US20090227550A1 - Controlled release delivery system for nasal application of neurotransmitters - Google Patents

Controlled release delivery system for nasal application of neurotransmitters Download PDF

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US20090227550A1
US20090227550A1 US12/418,917 US41891709A US2009227550A1 US 20090227550 A1 US20090227550 A1 US 20090227550A1 US 41891709 A US41891709 A US 41891709A US 2009227550 A1 US2009227550 A1 US 2009227550A1
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formulation
formulation according
weight
dopamine
oil
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Claudia Mattern
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Mattern Pharma AG
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M&P Patent AG
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Priority to US12/418,917 priority Critical patent/US20090227550A1/en
Assigned to M&P PATENT AKTIENGESELLSCHAFT reassignment M&P PATENT AKTIENGESELLSCHAFT ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MATTERN, CLAUDIA
Publication of US20090227550A1 publication Critical patent/US20090227550A1/en
Priority to US13/194,926 priority patent/US9186320B2/en
Assigned to MATTERN PHARMA AG reassignment MATTERN PHARMA AG MERGER (SEE DOCUMENT FOR DETAILS). Assignors: M & P PATNT AKTIENGESELLSCHAFT
Priority to US14/881,332 priority patent/US9801834B2/en
Priority to US15/716,337 priority patent/US20180200203A1/en
Assigned to ACERUS PHARMACEUTICALS SRL reassignment ACERUS PHARMACEUTICALS SRL RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: MIDCAP FUNDING V TRUST
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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • 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
    • A61K9/0043—Nose
    • 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
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/127—Liposomes
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • 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
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • 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

  • the invention generally relates to a formulation used for the controlled release and delivery of neurotransmitters and neuromodulator agents to the systemic circulation and/or to brain tissue via administration to the nasal cavity.
  • brain-acting compounds such as neurosteroids (e.g., androgens, progestins) or neurotransmitters (e.g., dopamine, derived from 3,4-dihydroxyphenylalanine (L-DOPA, or levodopa), serotonin, epinephrin, norepinephrine), have a modulatory role in the regulation of disorders influenced by receptors in the brain, such as depression, Parkinson's disease, Alzheimer's, psychiatric disorders and even loss of libido and aggression.
  • neurosteroids e.g., androgens, progestins
  • neurotransmitters e.g., dopamine, derived from 3,4-dihydroxyphenylalanine (L-DOPA, or levodopa), serotonin, epinephrin, norepinephrine
  • Neurosteroids act as modulators, either as stimulators or inhibitors, of several neurotransmitters.
  • Neurotransmitters are chemicals that relay, amplify and modulate electrical signals between a neuron and another cell. Some neurotransmitters are excitatory, while others are primarily inhibitory. In many cases, as with dopamine, it is the function of the receptor which determines whether the transmitter is excitatory or inhibitory.
  • CSF cerebrospinal fluid
  • the BBB creates a protected chemical environment wherein certain molecules are able to perform functions independent of the functions those molecules may perform elsewhere in the body.
  • One example of such a molecule is the neurotransmitter dopamine.
  • dopamine When applied as an infusion, dopamine may be used for the treatment of heart attacks or kidney failure, but this mode of administration of dopamine is not suitable for the treatment of neurological disorders, such as Parkinson's disease.
  • L-DOPA is typically used to increase dopamine levels in the brain for the treatment of Parkinson's disease and Dopa-Responsive deficiencies because it is able to cross the blood-brain barrier, whereas dopamine itself cannot.
  • CNS central nervous system
  • L-DOPA is administered to patients together with other compounds, including carbidopa, benserazide, and Entacapone/tolcapone.
  • other drugs or complimentary therapies may be administered to Parkinson's patients in concert with L-DOPA treatment, including dopamine agonists, MAO-B inhibitors, glial-derived neurotropic factor for gene therapy, and several neuroprotective agents.
  • a drug can reach the brain by different ways, including olfactory neuronal pathway, extraneuronal olfactory epithelial pathway, trigeminal nerve pathway, systemic pathway. It is also possible that more of the aforementioned pathways may contribute to the delivery of the molecule to the brain. Once a drug is in the brain, it's amount can be further influenced by BBB efflux transporter systems.
  • GB 1987000012176 relates to the use of bioadhesive microspheres to increase the length of time that molecules reside in the nasal cavity. It has also been found that the use of enhancers and stabilizers improves permeability of the nasal membrane and prevents drug degradation, respectively.
  • PCT/GB98/01147 U.S. Pat. No. 6,432,440 pertains to the use of in situ gelling pectin formulations for drug delivery.
  • Bayne, U.S. Reissue Patent No. RE29,892 pertains to a method of increasing the dopamine concentration in brain tissue through administration of a composition comprising dopamine and a hydrazine compound.
  • the method allows for administration of the composition topically, rectally, orally, or parenterally.
  • Preferred compositions include hydrazine compounds such as L- ⁇ -hydrazino- ⁇ -lower alkyl-3,4-dihydroxyphenyl propionic acid and L-DOPA and its pharmaceutically accepted salts.
  • Haffner et al. U.S. Pat. No. 4,826,852
  • Wenzel et al. U.S. Pat. No. 5,624,960, pertains to the treatment of Parkinson's disease through the oral administration of a composition containing levodopa and carbidopa (MK-486).
  • Mandel et al. U.S. Pat. No. 6,319,905
  • modulators such as tetrahydropterin (PH4) are used to control the generation of dopamine.
  • the formulation should have physical and chemical properties that facilitates brain uptake of molecules/drugs, such as dopamine.
  • the identification of a formulation that may increase the bioavailability of neurotransmitters to brain tissue would provide much-needed treatment options for diseases associated with, for example, dopamine or serotonin deficiency in the brain, including depression, Parkinson's disease, attention deficit hyperactivity disorder (ADHD), addiction to drugs and alcohol, and various psychiatric disorders.
  • ADHD attention deficit hyperactivity disorder
  • the presently claimed invention demonstrates that the incorporation of various neurotransmitter agents into a unique lipophilic or partly lipophilic formulation, which when delivered to the nasal cavity, results in clinically effective sustained serum levels in plasma and CSF. These levels in turn increase the bioavailability of drugs to the systemic circulation and to brain tissue.
  • the presently claimed invention comprises a formulation for nasal application comprising: (a) at least one active ingredient selected from the groups consisting of a neurotransmitter and a neuromodulator agent; (b) at least one lipophilic or partly lipophilic carrier; and (c) a compound or a mixture of compounds having surface tension decreasing activity, an amount effective for generation of contact of the formulation with a hydrophilic mucous membrane and optionally (d) a viscosity-regulating agent.
  • the formulation may also contain minor proportions of one or more compounds including but not limited to absorption promoters, substances that inhibit enzymatic degradation or efflux, preservatives, flavors and antioxidants.
  • the at least one active ingredient is a neurotransmitter.
  • the neurotransmitter may be dopamine, serotonin, epinephrine or norepinephrine.
  • the at least one active ingredient is a neurotransmitter or neuromodulator agent(s).
  • the formulation may comprise more than one neurotransmitter and/or neuromodulator agent.
  • the formulation may comprise dopamine or L-DOPA and their derivatives.
  • the active ingredient(s) may comprise 0.01 to 6% by weight, preferably 0.1 to 4% by weight, more preferably 0.5 to 2% by weight, and most preferably at around 2% by weight of the formulation.
  • the lipophilic carrier may comprise oil, fats and/or other lipids.
  • Lipids may be any lipophilic molecules, including but not limited to fats, oils, waxes, cholesterol, sterols, monoglycerides, diglycerides, phospholipids.
  • the oil is a vegetable oil. Most preferably, the oil is caster oil.
  • the oil may between 30% and 98% by weight, preferably between 60 and 98% by weight, more preferably between 75% and 95% by weight, even more preferably between 85% and 95% by weight and most preferably around 90% by weight of the formulation.
  • component (c) may comprise at least one surfactant selected from the group consisting of lecithin, fatty acid ester of polyvalent alcohols, of sorbitanes, of polyoxyethylensorbitans, of polyoxyethylene, of sucrose, of polyglycerol and/or at least one humectant selected from the group consisting of sorbitol, glycerine, polyethylene glycol, and macrogol glycerol fatty acid ester, or a mixture thereof.
  • component (c) may comprise an oleoyl macrogolglyceride or a mixture of oleoyl macrogolglycerides.
  • component (c) may comprise 1 to 20% by weight, preferably 1 to 10% by weight, more preferably 1 to 5% by weight, and most preferably at around 4% by weight of the formulation.
  • the viscosity-regulating agent may comprise a thickener or gelling agent selected from the group consisting of cellulose and cellulose derivatives, polysaccharides, carbomers, polyvinyl alcohol, povidone, colloidal silicon dioxide, cetyl alcohols, stearic acid, beeswax, petrolatum, triglycerides and lanolin, or a mixture thereof. More preferably, the viscosity-regulating agent is colloidal silicon dioxide.
  • the viscosity-regulating agent may comprise 0.5 to 10% by weight, preferably 0.5 to 5% by weight, more preferably 2 to 5% by weight, and most preferably at around 4% by weight of the formulation.
  • nasal administration of the galenical gel formulation of the presently claimed invention may be able to facilitate selective recruitment of molecules to brain tissue by providing access directly to the brain, which in turn may provide for new clinical applications, for example, the use of neurotransmitters to treat CNS disorders.
  • FIG. 1 shows the effect of nasal dopamine gel on immobility and climbing of depressed rats.
  • FIG. 2 shows the concentration of dopamine and metabolites in nucleus accumbens and neostriatum after nasal administration of dopamine.
  • the galenical gel formulation of the presently claimed invention is chemically and physically stable and can be in the form of a suspension or a solution of the pharmacologically active substance.
  • the galenical gel formulation of the invention is filled into a preservative-free device able to accurately deliver doses of the above formulation, even at a high viscosity.
  • the active ingredient or active ingredient particles are typically efficiently trapped at the deposition site and are typically absorbed at a predictable rate across the mucous membrane of the patient, thereby limiting possible deactivation by metabolizing enzymes and/or protein-binding.
  • higher availability or “higher bioavailability” shall mean that after application of the active ingredient(s), significant and constant in vivo therapeutic drug concentrations, especially in the brain, are maintained for an extended period of time.
  • composition of the invention may comprise a neurotransmitter and/or neuromodulator agent.
  • a neurotransmitter as used herein, may be a molecule used for signaling between nerve cells or neurons. Neurotransmitter molecules typically pass between neurons at synapses, and may causes a rapid, short-lived and dramatic response. Neurotransmitters may degrade rapidly, resulting in restoration of the resting membrane potential.
  • Examples include but are not limited to Acetylcholine, Monoamines (epinephrine, norepinephrine, dopamine, serotonin, melatonin, histamine), Amino acids (glutamate, gamma aminobutyric acid (GABA), aspartate, glycine), Purines (Adenosine, ATP, GTP, and their derivatives), neuroactive peptides (Substance P, N-Acetylaspartylglutamate), Neurohypophyseal transmitters (Oxytocin, Vasopressin), Opioids (Endorphin), zinc, nitric oxide, carbon monoxide, and chemical modifications of such molecules, such as esters.
  • Monoamines epinephrine, norepinephrine, dopamine, serotonin, melatonin, histamine
  • Amino acids glutamate, gamma aminobutyric acid (GABA), aspartate, glycine
  • Neurotransmitters such as dopamine, serotonin, epinephrine and norepinephrine contain the catechol moiety typically synthesized from the amino acid tyrosine.
  • Dopamine is commonly regarded as an endogenous catecholamine with ⁇ and ⁇ adrenergic activity.
  • L-DOPA is commonly synthesized from aminotyramine and converted into dopamine in the brain.
  • Other neurotransmitters are typically contained in synaptic vesicles in terminals of the presynaptic neuron, and upon stimulation of an action potential, are released into the synaptic cleft to induce a response in the post synaptic cell. Iontophoresis of the neurotransmitter into a synaptic cleft induces the same postsynaptic response. The neurotransmitter then degrades rapidly resulting in restoration of the resting potential.
  • catecholamines known to have various utilities include epinephrine, norepinephrine, and serotonin.
  • a neuromodulator agent may be a substance other than a neurotransmitter, released by a neuron at a synapse and conveying information to adjacent or distant neurons, either enhancing or dampening their activities.
  • Neuromodulation is the process in which several classes of neurotransmitters in the nervous system regulate diverse populations of neurons. Neuromodulators may act not only on the input system but may change the transformation itself to produce the proper contractions of muscles as output.
  • Neuromodulator agents may also include neurosteroids.
  • a variety of steroids are synthesized in the central and peripheral nervous system, especially in myelinating glial cells, from cholesterol or steroidal precursors imported from peripheral sources. Such steroids are defined as neurosteroids.
  • Neurosteroids may rapidly alter neuronal excitability through interaction with neurotransmitter-gated ion channels.
  • neurosteroids may also exert effects on gene expression via intracellular steroid hormone receptors. Examples include but are not limited to pregnenolone, dehydroepiandrosterone, their sulfates, and reduced metabolites such as the tetrahydroderivative of progesterone 3 ⁇ -hydroxy-5 ⁇ -pregnane-20-one.
  • Neuromodulator agents also include chemical modifications of neurosteroids, such as esters and synthetic neurosteroids such as minaxolone, ganaxolone.
  • the active ingredient may comprise 0.01 to 6% by weight, preferably 0.1 to 4% by weight, more preferably 0.5 to 2% by weight, and most preferably at around 2% by weight of the formulation.
  • the carrier of the invention functions to dissolve or suspend the drug and otherwise support the various constituents of the invention.
  • the carrier has a lipophilic nature or character.
  • Suitable families of oils include fatty acids and oils such as mineral and vegetable oils, in particular, fatty acids and oils derived from vegetable stock are especially useful. Both linear and branched chain acids and oils are useful including those oils and acids with various levels of saturation and substitution. Chain size including but is not limited to formic, acetic, propionic, butyric, valeric, caproic, emanthic, caprylic, pelargonic, capric, laurie, myristic, palmitic and stearic, among others, all represent useful oil and acid moieties.
  • lipophilic carrier may comprise, but is not limited to, fats and/or vegetable oil such as castor oil, soybean oil, sesame oil, or peanut oil, fatty acid esters such as ethyl- and oleyloleat, isopropylmyristate, medium chain triglycerides, glycerol esters of fatty acids, or polyethylene glycol, phospholipids, white soft paraffin, or hydrogenated castor oil, or a mixture thereof.
  • the active ingredient may also be incorporated into an oil mixture.
  • the vegetable oil is castor oil.
  • lipophilic carrier that constitutes an effective amount is dependent on the particular viscosity regulating agent used in the formulation. It is therefore not practical to enumerate specific amounts for use with specific formulations of the invention.
  • the lipophilic carrier may comprise between 30% and 98% by weight, preferably between 60 and 98% by weight, more preferably between 75% and 95% by weight, even more preferably between 85% and 95% by weight, and most preferably around 90% by weight of the formulation.
  • the surface active agent or surfactant of the invention functions to decrease surface tension in the composition of the invention.
  • Surfactants are generally regarded as those compositions which have both hydrophilic and lypophilic character.
  • the lypophilic character of the surfactant typically takes the form of a pendent moiety having little if any charge.
  • the hydrophilic character of the surfactant is typically charged and dictates the class into which the surfactant is identified.
  • surfactants typically used in the invention include nonionic surfactants, anionic surfactants, amphoteric surfactants, and cationic surfactants.
  • component (c), a compound or a mixture of compounds having surface tension decreasing activity may comprise at least a surfactant including, but not limited to, lecithin, fatty acid ester of polyvalent alcohols, fatty acid ester of sorbitanes, fatty acid ester of polyoxyethylensorbitans, fatty acid ester of polyoxyethylene, fatty acid ester of sucrose, fatty acid ester of polyglycerol, and/or at least one humectant such as sorbitol, glycerine, polyethylene glycol, or macrogol glycerol fatty acid ester.
  • surface tension decreasing activity shall mean having a surface tension that results in generating contact of the formulation to the hydrophilic mucous membranes of the nasal cavity.
  • the active ingredient/neurotransmitter may be incorporated into a surfactant mixture.
  • the particular amount of surfactant that constitutes an effective amount is dependent on the particular oil or oil mixture used in the formulation. It is therefore not practical to enumerate specific amounts for use with specific formulations of the invention.
  • the surfactant may comprise 1 to 20% by weight, preferably 1 to 10% by weight, more preferably 1 to 5% by weight, and most preferably at around 4% by weight of the formulation.
  • viscosity-regulating agent shall mean a thickener or gelling agent.
  • a viscosity-regulating agent examples include, but are not limited to, cellulose and derivatives thereof, polysaccharides, carbomers, polyvinyl alcohol, povidone, colloidal silicon dioxide, cetyl alcohols, stearic acid, beeswax, petrolatum, triglycerides, lanolin, or the like.
  • a preferred viscosity regulating agent is colloidal silicon dioxide (such as AEROSIL®, as available from Degussa).
  • the incorporation of the active ingredient is also possible into a mixture of thickeners or gelling agents.
  • the particular amount of thickener/gelling agent that constitutes an effective amount is dependent on the particular oil or oil mixture used in the formulation. It is therefore not practical to enumerate specific amounts for use with specific formulations of the invention.
  • the thickener/gelling agent(s) may comprise 0.5 to 10% by weight, preferably 0.5 to 5% by weight, more preferably 2 to 5% by weight, and most preferably at around 4% by weight of the formulation.
  • the galenical formulation of the invention can be prepared easily by the following conventional method:
  • the lipophilic carrier and surfactant are filled into a stirrer vessel and about 75% of the viscosity regulating agent is mixed in.
  • the active ingredient is added while stirring to obtain a homogenous dispersion of the active ingredient.
  • the formulation is adjusted to the necessary viscosity with the remainder of the viscosity regulating agent.
  • the formulation may be filled into a preservative-free container.
  • the active ingredient particularly a neurotransmitter
  • release from the formulation is the rate-limiting step for adsorption.
  • the presently claimed invention demonstrates that the incorporation of the active ingredient into an oily formulation containing a suitable surfactant leads to physiologically clinically effective serum and brain levels and to an appropriate sustained action of the active ingredient over time.
  • This sustained and clinically favorable release of the active ingredient is due to the interaction of the compounds in the oily carrier, which remains on the mucous membrane of the nasal cavity for a prolonged duration of time.
  • the active ingredient of this invention may be introduced into the formulation also in a processed form, such as microspheres, liposomes, among others.
  • the formulation according to this invention may also be processed into powder form, such as by lyophilization or spray-drying.
  • the formulation is administered to a patient. In a preferred embodiment, the formulation is administered to a human.
  • the formulation that optionally comprises a pharmaceutically acceptable vehicle may be administered by absorption through mucocutaneous linings and may be administered together with another biologically active agent. Administration may be local.
  • the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia or otherwise proven as safe for use in animals, mammals, and more particularly in humans.
  • vehicle refers to a diluent, adjuvant, excipient, or carrier with which a compound of the invention is administered.
  • Such pharmaceutical vehicles can be lipophilic semisolids or liquids such as oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • the amount of the formulation that will be effective in the treatment of a particular disease will depend on the nature of the disease, and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed will also depend on the seriousness of the disease, and should be decided according to the judgment of the practitioner and each patient's circumstances.
  • Effective doses for administration by inhalation are in the range of about 0.001 milligram to about 200 milligrams per kilogram of body weight per day. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems. Such animal models and systems are well known in the art.
  • the formulation is preferably assayed in vitro and in vivo, for the desired therapeutic or prophylactic activity, prior to use in humans.
  • Animal model systems can be used to demonstrate safety and efficacy.
  • a dopamine (DA) gel of the inventive formulation was nasally administered to rats used in the validated “forced swimming test.” As shown in FIG. 1 , the administration of dopamine results in anti-depressive-like effects. As shown in FIG. 2 , strong dopaminergic activity in the neostriatum and ventral striatum (nucleus accumbens) was observed after nasal application of dopamine with the inventive formulation.
  • antidepressants must be administered for an extended length of time before antidepressive effects are observed.
  • antidepressive effects occurred within hours and without any observable side effects, such as those side effects known to occur with desipramine (apathy) or fluoxetine (weight loss).
  • dopamine in the CSF was not metabolized to 3,4-dihydroxyphenyl acetic acid (DOPAC) or homovanillic acid (HVA) as is typically seen.
  • DOPAC 3,4-dihydroxyphenyl acetic acid
  • HVA homovanillic acid

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US12/418,917 2006-10-04 2009-04-06 Controlled release delivery system for nasal application of neurotransmitters Abandoned US20090227550A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US12/418,917 US20090227550A1 (en) 2006-10-04 2009-04-06 Controlled release delivery system for nasal application of neurotransmitters
US13/194,926 US9186320B2 (en) 2006-10-04 2011-07-30 Controlled release delivery system for nasal application of neurotransmitters
US14/881,332 US9801834B2 (en) 2006-10-04 2015-10-13 Controlled release delivery system for nasal application of neurotransmitters
US15/716,337 US20180200203A1 (en) 2006-10-04 2017-09-26 Controlled release delivery system for nasal application of neurotransmitters

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MX2009003654A (es) 2009-04-22
DK2068825T3 (da) 2011-05-16
ZA200902902B (en) 2010-07-28
WO2008040488A1 (en) 2008-04-10
US20120009249A1 (en) 2012-01-12
DE602007012276D1 (de) 2011-03-10
BRPI0717509B8 (pt) 2021-05-25
US20180200203A1 (en) 2018-07-19
PL2068825T3 (pl) 2011-06-30
HK1137658A1 (en) 2010-08-06
EP2068825A1 (en) 2009-06-17
JP2010505778A (ja) 2010-02-25
US9801834B2 (en) 2017-10-31
CA2664427A1 (en) 2008-04-10
KR20090098958A (ko) 2009-09-18
US20160089347A1 (en) 2016-03-31
NO20091695L (no) 2009-06-23
ES2358619T3 (es) 2011-05-12
RU2480208C2 (ru) 2013-04-27
CN101600417A (zh) 2009-12-09
NO339802B1 (no) 2017-02-06
JP5248510B2 (ja) 2013-07-31
PT2068825E (pt) 2011-02-11
RU2009116609A (ru) 2010-11-10
EP2068825B1 (en) 2011-01-26
CN101600417B (zh) 2012-05-30
BRPI0717509A2 (pt) 2016-05-17
ATE496617T1 (de) 2011-02-15
US9186320B2 (en) 2015-11-17
AU2007304471B2 (en) 2012-09-06
KR101307133B1 (ko) 2013-09-12
AU2007304471A1 (en) 2008-04-10
CA2664427C (en) 2012-06-05
BRPI0717509B1 (pt) 2019-11-26

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