Classifications

• • 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
  • A61K31/40—Heterocyclic 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
  • A61K31/403—Heterocyclic 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
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• • 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
  • A61K31/40—Heterocyclic 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
  • A61K31/403—Heterocyclic 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
  • A61K31/404—Indoles, e.g. pindolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4196—1,2,4-Triazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
  • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
• • 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
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • 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
  • 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
  • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• • 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
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/06—Antimigraine agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof

Definitions

• the present invention relates a stable and palatable triptan composition, and the pharmaceutical use thereof. More in particular, the present invention relates to an oral liquid (gel or spray) composition comprising a triptan, such as rizatriptan, able to mask the typical bitter taste thereof and to remain physically, chemically and microbiologically stable and free of impurity for the whole commercial life of the product, and to the use thereof in the treatment of migraines and cluster headaches.
• a triptan such as rizatriptan
• Triptans are a family of tryptamine-based drugs used in the treatment of migraines and cluster headaches. This drug class was first introduced in the 1990s. The drugs of this class act as agonists for serotonin 5-HT1 B and 5-HT1 D receptors at blood vessels and nerve endings in the brain. The first clinically available triptan was sumatriptan, which has been marketed since 1991 . Triptans have largely replaced ergotamines, an older clas s of medications used to relieve migraine and cluster headaches.
• triptan was the pioneer drug in this class.
• the second generation's triptans such as zolmitriptan, naratriptan, rizatriptan, almotriptan, eletriptan and frovatriptan soon became available.
• different triptans are available in different formulations and in different strengths.
• Triptans formulations may play an important role in the onset of action.
• the selection of anti-migraine drug for patients depends on their symptoms.
• the first selective 5-HT1 B/1 D agonist, sumatriptan was first formulated as a subcutaneous injection, then as an oral tablets and more recently as a nasal spray. It is also available in some countries as suppositories.
• the subcutaneous injection is the fastest way to stop a rapidly progressing migraine attack.
• the sumatriptan nasal spray provides faster onset of action than the tablets, but it produces a similar headache response at 2 hours.
• Nasal spray is although not suitable for all patients, because some patients experience bad taste and lack of consistency of response. Zolmitriptan was developed with the strategy to create a more lipophilic compound, with faster absorption and better ability to cross the blood brain barrier than sumatriptan. It is available as tablets, orally disintegrating tablets and as nasal spray in some countries.
• eletriptan 40 mg and rizatriptan 10 mg have the highest therapeutic gain compared with sumatriptan 100 mg, according to the most common efficacy variable of headache response at 2 hours. Treatment with eletriptan 40 mg and rizatriptan 10 mg was also associated with substantial functional improvement and patient satisfaction.
• rizatriptan is available as tablets and orally disintegrating tablets but naratriptan, almotriptan, eletriptan and frovatriptan are recently only available as tablets.
• liquid dosage forms are much easier to swallow and typically do not require separate water to administer.
• the common problem associated with liquid pharmaceutical dosage forms is the often disagreeable taste of a drug. Improving the palatability of these liquid medicinal products increases patient acceptability and improves therapeutic adherence. Furthermore, patient compliance is also easier to facilitate with the flavoring and colorant agents that are generally included in liquid dosage forms.
• Oral administration is the most common route of drug delivery to both young and older patients.
• Patient acceptability of a medicinal product is a key aspect in the development and prescribing of medicines.
• Oral liquids are generally regarded to be the most appropriate dosage form for children and holder people, despite having issues including taste masking and stability.
• a stable and palatable oral liquid composition comprising sumatriptan in a liquid carrier and one or more of a solubilizing agent, thickening agent, sweetening agent, flavoring agent, colorant agent, preservative agent, or antioxidant component, where preferably, the carrier includes glycerin, the sweetening agent is present and includes sorbitol or sucralose, the preservative agent is present and includes a sorbate-containing component, the flavoring agent is present and provides a mint flavor, or the antioxidant component is present and includes a gallate- containing component, or any combination thereof.
• WO201 1/063915 A1 discloses an aqueous liquid pharmaceutical composition
• WO20107072353 A1 discloses an aqueous liquid pharmaceutical composition
• aqueous liquid pharmaceutical composition comprising a) at least one triptan compound, pharmaceutically acceptable salts or hydrates thereof, and b) xylitol in an amount of from 25 to 55 weight %, claiming a better stability and palatability of comparable compositions comprising other polyhydric alcohols.
• the Applicant has faced the problem of developing an oral liquid composition, especially in the form of spray or gel, comprising a triptan having good palatability and physically, chemically and microbiologically stable.
• an oral liquid composition comprising a triptan and sucralose together with a preservative and a chelating agent, a liquid carrier, and, optionally, a gelling agent, is able to overcome the above mentioned problem.
• the Applicant has surprisingly found that the oral liquid composition of the invention can be administered orally without water and without any bad taste feeling.
• the Applicant has also found that other sweeteners, such as for example saccharine, acesulfame K, cyclamate and mixture thereof, can be used in addition or in replacement of the sucralose.
• other sweeteners such as for example saccharine, acesulfame K, cyclamate and mixture thereof, can be used in addition or in replacement of the sucralose.
• the oral liquid composition of the invention can increase patient compliance by providing a dosage form that reduce the bitterness taste of triptans and that can be conveniently assumed as such without water and without leaving any bad feeling in the mouth.
• the oral liquid composition of the invention is physically, chemically and microbiologically stable for at least twelve months when stored at 25°C and 60% RH, and for at least six months when stored at 30°C and 65% RH or even at 40°C and 75% RH.
• the present invention relates to an oral liquid composition comprising a triptan, or a pharmaceutically acceptable salt thereof, or an active metabolite thereof, a sweetener, a preservative, a chelating agent, a liquid carrier, and, optionally, a gelling agent.
• the present invention relates to an oral liquid composition for use in the treatment of migraine and cluster headaches, wherein said oral liquid composition comprises a triptan, or a pharmaceutically acceptable salt thereof, or an active metabolite thereof, a sweetener, a preservative, a chelating agent, a liquid carrier, and, optionally, a gelling agent.
• the present invention relates to a method for treating migraine and cluster headaches in a subject in need thereof comprising the administration of an effective amount of an oral liquid composition comprising a triptan, or a pharmaceutically acceptable salt thereof, or an active metabolite thereof, a sweetener, a preservative, a chelating agent, a liquid carrier, and, optionally, a gelling agent.
• the present invention relates to a monodose delivery system comprising an oral liquid composition comprising a triptan, or a pharmaceutically acceptable salt thereof, or an active metabolite thereof, a sweetener, a preservative, a chelating agent, a liquid carrier, and, optionally, a gelling agent.
• the present invention relates to a multidose spray delivery system comprising an oral liquid composition comprising a triptan, or a pharmaceutically acceptable salt thereof, or an active metabolite thereof, a sweetener, a preservative, a chelating agent, and a liquid carrier.
• Figure 1 the mean plasma concentration vs. time curves of Test product versus Reference product as measured in Example 3.
• the oral liquid composition according to the present invention comprises a triptan, or a pharmaceutically acceptable salt thereof, or an active metabolite thereof, a sweetener, a preservative, a chelating agent, a liquid carrier, and, optionally, a gelling agent.
• the oral liquid composition according to the present invention can be formulated as an oral spray formulation for a multidose spray delivery system and as an oral monodose formulation for a monodose delivery system.
• the oral liquid composition of the present invention does not comprise a gelling agent.
• the oral liquid composition of the present invention can optionally comprise a gelling agent.
• the oral liquid composition of the present invention comprises a gelling agent
• the viscosity of the composition is higher than 0.2 Pa * S and it is referred herein as an oral liquid gel composition.
• the viscosity of the composition is lower than 0.1 Pa * S and it is referred herein as an oral liquid aqueous composition.
• oral liquid composition encompasses both the oral liquid gel composition and the oral liquid aqueous composition as previously defined.
• the oral liquid aqueous composition of the present invention can be formulated both as an oral spray formulation for a multidose spray delivery system and as an oral monodose formulation for a monodose delivery system.
• the oral liquid gel composition of the present invention can be formulated as an oral monodose formulation for a monodose delivery system.
• triptan is used interchangeably with "indole serotonin receptor agonist” and refers to an agent that binds to one or more of a 5-HT1 B receptor, a 5-HT1 D receptor, and a 5-HT 1 F receptor and effects vasoconstriction of cerebral blood vessels and/or inhibition of pro- inflammatory neuropeptide release.
• An indole serotonin receptor agonist comprises an indole-3-alkylamine structure. Representatives of this class of compounds are e.g. almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan or zolmitriptan.
• the triptan is selected from the group consisting of almotriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan. According to a more preferred embodiment, the triptan is selected from the group of almotriptan, rizatriptan and sumatriptan. According to the most preferred embodiment the triptan is rizatriptan.
• the triptans are preferably employed as salts with pharmaceutically acceptable organic and inorganic acids.
• the pharmaceutically acceptable organic acids are selected from the group consisting of benzoic, oxalic, maleic, methanesulphonic, paratoluenesulphonic, succinic, citric, malic, tartaric, and lactic acid.
• the pharmaceutically acceptable inorganic acids are selected from the group consisting of hydrochloric, hydrobromic, phosphoric, and sulphuric acid.
• the oral liquid composition of the present invention can comprise an active triptan metabolite.
• active metabolite referred to triptans means the product obtained by the removal of one methyl group from the nitrogen atom of the starting triptan compound, such as for example N-monodesmethyl-rizatriptan.
• a suitable active triptan metabolite is an N-monodesmethyl-triptan, such as for example N- monodesmethyl-rizatriptan, N-monodesmethyl-eletriptan, N-monodesmethyl-zolmitriptan and N-monodesmethyl-sumatriptan.
• the triptan concentration expressed as grams of free base in 100 ml of composition, is preferably equal to or lower than 25.00% w/v, more preferably ranging from 0.01 % to 20.00% w/v.
• the oral liquid composition of the present invention when formulated as an oral monodose formulation for a monodose delivery system, comprises a triptan concentration, expressed as grams of free base in 100 ml of composition, preferably equal to or lower than 5.00% w/v, more preferably ranging from 0.01 % to 3.00% w/v.
• the sumatriptan concentration expressed as free base is equal to or lower than 5.00% w/v, more preferably from 0.10% to 4.00% w/v, and most preferably from 0.50% to 3.50% w/v.
• the sumatriptan concentration expressed as free base is ranging from 0.70% to 2.90% w/v.
• the zolmitriptan concentration expressed as free base is equal to or lower than 0.20% w/v, more preferably from 0.05% to 0.19% w/v, and most preferably from 0.05% to 0.17% w/v. According to preferred embodiments, the zolmitriptan concentration expressed as free base is ranging from 0.07% to 0.15% w/v.
• the rizatriptan concentration expressed as free base is equal to or lower than 0.50% w/v, more preferably from 0.05% to 0.40% w/v, and most preferably from 0.10% to 0.30% w/v.
• the rizatriptan concentration expressed as free base is ranging from 0.14% to 0.29% w/v.
• the almotriptan concentration expressed as free base is equal to or lower than 0.60% w/v, more preferably from 0.05% to 0.50% w/v, and most preferably from 0.10% to 0.40% w/v. According to preferred embodiments, the almotriptan concentration expressed as free base is ranging from 0.17% to 0.36% w/v.
• the frovatriptan concentration expressed as free base is equal to or lower than 0.20% w/v, more preferably from 0.05% to 0.19% w/v, and most preferably from 0.05% to 0.17% w/v. According to preferred embodiments, the frovatriptan concentration expressed as free base is ranging from 0.07% to 0.15% w/v.
• the eletriptan concentration expressed as free base is equal to or lower than 2.00% w/v, more preferably from 0.20% to 1 .90% w/v, and most preferably from 0.30% to 1 .50% w/v. According to preferred embodiments, the eletriptan concentration expressed as free base is ranging from 0.55% to 1 .15% w/v.
• the naratriptan concentration expressed as free base is equal to or lower than 0.20% w/v, more preferably from 0.005% to 0.15% w/v, and most preferably from 0.01 % to 0.10% w/v.
• the zolmitriptan concentration expressed as free base is ranging from 0.02% to 0.08% w/v.
• the oral liquid composition of the present invention when formulated as an oral spray formulation for a multidose spray delivery system, comprises a triptan concentration, expressed as grams of free base in 100 ml of composition, preferably equal to or lower than 25.00% w/v, more preferably ranging from 0.1 % to 20.00% w/v.
• the following paragraphs (A) to (G) define the preferred concentrations of each triptan in the oral liquid composition of the present invention when formulated as an oral spray formulation for a multidose spray delivery system.
• the sumatriptan concentration expressed as free base is equal to or lower than 25.00% w/v, more preferably from 2.10% to 20.00% w/v, and most preferably from 3.50% to 17.50% w/v.
• the sumatriptan concentration expressed as free base is ranging from 4.10% to 16.70% w/v.
• the zolmitriptan concentration expressed as free base is equal to or lower than 3.00% w/v, more preferably from 0.20% to 2.00% w/v, and most preferably from 0.30% to 1 .00% w/v. According to preferred embodiments, the zolmitriptan concentration expressed as free base is ranging from 0.41 % to 0.84% w/v.
• the rizatriptan concentration expressed as free base is equal to or lower than 6.00% w/v, more preferably from 0.40% to 4.00% w/v, and most preferably from 0.60% to 2.00% w/v.
• the rizatriptan concentration expressed as free base is ranging from 0.82% to 1 .70% w/v.
• the almotriptan concentration expressed as free base is equal to or lower than 6.00% w/v, more preferably from 0.30% to 4.50% w/v, and most preferably from 0.50% to 3.00% w/v.
• the almotriptan concentration expressed as free base is ranging from 1 .00% to 2.10% w/v.
• the frovatriptan concentration expressed as free base is equal to or lower than 3.00% w/v, more preferably from 0.20% to 2.00% w/v, and most preferably from 0.30% to 1 .00% w/v. According to preferred embodiments, the frovatriptan concentration expressed as free base is ranging from 0.41 % to 0.84% w/v.
• the eletriptan concentration expressed as free base is equal to or lower than 24.00% w/v, more preferably from 1 .60% to 16.00% w/v, and most preferably from 2.40% to 8.00% w/v.
• the eletriptan concentration expressed as free base is ranging from 3.20% to 6.70% w/v.
• the naratriptan concentration expressed as free base is equal to or lower than 2.00% w/v, more preferably from 0.05% to 1 .00% w/v, and most preferably from 0.10% to 0.50% w/v.
• the zolmitriptan concentration expressed as free base is ranging from 0.16% to 0.42% w/v.
• sweetener is used herein to identify a group of artificial sweeteners selected from the group consisting of sucralose, saccharine, acesulfame K, cyclamate, neohesperidin dihydrochalcone, stevia and neotame.
• the oral liquid composition according to the present invention can comprise one or more sweetener selected from the group consisting of sucralose, saccharine, acesulfame K, cyclamate, neohesperidin dihydrochalcone, stevia and neotame, preferably consisting of sucralose, saccharine and cyclamate.
• one or more sweetener selected from the group consisting of sucralose, saccharine, acesulfame K, cyclamate, neohesperidin dihydrochalcone, stevia and neotame, preferably consisting of sucralose, saccharine and cyclamate.
• the oral liquid composition according to the present invention comprises sucralose and one or more additional sweetener selected from the group consisting of saccharine, acesulfame K, cyclamate, neohesperidin dihydrochalcone, stevia, neotame and mixture thereof. More advantageously, the oral liquid composition only contains sucralose as sweetening agent.
• sodium sulcralose will be understood to include a chlorinated carbohydrate having the chemical name 1 ,6-dichloro-1 ,6-dideoxy- -D-fructofuranosyl-4-chloro-4-deoxy-a-D- galactopyranoside that has been assigned CAS Number 56038-13-2.
• Sucralose often may be referred to (in technical literature, material safety data sheets, marketing materials, and the like) by a number of synonyms, including, for example and without limitation: 1 ,6-dichloro-1 ,6-dideoxy- -D-fructofuranosyl-4-chloro-4-deoxy-a-D-galactose; trichlorogalactosucrose; TGS; 4,T,6'-trichlorogalactosucrose.
• Common brand names of sucralose-based sweeteners are Splenda, Zerocal, Sukrana, SucraPlus, Candys, Cukren, and Nevella.
• sucralose as used herein, includes all of these synonyms and others known to those skilled in the art. Particularly useful for the present invention is sucralose powder having D90 particle size equal to or lower than 12 pm commercially available from Merck under the tradename EMPROVE ® Essential.
• the sweetener total concentration is preferably equal to or lower than 0.5% w/v, more preferably lower than 0.4% w/v and most preferably ranging from 0.05% to 0.35% w/v.
• preservative relates to any kind of agent in a composition or in a dosage form that can prevent or reduce the physical and/or chemical degradation of the active substances.
• Preservatives suitable for use in the present invention include parabens, i.e., alkyl-p- hydroxybenzoates, benzoates, sorbates, and combinations thereof.
• the preservative is selected from the group consisting of benzoic acid, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, and mixtures and/or salts thereof. According to the most preferred embodiment of the present invention the preservative is selected from the group consisting of benzoic acid, methyl paraben, propyl paraben, and mixtures and/or salts thereof.
• the total preservative concentration is preferably equal to or lower than 1 .0% w/v, more preferably lower than 0.5% w/v, and most preferably the total preservative concentration is ranging from 0.05% to 0.4% w/v.
• the oral liquid composition of the present invention comprises sodium benzoate in a concentration ranging from 0.05% to 1 .0% w/v, more preferably from 0.1 % to 0.5% w/v, and most preferably from 0.2% to 0.4% w/v with respect to the total volume of the composition.
• the oral liquid composition of the present invention comprises a mixture of methyl paraben (MP) and propyl paraben (PP) in a MP/PP weight ratio ranging from about 20:1 to about 1 :1 , more preferably from about 10:1 to about 1 :1 , and most preferably from about 9:1 to about 4:1 .
• MP methyl paraben
• PP propyl paraben
• the methyl paraben concentration is ranging from 0.005 to 1 % w/v, preferably from 0.01 to 0.5% w/v, and more preferably from 0.1 to 0.3% w/v with respect to the total volume of the composition.
• the propyl paraben concentration is ranging from 0.001 to 0.5% w/v, preferably from 0.005 to 0.25% w/v, and more preferably from 0.01 to 0.1 % w/v with respect to the total volume of the composition.
• chelating agent means a molecule containing two or more electron donor atoms that can form coordinate bonds to a single metal ion.
• the term “chelating agent” is understood to include the chelating agent as well as salts thereof.
• the term“chelating agent” includes citric acid as well as its salt forms.
• the most common and widely used chelating agents coordinate to metal atoms through oxygen or nitrogen donor atoms, or both.
• Other less common chelating agents coordinate through sulfur in the form of -SH (thiol or mercapto) groups.
• a chelating agent may be bidentate, tridentate, tetradentate, etc., depending upon whether it contains two, three, four, or more donor atoms capable of binding to the metal atom.
• Chelating agents suitable for use in the present invention include diethylenetriaminepentaacetic acid (DTPA), ethylenedinitrilotetraacetic acid, (EDTA), nitrilotriacetic acid (NTA), citric acid, malic acid, tartaric acid, lactic acid, aspartic acid, glutamic acid, lysine, sodium hexametaphosphate, and combinations thereof.
• DTPA diethylenetriaminepentaacetic acid
• EDTA ethylenedinitrilotetraacetic acid
• NTA nitrilotriacetic acid
• citric acid malic acid, tartaric acid, lactic acid, aspartic acid, glutamic acid, lysine, sodium hexametaphosphate, and combinations thereof.
• the chelating agent is selected from the group consisting of DTPA, EDTA, and NTA. According to the most preferred embodiment of the present invention the chelating agent is EDTA.
• the chelating agent concentration is preferably equal to or lower than 0.5% w/v, more preferably lower than 0.3% w/v, and most preferably the chelating agent concentration is ranging from 0.05% to 0.2% w/v.
• liquid carrier generally means any suitable pharmaceutically acceptable liquid vehicle used in the pharmaceutical sciences for dilution or dissolution of oral formulation.
• Water including demineralized water, sterile water, deionized water, distilled water, and the like, is the preferred liquid carrier employed in the oral liquid composition of the present invention.
• the oral liquid composition of the present invention can comprise minor amounts of other conventional pharmaceutically acceptable solvents, diluents, or other vehicle, such as for example, alcohols, like ethanol, polyalcohols, like glycerol, glycols, like propylene glycol, and the like.
• gelling agent is defined herein to include any substance that is capable of increasing the viscosity of a fluid, for example, by forming a gel.
• polymeric gelling agents include, but are not limited to, guar gums and derivatives thereof, cellulose derivatives, biopolymers, and the like.
• Gelling agents suitable for use in the present invention include alginates, carbomers, polyacrylates, cellulose derivatives, such as hydroxyethyl-, hydroxypropyl- and carboxymethyl-cellulose, gums, such as xanthan gum, guar gum, proteins, such as gelatin and pectin, and high molecular weight polysaccharides such as carrageenan, and combinations thereof.
• the gelling agent is selected from the group consisting of cellulose derivatives and gums. According to the most preferred embodiment of the present invention the gelling agent is xanthan gum.
• the gelling agent concentration is preferably equal to or lower than 1 .5% w/v, more preferably ranging from 0.01 to 1 .0% w/v, and most preferably ranging from 0.20% to 0.80% w/v. According to the best preferred embodiments, the gelling agent concentration is ranging from 0.30% to 0.60% w/v.
• the oral liquid gel composition of the present invention has a viscosity preferably ranging from 0.4 Pa * S to 2.0 Pa * S, more preferably ranging from 0.5 Pa * S to 1 .5 Pa * S, and most preferably ranging from 0.7 Pa * S to 1 .3 Pa * S. According to the best preferred embodiments, the oral liquid gel composition of the present invention has a viscosity ranging from 0.9 Pa * S to 1 .1 Pa * S.
• the oral liquid composition of the present invention can comprise other conventional pharmaceutically acceptable ingredients, such as, for example, buffer agents, sugars, colorants, flavoring and perfuming agents.
• pharmaceutically acceptable and “physiologically acceptable” are intended to define, without any particular limitation, any material suitable for preparing a pharmaceutical composition to be administered to a living being.
• buffer agent relates to any suitable inorganic base, inorganic acid, organic base or organic acid, including acids and bases with one or multiple pKa values.
• Suitable buffer agents that can be used are sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid, sodium citrate, sodium hydroxide, hydrochloric acid, and mixtures thereof.
• the buffer agent is citric acid and/or sodium citrate.
• the pH of the oral liquid composition of the present invention is comprised from 3 to 8, preferably from 3.5 to 7.5, and more preferably from 4 to 6.5.
• flavoring agent includes artificial or natural flavors. Natural flavors can be derived from botanical matter such as leaves and seeds or from fruits of plants or they can be extracted or derived from animal materials. Artificial flavors are those which are prepared by chemical synthesis.
• flavor means a compound, which is used alone or in combination with other compounds, to impart a desired gustative effect. To be considered as a flavor, it must be recognized by a skilled person in the art as being able to modify in a desired way the taste of a composition.
• the oral liquid composition of the present invention can comprise one or more flavoring agent, such as, for example, grapefruit flavor, raspberry flavor, lemon flavor, orange flavor, caramel flavor, vanilla flavor, cream flavor, and the like. More advantageously, the oral liquid composition of the present invention is free of flavoring agents.
• flavoring agent such as, for example, grapefruit flavor, raspberry flavor, lemon flavor, orange flavor, caramel flavor, vanilla flavor, cream flavor, and the like.
• the oral liquid composition of the present invention is free of flavoring agents.
• the term“sugar” includes any edible product which comprises one or more saccharide groups.
• the term“sugar” includes all monosaccharide or simple sugars, such as glucose, dextrose, fructose and laevulose, the disaccharides, such as sucrose, also known as table sugar, lactose and maltose and polysaccharides derived from tragacanth.
• the term“sugar” as used herein includes all of the optical isomers and mixtures of such isomers.
• the oral liquid composition of the present invention can comprise one or more sugar, such as, for example, lactose, glucose, sucrose, and the like.
• colorant is meant a pigment, dye, stain, colorant, combinations thereof, or other agent employed to impart a particular color to or to mask a particular color.
• Suitable colorants that can be used in the oral liquid composition of the present invention include generally color additives presently certified for use in food and ingested drugs, including dyes such as FD&C Blue No. 1 , FD&C Blue No. 2, FD&C Green No. 3, D&C Green No. 5, D&C Orange No. 5, FD&C Red No. 3, D&C Red No. 21 , D&C Red No. 22, D&C Red No. 27, D&C Red No. 28, D&C Red No. 30, D&C Red No. 40, FD&C Yellow No. 5, FD& C Yellow No. 6 and D&C Yellow No. 10 and mixtures thereof in various proportions.
• dyes such as FD&C Blue No. 1 , FD&C Blue No. 2, FD&C Green No. 3, D&C Green No. 5, D&C Orange No. 5, FD&C Red No. 3, D&C Red No. 21 , D&C Red No. 22, D&C Red No. 27, D&C Red No. 28, D&C
• the oral liquid composition of the present invention is packed in monodose delivery systems.
• Such systems comprise sealed vessels holding dosed units selected from the group consisting of ampoule, sachet, vial, blister pack, tube, or a stick pack.
• the oral liquid composition of the present invention is packed in a sachet or a stick pack.
• sachet or "stick pack” as used herein refers to a small, sealed packet containing a quantity of material, which is a single use or unit dose quantity.
• a packaging of the stick pack type comprises normally: a flexible film, having at least one layer, which forms a hermetically sealed tubular body with mutually opposite longitudinal film flaps, a first band provided longitudinally to said body for inside/outside sealing of said mutually opposite longitudinal flaps of the film; second sealing bands provided transversely to said body for inside/outside sealing; a sealed extension region protruding from at least one of said second sealing bands on a respective portion of at least one edge of said tubular body; and preferably a transverse pre-weakening incisions that are provided in longitudinal alignment with said sealed extension region, along at least one of said mutually opposite longitudinal flaps.
• Suitable stick packs are described, for example, in WO9501921 .
• the vessels are made for instance of PVC or PVDC or composite materials comprising plastic materials reinforced with aluminium and/or glass layers.
• the oral liquid composition of the present invention is packed in a sachet or a stick pack having a volume of about 2 ml, about 4 ml or about 8 ml.
• the applicant has found that, using an overdose of only 0.5 ml for a nominal dose of 3.50 ml (i.e., an overdose of about 15% v/v), it is possible to obtain a monodose formulation in stick pack of the oral liquid composition of the present invention in compliance with the pharmaceutical criteria of Content Uniformity according to Ph. Eur, and pharmaceutical criteria of“Deliverable Volume” according to USP.
• the oral liquid composition of the present invention is packed in a multidose spray delivery system.
• spray delivery system is intended to mean any system suitable for dispensing a liquid, in spray, atomised or aerosol form, through a dispensing nozzle.
• the spray delivery system may comprise a pump dispenser, for example of the type currently used for the spray dispensing of perfume samples, with a tubular containment body and a pressurized operating plunger having a spray dispensing nozzle.
• the spray delivery system may comprise a pressurized container, for example in the form of a small cylinder, containing the liquid which has to be dispensed in combination with a propellant agent and a dispensing plunger.
• spray delivery systems are appropriate for pharmaceutical use and have volumes ranging from about 3 ml to about 100 ml.
• the oral liquid composition of the present invention is packed in a spray dispenser or container having a volume of from about 5 ml to about 50 ml.
• the formulations were prepared by first adding the preservatives (methylparahydroxybenzoate and propylparahydroxybenzoate or sodium benzoate) to water heated at a temperature between about 50° and about 80°C ( ⁇ 5°C) and mixing until complete solubilization. Then, the resulting solution is eventually cooled to about 50°C ⁇ 5°C, under a vacuum of about 400 mBar, added with sucralose, EDTA, citric acid monohydrate and sodium citrate, and mixed until complete solubilization. After that, still at about 50°C ⁇ 5°C and under vacuum of about 400 mBar, the solution is gelled by adding xanthan gum and mixing until complete solubilization.
• preservatives methylparahydroxybenzoate and propylparahydroxybenzoate or sodium benzoate
• Formulations 1 to 3 were employed to fill stick packs having different volumes and different amount of rizatriptan benzoate according to the following Table 12.
• the last column of Table 12 shows the amount of rizatriptan free base corresponding to the amount of rizatriptan benzoate given in the last but one column of Table 12.
• the samples of stick packs 2 were selected during production by taking, at regular production interval, twelve sticks for a total of five sampling. Three different batches were sampled. The samples for each batch were stored at different temperatures (25°C, 30°C, 40°C) and different relative humidity (RH 60%, 65%, 75%) up to twelve months and checked at the beginning of the test and each three months.
• All tested samples of stick packs 2 were stable at least for twelve months at 25°C and 60% RH and at least for six months at 30°C and 65% RH and at 40°C and 75% RH, with all tested feature within the specifications.
• the single center, open-label, randomized (order of treatments), balanced, single dose trial was performed in a 2-period, 2-sequence-crossover design. Forty-eight (48) healthy subjects aged 18-65 years of both sexes (29 female and 19 male) and normal weight (BMI 18.5-30.0 kg/m 2 ) were randomized.
• Maxalt® RPD 10 was an approved oral lyophilisate formulation (a freeze- dried wafer, referred to technically as an‘oral lyophilisate’, which dissolves in the mouth) available at the European market. Both immediate release preparations contained 14.53 mg rizatriptan benzoate corresponding to 10 mg rizatriptan.
• the IMPs (Investigational Medicinal Products) were administered in fasted state as single oral doses of 10 mg rizatriptan. Either one stick pack 2 containing 3.5 ml oral gel of Example 1 (Test product) or 1 rizatriptan benzoate wafer (Reference product) was administered in each period. Blood sampling was performed over 24 h post-dose in order to characterize pharmacokinetic parameters.
• the clinical trial was performed as a cross-over investigation with intra-individual comparison, thus reducing variability of the pharmacokinetic parameters, which was supposed to be higher between subjects than within an individual subject.
• the washout between administrations was at least 6 treatment-free days, in order to ensure that the entire active ingredient from the preceding treatment period was cleared from the body before administration of the subsequent treatment.
• bioequivalence was assessed for rizatriptan based on its plasma concentrations after administration of IMPs directly on the tongue without any fluid intake. Testing for bioequivalence was performed considering AUCo-tiast and Cmax obtained after oral single fasted doses of 10 mg rizatriptan. Sample collection was performed over 24 h after fasted administration. This time was considered adequate to characterize plasma concentration vs. time profiles long enough for reliable estimation of the extent of absorption, i.e. the AUC derived from measurements was expected to cover at least 80 % of the AUC extrapolated to infinity.
• Table 31 summarizes the mean pharmacokinetic parameters of rizatriptan after oral single dose administration of one stick pack 2 containing 3.5 ml oral gel of Example 1 (Test) under fasting conditions to 47 subjects (10 mg rizatriptan per treatment).
• Table 32 summarizes the mean pharmacokinetic parameters of rizatriptan after oral single dose administration of one wafer Maxalt® RPD 10 oral lyophilisate (Reference) under fasting conditions to 47 subjects (10 mg rizatriptan per treatment).
• Absolute residual area (extrapolated fraction of the AUCo- ⁇ ) exceeded in no case 20 % of AUCo-oo, being determined as only 0.88 % for Test and 0.82 % for Reference on average (geometric mean values).
• Geometric mean values for AUCo- ⁇ are as follows: 60.865 h * ng/ml after single dose administration of Test and 63.312 h * ng/ml after single dose administration of Reference.
• the time point of reaching maximum exposure represented by median values of t ma x, is slightly earlier for Test (0.8500 h) than for Reference (1 .3333 h).
• Figure 1 illustrates the mean plasma concentration vs. time curves of Test product versus Reference product.
• the mean curves of rizatriptan show a very similar course.
• they show very fast absorption of the active drug rizatriptan.
• the mean curve of the Test product reaches its maximum approximately 1 h p.a. with a value of around 17.5 ng/ml. In the case of the Reference curve a highly similar mean was observed but it was delayed by 0.5 h.
• the terminal elimination phase is comparable for both products. Both mean curves decrease until the end of the observed time period 24 h p.a. to mean values below 1 ng/ml.
• the palatability of the Test product regarding smell, taste, and texture (mouthfeel) was assessed using a questionnaire containing the following questions.
• the palatability of the Test product regarding taste is moderately liked by the majority of the subjects, while they had a neutral opinion on its smell. Most subjects rated the mouthfeel of the Test product as “watery”. Subjects, who recognized an aftertaste, assessed it as acceptable.
• Oral spray formulations having the compositions described in the following Table 51 were prepared according to the procedure described hereinbelow.
• the ingredients amounts of Table 51 are expressed as grams of ingredients per 100 ml of final solution, unless otherwise specified.
• the formulations were prepared by first adding the preservatives (methylparahydroxybenzoate and propylparahydroxybenzoate) to water heated at a temperature of about 80°C ( ⁇ 5°C) and mixing until complete solubilization. Then, the resulting solution was cooled to room temperature (25°C ⁇ 2°C), and added in sequence with the remaining ingredients, but flavour and Tween 20, to obtain solution 1 . These latter ingredients are separately dissolved in water at room temperature (25°C ⁇ 2°C), and the solution is added under stirring to solution 1 . After mixing, water was added up to the volume of 100 ml.
• preservatives methylparahydroxybenzoate and propylparahydroxybenzoate
• the samples 1 to 5 were stored at different temperatures (25°C, 30°C, 40°C) and different relative humidity (RH 60%, 65%, 75%) up to six months and checked at the beginning of the test and each three months.
• the reporting threshold (RT) for rizatriptan N-oxide and other unknown impurities was 0.1 %.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Epidemiology (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Engineering & Computer Science (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Nutrition Science (AREA)
• Physiology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Biochemistry (AREA)
• Molecular Biology (AREA)
• Inorganic Chemistry (AREA)
• Pain & Pain Management (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=63832239

Family Applications (1)

Country Status (2)

Family Cites Families (7)

• 2019
  • 2019-10-07 WO PCT/EP2019/077125 patent/WO2020074463A1/en unknown
  • 2019-10-07 EP EP19779928.1A patent/EP3863626A1/de not_active Withdrawn

Also Published As

Similar Documents

Legal Events