MXPA06010860A - Spray dried pharmaceutical compositions - Google Patents

Abstract

The present invention relates to novel compositions containing the NKg receptor antagonist talnetant which compositions have enhanced bioavailability. In addition, the invention relates to processes for the preparation and to uses of the compositions in therapy.

Description

SPRAY DRYING PHARMACEUTICAL COMPOSITIONS DESCRIPTIVE MEMORY The present invention relates to novel compositions containing the NK3 receptor antagonist talnetant, whose compositions have improved bioavailability. In addition, the invention relates to methods for the preparation and use of compositions in therapy. Talnetant, (S) - (-) - N- (a-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide (alternatively 3-hydroxy-2-phenyl-N - [( 1S) -1-phenylpropyl] -4-quinolinocarboxamide), has the chemical structure (A): Talnetant, its preparation and its use in the treatment of pulmonary disorders, central nervous system disorders and neurodegenerative disorders are described in published international patent application WO 95/32948. The published international patent applications WO 97/19927, WO 97/19928, WO 99/14196 and WO 02/094187 describe other therapeutic utilities for talnetant, pharmaceutically acceptable salts and processes for their preparation. The aforementioned patent applications are hereby incorporated by reference, as if indicating that each individual publication was specifically and individually incorporated herein in its entirety as a reference. Talnetant has low aqueous solubility (approximately 0.03 mg / ml at pH 1 and 0.001 mg / ml, at pH 7.0). Typically, drugs with low aqueous solubility are slowly absorbed through the walls of the gastrointestinal tract (GIT) due to poor dissolution of the solid in the GIT, leading to a small diffusive conduction force. There are many different methods that are used to improve the absorption of a particular drug substance. It may be possible to develop the so-called pro-drugs or salts of the active agent, ie, more soluble derivatives, by joining a solubilization group (for example, phosphate, succinate or polyethylene glycol) to the drug, thereby taking advantage of the high solubility and speed of the drug. dissolution of the salt / derivatized prodrug. Alternatively, it is known to use physical methods of formulation, such as the use of amorphous drugs or dispersion in a soluble vehicle, to increase the rate of dissolution of the drug product and hence the rate of absorption (JH Fincher, J. Pharm Sci. 1968, 57, 1825 and GL Amidon er a /., J. Pharm. Sci., 1980, 12, 1363). Another alternative is to decrease the particle size of the drug. The decrease in particle size increases the surface area of the drug particle, thereby increasing its rate of dissolution. A variety of processes have been developed to prepare fine particles of the drug substance. Typically, dry milling techniques are used for the preparation of particulate medicaments (see E. L. Parrott, J. Pharm, Sci., 1974, 63, 813). The grinding with air jet and the milling by energy of a fluid (micronization), have been favored due to the reduced risk of introduction of contamination by the materials of the milling. More recently, particles having a size smaller than 1 μm have been obtained using wet milling processes. For example, published European patent application EP-A-0 262 560, describes the use of wet milling techniques for preparing compositions containing benzoyl urea derivatives in which the average particle size is 1 μm or less. It is said that the provision of the fine particles improves the absorbability of the GIT of the benzoyl urea compounds which are poorly soluble in water, thus increasing their bioavailability. The published European patent application EP-A-0 499 299 describes a wet milling process for preparing particles of a crystalline drug substance, whose particles have a surface modifier adsorbed on the surface in an amount sufficient to maintain a " Effective average particle size "less than about 400 nm. Aqueous dispersions obtained from wet milling processes can be used directly as a therapeutic agent, if they are prepared under suitable hygiene conditions, for example, using water and other components that meet the standards of the European and United States Pharmacopoeia. For the preparation of formulations for use in human therapy, it is preferred that the aqueous dispersion be converted to a dried powder. This is conveniently carried out by spray drying the resulting aqueous dispersion, typically by collecting the product from the dryer using a cyclonic separator. The resulting aqueous dispersion can also be spray granulated. The objective of spray drying is to remove water from the dispersions of drug particles, so that the powder can be further processed to prepare capsules or tablets or other suitable oral dosage form. However, it is desirable that the particles obtained from the spray-dried powder be substantially the same size when dispersed in aqueous medium as freshly ground particles. If particles of the same size are obtained as freshly ground particles, this is referred to in the art (and hereafter) as "full recovery of particle size". However, the present inventors have found that by spray drying certain wet-milled talnetant dispersions, a poor recovery of particle size is achieved, i.e., a significant increase in particle size is observed when the spray-dried particles are add to aqueous media. The present inventors have discovered that by spray drying wet milled talnetant dispersions containing suitable excipients this problem is noted, resulting in increased recovery of particle size, and greatly improving bioavailability in vivo. According to a first aspect, the invention provides a process for the preparation of a spray-dried composition, the composition comprising, i) talnetant particles with a Dv90 in the range of 0.1 to 2.0 μm, ii) one or more surfactants ionics, and iii) one or more soluble carriers, the process comprising, a) wet milling a dispersion of the solid talnetant particles until the Dv90 is in the range of 0.1 to 2.0 μm, whose dispersion comprises the one or more agents ionic surfactants, and the one or more soluble carriers, and then b) spray-drying or spray-granulating the resulting dispersion. As used herein, the term Dv90 means that not less than 90% of the particles have a volume average diameter of Dv. Likewise, Dv50 and Dv10 mean that not less than 50% and 10%, respectively, have a mean diameter in volume of Dv. As used herein in relation to particle size, the term "mean diameter in volume" (Dv) means: - '¥ where, n is the number of particles, and D is the diameter of the particles, according to E. L. Parrott, "Milling", chapter 2, The Theory and Practice of industrial Pharmacy, ed. Lachman et al., 3a. edition, 1986, p. 26. Talnetant can be wet milled in any suitable aqueous, non-aqueous or organic solvent (eg, an oil). In one embodiment, the talnetant is wet milled in a water-based medium. Grinding apparatuses suitable for the preparation of compositions in accordance with the present invention include conventional wet bead mills, such as those manufactured by Nylacast (available from Nylacast Components, 200 Hastings Road, Leices ter. LE5 OHL, United Kingdom), Netzsch (available from Erich NETZSCH GmbH &Co. Holding KG Gebrüder-Netzsch-Straße 19, D-95100 Selb, Germany), Drais (available from Draiswerke, Inc., 40 Whitney Road, Mahwah, NJ 07430, USA), and others. Conveniently, the grinding chamber of the grinding apparatus is coated with an abrasion resistant polymer material, or constructed thereof. The milling chamber of the grinding apparatus can be coated with nylon, or it can be constructed therefrom. An example of a suitable grinding chamber is described in the international patent publication WO 02/00196. Suitable grinding media for use in the preparation of a pharmaceutical composition according to the present invention, include glass beads and ceramic beads, for example, those made of rare earth oxide materials. The diameter of said grinding media is, for example, within the range of 0.1 mm to 3 mm, conveniently within the range of 0.3 to 0.8 mm. The density of said grinding media is, for example, greater than 3 gcm "3, conveniently within the range of 5 to 10 gcm" 3. Suitable techniques of spray granulation and spray drying will be apparent to those skilled in the art (see, eg, Gilbert S. Banker, "Modern Pharmaceutics, Drugs and the Pharmaceutical Sciences", 1996, and references cited therein), and can be made using an atomizer, such as the SD 6.3R atomizer from Niro (Niro A / S, Gladsaxevej 305, 2860 Soeborg, Denmark), the Mobile Minor from Niro, the Yamato atomizer GA-32 (2-1-6) Nihonbashi Honcho, Chou-ku, Tokyo, 103-8432, Japan), or a fluid bed granulator, such as the Glatt fluid bed granulator. The particles prepared according to the present invention can be measured using conventional techniques known in the art, such as laser light diffraction and photonic correlation spectroscopy. A suitable apparatus for the determination of the particle size is the Malvern Mastersizer 2000 (available from Malvern Instruments Ltd, Malvern, United Kingdom). Another suitable apparatus for the determination of the particle size is the HELOS from Sympatec (available from Sympatec GmbH, System-Partikel-Technik, Am Pulverhaus 1, D-38678 Clausthal-Zellerfeld, Germany). The Malvern Mastersizer 2000 and the HELOS of Sympatec, and their operation, will be well known to those skilled in the art with regard to their operation manuals. In one embodiment, the dispersion contains 5 to 50% w / w of talnetant. In another embodiment, the dispersion contains 15 to 30% w / w of talnetant. The ionic surfactant may be an anionic surfactant or a cationic surfactant. In one embodiment, the ionic surfactant is an anionic surfactant. In another embodiment, the ionic surfactant is sodium lauryl sulfate or sodium dioctyl sulfosuccinate (sodium docusate). In another embodiment, the ionic surfactant is sodium lauryl sulfate. In one embodiment, the concentration of surfactant in the spray-dried composition is 0.5 to 3.0% by weight of talnetant. In one embodiment, the concentration of surfactant in the dispersion before spray drying is 0.05 to 5.0% by weight of the dispersion, and in another modality, it is 0.05 to 2.0%. In one embodiment, the dispersion contains 0.001 to 0.1 moles of ionic surfactant per mole of talnetant. In another embodiment, the dispersion contains 0.01 to 0.05 moles of surfactant per mole of talnetant. In one embodiment, the one or more soluble carriers are a soluble sugar. In one embodiment, the one or more soluble carriers are selected from the group consisting of mannitol, sorbitol, lactose, lactitol, xylitol, trehalose, dextrose, sucrose, maltose, fructose, maltitol, xylitol, erythritol, polydextrose, isomalt, cyclodextrin, and starch. . In another embodiment, the spray-dried composition comprises one or more soluble carriers selected from the group consisting of mannitol, lactose, erythritol, polydextrose, isomalt and lactitol. In one embodiment, the concentration of the one or more soluble carriers in the spray-dried composition is 10 to 75% by weight of talnetant. The one or more soluble carriers can be added to the dispersion before wet milling. Alternatively, the one or more soluble carriers can be added to the wet ground dispersion prior to spray drying. In one embodiment, the concentration of the one or more soluble vehicles in the dispersion before wet milling or after wet milling, is 0.1 to 30% by weight of the dispersion. In another embodiment, the concentration of the vehicle soluble in the dispersion before wet milling or after wet milling, is 5 to 15% by weight of the dispersion. In one embodiment, the spray-dried composition comprises one or more anti-agglomeration agents (eg, polyvinylpyrrolidone (PVP) or povidone, hydroxypropylmethylcellulose and hydroxyethylcellulose and hydroxypropylcellulose). In one embodiment, the concentration of the anti-agglomeration agent in the spray-dried composition is 2 to 10% by weight of talnetant. In one embodiment, the concentration of anti-agglomeration agent in the dispersion before spray drying is 0.1 to 10.0% by weight of the dispersion, and in another embodiment, 0.5 to 5.0%. According to a second aspect, the invention provides a spray-dried pharmaceutical composition, comprising i) talnetant particles with a Dv90 in the range of 0.1 to 2.0 μm, ü) one or more ionic surfactants, and iii) one or more soluble vehicles. It will be appreciated that the embodiments described for the first aspect extend to this second aspect. The spray dried composition and dispersion (before wet milling or after wet milling) may contain other suitable pharmaceutically acceptable excipients. Suitable excipients are described in the Handbook of Pharmaceutical Excipients, Pharmaceutical Press, 1986, published by The American Pharmaceutical Association and The Royal Pharmaceutical Society of Great Britain. Examples of other excipients include stabilizers that keep the particles in suspension. The spray-dried composition can be administered to the subject without further processing; however, it will be formulated in general in other dosage forms in conjunction with other pharmaceutically acceptable excipients selected with respect to the desired dosage form. These other excipients will typically be added to the spray-dried composition after spray drying. Therefore, according to a third aspect, a dosage form comprising a composition defined in the second aspect is provided.

It will be appreciated that the embodiments described for the first and second aspects extend to this third aspect. In one embodiment, the dosage form is administered orally. Oral administration will typically involve swallowing, so that the compound enters the GIT. Dosage forms for oral administration include solid formulations such as tablets, capsules (containing particulate matter, powders or non-aqueous suspension), sachets, vials, powders, granules, pellets, reconstitutable powders and liquid preparations (such as suspensions, emulsions). and elixirs). Oral dosage forms may contain other excipients such as binding agents (eg, syrup, acacia, gelatin, sorbitol, starch, PVP, HPMC and tragacanth); fillers (for example, lactose, sugar, corn starch, calcium phosphate, sorbitol and glycine); lubricants for making tablets (for example, magnesium stearate); and disintegrants (eg, starch, crospovidone, croscarmellose sodium, sodium starch glycolate and microcrystalline cellulose). In addition, the oral dosage form may contain preservatives, antioxidants, flavors, granulation binders, wetting agents and dyes. In one embodiment, the dosage form for oral administration is a tablet. Tablets can be prepared using standard technology well known to the formula scientist, for example, by direct compression, granulation, freezing of molten material and extrusion. The tablet can be coated or uncoated. The tablet can be formulated to be immediate or controlled release. Controlled release formulations include sustained release, pulsed or double release formulations. Excipients for making suitable tablets are described in the Handbook of Pharmaceutical Excipients, Pharmaceutical Press, 1986, published by The American Pharmaceutical Association and The Royal Pharmaceutical Soclety of Great Britain. Typical tabletting excipients include: vehicles [e.g., microcrystalline cellulose (Avicel PH 102)], lubricating agents (e.g., magnesium stearate), binding agents, wetting agents, colorants, flavors, slip agents [e.g. colloidal silicon dioxide (Cab-O-Sil M-5 P) and disintegrators [e.g., crospovidone (Polyplasdone XL)]. In another embodiment, the tablet consists of the excipients in composition A of example 2 below. Suitable excipients for the preparation of liquid dosage forms include: suspending agents (eg sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and hydrogenated edible fats); emulsifying agents (for example, lecithin, sorbitan monooleate and acacia); aqueous or non-aqueous vehicles, including edible oils (e.g., almond oil and fractionated coconut oil), oily esters (e.g., glycerin and propylene glycol esters), ethyl alcohol, glycerin, water, and normal saline; preservatives (e.g., methylpropyl p-hydroxybenzoate and sorbic acid); and, if desired, conventional flavoring or coloring agents. The effective dose of talnetant depends on the condition of the patient and the frequency and route of administration. A unit dose will generally contain from 20 to 1000 mg of talnetant, in a 30 to 500 mg modality, in another 200 or 400 mg modality. The unit dose may be administered one or more times per day (for example 2, 3 or 4 times per day). The total daily dose for an adult of 70 kg, will normally be in the range of 100 to 3000 mg. Alternatively, the unit dose will contain from 2 to 20 mg of active ingredient, and it will be administered in multiples, if desired, to give the previous daily dose. In one embodiment, the compositions and tablets of the invention are adapted for use in the medical or veterinary fields. For example, said preparations may be in the form of a package accompanied by written or printed instructions for use as an agent in the treatment of conditions. Antagonists of the NK3 receptor, including talnetant, are useful in the treatment and prevention of a wide variety of diseases and clinical conditions characterized by overstimulation of NK3 receptors. These diseases and conditions (hereinafter referred to as "diseases and conditions of the invention") include: CNS disorders such as depression (the term of which includes bipolar (manic) depression (including type I and type II), unipolar depression, episodes severe individual or recurrent depressants with or without psychotic features, catatonic features, melancholic features, atypical features (eg, lethargy, overeating / obesity, hyperinsomnia) or postpartum onset, seasonal affective disorder and dysthymia, anxiety related to depression, psychotic depression, and depressive disorders resulting from a general medical condition including, but not limited to, myocardial infarction, diabetes or abortion); anxiety disorders (which include generalized anxiety disorder, social anxiety disorder, agitation, tension, social or emotional withdrawal in psychotic patients, panic disorder and obsessive compulsive disorder); phobias (which include agoraphobia and social phobia); psychosis and psychotic disorders (including schizophrenia, schizoaffective disorder, schizophreniform diseases, acute psychosis, alcoholic psychosis, autism, delirium, mania (including acute mania), manic depressive psychosis, hallucination, endogenous psychosis, organic psychosis syndrome, disorders paranoid and delusional, puerperal psychosis and psychosis associated with neurodegenerative diseases such as Alzheimer's disease); post-traumatic stress disorder; hyperactive disorder due to attention deficit; cognitive impairment (for example, the treatment of impairment of cognitive functions that include attention, orientation, memory (memory disorders, amnesia, amnestic disorders and memory impairment associated with age) and language function, and that includes cognitive impairment as a result of stroke, Alzheimer's disease, dementia related to AIDS or other states of dementia, as well as other acute or subacute conditions that can cause cognitive decline such as delirium or depression (pseudo-dementia states)); seizure disorders such as epilepsy (including simple partial seizures, complex partial seizures, secondary generalized seizures, generalized seizures including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic clonic seizures, and atonic seizures); psychosexual dysfunction (including inhibited sexual desire (decreased libido), sexual arousal or arousal inhibited, orgasmic dysfunction, inhibited female orgasm and inhibited male orgasm, hypoactive sexual desire disorder, female sexual desire disorder, and sexual dysfunction-induced side effects the treatment with antidepressants of the SSRI class); sleep disorders (which include circadian rhythm disorders, dysomnia, insomnia, sleep apnea and narcolepsy); disorders of eating behaviors (including anorexia nervosa and bulimia nervosa); neurodegenerative diseases (such as Alzheimer's disease, amyotrophic lateral sclerosis, motor neuron disease and other motor disorders such as Parkinson's disease (which includes relief of locomotor deficits and / or motor disability, which includes slowly increasing incapacity in motion for a certain purpose , tremor, bradykinesia, hyperkinesia (moderate and severe), akinesia, rigidity, balance and coordination disorder and posture disorder), dementia in Parkinson's disease, dementia in Huntington's disease, neuroleptic-induced parkinsonism and tardive dyskinesias, consecutive neurodegeneration stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury, or the like, and demyelinating diseases, such as multiple sclerosis and amyotrophic lateral sclerosis); withdrawal from drug abuse, including smoking cessation or reduction in the level or frequency of such activities (such as cocaine abuse, ethanol, nicotine, benzodiazepines, alcohol, caffeine, phencyclidine and phencyclidine-like compounds, opiates such as cannabis, heroin , morphine, sedatives, hypnotics, amphetamines or drugs related to amphetamines, such as dextroamphetamine, methylamphetamine, or a combination thereof); pain (including neuropathic pain that includes diabetic neuropathy, sciatica, nonspecific lower back pain, pain from multiple sclerosis, pain associated with fibromyalgia or cancer, HIV-related and HIV-related neuropathy, neuropathy induced by chemotherapy, neuralgia, as post-herpetic neuralgia and trigeminal neuralgia; sympathetically maintained pain and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions such as rheumatoid arthritis and osteoarthritis; reflex sympathetic dystrophy such as shoulder and hand syndrome), acute pain (eg, musculoskeletal pain, post-operative pain and surgical pain), inflammatory pain and chronic pain, pain associated with normally non-painful sensations, such as "tingling" ( paresthesia and dysesthesia), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold or mechanical hyperalgesia), continuous pain sensation after removal of stimulation (hyperpathy), or an absence of, or deficit in, selective sensory pathways (hypoalgesia), pain associated with migraine and non-cardiac chest pain); certain disorders measured by the CNS (such as emesis, irritable bowel syndrome, and non-ulcer dyspepsia); and pulmonary disorders (such as asthma, chronic obstructive pulmonary disease, airway hyperreactivity and cough). More preferred diseases or conditions (hereinafter referred to as "preferred diseases and conditions of the invention") mediated by modulation of the NK3 receptor are depression; anxiety disorders; phobias; psychoses and psychotic disorders; post-traumatic stress disorder; hyperactive disorder due to attention deficit; withdrawal of drug abuse, including smoking cessation or reduction in the level or frequency of such activities; irritable bowel syndrome; cognitive impairment; convulsive disorders; psychosexual dysfunction; sleep disorders; eating disorders; neurodegenerative diseases; pain; emesis; irritable bowel syndrome; non-ulcer dyspepsia; and lung diseases (such as asthma, chronic obstructive pulmonary disease, airway hyperreactivity and cough). The following examples illustrate the present invention.

EXAMPLE 1 Preparation of spray-dried compositions and recovery of particle size after dispersion in water a) Composition 1 (according to the invention) Sodium lauryl sulfate (0.3% w / w) and povidone (Kollidone K30) (1.7% w / w) were dissolved in purified water (68.0% w / w) . Then, solid talnetant (20.0% w / w, D 90 from about 20 to 30 μm) was added slowly with continuous mixing, until a homogeneous suspension was obtained. The homogeneous suspension was passed through a Netzsch bead mill (containing 85% by volume of 0.3 mm zirconium oxide beads stabilized with yttrium). The dispersion was recirculated through the bead mill with continuous mixing, until a Dv90 > 0.4 μm < 1.0 μm. D 90 was measured using a Malvern Mastersizer 2000. The results are shown in table 1. Then, powdered mannitol USP (10.0% w / w) was added to the dispersion until a uniform suspension was obtained. This dispersion was spray-dried using a Niro Mobile Minor atomizer (operated according to the manufacturer's instructions) to the following values: two fluid nozzles: atomization pressure of 2 bars; flow quantity of the drying gas: 65 m3 / hr; sprinkling rate of the suspension: 35 mL / min; Inlet temperature: 150 ° C; Output temperature: 60 ° C. A sample of the spray dried composition was dispersed in water, and the Dy 90 was measured using a Malvern Mastersizer 2000. The results are shown in table 1. b) Composition 2 (according to the invention) Sodium dioctyl sulfosuccinate (30.2 g, 0.3% w / w), povidone (Kollidone K30) (170 g, 1.7% w / w) and USP powder mannitol were dissolved. (1001.9 g, 10.0% w / w) in purified water (6820 g, 68.0% w / w). Then, solid talnetant (2012 g, 20.0% w / w, D 90 from about 20 to 30 μm) was added slowly with continuous mixing, until a homogeneous suspension was obtained. The homogeneous suspension was passed through a Netzsch bead mill as described for composition 1. The dispersion was recirculated through the bead mill with continuous mixing, until a Dv90 > 0.4 μm < 1.0 μm. The Dv90 was measured using a Malvern Mastersizer 2000. The results are shown in Table 1. This dispersion was spray-dried using a Niro Mobile Minor atomizer (operated according to the manufacturer's instructions) to the following values: two fluid nozzles: atomization pressure of 2 bars; sprinkling rate of the suspension: 35 mL / min; Inlet temperature: 150 ° C; Output temperature: 60 ° C. The spray-dried composition was dispersed in water, and Dv90 was measured using a Malvern Mastersizer 2000. The results are shown in table 1. c) Composition 3 (according to the invention) Sodium lauryl sulfate (30 g, 0.3% w / w) was dissolved in purified water (6470.3 g, 64.7% w / w). To this stirred solution were povidone (Kollidone K30) (500.1 g, 5.0% w / w), lactose monohydrate (impalpable # 312) (999.7 g, 10.0% w / w) and solid talnetant (2000.5 g, 20.0) added slowly. % in w / w, Dv90 of approximately 20 to 30 μ), until a homogeneous suspension was obtained. The homogeneous suspension was passed through a Netzsch bead mill as described for composition 1. The dispersion was recirculated with continuous mixing, until a Dv90 > 0.4 μm < 1.0 μm. D 90 was measured using a Malvern Mastersizer 2000. The results are shown in Table 1. This dispersion was spray-dried using a Niro Mobile Minor atomizer (operated according to the manufacturer's instructions) to the following values: two fluid nozzles: atomization pressure of 2 bars; sprinkling rate of the suspension: 35 mL / min; Inlet temperature: 150 ° C; Output temperature: 60 ° C. The spray-dried composition was dispersed in water, and Dv90 was measured using a Malvern Mastersizer 2000. The results are shown in table 1. d) Composition 4 (comparative example - without ionic surfactant and soluble carrier) Pluronic F68 (a nonionic surfactant) (3.9% w / w) was added slowly to purified water (74.5% w / w), followed by solid talnetant (19.6% w / w, Dv90 of approximately 20 to 30 μm) with continuous mixing, until a homogeneous suspension was obtained. The homogeneous slurry was passed through a Netzsch bead mill as described for composition 1. The dispersion was recirculated through the bead mill with continuous mixing until a Dy 90 > 0.4 μm < 1.0 μm. The Dy90 was measured using a Malvern Mastersizer 2000. The results are shown in table 1. Povidone (Kollidone K30) dispersion (2.0% w / w) was then added to the dispersion until a uniform suspension was obtained. This dispersion was spray-dried using a Niro Mobile Minor atomizer (operated according to the manufacturer's instructions) to the following values: two fluid nozzles: atomization pressure of 2 bars; flow quantity of the drying gas: 65 m3 / hr; sprinkling rate of the suspension: 35 mL / min; Inlet temperature: 110 ° C; Output temperature: 40 ° C. A sample of a spray dried composition was dispersed in water, and the Dv90 was measured using a Malvern Mastersizer 2000. The results are shown in table 1. The granulometry after redispersion in water for compositions 1 to 4, is shown in table 1 (the values in parentheses are the corresponding D values of the wet ground suspension before drying by sprinkling). Table 1 shows that compositions 1, 2 and 3 gave virtually full recovery of particle size after redispersion in water, while composition 4 gave a poor recovery.

TABLE 1 EXAMPLE 2 Comparative study evaluating the effect on pK parameters of oral administration of talnetant compositions to conscious male hounds A catheter was placed in the cephalic vein of each of four fasting male hounds. One half of a tablet A (whose composition is shown in Table 2 - the dosage form of the invention) was administered to each dog. Blood samples were collected by means of the catheter before dosing and at the following times after dosing: 15, 30, 45, 60, 90, 120, 180, 240, 300, 360, 480, 600 and 1440 minutes. Plasma was prepared and stored frozen for analysis. Plasma talnetant concentrations (limit of quantification = 10 ng / mL) were quantified by means of an LC / MS / MS method. Non-compartmental analyzes were used for the pharmacokinetic analysis of the plasma concentration against the actual data of the sampling time. The dogs were fed 6 hours after the dose (after collection of the 6-hour blood sample), and the feed was removed one hour later. After a one week withdrawal period, the procedure was repeated in the same four dogs with the B tablet. After another one week withdrawal period, the procedure was repeated with the C tablet and with the D tablet (the tablets B, C and D are comparative examples).

The spray-dried compositions used in tablets A, B, C and D were prepared by combining the ingredients marked with the superscript "a" in a manner similar to the methods described in example 1. Each dispersion was wet-milled to give a Dv90 of 0.5 μm. After spray drying, the compositions were tabletted using the ingredients marked with the superscript "b" using standard tabletting technology well known to those skilled in the art. The results of the study are shown in table 3. The results show that the administration of tablet A (the composition of the invention), led to a significant improvement in bioavailability compared to the comparative examples (tablets B, C and D). In addition, the results show that the values for tablet A were the most consistent among the subjects. The average relative bioavailability for the three formulations against tablet C was calculated by determining the relative bioavailability for each animal, then calculating the average and the standard deviation of the individual relative bioavailability values. In general, the average relative bioavailability of tablet A was 1.96 ± 0.34, and the individual values were 1.81, 2.35 and 1.72. Cmax is the maximum concentration of talnetant in plasma achieved. Tmax is the time after the administration at which the maximum concentration was reached. AUC is the area under the curve of a plot of plasma concentration versus time. AUC (0-t) refers to the area from time zero to the last quantifiable concentration at time t. AUC (0-360) refers to the area from time zero to t = 360 minutes. TABLE 3

Claims (32)

NOVELTY OF THE INVENTION CLAIMS

1. - A process for the preparation of a spray-dried composition, the composition comprising, i) talnetant particles with a Dv90 in the range of 0.1 to 2.0 μm, ii) one or more ionic surfactants, and iii) one or more vehicles soluble, the process comprising, a) wet grinding a dispersion of the solid talnetant particles until the Dv90 is on the 0.1 to 2.0 μm scale, which dispersion comprises the one or more ionic surfactants, and the one or more vehicles soluble, and then b) spray-dried or granular by spray the resulting dispersion.

2. The process according to claim 1, further characterized in that the dispersion is wet milled in a water-based medium.

3. The process according to any of the preceding claims, further characterized in that the dispersion contains 5 to 50% w / w of talnetant.

4. The process according to any of the preceding claims, further characterized in that the dispersion contains 15 to 30% w / w of talnetant.

5. The process according to any of the preceding claims, further characterized in that the ionic surfactant is an anionic surfactant.

6. The process according to any of the preceding claims, further characterized in that the ionic surfactant is sodium lauryl sulfate or sodium dioctyl sulfosuccinate.

7. The process according to any of the preceding claims, further characterized in that the ionic surfactant is sodium lauryl sulfate.

8. The process according to any of the preceding claims, further characterized in that the concentration of surfactant in the spray-dried composition is 0.5 to 3.0% by weight of talnetant.

9. The process according to any of the preceding claims, further characterized in that the concentration of surfactant in the dispersion before spray drying is 0.05 to 5.0% by weight of the dispersion.

10. The process according to any of the preceding claims, further characterized in that the dispersion contains 0.001 to 0.1 mole of ionic surfactant per mole of talnetant.

11. The process according to any of the preceding claims, further characterized in that the one or more soluble carriers are a soluble sugar.

12. The process according to any of the preceding claims, further characterized in that the one or more soluble carriers are selected from the group consisting of mannitol, sorbitol, lactose, lactitol, xylitol, trehalose, dextrose, sucrose, maltose, fructose, maltitol, xylitol, erythritol, polydextrose, isomalt, cyclodextrin and starch.

13. The method according to any of the preceding claims, further characterized in that the spray-dried composition comprises one or more soluble carriers selected from the group consisting of mannitol, lactose, erythritol, polydextrose, isomalt and lactitol.

14. The process according to any of the preceding claims, further characterized in that the concentration of the one or more soluble carriers in the spray-dried composition is 10 to 75% by weight of talnetant.

15. The process according to any of the preceding claims, further characterized in that the concentration of the one or more soluble vehicles in the dispersion before wet milling or after wet milling, is 0.1 to 30% by weight of the dispersion.

16. The method according to any of the preceding claims, further characterized in that the spray-dried composition comprises one or more anti-agglomeration agents.

17. The method according to any of the preceding claims, further characterized in that the concentration of the anti-agglomeration agent in the spray-dried composition is 2 to 10% by weight of talnetant.

18. The process according to any of the preceding claims, further characterized in that the concentration of anti-agglomeration agent in the dispersion before spray drying is 0.1 to 10.0% by weight of the dispersion.

19. A spray-dried pharmaceutical composition comprising i) Talnetant particles with a D 90 in the range of 0.1 to 2.0 μm, ii) one or more ionic surfactants, and iii) one or more soluble carriers.

20. The pharmaceutical composition according to claim 19, characterized in that the ionic surfactant is an anionic surfactant.

21. The pharmaceutical composition according to claim 19 or 20, further characterized in that the ionic surfactant is sodium lauryl sulfate or sodium dioctyl sulfosuccinate.

22. The pharmaceutical composition according to any of claims 19 to 21, further characterized in that the ionic surfactant is sodium lauryl sulfate.

23. The pharmaceutical composition according to any of claims 19 to 22, further characterized in that the concentration of surfactant in the spray-dried composition is 0.5 to 3.0% by weight of talnetant.

24. - The pharmaceutical composition according to any of claims 19 to 23, further characterized in that the one or more soluble carriers are a soluble sugar.

25. The pharmaceutical composition according to any of claims 19 to 24, further characterized in that the one or more soluble carriers are selected from the group consisting of mannitol, sorbitol, lactose, lactitol, xylitol, trehalose, dextrose, sucrose, maltose , fructose, maltitol, xylitol, erythritol, polydextrose, isomalt, cyclodextrin and starch.

26. The pharmaceutical composition according to any of claims 19 to 25, further characterized in that the spray-dried composition comprises one or more soluble carriers selected from the group consisting of mannitol, lactose, erythritol, polydextrose, isomalt and lactitol.

27. The pharmaceutical composition according to any of claims 19 to 26, further characterized in that the concentration of the one or more soluble carriers in the spray-dried composition is 10 to 75% by weight of talnetant.

28. The pharmaceutical composition according to any of claims 19 to 27, further characterized in that the spray-dried composition comprises one or more anti-agglomeration agents.

29. The pharmaceutical composition according to any of claims 19 to 28, further characterized in that the concentration of the anti-agglomeration agent in the spray-dried composition is 2 to 10% by weight of talnetant.

30. A dosage form comprising a composition defined in any of claims 19 to 29. 31.- The dosage form according to claim 30, characterized in that it is administered orally. 32. The dosage form according to claim 31, further characterized in that it is administered as a tablet.