EP2306839A1 - Formulations de gacyclidine - Google Patents

Formulations de gacyclidine

Info

Publication number
EP2306839A1
EP2306839A1 EP09767730A EP09767730A EP2306839A1 EP 2306839 A1 EP2306839 A1 EP 2306839A1 EP 09767730 A EP09767730 A EP 09767730A EP 09767730 A EP09767730 A EP 09767730A EP 2306839 A1 EP2306839 A1 EP 2306839A1
Authority
EP
European Patent Office
Prior art keywords
gacyclidine
squalene
suspension
colloidal
formulation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09767730A
Other languages
German (de)
English (en)
Other versions
EP2306839A4 (fr
Inventor
Thomas Jay Lobl
John Vinton Schloss
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Neurosystec Corp
Original Assignee
Neurosystec Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Neurosystec Corp filed Critical Neurosystec Corp
Publication of EP2306839A1 publication Critical patent/EP2306839A1/fr
Publication of EP2306839A4 publication Critical patent/EP2306839A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • 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
    • A61K9/0046—Ear
    • 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
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0097—Micromachined devices; Microelectromechanical systems [MEMS]; Devices obtained by lithographic treatment of silicon; Devices comprising chips
    • 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
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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

Definitions

  • the invention relates to formulations of gacyclidine and other therapeutic agents with improved stability.
  • Gacyclidine is a promising neuroprotective drug with potential for tinnitus suppression.
  • gacyclidine is unstable at room or body temperature and decomposes at a rate that is incompatible with long-term drug therapy.
  • FIG. 1 compares the amount of gacyclidine over time in samples of a gacyclidine solution and in samples of a gacyclidine-squalene nanoparticle formulation.
  • FIG. 2 shows the size distribution of gacyclidine-squalene nanoparticles immediately after preparation and after storage for one month at room temperature (23-26 0 C), reflected by the slight change in the height of the bars representing the size of the nanoparticles.
  • FIG. 3 shows the concentration of gacyclidine in a gacyclidine-squalene formulation before and after passage through a 0.2 ⁇ m antibacterial filter.
  • FIG. 4 shows the concentration of gacyclidine over time in samples of a gacyclidine- squalene formulation delivered by a mini-osmotic pump (model 2004, DURECT Corporation) at 44 0 C.
  • FIG. 5 shows the concentration of gacyclidine over time in samples of a gacyclidine- squalene formulation after incubation in polytetrafiuoroethylene (PTFE) tubing at 44 0 C.
  • PTFE polytetrafiuoroethylene
  • the invention involves a method for improving the aqueous stability of gacyclidine and other hydrophobic compounds by co-formulation with squalene.
  • the basic form of gacyclidine is water insoluble, but it is much more stable than the water-soluble, but unstable acid form. Due to the low affinity of PLGA for the basic form of gacyclidine, initial attempts to use nanoparticles containing polylactic-glycolic acid (PLGA) polymers to improve gacyclidine stability were not successful. Unexpectedly, it was found that most excipients did not have sufficient affinity for the basic form of gacyclidine to provide a substantial increase in the stability of aqueous gacyclidine formulations.
  • PLGA polylactic-glycolic acid
  • Gacyclidine has improved thermal stability in stable squalene-water emulsions. It can pass through antibacterial membrane filters and exhibits reduced losses at equilibrium in the presence of various polymers relative to solution formulations of the acid form of gacyclidine. Squalene-water emulsions are a superior vehicle for gacyclidine formulations to be implanted at body temperature (37 0 C) or long-term storage at room temperature. Squalene-containing formulations can also be subjected to sterile filtration with minimal loss of gacyclidine from the formulation. Including squalene in the formulation also reduces losses of gacyclidine that may be encountered by binding of the drug to catheters or other components of delivery devices.
  • squalene formulations as described herein are useful for stabilizing a variety of hydrophobic compounds with are essentially insoluble in their free base form, including ketamine and other phencyclidine analogs.
  • Stable particulate formulations containing a mixture of squalene and gacyclidine or ketamine can be prepared as either squalene-water emulsions or where squalene is adsorbed to nanoparticles or microparticles made of other materials.
  • Either type of formulation can be used to treat or prevent various neurological disorders, such as age- related- noise- or drug-induced hearing loss; tinnitus; damage to hearing caused by the physical trauma of cochlear implant insertion; damage to hearing cause by blast or other types of physical trauma; physical or chemical trauma to the eye, vertigo or Meniere's Disease-related-, central nervous system (including the inferior colliculus and auditory cortex), or peripheral nerves; and any neurological damage mediated by activation of NMDA receptors.
  • various neurological disorders such as age- related- noise- or drug-induced hearing loss; tinnitus; damage to hearing caused by the physical trauma of cochlear implant insertion; damage to hearing cause by blast or other types of physical trauma; physical or chemical trauma to the eye, vertigo or Meniere's Disease-related-, central nervous system (including the inferior colliculus and auditory cortex), or peripheral nerves; and any neurological damage mediated by activation of NMDA receptors.
  • Stable squalene-water emulsions can easily be prepared by mixing squalene with water in a range of from 0.1 to 50 volume percent (e.g., 0.1, 0.2, 0.25, 0.3, 0.5, 0.75, 1, 2, 5, 7, 10, 15, 20, 25, 30, 35, 40, 45, or 50%) and adding one or more amphipathic excipients to this mixture at 0.1 to 20 volume or weight percent relative to squalene (e.g., 0.1, 0.2, 0.25, 0.3, 0.5, 0.75, 1, 2, 5, 7, 10, 15, 20%).
  • amphipathic excipients include, but are not limited to fatty acids and aqueous soluble lipids (e.g., cholic acid, chenic acid, deoxycholic acid, cardiolipin, cholylgly ⁇ ine, chenylglycine, deoxycholylglycine, cholyltaurine, chenyltaurine, deoxycholyltaurine); sulfatides (galactocerebrosides with a sulfate ester on the 3' position of the sugar); gangliosides; N- acetyl-D-neuraminic acid; phosphatidylinositol; surfactants such as polyoxy ethylene esters of 12-hydroxy stearic acid (e.g., SOLUTOL ® HS 15),
  • Gacyclidine or ketamine can be added to the formulation in the desired amount, up to their limit of solubility in the squalene phase.
  • gacyclidine this is 1 gram of gacyclidine for every 9 milliliters of squalene, and the solubility of ketamine is similar.
  • nanoparticle refers to particles generally having a size of 200 nanometers (nm) or less, exclusive of temporary aggregation of such particles that might occur at high particle concentrations. Because of their size, Brownian motion will keep nanoparticles suspended in a fluid medium for a very long (or even indefinite) amount of time. Nanoparticles with diameters less than 200 nanometers will also be able to pass through antibacterial filters.
  • nanoparticles are made of materials that lack a high affinity for gacyclidine or ketamine as disclosed herein, such as polylactic glycolic acid (PLGA, see EXAMPLE 1), then including squalene as part of the nanoparticle composition by admixture or adsorption, can increase the affinity of the nanoparticle for gacyclidine or other agent and thereby improve its stability.
  • PLGA polylactic glycolic acid
  • Various methods in addition to emulsion, can be employed to fabricate nanoparticles of suitable size. These methods include, but are not limited to, vaporization methods (e.g., free jet expansion, laser vaporization, spark erosion, electro explosion and chemical vapor deposition), physical methods involving mechanical attrition ⁇ e.g., the pearlmilling technology developed by Elan Nanosystems of Dublin, Ireland), and interfacial deposition following solvent displacement.
  • the solvent displacement method for forming nanoparticles can involve rapid mixing, such as mixing two streams containing water miscible and water-insoluble components with a T-mixer, ball mixer, or Wiskind mixer.
  • the amount of squalene included in a nanoparticle composition can be between 1 to 50% by weight of the nanoparticle (e.g., 1-10%, 5-15%, 10-20%, 15-25%, 20-30%, 25-35%, 25-40%, 25-50%, 35-45%, or 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50%).
  • the amount of drug included in the nanoparticle will be limited by the amount of squalene present.
  • gacyclidine this is less than a weight to volume ratio of 1 gram of gacyclidine for every 9 milliliters of squalene (e.g., 1, 0.9, 0.8, 07, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1 gram of gacyclidine for every 9 ml of squalene).
  • the two formulations can be incubated at room temperature or at an elevated temperature for an extended period of time (e.g., for several days at body temperature, 37 0 C), then analyzed for drug content (by high performance liquid chromatography) and particle size distribution (by dynamic light scattering).
  • the concentration of drug in formulations containing squalene remain essentially unchanged for longer periods of time than for solution formulations not containing squalene. Selection of other components for the .
  • squalene formulation such as amphipathic excipients for squalene-water emulsions or for particles containing other polymers mixed with squalene (e.g., mixtures of PLGA and squalene) will be guided by the ability of the formulation to maintain colloidal dispersion and constant particle size over an extended period of time (e.g., one month at room temperature, 23-26 0 C), as measured by dynamic light scattering.
  • Formulations described herein can be delivered by various methods to treat a variety of target tissues.
  • an implanted drug delivery system is used and may include electrode(s) for stimulating tissues of the inner or middle ear.
  • a catheter delivering drugs into the inner ear may be combined with an electrode array such as those used for restoring hearing.
  • a terminal component can be a retinal (or other intraocular) implant providing electrical stimulation and delivering drug-containing vehicle.
  • electrical stimulation and drug delivery may be used to treat the tissues of the deep brain (e.g., a treatment of Parkinson's disease), spine (e.g., a pain management), or inferior colliculus or auditory cortex for tinnitus or hearing related diseases.
  • Deep brain stimulation may be used in conjunction with drug delivery for treatment of chronic pain states that do not respond to less invasive treatments.
  • electrodes may be implanted in the somatosensory thalamus or the periventricular gray region.
  • the drug delivery system and implanted electrical stimulator may be located in two separate locations in the body. For example, stroke rehabilitation patients who receive electrical stimulation in their extremities (e.g., forearm or legs) to restore motor function may also receive plasticity-enhancing drugs in the brain (e.g., motor cortex) via an implanted drug delivery system.
  • Drug delivery systems preferably include a pump, such as a valveless impedence pump, MEMS (Micro-Electro-Mechanical System) pump, osmotic pump, or piezodiaphragm pump.
  • the drug delivery system preferably includes a rechargeable battery, a wireless remote control device, and a drug reservoir.
  • the pump and reservoir preferably are fully implanted, and the fully implanted pump and reservoir with electronic components and battery communicates wirelessly with the remote control device, which is enabled for wireless communication and instructing the battery recharging or communicating with a dedicated wireless recharging system.
  • a cannula or needle may have an insertion stop which controls the depth of insertion.
  • One preferred location for an incision in the eye is in the pars plana.
  • One preferred location for terminating the cannula for drug delivery may be in the vitreous or the anterior chamber, allowing drugs to be delivered in controlled doses to the precise area of the eye.
  • the terminal end of the catheter may be fixed, for example via suture, surgical tack, a tissue adhesive, or a combination thereof, to tissue near the outer surface of the eye. When attached, the catheter does not affect or otherwise restrict movement of the eye. Examples of devices and methods for ophthalmic drug delivery are disclosed in Serial No. 1 1/780,853.
  • Acetone was eliminated from the suspension of particles prepared by mixing water with solution B by stirring the suspension in an open beaker for three days.
  • the particle suspension was then passed through a 0.2 micrometer polyethersulfone syringe filter (VWR International) to eliminate larger particles.
  • VWR International 0.2 micrometer polyethersulfone syringe filter
  • the particles in suspension had an average diameter of 55 nanometers.
  • These nanoparticles were then concentrated by pressure dialysis with a 10,000 MWCO cellulose membrane (Amicon) to a final volume of 17 milliliters.
  • the average particle diameter in the concentrated suspension was determined to be 53 nanometers by dynamic light scattering.
  • Gacyclidine in the concentrated suspension was determined to be 0.68 millimolar (0.18 grams/liter; 3.1 milligrams gacyclidine base; 8% of the initial gacyclidine).
  • VWR International 0.2 micrometer polyethersulfone syringe filter
  • gacyclidine does not have a high affinity for PLGA. Very little of the gacyclidine in the initial nanoparticle preparation was bound to the PLGA nanoparticles, but was instead dissolved in the aqueous phase surrounding the particles.
  • a suspension of squalene was prepared by suspending 4.3 milliliters of squalene, 0.5 milliliters of polysorbate 80, and 0.5 milliliters of sorbitan trioleate in water and bringing the suspensions to a final volume of 100 milliliters in a volumetric flask.
  • the suspension of squalene in water was passed through a Microfluidics M-1 10S high pressure homogenizer equipped with a GlOZ 87 micrometer ceramic interaction chamber at 23,000 pounds per square inch. After one passage through the high pressure homogenizer, the particle diameter of the squalene emulsion was determined to be 128 nanometers by use of a Horiba LB-550 dynamic light scattering particle size analyzer.
  • the particle diameter of the squalene emulsion was determined to be 136 nanometers by use of the particle size analyzer.
  • the particle size of this emulsion remained constant in the range between 114 to 148 nanometers upon standing at room temperature for several days or following up to 11 additional passes through the homogenizer.
  • a suspension of squalene in Ringer's solution was prepared by suspending 4.3 milliliters of squalene, 0.5 milliliters of polysorbate 80, and 0.5 milliliters of sorbitan trioleate in water and bringing the suspension to a final volume of 100 milliliters with Ringer's solution in a volumetric flask.
  • the suspension of squalene in Ringer's solution was passed through a Microfluidics M-110S high pressure homogenizer equipped with a GlOZ 87 micrometer ceramic interaction chamber at 23,000 pounds per square inch.
  • the particle diameter of the squalene emulsion was determined to be 1 14 nanometers by use of a Horiba LB-550 dynamic light scattering particle size analyzer. After 7 additional passes of the emulsion through the homogenizer with the interaction chamber maintained in an ice bath, the average particle diameter was determined to be between 108 to 135 nanometers.
  • a suspension of gacyclidine- containing squalene was prepared by adding 4.3 milliliters of the gacyclidine solution in squalene (1 gram gacyclidine base dissolved in 9 milliliters squalene), 0.5 milliliters of polysorbate 80, 0.5 milliliters of sorbitan trioleate, 35 milligrams of dipotassium phosphate, 1 milligram of citric acid, and 877 milligrams of sodium chloride to a graduated cylinder and bringing the mixture to a final volume of 100 milliliters with water.
  • the suspension of squalene-gacyclidine in phosphate buffered saline was passed through a Microfluidics M-110S high pressure homogenizer equipped with a GlOZ 87 micrometer ceramic interaction chamber at 23,000 pounds per square inch. After 7 passes through the homogenizer with the interaction chamber maintained in an ice bath, the average particle diameter of the squalene-gacyclidine emulsion was determined to be 135 nanometers by use of a Horiba LB-550 dynamic light scattering particle size analyzer. After 7 additional passes of the emulsion through the homogenizer with the interaction chamber maintained in an ice bath, the average particle diameter was determined to be 122 nanometers.
  • the average particle diameter was determined to be 1 14 nanometers. After 7 additional passes of the emulsion through the homogenizer with the interaction chamber maintained in an ice bath, the average particle diameter was determined to be 1 12 nanometers. Extensive analysis of the squalene-gacyclidine emulsion determined that the average particle diameter was between 107 to 123 nanometers. The pH and osmolality of the squalene- gacyclidine emulsion were determined to be 7.6 and 279 milliosmolal, respectively.
  • the stability of the squalene-gacyclidine nanoparticle formulation was compared to a solution formulation containing 0.3 grams/liter of NST-001 hydrochloride salt dissolved in 10 millimolar aqueous hydrochloric acid.
  • One 5 milliliter sample of the squalene- gacyclidine nanoparticle formulation was placed in a 5 milliliter acid-washed borosilicate glass pharmaceutical vial and sealed with a fluoropolymer-faced stopper.
  • a second 5 milliliter sample consisting of 0.3 grams/liter of gacyclidine hydrochloride in 10 millimolar hydrochloric acid was placed in a 5 milliliter acid-washed borosilicate glass pharmaceutical vial and sealed with a fluoropolymer-faced stopper. Both vials were placed in an incubator that was maintained at 44 ⁇ 2 0 C. Periodically, samples were withdrawn from the 44 0 C incubator; aliquots were taken for analysis by high- performance liquid chromatography; the vials were resealed; and placed back in the incubator.
  • Figure 1 shows the results of these analyses over a period of 32 days at 44 0 C.
  • the osmotic pump was submerged in Ringer's solution, and the pump containing the formulation, sealed container, and collection tube were placed in an incubator at 44 0 C. Periodically the formulation in the collection tube was transferred to an autosampler vial, and the gacyclidine concentration in the output from the osmotic pump measured by high performance liquid chromatography. After two days at 44 0 C, the gacyclidine concentration in the formulation delivered from the osmotic pump was 5.1 millimolar, which was 39% of the initial concentration of gacyclidine in the squalene-gacyclidine nanoparticle formulation used to fill the pump (13.1 millimolar).
  • the osmotic pump output between 2 to 5 days incubation at 44 0 C was 1.6 millimolar, which was 12% of the initial gacyclidine concentration. Between 2 to 26 days of incubation at 44 0 C the concentration of gacyclidine in the osmotic pump output was relatively constant ( Figure 4). The average concentration of gacyclidine in the output of the osmotic pump after equilibrium had been established at 44 0 C (days 2 to 26) was 1.5 ⁇ 0.2 millimolar ( Figure 4).
  • the average recovery of gacyclidine was 92 ⁇ 14% (13.9 millimolar after 3 days; 106% recovery; 1 1.9 millimolar after 5 days; 91% recovery; and 10.3 millimolar after 7 days; 79% recovery).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
  • Emergency Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biophysics (AREA)
  • Neurology (AREA)
  • Dispersion Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des suspensions colloïdales qui comportent de la gacyclidine et du squalène. Le squalène se lie à la gacyclidine beaucoup plus étroitement que d'autres vecteurs de médicament, tels que l'acide glycolique polylactique. Le fait d'inclure du squalène dans la phase particulaire séquestre la gacyclidine et assure une stabilité supérieure à la température ambiante ou à la température du corps.
EP09767730A 2008-06-19 2009-06-18 Formulations de gacyclidine Withdrawn EP2306839A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7413408P 2008-06-19 2008-06-19
PCT/US2009/047801 WO2009155421A1 (fr) 2008-06-19 2009-06-18 Formulations de gacyclidine

Publications (2)

Publication Number Publication Date
EP2306839A1 true EP2306839A1 (fr) 2011-04-13
EP2306839A4 EP2306839A4 (fr) 2011-08-17

Family

ID=41434441

Family Applications (1)

Application Number Title Priority Date Filing Date
EP09767730A Withdrawn EP2306839A4 (fr) 2008-06-19 2009-06-18 Formulations de gacyclidine

Country Status (2)

Country Link
EP (1) EP2306839A4 (fr)
WO (1) WO2009155421A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116267896B (zh) * 2023-03-13 2024-03-08 重庆师范大学 角鲨烯在提高蜜蜂精子存活率中的应用及精液保存方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1861104A4 (fr) * 2005-03-04 2011-12-14 Neurosystec Corp Preparations ameliorees de gacyclidine
GB0601179D0 (en) * 2006-01-20 2006-03-01 Univ Cambridge Tech Therapies for psychotic disorders

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHUNG H ET AL: "Oil components modulate physical characteristics and function of the natural oil emulsions as drug or gene delivery system", JOURNAL OF CONTROLLED RELEASE, ELSEVIER, AMSTERDAM, NL, vol. 71, no. 3, 28 April 2001 (2001-04-28) , pages 339-350, XP004234531, ISSN: 0168-3659, DOI: DOI:10.1016/S0168-3659(00)00363-1 *
See also references of WO2009155421A1 *

Also Published As

Publication number Publication date
WO2009155421A1 (fr) 2009-12-23
EP2306839A4 (fr) 2011-08-17

Similar Documents

Publication Publication Date Title
JP6574228B2 (ja) 局所麻酔薬のデポー製剤及びその調製方法
CN109464395B (zh) 一种水包油包凝胶乳液及其制备方法和应用
US8771746B2 (en) Colloidal suspensions comprising a therapeutic agent and squalene
CN1085944C (zh) 以延缓释放速度硬膜外给予治疗性化合物
Tice et al. Parenteral drug delivery: injectables
JP5996526B2 (ja) 極微針を使用した、眼組織への薬物送達のための方法および装置
RU2642234C2 (ru) Композиции антагонистов нейрокинина-1 для внутривенного введения
CN103153281A (zh) 用于递送活性成分的液态药物组合物
WO2008016602A2 (fr) Formulations médicamenteuses nanoparticulaires
KR101722398B1 (ko) ｐＨ 조절제를 포함하는 탁산의 약학적 용액 및 이의 제조 방법
KR102135537B1 (ko) 제약 조성물 및 그의 용도
Burgess et al. An introduction to long acting injections and implants
Yang et al. Intravitreal administration of dexamethasone-loaded PLGA-TPGS nanoparticles for the treatment of posterior segment diseases
WO2018204515A1 (fr) Procédés d'administration ciblée de médicament au moyen d'une microaiguille
BR112020003956A2 (pt) nanopartículas magnéticas para entrega direcionada, composição e método de uso
Sharma et al. Recent advances in lipid-based long-acting injectable depot formulations
CN106794251A (zh) 阿立哌唑前体药物组合物
Prieto et al. Dexamethasone delivery to the ocular posterior segment by sustained-release Laponite formulation
Sepahvandi et al. Drug delivery systems to the posterior segment of the eye: implants and nanoparticles
JPWO2007083763A1 (ja) 生理活性ペプチドのエマルション製剤の調製方法、および当該製剤を調製するためのキット
WO2020210805A1 (fr) Nanoparticules pour l'administration de médicaments au cerveau
Chiang et al. In vitro and in vivo evaluation of an ocular delivery system of 5-fluorouracil microspheres
EP2306839A1 (fr) Formulations de gacyclidine
CN109381444A (zh) 一种右美托咪定纳米制剂及其制备方法
Vhora et al. Parenteral controlled and prolonged drug delivery systems: therapeutic needs and formulation strategies

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20110117

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA RS

A4 Supplementary search report drawn up and despatched

Effective date: 20110714

RIC1 Information provided on ipc code assigned before grant

Ipc: A61P 25/00 20060101ALI20110708BHEP

Ipc: A61K 9/107 20060101ALI20110708BHEP

Ipc: A61K 9/51 20060101ALI20110708BHEP

Ipc: A61K 9/00 20060101ALI20110708BHEP

Ipc: A61K 31/451 20060101ALI20110708BHEP

Ipc: A61K 31/445 20060101ALI20110708BHEP

Ipc: A61K 31/135 20060101ALI20110708BHEP

Ipc: A61K 31/13 20060101ALI20110708BHEP

Ipc: A61K 31/453 20060101AFI20110708BHEP

DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20120214