Classifications

• • 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
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• • 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
  • 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
  • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
• • 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
  • A61K47/16—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
  • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
• • 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
• • 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
  • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
  • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• Oral liquid pharmaceutical compositions containing as active ingredient Nepadutant, PGS as soiubiiizer and optionally a chelating agent. Such compositions are found to be very stable and suitable for paediatric use in the treatment of gastro-intestinal diseases.
• the present invention relates to novel pharmaceutical compositions containing an antagonist of tachykinin NK2 receptor, i.e. Nepadutant, very slightly soluble in aqueous solutions.
• compositions are stable solutions, designed for oral administration of the active ingredient and preferably intended for use in neonates and infants for paediatric gastrointestinal diseases.
• the high stability of the compositions is due to the use of TPGS as a soiubiiizer additive optionally with the addition of a chelating agent.
• NK2 receptors Contrary to what happens in most preparations of animal tissues where it is necessary to block both NK1 and NK2 receptors to obtain a more efficient antagonism against the spasmogenic effect induced by tachykinins, in other preparations, including preparations of isolated human intestine, the antagonists of NK2 receptor are already fully effective against the spasmogenic effect induced by exogenous or endogenous tachykinins.
• tachykinin NK2 receptors In addition to the stimulation role in the regulation of intestinal motility, the activation of tachykinin NK2 receptors, also triggers both intrinsic and extrinsic inhibitory mechanisms to the intestinal wall (Giuliani et al. J. Pharmacol. Exp Ther. 246:322-327 (1988)). Moreover NK2 tachykinin receptors regulate intestinal permeability (Hallgren et al. Am. J. Physiol. 273: G1077-G1086 (1997)) and are also involved in the regulation of the secretion of water and ions in the gut epithelium in rats and in humans (Tough et al. Naunyn-Schmiedeberg's Arch Pharmacol.
• tachykinins have suggested the assessment of selective antagonists of the tachykinin NK2 receptor in the development of drugs directed against gastrointestinal diseases characterized by gut motility disorders and visceral hypersensitivity such as, for example, irritable bowel syndrome in adults (Lecci et al. Curr. Opin. Invest. Drugs 3:589-601 (2002)).
• Nepadutant is a selective antagonist of the tachykinin NK2 receptor with formula (I), originally described in EP815126. It is bicyclic hexapeptide, with an excellent safety profile and tolerability.
• the NK2 antagonist, Nepadutant can be identified as [N -(2- acetylamino-2-deoxy- -D-glucopyranosyl)-L-asparaginyl-L-a-triptophan-L- phenylalanyl-L-2,3-diaminopropio-nil-L-leucil]-C-4.2-N-3.5-lattame-C-1 .6-N- 2.1 -lattame or cyclic[3-amino-L-alanil-L-leucil-N-[2-(acetylamino)-2-deoxy- - D-glucopyranosyl]-L-asparaginyl-L-a-aspartyl-L-triptophan-L- phenylalanyl](4 ⁇ 1 )-lattame (9CI) (CAS RN: 183747-35-5)) (alternatively known as MEN1 1420).
• Nepadutant has shown good activity in various in vitro and in vivo models and in humans in reversing the side effects of the activation of NK2 receptors in the intestine, such as visceral hyperalgesia or alterations of the intestinal motility.
• Nepadutant is absorbed when administered orally in new born animals (rats or mice), contrary to what is found in adult animals. Furthermore, the oral administration of Nepadutant in new born rats is able to block, up to 24 hours after its administration, the increase in intestinal transit induced by the activation of NK2 receptors, without altering the basal parameters. In addition Nepadutant has proven effective in a model of hyperalgesia in new born rats.
• the EMA recommends the use of oral solutions for newborns and infants (nurslings) (from 28 days to 23 months) as the preferred dosage form (EMEA/CHMP/PEG/194810/2005).
• the parenteral formulations e.g. intravenous
• Nepadutant for paediatric use in the gastrointestinal disorders.
• Nepadutant is poorly soluble in aqueous medium and has a bitter taste. Furthermore, it is stable in the dried state but the solutions of Nepadutant are sensitive to oxidative degradation.
• Nepadutant in liquid form are described (pages 7-8, Examples 1 -4), and such compositions are characterized by the use of polysorbate as solubilizer; such compositions appear to be not completely satisfactory for their storage limited duration at room temperature or at a high temperature.
• EP1464341 describes an ophthalmic solution/emulsion comprising
• TPGS (Vitamin E TPGS 1000 also referred to as d-alpha tocopheryl polyethylen glycol 1000 succinate) and the antioxidant active ingredient ubiquinone.
• Combinations of ubiquinone, TPGS and magnesium ascorbyl-2- phosphate show synergistic antioxidant effects. It is not described, however, any antioxidant effect on any active ingredient which is an antagonist of the tachykinin NK2 receptor in solutions containing TPGS.
• liquid formulations containing an HIV protease inhibitor, TPGS and a hydrophilic non-aqueous solvent miscible with TPGS is disclosed, preferred for the filling of soft gelatine capsules.
• the formulations show a higher bioavailability of the HIV protease inhibitor.
• the non-aqueous solvent is essential for this formulation.
• WO99/26607 describes a distribution system based on a liquid crystal structure, in which the drug is dissolved directly in TPGS.
• the solid structure of cyclosporine with TPGS does not require the presence or absence of emulsifiers, co-solvents, surfactants, or other solubilizer agents.
• the resulting products, such as controlled release capsules, tablets, pills are solid oral dosage forms. Because TPGS is used as the sole solvent, high amounts of TPGS (50% to 99.9%) are required.
• U.S. Patent 5,583, 105 describes pre-concentrated emulsion containing the active ingredient cyclosporine in a lipophilic and/or amphiphilic solvent.
• TPGS is mentioned as an emulsifier, adjuvant and antioxidant for fat oils.
• the antioxidant effect on a pharmaceutical active ingredient, and especially on a NK2 receptor antagonist, is not claimed.
• WO2006036614 describes materials like surfactants suitable for solid formulations.
• the TPGS row material of waxy consistency is converted into properly shaped solid that can be incorporated for example into tablets.
• the use of the solid form for the preparation of solutions and/or emulsions is not described.
• EP1216025 describes the use of a wide range of TPGS as a surfactant (from 0.1 % to 90%) in solid formulations comprising a dispersant soluble in water and a soluble compound in lipid medium as a lipase inhibitor.
• the solidified mixture is loaded into HPMC capsules that reveal an increase in the efficiency and power.
• Formulations for topical use containing TPGS and layers of alpha- tocopherol to solubilize or emulsify water insoluble drugs are mentioned in W09531217.
• TPGS is described as a stabilizer applied for the formation and stabilization of double-layer liposomes in acid environment (US5, 364.631 ).
• the present invention relates to stable oral, liquid, pharmaceutical compositions containing Nepadutant and TPGS, even for paediatric use for the treatment of newborns and infants (nurslings) in the period from birth to one year, and preferably, from birth to six months of age.
• the TPGS is a substance with solubilizer and antioxidant activity therefore acts as a stabilizer of substances which are highly unstable to oxidation.
• the TPSG is essentially tasteless and therefore suitable and acceptable for use in neonates and nurslings.
• the use of TPGS results in a solubilizing and antioxidant action allowing to obtain limpid, stable solutions of Nepadutant and acceptable from an organoleptic point of view. Additional excipients commonly used with TPGS, such as lipophilic or hydrophilic non-aqueous solvents or co-solvents, lipophilic antioxidant phases etc. are therefore not necessary to generate a stable liquid formulation.
• liquid aqueous oral pharmaceutical compositions comprising as active ingredient Nepadutant and TPGS as an additive.
• compositions contain the TPGS as the only solubilizer and / or stabilizing additive.
• compositions may further comprise a chelating agent.
• compositions comprise in addition to the TPGS other pharmaceutically acceptable excipients.
• a second object of the invention is the compositions containing Nepadutant, TPGS and optionally a chelating agent and other optional excipients for use in a paediatric treatment in neonates or nurslings, in particular for the paediatric treatment of gastrointestinal diseases.
• a further object of the present application is a process for the preparation of the composition of the invention.
• Formulations designed for paediatric use should be in liquid dosage forms for oral administration.
• the purified water is a solvent appropriate for paediatric formulations.
• Nepadutant due to the poor water solubility of Nepadutant, in order to dissolve a pharmaceutical effective amount, the use of at least one solubilizer, surfactant or emulsifier is essential.
• solubilizers, surfactants or emulsifiers are suitable for paediatric formulations, since most of the solubilizers/surfactants or emulsifiers produce side effects.
• Solubilizers which are very used are polymers of Poloxamer type, for example, the Poloxamer 188 ® (Poloxamer 188 termone indicates a copolymer between the polyoxypropilen and polyoxyethylene and polyoxypropilene of an approximately molecular mass of 1800 g / mol with a content of 80% w / w of polyoxyethylene).
• Poloxamer 188 it has not been possible to obtain the necessary solubilisation of Nepadutant in water with Poloxamer 188 (Tablel ).
• Table 1 Solubility in water of Nepadutant with different concentrations of solubilizer at 25 ° C.
• Polysorbates are widely used such as solubilizers, in oral, topical formulations and even in parenteral ones.
• the polysorbates are also accepted as a food additive in Europe (E433).
• Typical examples of compositions of Nepadutant with polysorbate 80 are those described in WO2006045820 (e.g. 1 -4 on page 7-8).
• a disadvantage of polysorbates is the bitter taste of the excipient.
• the use of flavourings and / or sweeteners to mask the bitter taste of active ingredients and/or excipients is the approach mostly used in paediatric oral formulations, with raspberry and cream aromas frequently identified as possible excipients masking the flavour, that generate the preferred taste sensation.
• the formulations containing polysorbates Nepadutant proved poorly stable at room temperature.
• a potential alternative to the conditions of deaeration may be the use of an antioxidant.
• various compositions containing different antioxidants have been studied.
• the propyl gallate is not allowed in foods for infants and young children, because of the known tendency to cause the blood disorder methemoglobinemia.
• Nepadutant content in paediatric formulations in oral solution containing different amounts of antioxidants and their mixtures after storage at 40° C/75% RH in percentage of the initial Nepadutant content.
• Nepadutant content in paediatric formulations in oral solution containing different amounts of antioxidants and their mixtures after storage at 40° C/75% RH in percentage of the initial Nepadutant content.
• TPGS TPGS
• the use of TPGS according to the present invention offers solution to all the problems related to the compositions of the prior art, specifically connected to the difficult solubilisation of Nepadutant, to its instability to oxidation and the need to achieve the organoleptic characteristics of the composition also acceptable from the paediatric population.
• TPGS Vitamin E selected from the group: TPGS (Vitamin E TPGS 1000 or d-alpha tocopheryl polyethylen glycol 1000 succinate), L- ascorbic acid dl-alpha-tocopherol phosphate potassium salt and dispersible pre-formulated such as dried mixtures of tocopherols at 30% (vitamin E finely dispersed in a matrix of modified food starch) and vitamin E dried at 15% CC (alpha tocopherol acetate finely dispersed in a matrix of modified food starch), were added to a typical pharmaceutical composition containing polysorbate (example 2) to study the increase in the stability of dissolved Nepadutant (table 5).
• inert gases such as nitrogen or argon has been used.
• Example 2 Dry mixed tocopherols 30% 0 100.0
• Example 2 Dry vitamin E 15% 0 100.0
• composition with TPGS as antioxidant proves to be very stable, making unnecessary the addition of antioxidants as well as the procedure of deaeration with inert gases.
• TPGS can also function as a powerful and efficient solubilizer for Nepadutant to get the preferred concentrations in aqueous solutions (Table 6).
• TPGS can be used as solubilizer instead of polysorbate
• the formulation containing TPGS shows a better acceptance from the organoleptic point of view.
• compositions were tasted, in double-blind, by six researchers who have expressed a qualitative judgment on three possibilities:
• a preferred composition in the form of aqueous solution, according to the present invention, comprises:
• TPGS from 0.1 % to 20% w/v (i.e. from 1 mg/ml to 200 mg/ml) of TPGS c) optionally from 0.001 % to 0.1 % w/v (i.e. from 0.01 mg/ml to 1 mg/ml) of a chelating agent
• the liquid oral pharmaceutical composition comprises the active ingredient Nepadutant in an amount from 0.01 % to 1 % w/v and preferably from 0.025% to 0.5% w/v.
• the composition comprises as solubilizer and / or stabilizing the TPGS in an amount of at least 0.1 % w/v, preferably from 0.1 % to 20% w/v, for example from 0.5% to 5% w/v.
• the weight ratio between Nepadutant and the solubilizer TPGS is in the range from 1 : 1 to 1 :50, preferably in the range from 1 :2 to 1 :40 for example in the range from 1 :4 to 1 :30.
• the composition according to the present invention can possibly comprise a chelating agent selected from the group of ethylenediaminetetraacetic acid (EDTA), disodium (ethylendinitrile) tetraacetate dihydrate (disodium edetate), and disodium-[(ethylenedinitryl) tetraacetate] hydrocalcium (calcium sodium diedetate).
• EDTA ethylenediaminetetraacetic acid
• disodium-[(ethylenedinitryl) tetraacetate] hydrocalcium (calcium sodium diedetate) ethylenediaminetetraacetic acid
• the chelating agent may be present in the composition in an amount of from 0.001 % to 0.1 % w/v, preferably from 0.005% to 0.05%, or from 0.005% to 0.02% w/v.
• sweeteners such as sugars, including dextrose
• additional solubilizer agents such as polyvinylpyrrolidone, sodium carboxymethylcellulose
• preservatives e.g. Sorbic acid and ascorbic acid
• compositions according to the invention include:
• compositions used for the nutrition of infants may be added to foods used for the nutrition of infants, particularly to milk, in beverages or liquid foods.
• composition may be administered in a single or multiple daily dose, depending on doctor's advice, for the treatment of gastrointestinal disease in neonates and infants aged from birth to one year, and preferably, from birth to six months.
• the present invention further relates to a process for the preparation of pharmaceutical compositions such as those described above, which process comprises mixing Nepadutant with TPGS, and optionally a chelating agent, with one or more pharmaceutically acceptable excipients.
• the formulation is quite similar to that described in WO2006045820 and was prepared in an inert atmosphere.
• a dry premix consisting of dextrose, sorbic acid, sodium carboxymethylcellulose, and flavourings was prepared. Such a premix is dissolved in purified water (ca. 60% of the total amount) to a temperature of 35° C- 40° C while stirring and homogenizing in a special machine for mixing.
• the solution is cooled to a temperature of 20° C-25° C and polysorbate 80, Nepadutant and the remaining amount of water (40% of the total quantity) is added by shaking and homogenising in an inert gas atmosphere.
• the formulation is stirred until obtaining a limpid and homogeneous solution.
• This formulation also corresponds to the formulation K in the Table 2, 3 and 4.
• compositions similar to those of Example 1 with in addition an antioxidant are prepared in accordance with Example 1 , containing in addition an antioxidant.
• the presence of antioxidant makes the deaeration with inert gas not required.
• a dry premix consisting of dextrose, sorbic acid, sodium carboxymethylcellulose, and flavourings is prepared.
• Such a premix is dissolved in purified water (ca. 60% of the total amount) to a temperature of 35 ° C - 40 ° C while stirring and homogenizing in a special machine for mixing.
• the solution is cooled to a temperature of 20 ° C - 25 ° C and to it is added polysorbate 80, the antioxidant, Nepadutant and the remaining amount of water (40% of the total quantity) by stirring and homogenizing.
• the formulation is stirred until obtaining a limpid and homogeneous solution.
• the antioxidant used is selected from the group: TPGS (vitamin E polyethylene glycol 1000 succinate or Vitamin E TPGS NF grade) 3 mg/ml, L- ascorbic acid dl-alpha-tocopherol phosphate potassium salt 2.3 mg/ml, vitamin E dried to 15% CC (alpha tocopherol acetate finely dispersed in a matrix of modified food starch) 3.9 mg/ml, mixtures of tocopherols dried to 30% (vitamin E finely dispersed in a matrix of modified food starch) 1 .8 mg/ml.
• TPGS vitamin E polyethylene glycol 1000 succinate or Vitamin E TPGS NF grade
• L- ascorbic acid dl-alpha-tocopherol phosphate potassium salt 2.3 mg/ml
• vitamin E dried to 15% CC alpha tocopherol acetate finely dispersed in a matrix of modified food starch
• mixtures of tocopherols dried to 30% vitamin E finely dispersed in a
• This example illustrates a liquid formulation comprising aqueous Nepadutant TPGS as solubilizer. This formulation was packaged without deaeration with inert gas.
• a dry premix consisting of dextrose, sorbic acid and sodium carboxymethylcellulose is prepared.
• Such a premix is dissolved in purified water (ca. 60% of the total amount) to a temperature of 35° C-40° C while stirring and homogenizing in a special machine for mixing, in an inert gas atmosphere.
• the solution is cooled to a temperature of 20° C- 25° C and to it is added 20% w/v solution of TPGS, Nepadutant and the remaining amount of water (40% of the total quantity) by stirring and homogenizing.
• the formulation is stirred until obtaining a limpid and homogeneous solution.
• This example illustrates a liquid formulation comprising aqueous Nepadutant TPGS as solubilizer.
• This formulation was packaged without deaeration with inert gas and comprises in addition edetate disodium as a chelating agent.
• a dry premix consisting of dextrose, sorbic acid and sodium carboxymethylcellulose is prepared. Such a premix is dissolved in purified water (ca. 60% of the total amount) to a temperature of 35 ° C - 40 ° C while stirring and homogenizing in a special machine for mixing.
• the solution is cooled to a temperature of 20° C-25° C and to it is added 20% w/v solution of TPGS, edetate sodium, Nepadutant and the remaining amount of water (40% of the total amount) by stirring and homogenizing in an inert gas atmosphere.
• the formulation is stirred until obtaining a limpid and homogeneous solution.

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