WO2013186311A1 - Extended release formulations - Google Patents
Extended release formulations Download PDFInfo
- Publication number
- WO2013186311A1 WO2013186311A1 PCT/EP2013/062273 EP2013062273W WO2013186311A1 WO 2013186311 A1 WO2013186311 A1 WO 2013186311A1 EP 2013062273 W EP2013062273 W EP 2013062273W WO 2013186311 A1 WO2013186311 A1 WO 2013186311A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- extended release
- release formulation
- formulation according
- disorders
- active ingredient
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—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
- A61K9/5073—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 having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—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 having two or more different coatings optionally including drug-containing subcoatings with drug-free core
Definitions
- the present invention relates to extended release formulations comprising dipraglurant, a metabotropic glutamate receptor 5 (mGluR 5 ) negative allosteric modulator, or a pharmaceutically acceptable salt thereof, for oral administration.
- the invention further provides a process for preparing these extended releases formulations and their use in the prevention or treatment of disorders related to mGluR 5 negative allosteric modulators.
- Dipraglurant is the approved name for 6-fluoro-2-[4-(pyridin-2-yl)but-3-yn-l- yl]imidazo[l,2-a]pyridine and is described in WO05123703 (Example 74) as a negative allosteric modulator of the metabotropic glutamate receptor 5 (mGluR 5 ).
- the compound has the following structure:
- Dipraglurant is also known under the reference name ADX48621 (Rocher J.-P. et al, Current Topics in Med. Chem. 2011, 11, 680-95).
- Dipraglurant can exist as a pharmaceutically acceptable salt, co-crystal, solvate, amorphous form or complex with other ingredients. From several salts, the phosphate of dipraglurant has been selected and has shown to be a highly soluble and highly permeable molecule. This means that after the administration in a conventional immediate release dosage form, the active substance is rapidly dissolved in the gastrointestinal tract and rapidly absorbed to the systemic circulation. The duration of exposure is mainly controlled by the elimination half life. Dipraglurant is characterized by a short half life of less than 1 hour. This is suitable for some indications where a high plasmatic concentration is required rapidly for a short time but this is not suitable for chronic indications where a sustainable plasmatic concentration is needed.
- an extended release formulation (alternatively named as a prolonged release formulation) is defined as a modified release dosage form from which the release of the active substance and its subsequent absorption are prolonged in comparison with a conventional unmodified (immediate-release) dosage form administered by the same route.
- Numerous extended release formulations are known in the art. Specifically, they are often designed to maintain adequate plasma concentration and minimise peak-to- trough variation in drug plasma levels associated with conventional frequent dosage regimes. However, up to now it has not been considered feasible to make a formulation with a sufficiently extended release profile for molecules with such short half life.
- Thombre stated in his assessment of the feasibility of the oral controlled release that molecules with half life which is less than 1-2 hours are too short for controlled release development (Thombre A. V., Drug Discovery Today, 2005, 10, 17, 1159-66). This is the case with dipraglurant, which has a very short half life of less than one hour.
- dipraglurant phosphate An additional challenge to produce an extended release formulation of dipraglurant phosphate is its high aqueous solubility (21.0 to 32.5 mg/mL) at all relevant physiological pH.
- a drug with very high solubility and a rapid dissolution rate it is often quite difficult to decrease its dissolution rate and slow its absorption.
- a drug of high water solubility can dissolve in water or gastrointestinal milieu readily and tends to release from its dosage form in a burst and thus is absorbed quickly, leading to a sharp increase in the drug blood concentration.
- the present invention seeks to provide an extended release formulation of dipraglurant which allows prolonged plasmatic concentration.
- a prolonged plasmatic concentration above the efficient concentration is mandatory to achieve pharmacological efficiency. This helps to reduce the number of doses per day and helps achieve better patient compliance.
- Another object of the invention is to provide extended release formulations of dipraglurant with different in vivo release profiles so that the best profile could be chosen to match the intended indication requirements in terms of exposure duration.
- An important object of the invention is to provide an extended release formulation of dipraglurant with an in vivo release profile that could be adjusted based on an in vitro release profile.
- This in vitro I in vivo correlation (IVIVC) is highly helpful in predicting the impact of the formulation modifications on the pharmacokinetic profile.
- Figure 1 shows the dissolution profile of multiparticulates coated at 7% level
- Figure 2 shows the dissolution profile of multiparticulates coated at 10% level
- Figure 3 shows the pharmacokinetic profile of multiparticulates coated at 7% and 10% level vs. dipraglurant solution
- Figure 4 shows the multiparticulates formulation coated at 7% and 10% level, In vitro - In vivo correlation in Cynomolgus monkeys;
- Figure 5 shows the dissolution profile of Matrix tablet (Batch 29);
- Figure 6 shows the pharmacokinetic profile of Matrix tablet (Batch 29) vs. dipraglurant solution
- Figure 7 shows Matrix tablet formulation In vitro - In vivo correlation in Cynomolgus monkeys.
- the purpose of the present invention is to provide a controlled (e.g. extended) release formulation of dipraglurant (or a pharmaceutically acceptable salt, co-crystal, solvate or amorphous form thereof, or a complex of dipraglurant with other acceptable ingredients) which satisfy the objectives detailed above.
- the extended release formulations of the present invention are suitable for oral administration (i.e. orally administrable).
- the extended release formulation comprises multiparticulates (e.g. pellets, beads, or mini-tablets) comprising an active ingredient selected from dipraglurant, or a pharmaceutically acceptable salt, co-crystal, solvate, or amorphous form thereof, or a complex of dipraglurant with other acceptable ingredients.
- the multiparticulates may be coated with a barrier layer.
- the barrier layer may comprise (or may consist of) a component that is insoluble in the gastrointestinal fluid (referred to hereinafter as the "insoluble component”), mixed with a pore forming component that is soluble in the gastrointestinal fluid (referred to hereinafter as "soluble component").
- the barrier layer assures a prolonged release of dipraglurant in the gastrointestinal fluid.
- the multiparticles may be filled in capsules.
- the insoluble component of the barrier layer which is insoluble in the gastrointestinal fluids, may comprise one or more materials, which may be a natural or synthetic polymers such as ethyl cellulose, cellulose acetate, polymethacrylates (such as Eudragit RS, RL and NE), polyvinyl chloride, polyvinyl acetate, silicone elastomers, shellac, or natural or synthetic waxes (such as carnauba wax).
- the insoluble component of the barrier layer is ethyl cellulose.
- Ethyl cellulose is an especially suitable insoluble material which is available in different grades and in special qualities for aqueous based barrier coatings.
- the soluble component of the barrier layer which is soluble in gastrointestinal fluids, may be a water soluble polymer such as hydroxypropyl methylcellulose, hydroxypropyl cellulose and some Eudragit grades. Instead of water soluble polymers, other water soluble substances as sugar, lactose and different salts can be used.
- the soluble compounent of the barrier layer is hydroxypropyl cellulose.
- the multiparticulates may comprise a binder and/or suspension agent.
- the binder and/or suspension agent is used to prepare a homogenous suspension of dipraglurant during the layering process and to produce a proper adhesion on the core.
- the binder/suspension agent may in general be a cellulose ether.
- the binder/suspension agent is hydroxypropyl methylcellulose.
- Plasticizers and pigments may optionally be used to modify the technical properties or change the permeability of the coating.
- Suitable plasticizers include triethylcitrate, dibutylsebacate, acetylated triacetin, tributylcitrate, glyceroltributyrate, propylene glycol, acetylated monoglycerides, rape oil, sesame oil, castor oil, acetylbutylcitrate, acetyltriethylcitrate, glycerine sorbitol, diethyloxalate, diethylphthalate, dibutylphthalate, diethylmalate, dibutylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate and the like, or combinations thereof.
- multiparticulates may be coated with a second polymeric film.
- This could be an enteric coating or a coating to provide protection from moisture.
- the said coating polymer could be selected from a group of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, methacrylic acid polymer, or other functional coating agent.
- the active ingredient dipraglurant may be within the range of 15-75% of the formulation (or multiparticulates) (w/w). Preferably, dipraglurant is within the range of 20-50% (w/w).
- the insoluble component (or "barrier coating polymer”) may be within the range of 1- 40 % of the formulation (or multiparticulates) (w/w). Preferably, the insoluble component is within the range of 3-20%> (w/w).
- the (water) soluble component may be within the range of 15 to 70% (w/w) related to the quantity of the barrier coating.
- the binder/suspending agent may be within the range of 16 to 60% (w/w) related to the quantity of dipraglurant.
- multiparticulates is a very well known technology to those skilled in the art. This could be performed by granulating the active ingredient with suitable excipients then extrusion/spheronisation to produce pellets or compression into mini tablets. Other preferred technology is to spray the active ingredient on nonpareils beads.
- the composition of beads could be sugar beads, microcrystalline cellulose beads or starch beads.
- the multiparticulates produced by any of the above technologies should be coated with a barrier layer (e.g. a barrier coating film).
- a barrier layer e.g. a barrier coating film
- dipraglurant may be included in the form of a pharmaceutically acceptable salt, co-crystal, solvate, or amorphous form thereof, or as a complex with other acceptable ingredients.
- dipraglurant is in the form of the monophosphate salt.
- Table 1 Composition of Multiparticulates at two different coating levels (7% and 10%)
- the production of the multiparticulates is performed as follows.
- the required amount of HPMC E5 is dispersed in hot water and cooled down to room temperature.
- the amount of water lost during heating is replaced.
- the required amount of drug is added to the HPMC-solution and thoroughly dispersed.
- the suspension is sieved through a 150 ⁇ sieve to guarantee the absence of lumps
- the suspension is sprayed on sugar beads using a Miniglatt lab-coater at a spray rate of 1.8 g/min with inlet air temperature of 68 °C, to form dipraglurant beads.
- Ethyl cellulose and hydroxypropyl cellulose are dissolved in isopropanol: water solution which has the ratio of 88: 12 parts to form a film barrier solution.
- This film barrier solution is sprayed on the previously prepared dipraglurant beads using a Miniglatt lab- coater at a spray rate of 1.2 g/min with inlet air temperature of 54 °C.
- the release profile is presented in Figure 1. Around 80%> of dipraglurant had been released over a 6 hours period for the multiparticulates which had been coated at 7% coating level; increasing the coating level to 10% allowed the release of 80% over 10 hours. These are very satisfactory in vitro profiles which confirm the possibility of modulating the duration of in vitro release by changing the thickness of coating layer. Following this satisfactory in vitro result, an in vivo test was performed to confirm the in vitro findings. Cynomolgus monkey was chosen as the closest animal model to human for testing an extended release formulation.
- the multiparticulates formulation fulfills the objectives of this invention by providing an extended release profile of dipraglurant. Furthermore, the results show that the extended release profile could be modulated according the required duration of exposure.
- the extended release formulation is a matrix tablet formulation.
- the matrix tablet formulation may comprise an active ingredient selected from dipraglurant, a pharmaceutically acceptable salt, co-crystal, solvate, or amorphous form thereof, or a complex of dipraglurant with other acceptable ingredients, and one or more (suitable) matrix forming gelling agents.
- the matrix forming gelling agents may be selected from the group consisting of hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, carbomer, acrylic acid- based polymers, polyethylene oxide polymers, carboxy methylcellulose, gum tragacanth, gum acacia, guar gum, pectin, modified starch derivatives, xanthan gum, locusta bean gum, sodium alginate or combinations thereof.
- the matrix forming gelling agent On contact with gastrointestinal fluid the matrix forming gelling agent swells and gels, forming a matrix structure that releases the active agent in a controlled manner.
- the matrix forming gelling agent is preferably hydroxypropyl methylcellulose (HPMC) (e.g. Methocel®).
- the matrix tablet formulation may be a pharmaceutical composition which can also comprise any other suitable ingredient well known to those skilled in the art, such as adsorbents, fillers, antioxidants, buffering agents, colorants, fiavorants, sweetening agents, tablet antiadherents, lubricants, tablet binders, diluents, tablet direct compression excipients, tablet glidants, polishing agents, and other equivalent excipients selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, powdered stearic acid, hydrogenated vegetable oils, talc, polyethylene glycol, mineral oil, modified cellulose, gelatin, starch paste, acacia, tragacanth, povidone, polyethylene glycol, colloidal silicon dioxide, talc, sodium lauryl sulfate, quaternary ammonium salts, mannitol, sodium chloride, sodium sulfate, sodium phosphate, magnesium chloride, magnesium sulfate, magnesium
- the matrix tablet formulation of the present invention may be coated with a polymeric film.
- This could be an enteric coating or a coating to provide protection from moisture or merely to add color to help patients distinguish among different drugs they may use.
- the said coating polymer could be selected from a group of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, methacrylic acid polymer, or other functional coating agent.
- the extended release matrix tablet formulation may be a pharmaceutical composition which may further include one or more pharmaceutically inert excipients selected from the group of adsorbents, fillers, antioxidants, buffering agents, colorants, fiavorants, sweetening agents, tablet antiadherents, lubricants, tablet binders, diluents, tablet direct compression excipients, tablet glidants, polishing agents and the like.
- adsorbents fillers, antioxidants, buffering agents, colorants, fiavorants, sweetening agents, tablet antiadherents, lubricants, tablet binders, diluents, tablet direct compression excipients, tablet glidants, polishing agents and the like.
- the above composition could be administrated to patients as tablet, mini tablet or pellets in capsule.
- the dosage form is a matrix tablet.
- the active ingredient dipraglurant may be within the range of 15-75 % of the tablet (w/w). Preferably, dipraglurant is within the range of 20-50% of the tablet (w/w).
- the matrix forming gelling agent (also known as the matrix forming polymer) may be within the range of 10-80 % (w/w) of the tablet. Preferably, the matrix forming gelling agent is within the range of 20-60% of the tablet (w/w).
- the process for producing the matrix tablet could be direct compression, wet granulation or dry granulation, which are well known to those skilled in the art.
- the matrix tablet is produced by direct compression of all components as this is the easiest manner to produce a tablet.
- dipraglurant may be included in the form of a pharmaceutically acceptable salt, co-crystal, solvate, or amorphous form thereof, or as a complex with other acceptable ingredients.
- dipraglurant is in the form of the monophosphate salt.
- composition is detailed in Table 2.
- Table 2 Composition of Matrix Tablet (Batch 29)
- Methocel K4M Premium DC, dipraglurant phosphate, magnesium stearate, Aerosil 200, and Avicel PH200 were sieved ⁇ into a 2L Turbula jar. The jar was sealed and the materials blended for 20 minutes using the Turbula blender.
- Tablets were produced on a Kilian RTS 2 ID rotary compression machine fitted with two stations of 8.0mm diameter round, plain, normal curvature tooling. The machine was run at 24rpm and the batch was compressed at a breaking strength of 8kp. All in process controls were satisfactory.
- the in vitro release profile was evaluated using the following dissolution method: USP II apparatus, 100 rpm, 900 mL acetate buffer 4.6 pH.
- the release profile is presented in Figure 1. Around 80% of dipraglurant had been released of the matrix tablet over 6 hours period, which is a satisfactory in vitro profile (Figure 5).
- Other different profiles with longer or shorter release duration were obtained using different grades of HPMC and/or combination with other polymers.
- Cynomolgus monkey was chosen as the closest animal model to human for testing an extended release formulation.
- the matrix tablet formulation is a second technology which fulfills the objectives of this invention, by providing an extended release profile of dipraglurant. Furthermore, the extended release profile can be modulated according to the required duration of exposure.
- the extended release pharmaceutical compositions of the invention are for the treatment or prevention of a condition which is affected or facilitated by the neuromodulatory effect of mGluR 5 negative allosteric modulators.
- Excessive glutamate levels in the basal ganglia motor circuitry is therefore proposed to play a key driver in PD symptoms and L-DOPA-induced (Levodopa-induced) motor complications such as dyskinesia (see Rouse et al. (2000) Pharmacol Ther., 88:427-35).
- One way to reduce the excessive glutamate transmission is to modulate the activity of different subtypes of glutamate receptors (for a review see Conn et al. (2005) Nat. Rev. Neurosci., 6:787-98).
- mGluR 5 is found abundantly in the striatum and therefore is likely to be implicated in the excess glutamate activity in PD.
- mGluR 5 is the only mGlu receptor type involved in substantia nigra neurons depolarisation.
- mGluR 5 antagonists or receptor KO decrease the toxic effects of MPTP and 6-OHDA (Battaglia et al. (2004) J. Neurosci., (4):828-35; Armentero M.T. et al. (2006) Neurobiol. Dis., 1 : 1-9).
- mGluR 5 is upregulated in animal lesion models (Sanchez- Pernaute R. et al. (2008) Neuroimage, (1):248-51).
- L-DOPA and non L-DOP A- induced dyskinesia, dystonia, generalized dystonia, tardive dyskinesia, L-DOPA non responsive PD syndrome and multiple system atrophy chorea, ataxia, tremor, restless legs syndrome and gait disorders.
- mGluR 5 blockade may also have beneficial effects on PD comorbid symptoms such as cognitive deficits induced by dopamine depletion (De Leonibus et al. (2009) Neuropsychopharmacology, (34):729-738) and in gastrointestinal dysfunction that is a frequent and occasionally dominating symptom of PD: mGluR 5 blockade, that increases bowel motility, might also help relief of these symptoms.
- Metabotropic glutamate receptor 5 negative allosteric modulators have also been efficacious in animal models of Amyotrophic lateral sclerosis and Huntington's disease, both of which with high-unmet medical need (Rossi D. et al. (2008) Cell Death Differ., 15(11): 1691-700; Schiefer J. et al. (2004) Brain Res., 1019(l-2):246-54.
- mGluR 5 receptor is therefore being considered as a potential drug target for treatment of psychiatric and neurological disorders.
- Treatable diseases in this connection are anxiety and depression disorders, attentional disorders, eating disorders, mood disorders, psychotic disorders, cognitive disorders, personality disorders and substance-related disorders.
- mGluR 5 receptors play a prominent role at gastroesophageal vagal afferent endings and a minor role in central gastric vagal pathways.
- Peripheral mGluR 5 receptors may therefore prove a suitable target for reducing mechanosensory input from the periphery for therapeutic benefit with mGluR 5 antagonists (Young R.J. et al. (2007) Am. J. Physiol. Gastrointest. Liver. Physiol, 292(2):501-11; Jensen J. (2005) Eur. J. Pharmacol, 519: 154-7).
- the extended release formulation (e.g. multiparticulates composition or matrix tablet formulation (solid oral dosage form)) of the invention is for the treatment or prevention of a disorder selected from epilepsy, ischemia, neuropathic or inflammatory pain, psychiatric disorders such as psychotic disorders, central nervous system disorders selected from addiction, tolerance or dependence, affective disorders, such as depression and anxiety, attention- deficit/hyperactivity disorder, bipolar disorder, movement disorders, neuroprotection, migraine, neurological disorders such as neurodegeneration, neurotoxicity, Parkinson's disease, PD-LID, dystonia, memory impairment, Alzheimer's disease, dementia, delirium tremens, attentional disorders, eating disorders, mood disorders, cognitive disorders, personality disorders, behavioural disorders, substance of abuse related disorders, including alcohol, nicotine, cocaine, amphetamine, benzodiazepine, analgesics, opiate or other substance tolerance or dependence, bulimia nervosa, anorexia nervosa, gambling dependence, sex
- the extended release formulation of the invention is for the treatment of dystonia.
- the extended release formulation of the invention is for the treatment of autism.
- the extended release formulation of the invention is for the treatment of Fragile X.
- the extended release formulation of the invention is for the treatment of anxiety.
- the extended release formulation of the invention is for the treatment of depression.
Abstract
The present invention relates to extended release formulations comprising dipraglurant, a metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator, or a pharmaceutically acceptable salt thereof, for oral administration. The invention further provides a process for preparing these extended releases formulations and their use in the prevention or treatment disorders related to mGluR5 negative allosteric modulators.
Description
EXTENDED RELEASE FORMULATIONS
SUMMARY OF THE INVENTION
The present invention relates to extended release formulations comprising dipraglurant, a metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator, or a pharmaceutically acceptable salt thereof, for oral administration. The invention further provides a process for preparing these extended releases formulations and their use in the prevention or treatment of disorders related to mGluR5 negative allosteric modulators.
BACKGROUND TO THE INVENTION
Dipraglurant is the approved name for 6-fluoro-2-[4-(pyridin-2-yl)but-3-yn-l- yl]imidazo[l,2-a]pyridine and is described in WO05123703 (Example 74) as a negative allosteric modulator of the metabotropic glutamate receptor 5 (mGluR5). The compound has the following structure:
Dipraglurant is also known under the reference name ADX48621 (Rocher J.-P. et al, Current Topics in Med. Chem. 2011, 11, 680-95).
Dipraglurant can exist as a pharmaceutically acceptable salt, co-crystal, solvate, amorphous form or complex with other ingredients. From several salts, the phosphate of dipraglurant has been selected and has shown to be a highly soluble and highly permeable molecule. This means that after the administration in a conventional immediate release dosage form, the active substance is rapidly dissolved in the
gastrointestinal tract and rapidly absorbed to the systemic circulation. The duration of exposure is mainly controlled by the elimination half life. Dipraglurant is characterized by a short half life of less than 1 hour. This is suitable for some indications where a high plasmatic concentration is required rapidly for a short time but this is not suitable for chronic indications where a sustainable plasmatic concentration is needed.
In the framework of the present invention and in line with the European Pharmacopeia, an extended release formulation (alternatively named as a prolonged release formulation) is defined as a modified release dosage form from which the release of the active substance and its subsequent absorption are prolonged in comparison with a conventional unmodified (immediate-release) dosage form administered by the same route. Numerous extended release formulations are known in the art. Specifically, they are often designed to maintain adequate plasma concentration and minimise peak-to- trough variation in drug plasma levels associated with conventional frequent dosage regimes. However, up to now it has not been considered feasible to make a formulation with a sufficiently extended release profile for molecules with such short half life. A. G. Thombre stated in his assessment of the feasibility of the oral controlled release that molecules with half life which is less than 1-2 hours are too short for controlled release development (Thombre A. V., Drug Discovery Today, 2005, 10, 17, 1159-66). This is the case with dipraglurant, which has a very short half life of less than one hour.
An additional challenge to produce an extended release formulation of dipraglurant phosphate is its high aqueous solubility (21.0 to 32.5 mg/mL) at all relevant physiological pH. For a drug with very high solubility and a rapid dissolution rate, it is often quite difficult to decrease its dissolution rate and slow its absorption. A drug of high water solubility can dissolve in water or gastrointestinal milieu readily and tends to release from its dosage form in a burst and thus is absorbed quickly, leading to a sharp increase in the drug blood concentration.
Compared to less soluble drugs, it is often difficult to sequester a highly water soluble drug in the dosage form (such as tablet or capsule) and retard the drug release (Ranjith
Kumar Mamidala et al., International Journal of Pharmaceutical Sciences and Nanotechnology, 2009, 2 (3), 583-94).
The present invention seeks to provide an extended release formulation of dipraglurant which allows prolonged plasmatic concentration. A prolonged plasmatic concentration above the efficient concentration is mandatory to achieve pharmacological efficiency. This helps to reduce the number of doses per day and helps achieve better patient compliance.
Another object of the invention is to provide extended release formulations of dipraglurant with different in vivo release profiles so that the best profile could be chosen to match the intended indication requirements in terms of exposure duration.
An important object of the invention is to provide an extended release formulation of dipraglurant with an in vivo release profile that could be adjusted based on an in vitro release profile. This in vitro I in vivo correlation (IVIVC) is highly helpful in predicting the impact of the formulation modifications on the pharmacokinetic profile.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows the dissolution profile of multiparticulates coated at 7% level;
Figure 2 shows the dissolution profile of multiparticulates coated at 10% level;
Figure 3 shows the pharmacokinetic profile of multiparticulates coated at 7% and 10% level vs. dipraglurant solution;
Figure 4 shows the multiparticulates formulation coated at 7% and 10% level, In vitro - In vivo correlation in Cynomolgus monkeys;
Figure 5 shows the dissolution profile of Matrix tablet (Batch 29);
Figure 6 shows the pharmacokinetic profile of Matrix tablet (Batch 29) vs. dipraglurant solution;
Figure 7 shows Matrix tablet formulation In vitro - In vivo correlation in Cynomolgus monkeys.
DETAILED DESCRIPTION OF THE INVENTION
The purpose of the present invention is to provide a controlled (e.g. extended) release formulation of dipraglurant (or a pharmaceutically acceptable salt, co-crystal, solvate or amorphous form thereof, or a complex of dipraglurant with other acceptable ingredients) which satisfy the objectives detailed above. This was achieved using two different formulation technologies which are Multiparticulates and Matrix tablets formulations.
The extended release formulations of the present invention are suitable for oral administration (i.e. orally administrable).
The extended release formulations of the present invention are further defined in the appended claims, to which reference is now made.
A. Multiparticulates Formulation
According to one aspect of the present invention, the extended release formulation comprises multiparticulates (e.g. pellets, beads, or mini-tablets) comprising an active ingredient selected from dipraglurant, or a pharmaceutically acceptable salt, co-crystal, solvate, or amorphous form thereof, or a complex of dipraglurant with other acceptable ingredients. The multiparticulates may be coated with a barrier layer. The barrier layer may comprise (or may consist of) a component that is insoluble in the gastrointestinal fluid (referred to hereinafter as the "insoluble component"), mixed with a pore forming component that is soluble in the gastrointestinal fluid (referred to hereinafter as "soluble component"). The barrier layer assures a prolonged release of dipraglurant in the gastrointestinal fluid. The multiparticles may be filled in capsules.
The insoluble component of the barrier layer, which is insoluble in the gastrointestinal fluids, may comprise one or more materials, which may be a natural or synthetic polymers such as ethyl cellulose, cellulose acetate, polymethacrylates (such as Eudragit RS, RL and NE), polyvinyl chloride, polyvinyl acetate, silicone elastomers, shellac, or natural or synthetic waxes (such as carnauba wax). Preferably, the insoluble component of the barrier layer is ethyl cellulose.
Ethyl cellulose is an especially suitable insoluble material which is available in different grades and in special qualities for aqueous based barrier coatings.
The soluble component of the barrier layer, which is soluble in gastrointestinal fluids, may be a water soluble polymer such as hydroxypropyl methylcellulose, hydroxypropyl cellulose and some Eudragit grades. Instead of water soluble polymers, other water soluble substances as sugar, lactose and different salts can be used. Preferably, the soluble compounent of the barrier layer is hydroxypropyl cellulose.
The multiparticulates may comprise a binder and/or suspension agent. The binder and/or suspension agent is used to prepare a homogenous suspension of dipraglurant during the layering process and to produce a proper adhesion on the core. The binder/suspension agent may in general be a cellulose ether. Preferably, the binder/suspension agent is hydroxypropyl methylcellulose.
Plasticizers and pigments may optionally be used to modify the technical properties or change the permeability of the coating.
Suitable plasticizers include triethylcitrate, dibutylsebacate, acetylated triacetin, tributylcitrate, glyceroltributyrate, propylene glycol, acetylated monoglycerides, rape oil, sesame oil, castor oil, acetylbutylcitrate, acetyltriethylcitrate, glycerine sorbitol, diethyloxalate, diethylphthalate, dibutylphthalate, diethylmalate, dibutylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate and the like, or combinations thereof.
Furthermore, multiparticulates may be coated with a second polymeric film. This could be an enteric coating or a coating to provide protection from moisture. The said coating polymer could be selected from a group of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, methacrylic acid polymer, or other functional coating agent.
The active ingredient dipraglurant may be within the range of 15-75% of the formulation (or multiparticulates) (w/w). Preferably, dipraglurant is within the range of 20-50% (w/w).
The insoluble component (or "barrier coating polymer") may be within the range of 1- 40 % of the formulation (or multiparticulates) (w/w). Preferably, the insoluble component is within the range of 3-20%> (w/w).
The (water) soluble component may be within the range of 15 to 70% (w/w) related to the quantity of the barrier coating.
The binder/suspending agent may be within the range of 16 to 60% (w/w) related to the quantity of dipraglurant.
The production of multiparticulates is a very well known technology to those skilled in the art. This could be performed by granulating the active ingredient with suitable excipients then extrusion/spheronisation to produce pellets or compression into mini tablets. Other preferred technology is to spray the active ingredient on nonpareils beads. The composition of beads could be sugar beads, microcrystalline cellulose beads or starch beads.
The multiparticulates produced by any of the above technologies should be coated with a barrier layer (e.g. a barrier coating film).
In any multiparticulates formulation according to the present invention, dipraglurant may be included in the form of a pharmaceutically acceptable salt, co-crystal, solvate, or amorphous form thereof, or as a complex with other acceptable ingredients. Preferably, dipraglurant is in the form of the monophosphate salt.
The invention is further illustrated, but should not be limited, to the following example.
Example of Multiparticulates formulation
The composition is detailed in Table 1.
Table 1 : Composition of Multiparticulates at two different coating levels (7% and 10%)
The production of the multiparticulates is performed as follows. The required amount of HPMC E5 is dispersed in hot water and cooled down to room temperature. The amount of water lost during heating is replaced. The required amount of drug is added to the HPMC-solution and thoroughly dispersed. The suspension is sieved through a 150 μιη sieve to guarantee the absence of lumps
The suspension is sprayed on sugar beads using a Miniglatt lab-coater at a spray rate of 1.8 g/min with inlet air temperature of 68 °C, to form dipraglurant beads. Ethyl cellulose and hydroxypropyl cellulose are dissolved in isopropanol: water solution which has the ratio of 88: 12 parts to form a film barrier solution. This film barrier solution is sprayed on the previously prepared dipraglurant beads using a Miniglatt lab- coater at a spray rate of 1.2 g/min with inlet air temperature of 54 °C.
The in vitro release profile was evaluated using the following dissolution method: USP II apparatus, 100 rpm, 900 mL phosphate buffer pH = 6.8. The release profile is presented in Figure 1. Around 80%> of dipraglurant had been released over a 6 hours period for the multiparticulates which had been coated at 7% coating level; increasing the coating level to 10% allowed the release of 80% over 10 hours. These are very satisfactory in vitro profiles which confirm the possibility of modulating the duration of in vitro release by changing the thickness of coating layer.
Following this satisfactory in vitro result, an in vivo test was performed to confirm the in vitro findings. Cynomolgus monkey was chosen as the closest animal model to human for testing an extended release formulation.
The expected sustained release profile with the multiparticulates formulation was compared with the immediate release dipraglurant solution (Figure 3).
In addition to the significant increase in the duration of exposure, an excellent correlation coefficient (R2 = 0.97%) between the in vitro release and the absorbed fraction is observed (Figure 4). This in vitro I in vivo correlation is highly useful to modulate the absorption profile based on dissolution data.
Based on these results, we can see that the multiparticulates formulation fulfills the objectives of this invention by providing an extended release profile of dipraglurant. Furthermore, the results show that the extended release profile could be modulated according the required duration of exposure.
B. Matrix Tablet Formulation
According to another aspect of the present invention, the extended release formulation is a matrix tablet formulation. The matrix tablet formulation may comprise an active ingredient selected from dipraglurant, a pharmaceutically acceptable salt, co-crystal, solvate, or amorphous form thereof, or a complex of dipraglurant with other acceptable ingredients, and one or more (suitable) matrix forming gelling agents. The matrix forming gelling agents may be selected from the group consisting of hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, carbomer, acrylic acid- based polymers, polyethylene oxide polymers, carboxy methylcellulose, gum tragacanth, gum acacia, guar gum, pectin, modified starch derivatives, xanthan gum,
locusta bean gum, sodium alginate or combinations thereof. On contact with gastrointestinal fluid the matrix forming gelling agent swells and gels, forming a matrix structure that releases the active agent in a controlled manner. The matrix forming gelling agent is preferably hydroxypropyl methylcellulose (HPMC) (e.g. Methocel®).
The matrix tablet formulation may be a pharmaceutical composition which can also comprise any other suitable ingredient well known to those skilled in the art, such as adsorbents, fillers, antioxidants, buffering agents, colorants, fiavorants, sweetening agents, tablet antiadherents, lubricants, tablet binders, diluents, tablet direct compression excipients, tablet glidants, polishing agents, and other equivalent excipients selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, powdered stearic acid, hydrogenated vegetable oils, talc, polyethylene glycol, mineral oil, modified cellulose, gelatin, starch paste, acacia, tragacanth, povidone, polyethylene glycol, colloidal silicon dioxide, talc, sodium lauryl sulfate, quaternary ammonium salts, mannitol, sodium chloride, sodium sulfate, sodium phosphate, magnesium chloride, magnesium sulfate, magnesium phosphate, microcrystalline cellulose, sodium starch glycolate, lactose, microcrystalline cellulose, sucrose, glucose, mannitol, calcium carbonate, colloidal anhydrous silica, polyethylene glycols, waxes, hydrogenated castor oil, starch, polyvinyl pyrrolidone derivatives and combinations thereof.
Furthermore, the matrix tablet formulation of the present invention may be coated with a polymeric film. This could be an enteric coating or a coating to provide protection from moisture or merely to add color to help patients distinguish among different drugs they may use. The said coating polymer could be selected from a group of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, methacrylic acid polymer, or other functional coating agent.
The extended release matrix tablet formulation may be a pharmaceutical composition which may further include one or more pharmaceutically inert excipients selected from the group of adsorbents, fillers, antioxidants, buffering agents, colorants, fiavorants,
sweetening agents, tablet antiadherents, lubricants, tablet binders, diluents, tablet direct compression excipients, tablet glidants, polishing agents and the like.
The above composition could be administrated to patients as tablet, mini tablet or pellets in capsule. In a preferred embodiment, the dosage form is a matrix tablet.
The active ingredient dipraglurant may be within the range of 15-75 % of the tablet (w/w). Preferably, dipraglurant is within the range of 20-50% of the tablet (w/w).
The matrix forming gelling agent (also known as the matrix forming polymer) may be within the range of 10-80 % (w/w) of the tablet. Preferably, the matrix forming gelling agent is within the range of 20-60% of the tablet (w/w).
The process for producing the matrix tablet could be direct compression, wet granulation or dry granulation, which are well known to those skilled in the art. Preferably, the matrix tablet is produced by direct compression of all components as this is the easiest manner to produce a tablet.
In any matrix tablet formulation according to the present invention, dipraglurant may be included in the form of a pharmaceutically acceptable salt, co-crystal, solvate, or amorphous form thereof, or as a complex with other acceptable ingredients. Preferably, dipraglurant is in the form of the monophosphate salt.
The invention is further illustrated, but should not be limited, to the following example.
Example of Matrix tablet formulation
The composition is detailed in Table 2.
Table 2: Composition of Matrix Tablet (Batch 29)
The Methocel K4M Premium DC, dipraglurant phosphate, magnesium stearate, Aerosil 200, and Avicel PH200 were sieved ΙΟΟΟμιη into a 2L Turbula jar. The jar was sealed and the materials blended for 20 minutes using the Turbula blender.
Tablets were produced on a Kilian RTS 2 ID rotary compression machine fitted with two stations of 8.0mm diameter round, plain, normal curvature tooling. The machine was run at 24rpm and the batch was compressed at a breaking strength of 8kp. All in process controls were satisfactory.
The in vitro release profile was evaluated using the following dissolution method: USP II apparatus, 100 rpm, 900 mL acetate buffer 4.6 pH. The release profile is presented in Figure 1. Around 80% of dipraglurant had been released of the matrix tablet over 6 hours period, which is a satisfactory in vitro profile (Figure 5). Other different profiles with longer or shorter release duration were obtained using different grades of HPMC and/or combination with other polymers.
Following this satisfactory in vitro result, an in vivo test was performed to confirm the in vitro findings. Cynomolgus monkey was chosen as the closest animal model to human for testing an extended release formulation.
The expected sustained release profile with matrix tablet was compared with immediate release dipraglurant solution (Figure 6).
In addition to the significant increase in the duration of exposure, an excellent correlation coefficient (R2 = 0.99%) between the in vitro release and the absorbed fraction (FD) is observed (Figure 7). This in vitro I in vivo correlation is highly useful to modulate the absorption profile based on dissolution data.
Based on these results, we can see that the matrix tablet formulation is a second technology which fulfills the objectives of this invention, by providing an extended release profile of dipraglurant. Furthermore, the extended release profile can be modulated according to the required duration of exposure.
C. Use of dipraglurant in disorders related to mGluR¾
The extended release pharmaceutical compositions of the invention are for the treatment or prevention of a condition which is affected or facilitated by the neuromodulatory effect of mGluR5 negative allosteric modulators.
A variety of potential clinical indications have been suggested to be targets for the development of subtype selective mGluR5 negative modulators. These include epilepsy (Mares et al. (2009) Epilepsy Res., 83:215-23), pain (neuropathic and inflammatory pain; visceral and post-operative pain; pain symptoms associated with migraine; see in Dolan and Nolan (2007) A.M. Eur. J. Pain., 11 :644-51; Lindstrom et al. (2008) Pain, 137:295-305; Dray (2008) Br. J. Anaesth., 101 :48-58) numerous psychiatric disorders (e.g. anxiety, depression, schizophrenia and related psychotic disorders), neuroprotection (stroke and head injury), migraine and addiction/drug dependency (for reviews, see Bordi and Ugolini (1999) Prog. Neurobiol, 59:55-79; Brauner-Osborne et al. (2000) J. Med. Chem., 43 :2609-45; Spooren et al. (2003) Behav. Pharmacol, 14:257-77; Marino and Conn (2006) Curr. Opin. Pharmacol, 6: 98-102).
The loss of striatal dopaminergic modulation in Parkinson's Disease (PD) results in an increase in glutamatergic output from substantia nigra. Excessive glutamate levels in the basal ganglia motor circuitry is therefore proposed to play a key driver in PD symptoms and L-DOPA-induced (Levodopa-induced) motor complications such as dyskinesia (see Rouse et al. (2000) Pharmacol Ther., 88:427-35). One way to reduce the excessive glutamate transmission is to modulate the activity of different subtypes of glutamate receptors (for a review see Conn et al. (2005) Nat. Rev. Neurosci., 6:787-98). Among these receptors present in the basal ganglia circuit, mGluR5 is found abundantly in the striatum and therefore is likely to be implicated in the excess glutamate activity in PD. mGluR5 is the only mGlu receptor type involved in substantia nigra neurons depolarisation.
There is substantial evidence that chronic mGluR5 blockade reverses Parkinsonian symptoms and deficits in rodents, including reversal of akinesia in 6-OHDA-lesioned rats and the decrease of STN hyperactivity (Ossowska et al. (2001) Neuropharmacology, 41 :413-20; Breysse N. et al. (2002) J. Neurosci., 22(13):5669-78; Armentero M.T. et al. (2006) Neurobiol. Dis., 1 : 1-9) and mGluR5 antagonists decrease L-DOPA-induced dyskinesias (Dekundy A. et al. (2006) Brain Res. Bull, (3):318-26; Levandis G. et al. (2008) Neurobiol. Dis., (1): 161-8). Furthermore it was shown that the specific blockage of mGluR5 receptors with MPEP and MTEP led to improvement of L-DOPA efficacy in treating Parkinsonian symptoms in MPTP-lesioned non human primates (Morin et al. (2010) Neuropharmacology, 58(7):981-986).
In addition, mGluR5 antagonists or receptor KO decrease the toxic effects of MPTP and 6-OHDA (Battaglia et al. (2004) J. Neurosci., (4):828-35; Armentero M.T. et al. (2006) Neurobiol. Dis., 1 : 1-9). mGluR5 is upregulated in animal lesion models (Sanchez- Pernaute R. et al. (2008) Neuroimage, (1):248-51).
Taken together these data strongly highlight the potential of mGluR5 antagonists or mGluR5 modulators in treating different Parkinson's disease symptoms and movements disorders: L-DOPA and non L-DOP A- induced dyskinesia, dystonia, generalized dystonia, tardive dyskinesia, L-DOPA non responsive PD syndrome and multiple system atrophy chorea, ataxia, tremor, restless legs syndrome and gait disorders.
Interestingly mGluR5 blockade may also have beneficial effects on PD comorbid symptoms such as cognitive deficits induced by dopamine depletion (De Leonibus et al. (2009) Neuropsychopharmacology, (34):729-738) and in gastrointestinal dysfunction that is a frequent and occasionally dominating symptom of PD: mGluR5 blockade, that increases bowel motility, might also help relief of these symptoms.
Metabotropic glutamate receptor 5 negative allosteric modulators have also been efficacious in animal models of Amyotrophic lateral sclerosis and Huntington's disease, both of which with high-unmet medical need (Rossi D. et al. (2008) Cell Death Differ., 15(11): 1691-700; Schiefer J. et al. (2004) Brain Res., 1019(l-2):246-54.
mGluR5 receptor is therefore being considered as a potential drug target for treatment of psychiatric and neurological disorders. Treatable diseases in this connection are anxiety and depression disorders, attentional disorders, eating disorders, mood disorders, psychotic disorders, cognitive disorders, personality disorders and substance- related disorders.
Other research supports a role of mGluR5 modulation in the treatment of Fragile X syndrome (Weiler I.J. (1997) Proc. Natl. Acad. Sci. USA, 94:5395-5400; Antar L.N. et al. (2004) J. Neurosci., 24-11 :2648-2655; Yan et al. (2005) Neuropharmacology, 49(7): 1053-66), Obesity (Bradbury M.J. (2005) J. Pharmacol. Exp. Ther., 313:395-402) and Gastro -Esophageal Reflux Disease (GERD). For GERD, it has been recently demonstrated that mGluR5 receptors play a prominent role at gastroesophageal vagal afferent endings and a minor role in central gastric vagal pathways. Peripheral mGluR5
receptors may therefore prove a suitable target for reducing mechanosensory input from the periphery for therapeutic benefit with mGluR5 antagonists (Young R.J. et al. (2007) Am. J. Physiol. Gastrointest. Liver. Physiol, 292(2):501-11; Jensen J. (2005) Eur. J. Pharmacol, 519: 154-7).
A recent study in rodents using MPEP has shown that besides ionotropic glutamate receptors NMD A and AMP A, mGluR5 receptors facilitated the control of micturition and visceral nociception from the urinary bladder. Central rather than peripheral mGluR5 receptors appear to be responsible (Y. Hu et al. (2009) Neurosc. Lett., 450: 12- 17).
Thus, according to one embodiment of the invention, the extended release formulation (e.g. multiparticulates composition or matrix tablet formulation (solid oral dosage form)) of the invention is for the treatment or prevention of a disorder selected from epilepsy, ischemia, neuropathic or inflammatory pain, psychiatric disorders such as psychotic disorders, central nervous system disorders selected from addiction, tolerance or dependence, affective disorders, such as depression and anxiety, attention- deficit/hyperactivity disorder, bipolar disorder, movement disorders, neuroprotection, migraine, neurological disorders such as neurodegeneration, neurotoxicity, Parkinson's disease, PD-LID, dystonia, memory impairment, Alzheimer's disease, dementia, delirium tremens, attentional disorders, eating disorders, mood disorders, cognitive disorders, personality disorders, behavioural disorders, substance of abuse related disorders, including alcohol, nicotine, cocaine, amphetamine, benzodiazepine, analgesics, opiate or other substance tolerance or dependence, bulimia nervosa, anorexia nervosa, gambling dependence, sex dependence, obsessive compulsive disorders, panic disorder, phobia, post-traumatic stress disorder, generalized anxiety disorder, seasonal affective disorders, acute stress disorder, inherited disorders such as Fragile X syndrome, autism, obesity and gastrointestinal disorders, for example, gastroesophageal reflux disease (GERD), lower esophageal sphincter diseases or disorders, diseases of gastrointestinal motility, colitis, Crohn's disease or irritable bowel syndrome (IBS).
In one preferred embodiment, the extended release formulation of the invention is for the treatment of Parkinson's disease L-DOPA induced dyskinesia.
In one preferred embodiment, the extended release formulation of the invention is for the treatment of dystonia.
In one preferred embodiment, the extended release formulation of the invention is for the treatment of autism.
In one preferred embodiment, the extended release formulation of the invention is for the treatment of Fragile X.
In one preferred embodiment, the extended release formulation of the invention is for the treatment of anxiety.
In one preferred embodiment, the extended release formulation of the invention is for the treatment of depression.
Claims
1. An extended release formulation comprising an active ingredient selected from dipraglurant, a pharmaceutically acceptable salt, co-crystal, solvate, or amorphous form thereof, or a complex of dipraglurant with other acceptable ingredients, suitable for oral administration.
An extended release formulation according to claim 1, wherein the pharmaceutically acceptable salt is a monophosphate salt.
An extended release formulation according to claims 1 and 2, wherein the formulation comprises multiparticulates comprising the active ingredient.
An extended release formulation according to claim 3, wherein the multiparticulates are coated with a barrier layer.
An extended release formulation according to claim 4, wherein the barrier layer comprises: a component that is insoluble in gastrointestinal fluid; and a component that is soluble in gastrointestinal fluid.
6. An extended release formulation according to claim 5, wherein the component that is soluble in gastrointestinal fluid is a suitable water soluble component.
7. An extended release formulation according to any of claims 3 to 6, wherein the extended release formulation further comprises a suitable binder/suspension agent.
An extended release formulation according to any of claims 5 to 7, wherein the insoluble component is selected from a natural or synthetic polymer, including ethyl cellulose, cellulose acetate, polymethacrylates, including Eudragit RS, RL and NE, polyvinyl chloride, polyvinyl acetate, silicone elastomers, shellac, or natural or synthetic waxes, including carnauba wax.
9. An extended release formulation according to claim 5, wherein the insoluble component is ethyl cellulose.
An extended release formulation according to any of claims 5 to 9, wherein the soluble component is selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, water soluble grades of Eudragit, sugar, or lactose.
An extended release formulation according to any of claims 7 to 10, wherein the binder/suspension agent is a cellulose ether, preferably hydroxypropyl methylcellulose.
12. An extended release formulation according to any of claims 5 to 1 1, wherein the amount of the active ingredient is 15 to 75% w/w of the formulation.
13. An extended release formulation according to any of claims 5 to 12, wherein the amount of the insoluble component is 1 to 40% w/w of the formulation.
14. An extended release formulation according to any of claims 5 to 13, wherein the amount of the soluble component is 15 to 70%> w/w of the insoluble component.
15. An extended release formulation according to any of claims 7 to 14, wherein the amount of the binder/suspension agent is 10 to 60% w/w of the active ingredient.
16. An extended release formulation according to claim 7, wherein the formulation comprises: i) the active ingredient in an amount of 20 to 50% w/w of the formulation; ii) the insoluble component in the form of ethyl cellulose in an amount of 3 to 20%) w/w of the formulation; iii) the soluble component in the form of hydroxypropyl cellulose in an amount of 15 to 70%o w/w of ethyl cellulose; and iv) the binder/suspension agent in the form of hydroxypropyl methylcellulose in an amount of 10 to 60% w/w of the active ingredient.
17. An extended release formulation according to any preceding claim wherein the formulation comprises one or more pharmaceutically acceptable plasticizers and/or pigments.
18. A method of preparing the extended release formulation of any of the claims 3 to 17 wherein the active ingredient is layered on an inert core and was coated with barrier film in a conventional manner.
19. An extended release formulation according to claims 1 and 2, wherein the formulation comprises matrix tablets.
20. An extended release formulation according to claims 1, 2 or 19, wherein the formulation comprises: i) the active ingredient; and
a suitable gelling agent.
21. An extended release formulation according to claim 20, wherein the formulation comprises: i) the active ingredient; and ii) a suitable gelling agent selected from the group hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, carbomer, acrylic acid-based polymers, polyethylene oxide polymers, carboxy methylcellulose, gum tragacanth, gum acacia, guar gum, pectin, modified starch derivatives, xanthan gum, locusta bean gum, sodium alginate or combinations thereof.
22. An extended release formulation according to claim 21, wherein the gelling agent is hydroxypropyl methylcellulose.
23. An extended release formulation according to any of claims 20 to 22, wherein the amount of the active ingredient is 15 to 75% w/w of the formulation.
24. An extended release formulation according to any of claims 20 to 23, wherein the amount of the gelling agent is 10 to 80% w/w of the formulation.
25. An extended release formulation according to any of claims 20 to 24, wherein the formulation comprises: i) the active ingredient in an amount of 20 to 50% w/w of the formulation; and ii) the gelling agent in the form of hydroxypropyl methylcellulose in an amount of 20 to 60% of the formulation.
26. An extended release formulation according to any of claims 19 to 25, wherein the formulation further comprises one or more components selected from the
group of adsorbents, fillers, antioxidants, buffering agents, colorants, flavorants, sweetening agents, tablet antiadherents, lubricants, tablet binders, diluents, tablet direct compression excipients, tablet glidants, polishing agents or other equivalent excipients.
An extended release formulation according to any of claims 19 to 26, wherein the formulation further comprises a diluent/binder, a tablet glidant and/or a lubricant.
An extended release formulation according to claim 27, wherein the diluent/binder is microcrystalline cellulose, wherein the tablet glidant is Aerosil, and wherein the lubricant is magnesium stearate.
A method of preparing an extended release formulation according to any of claims 19 to 28 wherein the active ingredient is mixed and/or granulated with a suitable gelling agent and then mixed with a suitable excipient for compression.
An extended release formulation according to any preceding claim for treating or preventing a condition, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of mGluR5 negative allosteric modulators.
31. An extended release formulation according to any preceding claim for treating or preventing disorders selected from the group consisting of: epilepsy, ischemia, neuropathic or inflammatory pain, psychiatric disorders such as psychotic disorders, central nervous system disorders selected from addiction, tolerance or dependence, affective disorders, such as depression and anxiety, attention-deficit/hyperactivity disorder, bipolar disorder, movement disorders,
neuroprotection, migraine, neurological disorders such as neurodegeneration, neurotoxicity, Parkinson's disease, Parkinson's disease L-DOPA induced dyskinesia, dystonia, memory impairment, Alzheimer's disease, dementia, delirium tremens, attentional disorders, eating disorders, mood disorders, cognitive disorders, personality disorders, behavioural disorders, substance of abuse related disorders, including alcohol, nicotine, cocaine, amphetamine, benzodiazepine, analgesics, opiate or other substance tolerance or dependence, bulimia nervosa, anorexia nervosa, gambling dependence, sex dependence, obsessive compulsive disorders, panic disorder, phobia, post-traumatic stress disorder, generalized anxiety disorder, seasonal affective disorders, acute stress disorder, inherited disorders such as Fragile X syndrome, autism, Huntington's disease, obesity and gastrointestinal disorders, for example, gastro-esophageal reflux disease (GERD), lower esophageal sphincter diseases or disorders, diseases of gastrointestinal motility, colitis, Crohn's disease or irritable bowel syndrome (IBS).
32. An extended release formulation according to any of claims 1 to 30 for treating, preventing or delaying progression of Parkinson's disease L-DOPA induced dyskinesia and non L-DOPA induced dyskinesia.
33. An extended release formulation according to any of claims 1 to 30 for treating, preventing or delaying progression of dystonia.
34. An extended release formulation according to any of claims 1 to 30 for treating, preventing or delaying progression of autism.
35. An extended release formulation according to any of claims 1 to 30 for treating, preventing or delaying progression of Fragile X.
36. An extended release formulation according to any of claims 1 to 30 for treating, preventing or delaying progression of anxiety.
37. An extended release formulation according to any of claims 1 to 30 for treating, preventing or delaying progression of depression.
38. An extended release formulation as hereinbefore described with reference to the Example of Multiparticulates Formulation or Example of Matrix Tablet Formulation.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1210530.0 | 2012-06-13 | ||
| GB201210530A GB201210530D0 (en) | 2012-06-13 | 2012-06-13 | Extended release formulations |
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| WO2013186311A1 true WO2013186311A1 (en) | 2013-12-19 |
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| PCT/EP2013/062273 WO2013186311A1 (en) | 2012-06-13 | 2013-06-13 | Extended release formulations |
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| WO2015044270A1 (en) * | 2013-09-25 | 2015-04-02 | Addex Pharma S.A. | Mono-phosphate salt of 6-fluoro-2-[4-(pyridin-2-yl)but-3-yn-1-yl]imidazo[1,2a]pyridine and polymorphs thereof as negative allosteric modulator of mglu5 receptor |
| US10166183B2 (en) | 2014-02-07 | 2019-01-01 | Auspex Pharmaceuticals, Inc. | Pharmaceutical formulations |
| US10835488B2 (en) | 2016-06-16 | 2020-11-17 | Dexcel Pharma Technologies Ltd. | Stable orally disintegrating pharmaceutical compositions |
| US11077055B2 (en) | 2015-04-29 | 2021-08-03 | Dexcel Pharma Technologies Ltd. | Orally disintegrating compositions |
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| WO2005123703A2 (en) * | 2004-06-17 | 2005-12-29 | Addex Pharmaceuticals Sa | Alkynyl derivatives as modulators of metabotropic glutamate receptors |
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| WO2005123703A2 (en) * | 2004-06-17 | 2005-12-29 | Addex Pharmaceuticals Sa | Alkynyl derivatives as modulators of metabotropic glutamate receptors |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015044270A1 (en) * | 2013-09-25 | 2015-04-02 | Addex Pharma S.A. | Mono-phosphate salt of 6-fluoro-2-[4-(pyridin-2-yl)but-3-yn-1-yl]imidazo[1,2a]pyridine and polymorphs thereof as negative allosteric modulator of mglu5 receptor |
| EA028037B1 (en) * | 2013-09-25 | 2017-09-29 | Аддекс Фарма С.А. | MONO-PHOSPHATE SALT OF 6-FLUORO-2-[4-(PYRIDIN-2-YL)BUT-3-YN-1-YL]IMIDAZO[1,2-a]PYRIDINE AND POLYMORPHS THEREOF AS NEGATIVE ALLOSTERIC MODULATOR OF mGluRECEPTOR |
| AU2014327236B2 (en) * | 2013-09-25 | 2018-03-22 | Addex Pharma S.A. | Mono-phosphate salt of 6-fluoro-2-[4-(pyridin-2-yl)but-3-yn-1-yl]imidazo[1,2a]pyridine and polymorphs thereof as negative allosteric modulator of mGlu5 receptor |
| US9938270B2 (en) | 2013-09-25 | 2018-04-10 | Addex Pharma S.A. | Mono-phosphate salt of 6-fluoro-2-[4-(pyridin-2-yl)but-3-yn-1-yl]imidazo[1,2A]pyridine (dipraglurant) and polymorphs thereof as negative allosteric modulator of MGLU5 receptor |
| EP3693370A1 (en) * | 2013-09-25 | 2020-08-12 | Addex Pharma S.A | Crytalline mono-phosphate salt of 6-fluoro-2-[4-(pyridin-2-yl)but-3-yn-1-yl] imidazo[1,2a]pyridine as negative allosteric modulator of mglu5 receptor |
| US10166183B2 (en) | 2014-02-07 | 2019-01-01 | Auspex Pharmaceuticals, Inc. | Pharmaceutical formulations |
| US10966922B2 (en) | 2014-02-07 | 2021-04-06 | Auspex Pharmaceuticals, Inc. | Pharmaceutical formulations |
| US11077055B2 (en) | 2015-04-29 | 2021-08-03 | Dexcel Pharma Technologies Ltd. | Orally disintegrating compositions |
| US10835488B2 (en) | 2016-06-16 | 2020-11-17 | Dexcel Pharma Technologies Ltd. | Stable orally disintegrating pharmaceutical compositions |
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| GB201210530D0 (en) | 2012-07-25 |
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