WO1997045135A1 - Stable pharmaceutical composition of bdnf - Google Patents
Stable pharmaceutical composition of bdnf Download PDFInfo
- Publication number
- WO1997045135A1 WO1997045135A1 PCT/JP1997/001746 JP9701746W WO9745135A1 WO 1997045135 A1 WO1997045135 A1 WO 1997045135A1 JP 9701746 W JP9701746 W JP 9701746W WO 9745135 A1 WO9745135 A1 WO 9745135A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- bdnf
- pharmaceutical composition
- composition
- solution
- lyophilized
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
-
- 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
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- 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
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
Definitions
- the present invention relates to a pharmaceutical composition containing a brain derived neurotrophic factor (BDNF) in the form of an aqueous solution or a lyophilized one, the latter being prepared by lyophilizing said aqueous solution composition.
- BDNF brain derived neurotrophic factor
- Nerve cells of vertebrala need a certain group of polypeptides, called a neurotrophic factor, for their survival.
- a brain derived neurotrophic factor (BDNF) has been known.
- BDNF has first been isolated from porcine brain by Barde, Y.E. et al. (cf., The EMBO Journal, 5, 549-553 (1982)), and thereafter BDNF genes of pig, human and mouse have been cloned in 1989 whereby it has been confirmed that it has a primary structure consisting of 119 amino acids (cf, Leibrock, J. et al., Nature, 341, 149 (1989)).
- BDNF is a polypeptide exhibiting various pharmacological activities in the nervous system, and the pharmacological activities thereof have been disclosed in Seitai no Kagaku (Science of Living body), 43 (6), 616-625 (1992).
- BDNF has been expected to be useful as an agent for treatment of various diseases such as amyotrophic lateral sclerosis (ALS), anticancer agent- intoxicated neuropathy, diabetic neuropathy, retinal pigment degeneration, glaucoma, Huntington's chorea, Parkinson disease, Alzheimer's disease, terminal cancer ache, depression, obesity, etc., based on the pharmacological activities thereof (cf., USP 5180820, Seitai no Kagaku, 43 (6), pages 616-625, (1992)).
- a compound to be used as a medicament is usually required to be stable without changing of activity thereof with time under conventional storage conditions when formulated in a form of a conventional pharmaceutical composition.
- BDNF highly purified polypeptides
- BDNF has many problems to be solved in order to be kept stably for a long time.
- BDNF when keeping BDNF in the form of a solution in a conventional physiological saline solution, BDNF has a tendency to aggregate even by storage for several days to dozens of days, which is a very serious problem.
- the aggregate of BDNF is known to cause immune toxicity to the living body, so that the prevention of the production of BDNF aggregate is very important.
- denatured and/Or polymerized BDNF are often produced as well. Hitherto, there has been no report on effective ways to solve these serious problems of BDNF.
- BDNF When keeping BDNF at a low temperature or room temperature for several days to dozens of days, BDNF aggregates, shows va ⁇ ed properties, and denatured and/or polymerized BDNF are produced.
- the physicochemical stability of BDNF is low so that BDNF cannot be kept for a long time.
- the instability has prohibited from the development of BDNF as a medicament for human or for other animals in the form of a pharmaceutical preparation such as an injection preparation.
- the present inventors Under the above-mentioned circumstances, the present inventors have intensively studied to develop a pharmaceutical composition of BDNF, and have found that the addition of a surfactant is quite effective for stabilization of BDNF, and have accomplished the present invention.
- the present invention provides a stable pharmaceutical composition of a brain derived neurotrophic factor (BDNF), which comprises as an active ingredient a BDNF and as a stabilizer a surfactant, preferably a nonionic surfactant, and optionally a salt and/or a buffe ⁇ ng agent, and further optionally an additional stabilizer such as an amino acid and a sugar alcohol, which may be in the form of an aqueous solution, or in a lyophilized form.
- BDNF brain derived neurotrophic factor
- the present invenuon provides also a method for stabilizing a BDNF in a pharmaceutical composition by incorporating a surfactant as a stabilizer into the composition and optionally further adding a salt and/or a buffering agent and further optionally adding an additional stabilizer such as an ammo acid and a sugar alcohol.
- a stable pharmaceutical composition which comprises a BDNF and a surfactant.
- BDNF BDNF
- surfactant is a nonionic surfactant.
- composition according to (5) wherein the salt is sodium chloride.
- pharmaceutical composition according to (1) which further comprises a buffering agent.
- a lyophilized pharmaceutical composition of BDNF which contains as a stabilizer Tween 80 and as an additional stabilizer mannitol in the total amount of from 0.01 % (w/v) to 10 % (w/v), based on the whole weight of the composition reconstituted.
- the BDNF used in the present invention may be any one of any animal origins, such as mouse, pig, or human, and can be prepared by various processes.
- a BDNF isolated from animal tissues is used in the present invention, it may be purified to such a degree that it can be used as a medicament (cf., The EMBO Journal, 5, 549-553 (1982)).
- a BDNF can be obtained by culturing a primary culture cell or an established cell line which can produce BDNF, and isolating from the culture broth thereof (e.g., culture supernatant, cultured cells).
- a recombinant BDNF which can be obtained by a conventional gene engineering technique, e.g., by inserting a gene coding for BDNF into a suitable vector, transforming a suitable host with the recombinant vector, and isolating from the culture supernatant of the resulting transformant (cf., Proc. Natl. Acad. Sci. USA, 88, 961 (1991); Biochem. Biophys. Res. Commun., 186, 1553 (1992)), which ⁇ s> suitable for production of BDNF of uniform property in a large scale.
- the host cells to be used in the above process is not critical, and may be any conventional host cells which have been used in gene engineering technique, for example, Eschenchia coli, Bacillus subtilis, yeasts, vegetable cells or animal cells
- a modified protein of BDNF can be obtained by addition, substitution, deletion or removal of a part of amino acid sequence of a natural BDNF by a gene engineering technique. Any modified protein of BDNF thus obtained is also included m the BDNF to be used in the present invention even though a part of the amino acid sequence thereof is deleted, or substituted by other amino acid, or inserted thereto a part of other amino acid sequence, or bonded with one or more amino acids at the N-terminus and/or C-terrninus, as long as said modified protein of BDNF shows the biological activities of the same quality as those of BDNF, i.e., the biological activities on the nerve cells, such as an activity of survival of nerve cells, activity of extending neurodendrite, activity of promoting the production of neurotransmitter.
- the "surfactant" used in the present invention means any pharmaceutically acceptable surfactant which is useful in medicaments for human, or for other animals, and includes, for example, a nonionic surfactant.
- the surfactant is added to the pharmaceutical composition of the present invention in an amount of from 0.001 to 10 % by weight, preferably in an amount of from 0.001 to 0.1 % by weight, to the weight of water in the aqueous composition.
- the “salt” may be a pharmaceutically acceptable salt which is useful in medicaments for human, or for other animals, and includes, for example, sodium chloride.
- Sodium chloride is used in order to keep the osmotic pressure of the present phar ⁇ iaceutical composition suitable for an injection preparation, especially in an amount of 150 to 300 mM by which the injection preparation shows an osmotic pressure ratio of 1 to 2.
- the “buffering agent” means a buffering agent which is added to the composition in order to adjust the pH value in a solution preparation or in a lyophilized preparation, in the latter preparation, the pH when reconstituted.
- the representative buffering agent is, for example, phosphate buffer, Tris buffer and citrate buffer.
- the buffering agent adjusts the pH value of the solution so that the stability of BDNF is maintained.
- the pH value of the present composition is not critical, but it is preferably in the range of 5.5 to 7.5.
- BDNF is hydrolyzed under acidic conditions to produce many fragments derived from BDNF, and is further de-amidated or hydrolyzed under basic conditions.
- the final concentration of the buffering agent in the composition is in the range of 1 mM to 100 mM.
- the “additional stabilizer” includes, for example, ammo acids such as glycine or sugar alcohols such as mannitol, and these additional stabilizers may be used together.
- the additional stabilizer for example, glycine or mannitol, is added in an amount of from 0.01 to 100 times by weight, more preferably 0.1 to 10 times by weight, of the weight of BDNF.
- Glycine and/or mannitol can be used in a solution composition of the present invention, but can show more excellent stabilization effects in the lyophilized composition of the present invention.
- These amino acid and sugar alcohol may be used individually, but preferably in combination.
- the "lyophilized composition" of the present invention can be prepared by subjecting a solution composition of BDNF to lyophilization by a conventional lyophilization, or freeze-drying technique.
- BDNF is dissolved in a suitable aqueous solvent such as a distilled water for injection, a buffer solution, a physiological saline solution, etc., and thereto is added a stabilizer, a buffering agent, or a salt, if necessary, and the solution thus obtained is sterilized by filtration through a filter, and then lyophilized to give a lyophilized composition of the present invention.
- compositions of the present invention may additionally contain a conventional additive which is usually used for pharmaceutical preparations, for example, a solubilizer, antioxidant, anaesthetic agent, isotonic agent, etc.
- the lyophilizing method is, for example, a method consisting of three steps: a step of freezing a solution under atmospheric pressure, a primary drying step of sublimation of a free water which is not adsorbed by or bound to a solute under reduced pressure, and a secondary drying step of removing water adsorbed by or bound to a solute (cf., Pharm. Tech. Japan, 8 (1), 75-87 (1992)).
- BDNF to be contained in the composition can be kept very stably during the procedures of preparing the composition of the present invention, such as dissolving in a solvent, freeze-drying thereof, as well as reconstituting a lyophilized composition.
- the content of BDNF in the compositions may be varied depending on the kinds of diseases to be cured, or the administration route thereof.
- the pharmaceutical composition of BDNF of the present invention may be filled in a vial by putting in a vial, fulfilling with nitrogen gas, and then sealing the vial.
- BDNF contained therein is prevented from denature and hence can be kept more stably.
- BDNF was dissolved in 10 mM phosphate buffer (pH 7.0, 150 mM sodium chloride) to give an aqueous BDNF solution (20 mg/ml).
- the solution thus obtained was put into vials aseptically to give a solution composition of
- BDNF was dissolved in 10 mM phosphate buffer (pH 7.0, 150 mM sodium chloride, 0.01 % Tween 80) to give an aqueous BDNF solution (20 mg/ml). The solution thus obtained was put into vials aseptically to give a solution composition of BDNF containing a surfactant.
- composition 1 the inhibitory effect of a surfactant on the production of aggregates was tested.
- the compositions were kept at 25°C at a vibration of 5 cm x 75 strokes/min. The period (days) till the production of aggregates was determined by visual observation. The results are shown in Table. 1 • From the resulting data, it is proved that the addition of Tween 80 inhibited the production of aggregates of BDNF in a solution composition.
- BDNF was dissolved in 10 mM phosphate buffer (pH 7.0, 150 mM sodium chlo ⁇ de) to give an aqueous BDNF solution (0 1 mg/ml)
- the solution thus obtained was put into vials aseptically to give a solution composition of BDNF containing no surfactant.
- BDNF was dissolved in 10 mM phosphate buffer (pH 7.0, 150 mM sodium chloride, 0 01 % Tween 80) to give an aqueous BDNF solution (0 1 mg/ml)
- the solution thus obtained was put into vials aseptically to give a solution composition of BDNF containing a surfactant.
- BDNF was dissolved in 10 mM phosphate buffer (pH 7.0, 150 mM sodium chloride, 0.01 % Tween 80) to give an aqueous BDNF solution (5 mg/ml).
- the pH value of the aqueous BDNF solution thus obtained was adjusted with IN HCl or IN NaOH to six degrees of pH 4, 5, 6, 7, 8 or 9.
- the solutions thus obtained was put into vials aseptically to give a solution composition of BDNF.
- BDNF was dissolved in 10 mM phosphate buffer (pH 7.0, 150 mM sodium chloride, 0.01 % Tween 80) to give an aqueous BDNF solution (20 mg/ml).
- the solution thus obtained was put into vials aseptically, and lyophilized under the conditions as shown in Table 3 to give a lyophilized
- composition 3 the effects of pH value on the storage stability of BDNF was studied.
- the compositions obtained above were kept at 25°C or 40°C for three months, and the contents of BDNF, polymerized BDNF and denatured BDNF were determined by the methods mentioned hereinbelow.
- Table 4 the content of BDNF was reduced under basic conditions, but slightly reduced under acidic conditions.
- the polymerized BDNF was hardly produced under acidic conditions, but increased under basic conditions.
- the content of the denatured BDNF was more increased under acidic conditions than under basic conditions.
- BDNF was diluted to 2 mg/ml, and the concentration thereof was determined by reverse phase chromatography under the following conditions.
- Solution A 0.1 % aqueous trifluoroacetic acid solution
- Solution B 0.1 % Irifluoroacetic acid solution in acetonitrile Graduation conditions:
- the concentration (%) of Solution B was 26, 35, 35, 90, 26 and 26 at a time (minutes) of 0, 36, 42, 46, 47, 66, respectively. Detection: 215 nm
- BDNF was diluted to 2 mg/ml, and the concentration thereof was determined by gel filtration chromatography under the following conditions.
- Solvent 300 mM sodium phosphate, 500 mM sodium chloride, 5 % n-propanol, pH 6
- BDNF was dissolved in 10 mM phosphate buffer (pH 7.0, 150 mM sodium chloride, 0.01 % Tween 80) to give an aqueous BDNF solution (5 mg/ml).
- the solution thus obtained was put into vials aseptically, and the vials were fulfilled with nitrogen gas, and then sealed to give a solution composition of BDNF.
- BDNF a lyophilized composition of BDNF
- 10 mM phosphate buffer pH 7.0, 150 mM sodium chloride, 0.01 % Tween 80
- the solution thus obtained was put into vials aseptically, and lyophilized under the conditions as shown in Table 3 to give a lyophilized composition of BDNF.
- the vials were fulfilled with nitrogen gas and were sealed.
- the biological activities of BDNF were determined based on the cell proliferation potency of BAF-trkB cells when treated with BDNF.
- Said BAF- trkB cells were prepared by introducing a trkB gene (a BDNF receptor) into BDNF.
- the BDNF contents in the compositions prepared in Example 4 were determined immediately after the preparation thereof, or after three-month storage at 25 "C, or 40 ° C. The results are shown in Table 6.
- the content of polymerized BDNF was slightly higher than that in the solution composiuon, but the content of BDNF per se is higher, and the content of the denatured BDNF was lower, than that in the solution composition.
- a lyophilized composition of BDNF was prepared by the same method as m Example 4 to give Present Lyophilized Composition 5
- BDNF was dissolved in 10 mM phosphate buffer (pH 7.0, 150 mM sodium chloride) to give an aqueous BDNF solution (5 mg/ml)
- the solution thus obtained was put into vials aseptically, and lyophilized under the same conditions as shown in Table 3 to give a lyophilized composition of BDNF
- the vials were fulfilled with nitrogen gas and sealed.
- Composition 5 and Present Lyophilized Composition 5 were dissolved in purified water, and the appearance of these solutions was visually observed.
- Lyophilized Composition 5 wherein no surfactant was added was turbid after the dissolution thereof.
- Example 6 (Effects of stabilizer on the stability of the lyophilized composition of BDNF) Preparation of a lvophilized composition of BDNF with a surfactant (Present Lvophilized Composition 6A)
- a lyophilized composition of BDNF was prepared by the same method as in Example 4 to give Present Lyophilized Composition 6A.
- BDNF was dissolved in 10 mM phosphate buffer (pH 7.0, 150 mM sodium chloride, 0.01 % Tween 80) to give an aqueous BDNF solution (5 mg/ml). To the solution was added mannitol so that the final concentration of mannitol was 10 mg/ml.
- the aqueous solution of BDNF thus obtained was put into vials aseptically, and lyophilized under the same conditions as shown in Table 3 to give a lyophilized composition of BDNF.
- the vials were fulfilled with nitrogen gas and sealed.
- the pharmaceutical composition of BDNF of the present invention can maintain BDNF stable for a long time by adding thereto a surfactant.
- the present compositions of BDNF show the following effects: (1) prevention of the production of turbidness or aggregations of BDNF in a pharmaceutical solution composition of BDNF of the present invention, during the storage thereof;
- the pharmaceutical composition of BDNF containing a salt as an isotonic agent, a buffering agent for keeping an optimal pH value, or containing both of these salt and buffering agent may be in the form of a pharmaceutical composition being suitable for clinical use.
- the stability of BDNF contained in the pharmaceutical solution composition of the present invention is more improved when lyophilized.
- the lyophilized pharmaceutical composition of BDNF of the present invention addiuonally containing as an additional stabilizer an ammo acid and/or a sugar alcohol is more stable.
- the lyophilized composition of BDNF containing glycine as an amino acid and/or mannitol as a sugar alcohol is the most stable composition.
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002256410A CA2256410C (en) | 1996-05-27 | 1997-05-26 | Stable pharmaceutical composition of bdnf |
AT97922156T ATE223728T1 (en) | 1996-05-27 | 1997-05-26 | STABILIZED PHARMACEUTICAL COMPOSITION OF BDNF |
DK97922156T DK0910399T3 (en) | 1996-05-27 | 1997-05-26 | Stable pharmaceutical BDNF preparation |
DE69715414T DE69715414T2 (en) | 1996-05-27 | 1997-05-26 | STABILIZED PHARMACEUTICAL COMPOSITION OF BDNF |
AU27923/97A AU715571B2 (en) | 1996-05-27 | 1997-05-26 | Stable pharmaceutical composition of BDNF |
EP97922156A EP0910399B1 (en) | 1996-05-27 | 1997-05-26 | Stable pharmaceutical composition of bdnf |
US09/180,884 US6077829A (en) | 1996-05-27 | 1997-05-26 | Stable pharmaceutical composition of BDNF |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP8/156070 | 1996-05-27 | ||
JP8156070A JPH10212241A (en) | 1996-05-27 | 1996-05-27 | Preparation stably containing bdnf |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997045135A1 true WO1997045135A1 (en) | 1997-12-04 |
Family
ID=15619654
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1997/001746 WO1997045135A1 (en) | 1996-05-27 | 1997-05-26 | Stable pharmaceutical composition of bdnf |
Country Status (11)
Country | Link |
---|---|
US (1) | US6077829A (en) |
EP (1) | EP0910399B1 (en) |
JP (1) | JPH10212241A (en) |
AT (1) | ATE223728T1 (en) |
AU (1) | AU715571B2 (en) |
CA (1) | CA2256410C (en) |
DE (1) | DE69715414T2 (en) |
DK (1) | DK0910399T3 (en) |
ES (1) | ES2183170T3 (en) |
PT (1) | PT910399E (en) |
WO (1) | WO1997045135A1 (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0958831A1 (en) * | 1996-09-13 | 1999-11-24 | Advanced Medicine Research Institute | Ophthalmic compositions of neurotrophic factors, remedies for optic nerve function disorders and method for treating optic nerve function disorders |
WO2000075176A1 (en) * | 1999-06-08 | 2000-12-14 | The University Of Melbourne | Small cyclic mimics of brain-derived neurotrophic factor (bdnf) |
WO2002005855A1 (en) * | 2000-07-13 | 2002-01-24 | Daiichi Pharmaceutical Co., Ltd. | Pharmaceutical compositions containing dds compounds |
WO2011058449A2 (en) | 2009-11-16 | 2011-05-19 | Hmfra Hungary Limited Liability Company | Ophthalmic preparations based on bdnf (brain-derived neurotrophic factor) and their use |
US9138456B2 (en) | 2009-11-23 | 2015-09-22 | Cubist Pharmaceuticals Llc | Lipopeptide compositions and related methods |
US9803195B2 (en) | 2005-12-28 | 2017-10-31 | The Scripps Research Institute | Natural antisense and non-coding RNA transcripts as drug targets |
US10214745B2 (en) | 2012-03-15 | 2019-02-26 | The Scripps Research Institute | Treatment of brain derived neurotrophic factor (BDNF) related diseases by inhibition of natural antisense transcript to BDNF |
US11173189B2 (en) | 2020-03-12 | 2021-11-16 | Baxter International Inc. | Daptomycin formulations containing a combination of sorbitol and mannitol |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040120891A1 (en) * | 1998-12-21 | 2004-06-24 | Craig Hill | Compounds for intracellular delivery of therapeutic moieties to nerve cells |
EP1182204B1 (en) * | 1999-06-03 | 2004-04-07 | Eisai Co., Ltd. | Crystals of carbapenem derivatives and pharmaceutical preparations for injection |
US7223406B2 (en) | 2000-07-21 | 2007-05-29 | The Regents Of The University Of California | Methods and compositions for preventing and treating male erectile dysfunction and female sexual arousal disorder |
WO2002007757A2 (en) * | 2000-07-21 | 2002-01-31 | Lue Tom F | Prevention and treatment of sexual arousal disorders |
EP1575477B1 (en) * | 2001-05-25 | 2012-04-25 | Cornell Research Foundation, Inc. | HIGH AFFINITY LIGAND FOR p75 NEUROTROPHIN RECEPTOR |
DE10149030A1 (en) * | 2001-10-05 | 2003-04-10 | Viscum Ag | Preparation of storage-stable medicaments containing recombinant carbohydrate-binding polypeptides, especially r-viscumin, useful e.g. as cytotoxic agent, comprises cooling, freezing, spray-drying or lyophilizing solution of pH more than 6 |
US20040096828A1 (en) * | 2002-01-04 | 2004-05-20 | Lu Dyung Aina M | Cytoskeleton-associated proteins |
US20030219696A1 (en) * | 2002-05-23 | 2003-11-27 | Moreland Gerald W. | Method and apparatus for preventing backflow in dental saliva evacuators |
KR20060002745A (en) * | 2003-01-13 | 2006-01-09 | 마헨드라 에스 라오 | Persistent expression of candidate molecule in proliferating stem and progenitor cells for delivery of therapeutic products |
US20050048041A1 (en) * | 2003-01-13 | 2005-03-03 | Rao Mahendra S. | Persistent expression of candidate molecule in proliferating stem and progenitor cells for delivery of therapeutic products |
AU2006255101A1 (en) | 2005-06-06 | 2006-12-14 | Wyeth | Anti-TrkB monoclonal antibodies and uses thereof |
WO2008019431A1 (en) * | 2006-08-14 | 2008-02-21 | Brc Operations Pty Limited | Method and compositions for simultaneously regulating memory and mood |
CA3105879A1 (en) | 2018-07-18 | 2020-01-23 | Manzanita Pharmaceuticals, Inc. | Conjugates for delivering an anti-cancer agent to nerve cells, methods of use and methods of making thereof |
JP2021019532A (en) * | 2019-07-26 | 2021-02-18 | 花王株式会社 | Blood-brain barrier protective agent |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1991007947A1 (en) * | 1989-12-05 | 1991-06-13 | Ramsey Foundation | Neurologic agents for nasal administration to the brain |
US5604202A (en) * | 1990-11-13 | 1997-02-18 | Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Use of NGF growth factors to treat drug-induced neuropathy |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5180820A (en) * | 1989-08-30 | 1993-01-19 | Barde Yves Alain | Brain-derived neurotrophic factor |
US5770577A (en) * | 1994-11-14 | 1998-06-23 | Amgen Inc. | BDNF and NT-3 polypeptides selectively linked to polyethylene glycol |
-
1996
- 1996-05-27 JP JP8156070A patent/JPH10212241A/en active Pending
-
1997
- 1997-05-26 US US09/180,884 patent/US6077829A/en not_active Expired - Fee Related
- 1997-05-26 AT AT97922156T patent/ATE223728T1/en not_active IP Right Cessation
- 1997-05-26 PT PT97922156T patent/PT910399E/en unknown
- 1997-05-26 ES ES97922156T patent/ES2183170T3/en not_active Expired - Lifetime
- 1997-05-26 DK DK97922156T patent/DK0910399T3/en active
- 1997-05-26 WO PCT/JP1997/001746 patent/WO1997045135A1/en active IP Right Grant
- 1997-05-26 EP EP97922156A patent/EP0910399B1/en not_active Expired - Lifetime
- 1997-05-26 AU AU27923/97A patent/AU715571B2/en not_active Ceased
- 1997-05-26 CA CA002256410A patent/CA2256410C/en not_active Expired - Fee Related
- 1997-05-26 DE DE69715414T patent/DE69715414T2/en not_active Expired - Lifetime
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1991007947A1 (en) * | 1989-12-05 | 1991-06-13 | Ramsey Foundation | Neurologic agents for nasal administration to the brain |
US5604202A (en) * | 1990-11-13 | 1997-02-18 | Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Use of NGF growth factors to treat drug-induced neuropathy |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0958831A1 (en) * | 1996-09-13 | 1999-11-24 | Advanced Medicine Research Institute | Ophthalmic compositions of neurotrophic factors, remedies for optic nerve function disorders and method for treating optic nerve function disorders |
EP0958831A4 (en) * | 1996-09-13 | 2004-04-07 | Advanced Medicine Res Inst | Ophthalmic compositions of neurotrophic factors, remedies for optic nerve function disorders and method for treating optic nerve function disorders |
WO2000075176A1 (en) * | 1999-06-08 | 2000-12-14 | The University Of Melbourne | Small cyclic mimics of brain-derived neurotrophic factor (bdnf) |
WO2002005855A1 (en) * | 2000-07-13 | 2002-01-24 | Daiichi Pharmaceutical Co., Ltd. | Pharmaceutical compositions containing dds compounds |
US6815435B2 (en) | 2000-07-13 | 2004-11-09 | Daiichi Pharmaceutical Co., Ltd. | Pharmaceutical compositions containing DDS compounds |
US9803195B2 (en) | 2005-12-28 | 2017-10-31 | The Scripps Research Institute | Natural antisense and non-coding RNA transcripts as drug targets |
US10472627B2 (en) | 2005-12-28 | 2019-11-12 | The Scripps Research Institute | Natural antisense and non-coding RNA transcripts as drug targets |
WO2011058449A2 (en) | 2009-11-16 | 2011-05-19 | Hmfra Hungary Limited Liability Company | Ophthalmic preparations based on bdnf (brain-derived neurotrophic factor) and their use |
US9138456B2 (en) | 2009-11-23 | 2015-09-22 | Cubist Pharmaceuticals Llc | Lipopeptide compositions and related methods |
US9662397B2 (en) | 2009-11-23 | 2017-05-30 | Merck Sharp & Dohme Corp. | Lipopeptide compositions and related methods |
US10214745B2 (en) | 2012-03-15 | 2019-02-26 | The Scripps Research Institute | Treatment of brain derived neurotrophic factor (BDNF) related diseases by inhibition of natural antisense transcript to BDNF |
US11173189B2 (en) | 2020-03-12 | 2021-11-16 | Baxter International Inc. | Daptomycin formulations containing a combination of sorbitol and mannitol |
Also Published As
Publication number | Publication date |
---|---|
DE69715414T2 (en) | 2003-05-15 |
DK0910399T3 (en) | 2003-01-06 |
US6077829A (en) | 2000-06-20 |
EP0910399B1 (en) | 2002-09-11 |
PT910399E (en) | 2002-11-29 |
CA2256410C (en) | 2007-02-27 |
AU715571B2 (en) | 2000-02-03 |
ES2183170T3 (en) | 2003-03-16 |
AU2792397A (en) | 1998-01-05 |
CA2256410A1 (en) | 1997-12-04 |
DE69715414D1 (en) | 2002-10-17 |
ATE223728T1 (en) | 2002-09-15 |
EP0910399A1 (en) | 1999-04-28 |
JPH10212241A (en) | 1998-08-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0910399B1 (en) | Stable pharmaceutical composition of bdnf | |
US6020469A (en) | Stem cell factor formulations and methods | |
US9907829B2 (en) | Stable MIA/CD-RAP formulation | |
JP3927248B2 (en) | HGF lyophilized formulation | |
KR100236393B1 (en) | A pharmaceutical preparation containing a human growth hormone | |
WO1997040850A1 (en) | Erythropoietin solution preparation | |
US5714458A (en) | Stable pharmaceutical compositions containing a fibroblast growth factor | |
KR880002037B1 (en) | Interferon composition and its preparation method | |
CA2087430A1 (en) | Stable pharmaceutical compositions containing a fibroblast growth factor | |
AU629549B2 (en) | Homogeneous dimeric m-csf and storage stable formulations thereof | |
WO1999045953A1 (en) | Heparin cofactor ii-containing compositions and method for stabilizing the same | |
AU4027601A (en) | Lyophilized HGF preparations |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU CA US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 09180884 Country of ref document: US |
|
ENP | Entry into the national phase |
Ref document number: 2256410 Country of ref document: CA Ref country code: CA Ref document number: 2256410 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1997922156 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1997922156 Country of ref document: EP |
|
WWG | Wipo information: grant in national office |
Ref document number: 1997922156 Country of ref document: EP |