of metabotropic glutamate 5 receptor (mglu5) antagonists

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Kerper et al. (PLOS ONE, 7(12), e5167-e51167, 2012) Persistence of Psychological Distress in….. *
Kerper PLOS ONE, 7(12), e5167-e51167, 2012 *
Nokhodchi et al. (BioImpacts, 2(4) 1-13, 2012) The role of Oral Controlled……. *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019025931A1 (en) * 2017-07-31 2019-02-07 Novartis Ag USE OF A MUSSEL FOR REDUCING THE USE OF COCAINE OR FOR PREVENTING A RECHUTE IN THE USE OF COCAINE
WO2019025932A1 (en) * 2017-07-31 2019-02-07 Novartis Ag USE OF MUSSELUROUS IN REDUCING THE USE OF ALCOHOL OR IN THE PREVENTION OF RECHUTE IN THE USE OF ALCOHOL
CN110891564A (zh) * 2017-07-31 2020-03-17 诺华股份有限公司 玛沃谷兰在减少酒精使用或在预防复用酒精中的用途
CN110958879A (zh) * 2017-07-31 2020-04-03 诺华股份有限公司 玛沃谷兰在减少可卡因使用或预防复用可卡因中的用途
AU2018310881B2 (en) * 2017-07-31 2021-05-27 Novartis Ag Use of mavoglurant in the reduction of cocaine use or in preventing relapse into cocaine use
AU2018310882B2 (en) * 2017-07-31 2021-08-26 Novartis Ag Use of mavoglurant in the reduction of alcohol use or in preventing relapse into alcohol use
AU2018310882C1 (en) * 2017-07-31 2021-12-09 Novartis Ag Use of mavoglurant in the reduction of alcohol use or in preventing relapse into alcohol use
AU2018310881C1 (en) * 2017-07-31 2021-12-16 Novartis Ag Use of mavoglurant in the reduction of cocaine use or in preventing relapse into cocaine use
RU2804834C2 (ru) * 2017-07-31 2023-10-06 Новартис Аг Применение мавоглуранта при снижении употребления кокаина или при предупреждении рецидива употребления кокаина
RU2806869C2 (ru) * 2017-07-31 2023-11-08 Новартис Аг Применение мавоглуранта при снижении употребления алкоголя или при предупреждении рецидива употребления алкоголя
US11878001B2 (en) 2017-07-31 2024-01-23 Novartis Ag Use of mavoglurant in the reduction of cocaine use or in preventing relapse into cocaine use

Also Published As

Publication number Publication date
CN111467313A (zh) 2020-07-31
PE20160183A1 (es) 2016-04-28
MX2015017202A (es) 2016-11-11
US20230355582A1 (en) 2023-11-09
CA2911486A1 (en) 2014-12-18
EP3007682A1 (en) 2016-04-20
JP2016520663A (ja) 2016-07-14
WO2014199316A1 (en) 2014-12-18
BR112015030431A2 (pt) 2017-07-25
MA38646A1 (fr) 2017-09-29
PT3007682T (pt) 2017-11-02
SG11201509178TA (en) 2015-12-30
CA2911486C (en) 2021-09-21
AU2014279743B2 (en) 2017-05-25
EA201690005A1 (ru) 2016-04-29
US20210069150A1 (en) 2021-03-11
BR112015030431B1 (pt) 2023-02-28
MX369742B (es) 2019-11-20
ZA201508228B (en) 2016-11-30
MA38646B1 (fr) 2018-04-30
CL2015003596A1 (es) 2016-09-02
TN2015000498A1 (en) 2017-04-06
ES2644698T3 (es) 2017-11-30
PL3007682T3 (pl) 2017-12-29
KR20160018702A (ko) 2016-02-17
PH12015502556A1 (en) 2016-02-22
CN105263479A (zh) 2016-01-20
AU2014279743A1 (en) 2015-11-26
EP3007682B1 (en) 2017-07-26
EA031395B1 (ru) 2018-12-28
KR102290249B1 (ko) 2021-08-17
JP6444996B2 (ja) 2018-12-26
HK1216839A1 (zh) 2016-12-09

Similar Documents

Publication Publication Date Title
US20230355582A1 (en) Modified release formulation
EP2974720B1 (en) Mosapride sustained-release preparation for providing pharmacological clinical effects with once-a-day administration
KR101084832B1 (ko) 네라멕산 변형 방출 매트릭스 정제
KR101858797B1 (ko) 히드로모르폰 및 날록손을 포함하는 제약 조성물
JP2017501201A (ja) Azd9291を含む医薬組成物
JP6232135B2 (ja) 疼痛およびオピオイドによる腸機能障害症候群の治療のためのヒドロモルホンおよびナロキソン
TWI548425B (zh) 高載率控制釋放之鎂口服劑型及其製造及使用方法
KR102197465B1 (ko) 디메틸푸마르산염을 함유한 장용성 정제
WO2009027786A2 (en) Matrix dosage forms of varenicline
JP2009507875A (ja) 3−(2−ジメチルアミノメチル−シクロヘキシル)−フェノールの徐放性製剤
TW201609197A (zh) 每日一次投藥之提供藥學及臨床效果之莫沙必利持續釋放製劑
OA16241A (en) Pharmaceutical compositions comprising hydromorphone and naloxone.
EP2363120A1 (en) Combinations of dimebolin and memantine

Legal Events

Date Code Title Description
AS Assignment

Owner name: NOVARTIS AG, SWITZERLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NOVARTIS PHARMA AG;REEL/FRAME:046705/0374

Effective date: 20120510

Owner name: NOVARTIS PHARMA STEIN AG, SWITZERLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:SPICKERMANN, DIRK;REEL/FRAME:046705/0368

Effective date: 20140514

Owner name: NOVARTIS PHARMA AG, SWITZERLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:THOMA, HUBERT;PUTZBACH, KARSTEN;MOLL, KLAUS-PETER;AND OTHERS;SIGNING DATES FROM 20140514 TO 20140607;REEL/FRAME:046944/0628

Owner name: NOVARTIS AG, SWITZERLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NOVARTIS PHARMA STEIN AG;REEL/FRAME:047523/0808

Effective date: 20140602

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: FINAL REJECTION MAILED

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION