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WO2019161470A1 - Composition pharmaceutique sous forme de suspension aqueuse et utilisation d'une composition pharmaceutique sous forme de suspension aqueuse - Google Patents

Composition pharmaceutique sous forme de suspension aqueuse et utilisation d'une composition pharmaceutique sous forme de suspension aqueuse Download PDF

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Publication number
WO2019161470A1
WO2019161470A1 PCT/BR2019/050050 BR2019050050W WO2019161470A1 WO 2019161470 A1 WO2019161470 A1 WO 2019161470A1 BR 2019050050 W BR2019050050 W BR 2019050050W WO 2019161470 A1 WO2019161470 A1 WO 2019161470A1
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Prior art keywords
composition according
melatonin
sleep
mixture
nasal
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English (en)
Portuguese (pt)
Inventor
Leonardo de Souza TEIXEIRA
Jeane Roberta Santana de FARIA
Sarah Rodrigues FERNANDES
Iram Moreira MUNDIM
Carina Pimentel Itapema ALVES
Karini Bruno BELLORIO
Gílbia de Castro Melo NOGUEIRA
Viviane Pimentel Itapema ALVES
Juliana Oyan Roque CERONI
Ana Lucia NOBUSA
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Cosmed Industria de Cosmeticos e Medicamentos SA
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Cosmed Industria de Cosmeticos e Medicamentos SA
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    • 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
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • 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
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • the present invention relates to pharmaceutical compositions in aqueous suspension form for mucosal administration of melatonin comprising a drug solubilization system and a polymeric system comprising a gelling agent and a thixotropic suspending agent.
  • the compositions are useful for treating or aiding in combating sleep disorders, particularly for primary insomnia.
  • Primary insomnia is characterized by difficulty in initiating or maintaining sleep (poor sleep quality) and the feeling of not having restful sleep for a period of not less than one month.
  • Melatonin is a neurohormonium, secreted by the pineal gland, responsible for controlling the synchronization of body rhythms with night and day cycles and thus can be used to improve sleep quality and latency, and even alleviate time zone effects. and other disorders arising from sleep imbalance.
  • the most accepted hypothesis for the mechanism of action of melatonin would be through its probable action on receptors in peripheral blood vessels, resulting in vasodilation and consequent activity in the sleep and wake centers of the hypothalamus, causing a reduction in body temperature.
  • melatonin In addition to its effects on circadian rhythm, melatonin is considered a powerful antioxidant. There is evidence in the literature that melatonin decreases free radicals (hydroxyl and peroxyl), presenting direct and indirect activity on these substances (Bonnefont-Rousselot .; Collin, 2010).
  • melatonin administered at night, in doses ranging from 0.3 to 12 mg significantly improved subjective and / or objective sleep parameters in patients suffering from insomnia (reduced sleep latency, increased sleep time). total sleep and sleep effectiveness).
  • the low bioavailability of melatonin after oral administration is due to its low oral absorption, its first pass metabolism or the combination of both factors.
  • one of the possibilities is the administration of the drug by a second route that does not present first pass hepatic metabolism in an area with high vascularization, making it a promising strategy to increase it. absorption of the drug and consequently improves bioavailability.
  • a transmucosal route of administration is inserted as an alternative for improving the drug delivery system.
  • transmucosal route of administration presents interesting factors for melatonin administration, since the passage of the drug occurs by diffusion through the mucosa, which are relatively permeable and highly vascularized membranes. In this way rapid absorption can be achieved which, together with the absence of first pass hepatic metabolism, can achieve high bioavailability, while avoiding the harsh environment of the stomach.
  • the sublingual route is considered as a convenient, easily accessible and generally well-accepted route for drug administration.
  • the obstacles are related to ensuring the deposition, application and effective adhesion of the formulation to the mucosa, taking into account the permeation / diffusion processes by the physical mucus barrier and local irritation.
  • the development rationale should ensure that the formulation is distributed and in contact with the mucosa long enough for drug absorption without causing irritant processes.
  • melatonin has low solubility in water due to its lipophilic character, as well as being easily oxidized and sensitive to the presence of light, making development even more complex. Solubility is considered a critical factor for mucosal drug application as it may directly impact the pharmacokinetics of the drug, including absorption and bioavailability, as well as formulation stability.
  • melatonin oxidation highlights its potential antioxidant effect and has beneficial health effects, it becomes a major challenge to ensure the stability of the product under development.
  • the oxidation reaction of melatonin can be catalyzed by UV exposure showing greater degradation when at higher pH. Within this context, avoiding the melatonin oxidation process becomes an additional challenge in developing a stable formulation.
  • WO1996030013 describes transmucosal melatonin release system 0.05 to 5 mg in mucoadhesive matrix, particularly a polymeric resin matrix for frequency reduction or prevention of migraine.
  • Examples of the document disclose a patch system for oral mucosa administration.
  • Japanese patent JP55057563 described intranasal compositions comprising 100 mg melatonin dissolved in 10 ml 5% ethanol solution, but there were serious side effects.
  • the document also disclosed a composition in which propylene glycol was used instead of ethanol.
  • CN1969814 describes a nasal administration preparation containing 0.1 to 100 mg melatonin and at least one type of polyethylene glycol.
  • melatonin in PEG solution demonstrated moderate to high irritation after nasal administration in two healthy subjects (Bechgaard E et al ., Int J Pharm 1999).
  • US6007834 also describes a nasal formulation containing melatonin which uses cyclodextrin or glycerol for solubilization.
  • the document describes an aqueous solution or melatonin powder for human sleep induction.
  • nasal solutions do not have adequate viscosity for adhesion and permanence on mucosal surfaces. The high viscosity of nasal mucus prevents drug diffusion, while rapid nasal mucociliary clearance reduces contact time with the epithelium.
  • the inventors have found that US6007834 nasal solutions cause burning at the site of application, poor sleep induction and shorter duration of pharmacological effect.
  • WO2008141264 describes compositions for the treatment of insomnia in oral spray form comprising zolpidem, water and solvent, particularly propylene glycol or ethanol.
  • the composition includes a taste masking or flavoring and propelling agent.
  • US20150352038 describes a dosage form for buccal transmucosal administration of an active ingredient for accelerated sleep induction and / or treatment of sleep disorders, wherein the active ingredient is lipophilic or amphiphilic and is present in a hydroalcoholic solution. comprising ethanol and water.
  • Alcohols are commonly employed to increase the solubility of lipophilic drugs.
  • use of alcohols, such as ethanol may cause burning or irritation when in contact with sensitive mucous membranes such as nasal or sublingual, including possible irreversible effects on the nasal mucociliary membrane.
  • aqueous suspension formulations for melatonin delivery through the mucosae comprising a drug solubilization system and a polymeric system comprising a gelling agent and a Thixotropic suspending agents have excellent results in drug solubility, system performance and stability, as well as excellent adhesion of the formulation to mucous membranes such as nasal and sublingual mucosae.
  • the present invention aims to develop a stable transmucosal pharmaceutical composition which ensures melatonin solubility while ensuring a safe dose, effective distribution and adhesion of the formulation to the mucosae, rapid absorption without causing irritation at the site of application and consequently dose reduction required for sleep induction compared with formulations described above or available on the international market.
  • an aqueous suspension formulation for mucosal administration of melatonin comprising a drug solubilization system and a polymeric system comprising an in situ gel-forming gelling agent and a suspending agent with thixotropic characteristics capable of ensuring system stability and formulation adherence in mucous membranes, particularly nasal and sublingual mucosa.
  • compositions of the present invention are particularly suitable for spraying through a nasal or sublingual spray or other metered / accurate dose delivery device.
  • compositions according to the present invention are useful for treating or aiding in the fight against sleep disorders, such as circadian rhythm disorders and insomnia in general, particularly for primary insomnia.
  • Figure 1 Mean plasma melatonin concentration following administration of 0.2 mg melatonin equivalent to 2 applications of the test drug nasal suspension or 1.75 mg of Melatonin Pura® equivalent to 10 drops of the oral solution of test drug 3.
  • Figure 2 Mean plasma melatonin concentration after administration of 0.5mg Melatonin equivalent to 1 sublingual spray application (Test 4) or 1.75mg Melatonin equivalent to 10 drops of oral solution (Test 3).
  • aqueous suspensions of the present invention are suitable for mucosal administration of melatonin and comprise a drug solubilization system and a polymeric system comprising a gelling agent and a thixotropic suspending agent.
  • the transmucosal route includes oral, buccal, labial, sublingual, gingival / palatal, nasal, vaginal, urethral, esophageal, gastric, intestinal, olfactory, bronchial, endometrial mucosa.
  • the route of administration is the oral, buccal, labial, sublingual, gingival / palatal, or nasal mucosa; more particularly, the sublingual and nasal routes.
  • melatonin Although melatonin has significant pharmacological properties, its use is limited due to the low solubility of the compound in water. Thus, the first challenge for formulation development was the solubilization of melatonin.
  • compositions according to the present invention contain a solubilizing system capable of ensuring solubility and stability and thus contributing to uniformity and increased absorption of the drug.
  • the solubilizing system according to the invention acts as a vehicle of the drug (melatonin).
  • the melatonin solubilizing system is an emulsified system. This alternative is particularly suitable for the preparation of a suspension for nasal administration of melatonin.
  • Emulsions are biphasic systems defined as dispersions in which the dispersed phase (discontinuous or internal) consists of small droplets of liquid distributed in a vehicle (continuous or external phase) in which they are immiscible.
  • the mixture of the two constituent phases is stabilized by the action of one or more hydrophilic and / or lipophilic surfactant emulsifiers and may be of liquid or semi-solid consistency.
  • the emulsified system according to this alternative of the invention is composed of an aqueous external phase and an oily dispersed or internal phase, thus being an oil in water (O / W) emulsion.
  • the drug melatonin is solubilized in the internal (oily) phase of the emulsified system.
  • melatonin may be solubilized in different oils and solubilizing agents.
  • suitable oils and solubilizing agents for this function are: caprylic caprylic acid triglyceride oil, diethylene glycol monoethyl ether, medium chain mono-diglyceride, castor oil, polyethylene glycol 400, Acconon CCG, monoglyceride, glycerol 99%, mineral oil , refined sesame oil, coconut oil, oleic acid, medium chain triglycerides (Miglyol), or a mixture thereof.
  • melatonin is solubilized in diethylene glycol monoethyl ether.
  • melatonin is solubilized in a mixture of caprylic caprylic acid triglyceride oil and diethylene glycol monoethyl ether.
  • the surfactants (emulsifiers) used in stabilizing the emulsions of the present invention were chosen from the EHL (hydrophilic / lipophilic balance) required by the oil to form a stable system.
  • Surfactants may be natural (saponins, cholesterol, lecithin, lanolin, gums) or synthetic, which are subdivided into: anionic (sodium stearate, sodium oleate, sodium lauryl sulfate); cationics (benzalkonium chloride, cetylpyridine chloride); nonionic (sorbitan esters, alkyl sorbitan esters); and amphoteric (amino acid) surfactants.
  • Nonionic surfactants selected from sorbitan monooleate 80 (Span 80), PEG-40 (Kolliphor RH40), polysorbate 80 (Tween 80), propylene glycol and sorbitan monostearate (Span 60) are preferred.
  • the following surfactant pairs are suitable: sorbitan monooleate 80 / PEG-40, polysorbate 80 / propylene glycol, sorbitan monostearate / polysorbate 80, sorbitan monooleate 80 / polysorbate 80.
  • the compositions of the present invention comprise sorbitan 80 (Span 80) and hydrogenated castor oil PEG-40 (Kolliphor RH40).
  • the intermediate phase of the handling process of the present invention specific to the formation of an emulsified system has a droplet size distribution of the internal phase of the colloidal dispersion in the range of 20 to 200 nm, particularly with an average diameter of 100 nm.
  • a solubilizing agent is used to ensure melatonin solubilization.
  • the compositions comprise a solubilizing agent. This alternative is particularly suitable for preparing a suspension for sublingual administration of melatonin.
  • the solubilizing agent according to this alternative of the invention is one selected from polyethylene glycol, propylene glycol, glycerol and mineral oil.
  • the solubilizing agent is polyethylene glycol 400.
  • melatonin is present in an amount of 0.1-10%, preferably 0.1-1.5%, by weight / weight of the composition.
  • compositions of the present invention further comprise a polymeric system comprising a gelling agent and a suspending agent having thixotropy characteristics.
  • the first component of the polymeric system is the gelling agent, which acts as a gelled matrix that ensures deposition, application distribution and effective adhesion of the formulation to mucosal surfaces.
  • the gelled matrix contains a gelling agent capable of forming a gel in situ .
  • gelling agent is defined as a biocompatible polymeric agent having adhesion and gelling ability in situ .
  • the in situ gelation process that is gelation when in contact with mucosal surfaces, is interesting because it allows the formulation to easily spray through a delivery device, such as through a spray valve, and disperse more easily before forming a gel and when in contact with the mucosal surface, viscosity gain occurs, ensuring formulation adherence and the desired effect.
  • Addition of the gelling agent in situ increases the residence time of the formulation in the mucosae and enables diffusion and increased absorption of the drug. This property has been exploited for sustained drug delivery, generally as matrix devices that have the ability to form gel.
  • the in situ gelation strategy has been demonstrated in several studies for oral and ophthalmic application using polymers for this purpose, but there are still few studies regarding its use in nasal and sublingual mucosae.
  • the gelling agents according to the present invention are mucoadhesive polymers selected from natural or semi-natural polymers such as chitosan, gums, pectins and the alginate or derivatives thereof such as sodium alginate and calcium alginate; or synthetic polymers such as cellulose derivatives being carboxymethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, methylcellulose, poly (oxyethylene), polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid, carbopol, polycarbofil.
  • the gelling agent is selected from pectin or sodium alginate.
  • the purpose of incorporating melatonin into a polymer blend was to ensure the physicochemical stability of the system by forming a continuous phase extended web which makes it highly viscous, keeping the formulation in suspension when at rest.
  • the polymeric system of the compositions of the present invention further comprises a second polymeric component to ensure performance, system stability and adhesion of the formulation to mucosal surfaces.
  • the addition of the second polymeric component is important because the gelling agent forms a gel only when in contact with mucosal surfaces. Thus, it is necessary to add a second polymer to help stabilize the system when at rest by increasing viscosity.
  • the second polymeric component is a thixotropic suspending agent.
  • a thixotropic fluid is characterized by being time dependent, ie its viscosity increases with time during a decrease in shear rate (rest formulation), however, this change in viscosity is easily reversible with increasing shear rate (agitation). ).
  • the thixotropic effect of the compositions of the present invention is advantageous compared to the state of the art as it simultaneously provides: stability of the composition by viscosity gain, rapid fluid formation with uniformity suitable for mucosal administration and superior mucoadhesive properties.
  • Thixotropic suspending agent is one capable of providing the rheological characteristics necessary for formation of a thixotropic system.
  • the thixotropic suspending agent according to the present invention may be selected from: agar, carrageenan, carboxymethylcellulose, microcrystalline cellulose, colloidal silicon dioxide, xanthan gum, gelatin gum or a mixture thereof.
  • carboxymethylcellulose (CMC) and microcrystalline cellulose is preferred.
  • the final pharmaceutical form of the invention is a suspension, due to the presence of insoluble suspending agent particles in the aqueous medium.
  • Suspension is understood to be formulation containing solid particles dispersed in a liquid carrier in which the particles are not soluble.
  • the final suspension obtained in the handling process of the present invention has a particle size distribution in the range of 5 to 50 ⁇ m, particularly with an average diameter of between 10.0 - 15.0 ⁇ m with 90% ⁇ 30%. ⁇ m.
  • compositions of the present invention are even more advantageous as it facilitates the manufacturing process of the medicament, especially during the product filling phase in the pharmaceutical manufacturing area.
  • agitation provided to the system, the formulation becomes fluid with easy flow assisting transport and transfer between tanks during the process.
  • a thixotropic suspending agent assists in the process of adhesion of the formulation to the mucosae.
  • the polymer is easily dispersed in water, resulting in a high initial drug release rate, but after dispersion forms a viscous liquid extending the retention time of the formulation at the site of action. Mucoadhesion of the suspending agent occurs after polymer hydration (polymer-mucus mixture). For these reasons, the use of this agent may contribute to better absorption and increased bioavailability.
  • the performance of the invention is even more surprising because, by incorporating the melatonin solubilization system into a mucoadhesive gelled matrix, thereby obtaining a suspension, the skilled artisan would expect to find a reduction in the rate of absorption of the drug, as that it is necessary to break the viscous barrier of the polymeric network and thus allow the permeation of the drug.
  • the gelled matrix when in close contact with the mucosa forms a physical barrier which would modulate the pharmacokinetics of the drug.
  • excellent pharmacokinetic parameters were observed when compared with the state of the art.
  • compositions of the present invention have a final viscosity of 5.0 - 250.0 centipoise (cp), preferably a nasal suspension has a viscosity of 15.0 - 25.0 cp and a sublingual suspension has a viscosity of 190.0 - 230, 0 cp.
  • cp centipoise
  • compositions of the present invention further comprise a preservative system for ensuring microbial control, thereby ensuring the stability and functionality of the developed formulation.
  • compositions of the present invention may comprise the use of a microbiological preservative.
  • microbiological preservatives that may be incorporated into the composition are benzalkonium chloride, benzoic acid, phenylethyl alcohol, bronopol, benzyl alcohol, methylparaben, propylparaben, paraben mixture, thymol, sodium benzoate and potassium sorbate, or a mixture thereof.
  • the composition comprises the following preservatives, methylparaben, propylparaben, sodium benzoate and potassium sorbate, or a mixture thereof.
  • compositions of the present invention optionally comprise an antioxidant system to prevent melatonin oxidation process, thereby ensuring the stability and functionality of the developed formulation.
  • the antioxidant system comprises the use of the nitrogen technique, which consists of the use of nitrogen conditioning an inert system in the handling steps until the formulation is filled in order to avoid product exposure and minimal contact. of the drug with atmospheric oxygen, which is responsible for the oxidation reaction.
  • the antioxidant system comprises the use of photoprotective primary packaging, ensuring as much as possible controlling the exposure of the product to UV radiation and avoiding catalysis of the oxidation reaction.
  • the packages may be composed of aluminum, PET, HDPE or amber glass, preferably in the HDPE package.
  • the antioxidant system comprises an antioxidant agent in the formulation which may retard the oxidative reaction of melatonin, that is, acts by "preventing oxidation of another chemical and oxidizing", thereby ensuring the stability of the main drug.
  • Suitable antioxidants suitable for use according to the invention include: Tocopherol in alpha, gamma and beta form; Ascorbic acid; ascorbyl palmitate; butylated hydroxytoluene; erythorbic acid; fumaric acid; malic acid; methionine, monothioglycerol; metabisulfite and bisulfite; N-acetylcysteine; propionic acid; sodium ascorbate; sodium formaldehyde sulfoxylate; sodium sulfite; sodium thiosulfate; sulfur dioxide; thymol and polyethylene glycol succinate of vitamin E, or a mixture thereof.
  • tocopherol at a concentration of 0.001-0.05%, metabisulfite at a concentration of 0.01-1.0%, N-acetylcysteine at a concentration of 0.05-0.2%, or a mixture thereof.
  • compositions of the present invention may contain pH regulators, tonicity agents, sweeteners, emollients.
  • the compositions contain an emollient agent to ensure mucosal hydration and thus to prevent dryness and irritation upon application of the formulation.
  • emollient agents for this purpose may be selected from D-panthenol, silicone, glycerol, vitamin E, sorbitol, allantoin, hyaluronic acid, or a mixture thereof.
  • D-panthenol is present in the composition acting as an emollient.
  • compositions of the present invention further comprise sweeteners for improving the organoleptic characteristics of the invention.
  • suitable sweeteners are selected from sucralose, sodium cyclamate, saccharin, aspartame, citric acid, sweetening solutions with menthol, peppermint, mint, strawberry, grape, green apple, raspberry, banana and a mixture thereof, as well as colorants.
  • compositions of the present invention are suitable for administration to the mucous membranes in the form of drops, jet, aerosol or by a nebulizer or spray by a nebulization process.
  • the compositions are suspensions for administration as a spray or jet or other metered / accurate dose delivery device.
  • the final pharmaceutical form of the invention is an aqueous nasal or sublingual spray suspension.
  • Nasal or sublingual administration with a metering valve device ensures spreadability, increased contact surface and improved mucosal absorption ensuring greater ease and uniformity and spreadability of the product when sprayed.
  • aqueous melatonin suspensions of the invention are suitable for the treatment or aid in combating sleep disorders and circadian biological rhythms.
  • insomnia and circadian biological rhythm disorders such as primary insomnia, delayed phase insomnia, sleep-wake cycle with periods other than 24h, prolonged sleep latency, sleep fragmentation, sleep behavioral disorders.
  • REM sleep corrections of the elderly, desynchronization between the sleep-wake cycle and day and night, and jet lag disorders.
  • compositions are particularly useful for treatment for primary insomnia.
  • percentage refers to the percentage by weight (ie,% weight / total weight of the composition).
  • Example 1-A The compositions of Example 1-A are prepared as follows:
  • a container of suitable capacity add the hydrogenated castor oil PEG-40 and pectin and mix to a homogeneous mass.
  • caprylic capric acid triglycerides diethylene glycol monoethyl ether, sorbitan monooleate 80 and melatonin under stirring and heating to complete solubilization.
  • In a container of suitable capacity add water and Microcrystalline Cellulose / Carboxymethylcellulose, homogenize under stirring. Pour the gel obtained in this step over the emulsion previously obtained under stirring.
  • Example 2-A The compositions of Example 2-A are prepared as follows:
  • a container of suitable capacity add polyethylene glycol 400 and add under stirring and heating to melatonin until complete solubilization.
  • water and sodium alginate until complete solubilization and uniform gel formation.
  • water, sodium benzoate and potassium sorbate until complete homogenization.
  • Microcrystalline Cellulose / Carboxymethylcellulose homogenize under agitation. Pour Microcrystalline Cellulose / Carboxymethylcellulose gel onto the sodium alginate gel under stirring for 10-30 minutes. At the end of the mixture pour the melatonin solution on the mixture with stirring.
  • water, and the other excipients until complete solubilization.
  • the inventors conducted a comparative pilot study to evaluate the pharmacokinetic behavior of Melatonin present in three formulations, Test 1 - Melatonin 2mg / mL as nasal spray solution (formulation equivalent to US6007834), Test 2 - Melatonin 2mg / mL in the form of nasal spray suspension of the present invention and Test 3 - Pure Melatonin 1.9 mg oral drops (ESI spa) in healthy and fasting healthy research participants using quantification techniques of plasma concentration by High Performance Liquid Chromatography coupled to Mass Spectrometry (LC / MS). Male research participants aged 18 to 35 years were selected. The study was completed with 5 (five) participants.
  • the tested formulation is in aqueous suspension pharmaceutical form and contains in its manufacturing process an emulsion formed by the oil phase to ensure the solubilization of the hydrophobic drug.
  • the oil phase of the emulsion promotes improved drug absorption compared to the oral solution.
  • the incorporation of the final emulsion into a matrix with in vitro gelling properties makes it mucoadhesive, in addition to the addition of the thixotropic suspending agent that defined the formulation as a suspension.
  • Nasal burning evaluation for the nasal formulations Test 1 (Nasal Spray Solution) and Test 2 (Nasal Spray Suspension) was performed immediately after the application of the medication by the nursing team by completing the Visual Analog Scale - VAS being 0 ( zero) for total absence of burning and 10 (ten) for intense burning.
  • VAS visual analog scale
  • the objective was to describe the pharmacokinetic profile of Melatonin present in Test 2 and Test 3 formulations when administered in a fasted state.
  • the inventors conducted a pilot study to evaluate the pharmacokinetic behavior of Melatonin present in two formulations, Test 4 - Melatonin 5mg / mL suspension as a sublingual spray according to the present invention, and Test 3 - Melatonin Pure 1, 9 mg oral drops (ESI spa) in healthy and fasting healthy research participants using plasma chromatographic high performance liquid chromatography (LS / MS) quantified plasma concentration quantification techniques. Male research participants aged 18 to 35 years were selected. The study was completed with 6 (six) participants.
  • the results obtained are mainly related to the composition of the formulation which ensured the solubility of the drug, adhesion in the sublingual mucosa by in situ gel formation caused by sodium alginate and the high stability aided by the addition of carboxymethylcellulose / microcrystalline cellulose.
  • the spray system itself also helped to further increase the contact surface and enabled more efficient mucosal absorption.
  • the formulation can be considered effective and with better action when compared to the oral formulations available in the international market, besides presenting the convenience and ease of application by sublingual route.
  • compositions of the present invention have shown promise with rapid absorption, increased bioavailability and immediate onset of action and are considered effective in treating primary insomnia as compared to oral formulations available on the international market.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Inorganic Chemistry (AREA)
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  • Dispersion Chemistry (AREA)
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  • Oil, Petroleum & Natural Gas (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
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  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques sous forme de suspension aqueuse pour l'administration de mélatonine à travers les muqueuses, comprenant un système de solubilisation de l'agent pharmaceutique et un système polymère renfermant un agent gélifiant et un agent de suspension à caractéristique thixotrope. Ces compositions sont utiles pour traiter les troubles du sommeil ou pour faciliter la lutte contre ces troubles, notamment dans les cas d'insomnie primaire.
PCT/BR2019/050050 2018-02-22 2019-02-21 Composition pharmaceutique sous forme de suspension aqueuse et utilisation d'une composition pharmaceutique sous forme de suspension aqueuse Ceased WO2019161470A1 (fr)

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BRBR1020180034561 2018-02-22
BR102018003456A BR102018003456A2 (pt) 2018-02-22 2018-02-22 composição farmacêutica na forma de suspensão aquosa e uso de uma composição farmacêutica na forma de suspensão aquosa

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230143212A1 (en) * 2021-11-09 2023-05-11 Navinta, Llc Pharmaceutical Preparations Of Melatonin Suitable For Intranasal Administration
EP4186504A1 (fr) * 2021-11-25 2023-05-31 Alissa Healthcare Research Limited Solutions aqueuses pharmaceutiques orales comprenant de la mélatonine et leur utilisation
WO2024126775A1 (fr) * 2022-12-16 2024-06-20 Itf Research Pharma, S.L.U Formulations liquides de mélatonine

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US6007834A (en) * 1997-03-26 1999-12-28 Merkus, Franciscus W.H.M. Nasal melatonin composition
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US6007834A (en) * 1997-03-26 1999-12-28 Merkus, Franciscus W.H.M. Nasal melatonin composition
CN1969814A (zh) * 2005-11-24 2007-05-30 中国人民解放军军事医学科学院毒物药物研究所 褪黑素鼻腔给药制剂
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230143212A1 (en) * 2021-11-09 2023-05-11 Navinta, Llc Pharmaceutical Preparations Of Melatonin Suitable For Intranasal Administration
EP4186504A1 (fr) * 2021-11-25 2023-05-31 Alissa Healthcare Research Limited Solutions aqueuses pharmaceutiques orales comprenant de la mélatonine et leur utilisation
WO2024126775A1 (fr) * 2022-12-16 2024-06-20 Itf Research Pharma, S.L.U Formulations liquides de mélatonine

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