+

WO1995022560A1 - Formulations pharmaceutiques comprenant un facteur neurotrophique ciliaire - Google Patents

Formulations pharmaceutiques comprenant un facteur neurotrophique ciliaire Download PDF

Info

Publication number
WO1995022560A1
WO1995022560A1 PCT/US1995/002153 US9502153W WO9522560A1 WO 1995022560 A1 WO1995022560 A1 WO 1995022560A1 US 9502153 W US9502153 W US 9502153W WO 9522560 A1 WO9522560 A1 WO 9522560A1
Authority
WO
WIPO (PCT)
Prior art keywords
cntf
formulation
formulations
glycerol
propylene glycol
Prior art date
Application number
PCT/US1995/002153
Other languages
English (en)
Inventor
Daniel B. Dix
Andrew A. Kosky
Erwin Freund
Original Assignee
The Syntex-Synergen Neuroscience Joint Venture
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=22740901&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO1995022560(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by The Syntex-Synergen Neuroscience Joint Venture filed Critical The Syntex-Synergen Neuroscience Joint Venture
Priority to AU18476/95A priority Critical patent/AU1847695A/en
Publication of WO1995022560A1 publication Critical patent/WO1995022560A1/fr

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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators

Definitions

  • This invention relates to pharmaceutical
  • the peripheral nervous system consists of those nerve cells that extend axonal processes outside the spinal cord and brain.
  • the principle nerve cell types in the peripheral nervous system are primary motor neurons innervating skeletal muscle and controlling movement, autonomic neurons (both sympathetic and parasympathetic) innervating the cardiovascular system and other internal organs and regulating their
  • Nerve damage may occur from a wide variety of different causes. Nerve damage may occur through physical injury, which causes the degeneration of the axonal processes and/or nerve cell bodies near the site of injury. Nerve damage may also occur because of
  • Nerve damage may also occur because of intentional or accidental
  • Nerve damage may also occur because of chronic metabolic diseases, such as diabetes or renal dysfunction. Nerve damage may also occur because of neurodegenerative diseases such as
  • Parkinson's disease Alzheimer's disease
  • ALS Amyotrophic Lateral Sclerosis
  • Neurotrophic factors are naturally occurring proteins that promote the survival and functional activities of nerve cells. Neurotrophic factors have been found in the target cells to which an innervating nerve cell connects. Such target-derived neurotrophic factors regulate the number of contacts formed between innervating nerve cells and the target cell population, and are necessary for the survival and maintenance of these nerve cells.
  • Neurotrophic factors are also found in cells that are not innervated.
  • An example of such a neurotrophic factor is CNTF.
  • Human CNTF and the gene encoding human CNTF are described in detail in U. S. patent numbers 4,997,929, and 5,141,856, which are specifically incorporated herein by this reference.
  • CNTF Although the biological role of CNTF has not been conclusively established, CNTF appears to be released upon injury to the nervous system and may limit the extent of injury or neuronal damage. Highly-purified CNTF has been shown to support the survival in cell cultures of chick embryonic parasympathetic,
  • CNTF neurodegenerative diseases
  • ALS Amyotrophic Lateral Sclerosis
  • SMA Spinal Muscular Atrophy
  • CNTF neuropeptide
  • CNTF is subject to loss from solution by nonspecific adsorption to the surface areas of storage containers and dispensing devices.
  • nonspecific binding may occur to a variety of materials including glass and plastics, for example, polyethylene or polypropylene. These materials may be in the form of vials, tubing, syringes, inplantable infusion devices, or any other surface which may come in contact with CNTF during its manufacture, storage or
  • CNTF for certain applications for the treatment or prevention of peripheral nerve damage in humans it is desirable to administer the CNTF, in formulation, intrathecally.
  • Intrathecal administration necessitates that CNTF must be maintained in an aqueous solution for relatively long periods of time at elevated
  • CNTF formulations will be maintained at room temperature, while other administrations will actually require that the CNTF formulation will be held at body temperature. These are obviously relatively harsh conditions for a sensitive protein such as CNTF.
  • Lyophilization is one method of enabling the long term storage of biological proteins, impeding
  • the present invention includes formulations of CNTF which physically and thermally stabilize CNTF against degradation and precipitation under a wide variety of storage and administration regimes.
  • This invention further includes formulations of CNTF in which bioactivity is maintained after
  • the present invention includes therapeutically useful formulations of CNTF which greatly reduce the prior art problems of loss of CNTF from solutions due to chemical degradation, precipitation, and adsorption.
  • the present invention includes three types of stabilized CNTF formulations, characterized as
  • This invention provides physically and chemically stable aqueous formulations of CNTF. Preferred
  • lyophilization that comprise aqueous solutions of:
  • inventions of this invention are the lyophilized formulations from which the water has been substantially removed.
  • a reconstituting vehicle optionally including a
  • the lyophilized formulations of the present invention are suitable for administration to patients in need thereof.
  • Such reconstituted solutions of CNTF are also included within the scope of this invention.
  • neurotrophic factor formulation as described herein to a patient in need thereof.
  • the neurotrophic factor formulation as described herein to a patient in need thereof.
  • invention provides formulations for administering therapeutically effective amounts of CNTF in order to prevent and treat peripheral nerve damage, including neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, ALS, and SMA.
  • neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, ALS, and SMA.
  • invention also includes methods for preventing and treating peripheral nerve damage by administering to a patient in need thereof a therapeutically effective amount of CNTF formulated as described herein.
  • the present invention includes therapeutically useful formulations of CNTF for the prevention and treatment of peripheral nerve damage, including
  • neurodegenerative diseases such as Parkinson's and Alzheimer's diseases, ALS, and SMA.
  • the present invention includes the use of CNTF as a therapeutic agent by administering a therapeutic composition whose active ingredient consists of CNTF.
  • Such therapeutic compositions include compositions suitable for use in a wide variety of administration regimes which are stable under a variety of storage and administration conditions.
  • CNTF is chemically unstable even when stored at 4oC.
  • the therapeutic use of CNTF in the treatment of peripheral nerve damage requires formulations which are acceptable for rapid and easy administration to patients in need thereof, readily manufacturable, and stable for a prolonged period of time over a variety of storage conditions.
  • aqueous formulations suitable for intrathecal administration are suitable for
  • lyophilization formulations of CNTF are suitable for maintaining the stability and bioactivity of CNTF when subjected to lyophilization and subsequent
  • the most preferred embodiments of the present invention are aqueous formulations that are stable prior to lyophilization and that have retained their bioactivity following lyophilization, long term storage, and reconstitution.
  • CNTF may be formulated for use as a therapeutic agent when included in solution with agents that are effective in
  • Such agents include non-ionic surfactants such a
  • the preferred formulations of the present invention also may include other ingredients that function to improve the
  • Such other ingredients include sodium chloride, glycerol, human serum albumin, sodium phosphate, and tris
  • pharmaceutically effective amount means an amount of CNTF which is therapeutically effective in various administration regimes in the prevention and treatment of peripheral nerve damage.
  • Biologically acceptable applies to materials characterized by the absence of significant adverse biological effects in vivo.
  • Room temperature is between about 22oC to about 25oC.
  • “Lyophilizable formulation” refers to an aqueous formulation of CNTF which may be freeze dried to a moisture content of less than about 2% and which retains at least about 70% of the initial CNTF bioactivity upon reconstitution. "Isotonic” refers to a solution having approximately the same osmotic pressure as blood serum, about 300 mM per liter.
  • a “carrier” is any biologically acceptable emulsifier, dispersing agent, surfactant, or protein which
  • CNTF human CNTF
  • hCNTF human CNTF
  • rhCNTF recombinant hCNTF
  • Methods of obtaining CNTF suitable for use in the formulations of this invention are known to those skilled in the art.
  • suitable rhCNTF may be produced by the recombinant DNA procedures described in U.S. patent number 5,141,856, specifically incorporated herein by this reference.
  • the CNTF should be at least 65% pure, and most preferably at least 98% pure.
  • the purity of isolated CNTF for use in the formulations may be determined by silver-stained SDS-PAGE or other means known to those skilled in the art.
  • CNTF is present in therapeutically effective amounts.
  • CNTF comprises from about 0.01 to about 8.0 mg/ml.
  • the aqueous CNTF formulations optionally include carriers.
  • the presence of the carrier in the aqueous CNTF formulations optionally include carriers.
  • Suitable carriers include, but are not limited to, polysorbates such as Tween ® 80 and proteins such as serum albumin. Further, amino acids such as lysine and arginine have been shown to prevent adsorptive losses of CNTF.
  • human serum albumin HSA
  • Tween ® is particularly preferred.
  • a combination of lysine and arginine is preferred.
  • the CNTF formulations may also contain a
  • the aqueous CNTF formulations further contain a biologically acceptable buffer to maintain solution pH.
  • the preferred stable CNTF formulation is buffered with a biologically acceptable buffer to a pH between 4.5 to about 8.0, most preferably between about 5.0 and 7.6.
  • suitable buffers include citric acid, tris (hydroxymethyl) aminomethane, citrate, acetate, phosphate, tromethamine, and
  • the preferred amount of buffer will vary depending on the type of buffer used and its buffering capacity. The buffer should be present in the
  • the preferred concentration of buffer for stable CNTF formulations is 1 to 50 mM.
  • a non-ionic surfactant is added to stabilize CNTF in solution upon agitation.
  • the non-ionic surfactant is polysorbate-80 (Tween ® 80).
  • Tween ® 80 preferred concentration of Tween ® 80 was found to increase with increasing CNTF concentration.
  • CNTF is present in a concentration range of between 0.01 - 8.0 mg/ml and the non-ionic surfactant is polysorbate-80 (Tween ® 80) in the concentration range of between 0.1 - 1.0% weight/volume (w/v).
  • the formulation further comprises
  • glycerol in the concentration range between 4
  • the formulation comprises 0.01 - 8.0 mg/ml CNTF, 0.2 - 0.8% (w/v) Tween ® 80, 5 - 15% (w/v) glycerol, human serum albumin (HSA) in the
  • propylene glycol is added to prevent precipitation of CNTF in solution.
  • CNTF is present in the formulation in the concentration range of between 0.01 - 8.0 mg/ml and propylene glycol is present in the concentration range of between 1 - 30% (w/v).
  • the formulation is further comprised of glycerol in the concentration range between 4 - 20% (w/v).
  • the formulation is comprised of 0.01
  • an alcohol is added to stabilize CNTF in solution upon agitation.
  • alcohols that may be used include ethanol, propanol, t-butanol, and other simply alkyl alcohols.
  • the alcohol is ethanol.
  • CNTF is present in the concentration range of between 0.01 - 8.0 mg/ml and ethanol is present in the concentration range of 0.1 - 20% (v/v).
  • the formulation further comprises glycerol in the concentration range between 4 - 20% (w/v).
  • the formulation is comprised of 0.01 - 8.0 mg/ml CNTF, 8 - 13% (v/v) ethanol, and 5 - 20%
  • glycerol in the concentration range of 0.01 - 5% (w/v), 1 - 50 mM sodium phosphate, pH 6-8, 1 - 50 mM tris (hydroxymethyl) aminomethane, and 100 - 400 mM sodium chloride.
  • the intrathecal CNTF formulations of the present invention represent a major advance in solving the problems of CNTF instability and surface adsorption upon incubation and agitation.
  • An intrathecal CNTF formulation of the present invention represent a major advance in solving the problems of CNTF instability and surface adsorption upon incubation and agitation.
  • CNTF formulations appropriate for intrathecal delivery must also contain a sufficient amount of biologically acceptable salt to maintain fluid
  • the CNTF formulation contains sufficient salt to be isotonic, within physiologically acceptable limits, with human blood or cerebral spinal fluid.
  • the preferred salt is sodium chloride (NaCl), but other biologically acceptable salts may be used, such as potassium chloride (KCl), calcium chloride (CaCl 2 ), and magnesium chloride (MgCl 2 ).
  • the salt may be one salt or a combination of salts.
  • a preferred formulation comprises 100 to 400 mM salt of the aqueous formulation.
  • One intrathecal formulation of the present invention is comprised of 0.01 - 8.0 mg/ml CNTF, 10-13% (v/v) ethanol, and 5% lysine.
  • 0.01 - 8.0 mg/ml CNTF 0.01 - 8.0 mg/ml CNTF
  • 10-13% (v/v) ethanol 10-13% (v/v) ethanol
  • 5% lysine 0.01 - 8.0 mg/ml CNTF, 10-13% (v/v) ethanol, and 5% lysine.
  • the intrathecal formulation is further comprised of 10 mM phosphate (pH 7.0), 150 mM NaCl, and 0.1 - 20% glycerol.
  • An additional intrathecal formulation is comprised of 0.01 - 8.0 mg/ml CNTF, 20-25% propylene glycol, and 10% glycerol.
  • the intrathecal formulation is further comprised of 3-5% lysine.
  • the formulation is further comprised of 10 mM citrate acid (pH 6.0) and 150 mM NaCl.
  • An additional intrathecal formulation is comprised of 0.01 - 8.0 mg/ml CNTF, 4% polyethylene glycol 8000 (PEG 8000), and 10% glycerol.
  • PEG 8000 polyethylene glycol 8000
  • the formulation is further comprised of 5% lysine.
  • the formulation is further comprised of 5% lysine.
  • formulation is further comprised of 10 mM citrate acid (pH 6.0) and 150 mM NaCl.
  • a final intrathecal formulation is comprised of
  • the preferred embodiment is further comprised of 5% lysine, 10 mM citrate acid (pH 6.0), and 150 mM NaCl.
  • compositions of this invention may be administered intrathecally by continuous infusion from an implanted or an external pump.
  • Other effective administration forms such as parenterally slow-release formulations, parentally by injection, inhalant mists, orally active formulations, or suppositories, are also envisioned.
  • formulation of the present invention are specifically formulated to remain stable and bioactive during and after lyophilization, and upon reconstitution of the lyophilized material.
  • formulations of this invention are particularly useful for providing long term storage of CNTF.
  • lyophilizable formulations of this invention comprise CNTF, a biologically acceptable bulking agent, a buffer to maintain the pH of the formulation from about 5.0 to about 7.5, biologically acceptable salt, and optionally a biologically acceptable water soluble carrier.
  • CNTF is present in the lyophilizable formulations over the same concentration range as in the aqueous formulations described above.
  • the bulking agent generally provides mechanical support by allowing the matrix to maintain its conformation during and after the freeze drying process.
  • One or more sugars may be used as the bulking agent.
  • Sugars include but are not limited to, monosaccharides, oligosaccharides and polysaccharides. Examples of suitable sugars include fructose, glucose, mannose, ribose, xylose, maltose, lactose, sucrose, and dextran.
  • Sugar also includes sugar alcohols, such as mannitol, sorbitol, inositol, dulcitol, xylitol, and arabitol. Mixtures of sugars may also be used in accordance with this invention. In one embodiment of the
  • polyethylene glycol of average molecular weight 3500 is preferred.
  • the most preferred bulking agent of the present invention is sucrose.
  • the choice of buffer takes into account potential pH shifts during lyophilization caused by sequential crystallization of buffer components.
  • the basic component has a higher eutectic point than the acidic component, hence it crystallizes out first and the pH drops. This behavior may be acceptable and perhaps even beneficial in the formulations of the present invention.
  • citric acid buffer is preferred because it is thought that both buffer components have about the same eutectic point
  • the lyophilizable formulations may also comprise a biologically acceptable salt.
  • the salt which may be selected from the same salts useful in the aqueous formulations described above, is present in the
  • lyophilizable formulations at the same or reduced concentrations as that in the aqueous formulations. Because the salt concentration may increase during lyophilization, it may be desirable to reduce the concentration of salt present in the lyophilizable formulations to prevent protein denaturation.
  • formulations of this invention are the same as those that are suitable for use in the aqueous formulations.
  • lyophilizable formulations of this invention are generally lyophilized to a residual moisture content of less than about 2%; however, formulations which retain CNTF biological activity at higher or lower amounts of moisture content are also
  • An example of a formulation of CNTF which retains bioactivity after lyophilization and reconstitution is comprised of 0.5 mg/ml CNTF, 85 mg/ml sucrose, 2.0 mg/ml polysorbate 80 (Tween ® 80), 4.0 mg/ml cysteine, 0.1 mg/ml disodium EDTA, and 2.0 mg/ml citric acid (pH 5.0).
  • reconstitution is comprised of 0.5 mg/ml CNTF, 80 mg/ml polyethylene glycol 3350 (PEG 3350), 50 mg/ml lysine, 20 mg/ml arginine, 4 mg/ml cysteine, 0.58 mg/ml sodium chloride, and 1.6 mg/ml histidine (pH 7.5). Any higher molecular weight polyethylene glycol that is a solid at room temperature may be used in this formulation. In addition, glutathione may be used in place of cysteine, which may provide improved solution state stability.
  • the most preferred embodiment of the invention is a lyophilizable CNTF formulation comprised of CNTF, sucrose, polysorbate 80 (Tween ® 80), cysteine, disodium EDTA and tromethamine.
  • a specific formulation that represents the most preferred embodiment is comprised of 0.5 mg/ml CNTF, 85 mg/ml sucrose, 2.0 mg/ml
  • polysorbate 80 (Tween ® 80), 4.0 mg/ml cysteine, 0.1 mg/ml disodium EDTA, and 2.0 mg/ml tromethamine, buffered to pH 7.6.
  • kits of this invention are also useful as a component of a kit to provide a convenient and economical way of providing stable lyophilized CNTF in a form which may be rapidly and easily reconstituted in an appropriate vehicle for administration to a patient in need of treatment.
  • the kits of this invention also comprise a reconstituting vehicle.
  • the reconstituting vehicle may comprise sterile water and a sufficient amount of salt to make the final reconstituted formula essentially isotonic.
  • the reconstituting vehicle may further comprise
  • the total volume of reconstituting vehicle present in the kit should be sufficient to achieve a final CNTF concentration suitable for
  • CNTF which is administered in this fashion is encapsulated.
  • the capsule is designed so that the active portion of the formulation is released at that point in the gastrointestinal tract when bioavailability is maximized and pre-systemic degradation is minimized. Additional excipients may be included to facilitate absorption of CNTF. Diluents, flavorings, low melting point waxes, vegetable oils, lubricants, suspending agents, tablet disintegrating agents, and binders may also be employed.
  • the specific dose of CNTF is calculated according to the approximate body weight or surface area of the patient. Further refinement of the calculations necessary to determine the appropriate dosage for treatment
  • CNTF formulations described herein may be used for veterinary as well as human applications and that the term "patient” should not be construed in a limiting manner. In the case of veterinary applications, the dosage ranges should be the same as specified above.
  • Example 1 CNTF-containing solutions upon agitation or heating are described in Example 1.
  • the effect of sodium chloride on the chemical and thermal stability of CNTF is described in Example 2.
  • Example 3 describes the CNTF formulation which contains Tween ® 80. This composition is particularly suited to use in pulmonary dosing and in needleless jet injector guns.
  • Example 4 describes the formulation of CNTF containing 1 - 25% propylene glycol. Besides loss through degradation and
  • Example 5 describes the effect of human serum albumin (HSA) and lysine on prevention of CNTF loss through adsorption.
  • Example 6 describes the formulation of CNTF containing ethanol.
  • Example 7 describes a formulation of CNTF specific for use intrathecally. Also described is the effect of the molecular weight and concentration of PEG species on the physical and thermal stability of CNTF.
  • Example 9 describes experiments in which CNTF formulations were incubated for a period of days in catheter tubes or pump reservoirs.
  • Example 10 describes the physical and chemical stability of the lyophilizable CNTF
  • formulations of this invention under a variety of storage conditions. These experiments establish that the formulations of the present invention represent a major advance in solving the problems associated with the pharmaceutical administration of CNTF.
  • compositions when agitated was tested by vortexing CNTF-containing solutions using a Vortex Genie 2
  • Precipitation was determined by absorbance spectroscopy at OD 405 using a kinetic microplate reader (Molecular Devices) and a 96 well plate.
  • CEX Cation Exchange Chromatography
  • a salt such as sodium chloride in formulations of this invention provides both fluid tonicity and acts to maintain CNTF in solution.
  • NaCl was added in an amount equal to the tonicity of the human body.
  • Table 1 shows the effects of varying the concentration of sodium chloride on the rate of precipitation when 1.0 mg/ml CNTF (pH 6.2) was vortexed in the presence of 25% propylene glycol and 10% glycerol at room temperature (20oC).
  • Precipitation was lowest with 10 and 50 mM sodium chloride, intermediate with 400 mM sodium chloride, and highest with 100 and 200 mM sodium chloride.
  • Tween ® 80 and 10% glycerol is shown in Table 3.
  • Tween ® 80 significantly delayed with increasing concentrations of Tween ® 80, with the maximum inhibition of precipitation achieved with 0.75% Tween ® 80.
  • the inhibitory effect of Tween ® 80 on precipitation resulting from agitation was seen with CNTF solutions of up to 4 mg/ml (data not shown).
  • the effect of Tween ® 80 on thermal stability of CNTF is shown in Table 4. CNTF solutions (1.0 mg/ml, pH 7.0; 10% glycerol) were incubated at room temperature up to 20 hours, and the amount of
  • Table 5 shows the effect of 25% propylene glycol on precipitate formation when a 1.0 mg/ml CNTF solution (pH 5.0, 5.75, or 6.0) (with 10% glycerol) was vortexed for up to 420 minutes.
  • Table 8 shows the effect of 25% propylene glycol on the amount of precipitate formed as a function of time when CNTF solutions (0.05 - 4.0 mg/ml) were vortexed at room temperature.
  • CNTF quickly precipitates out of solution upon vortexing.
  • the addition of 25% PEG 300 resulted in a greater total amount of precipitate formed although the initial formation of precipitate was delayed.
  • the addition of 12.5% polyethylene glycol and 12.5% PEG 300 inhibited precipitate formation.
  • propylene glycol stabilizes CNTF against precipitation from agitation while having little effect on thermal stability.
  • EXAMPLE 5 THE EFFECT OF HSA ON LOSS OF CNTF
  • CNTF is readily lost from solution by absorption to surface areas of the container in which the solution is stored and of the dispensing devices.
  • the problem of adsorption was studied with delivery of CNTF solutions from catheter tubes. The assumption was that if CNTF adsorptive losses could be prevented from catheter tubes, loss from the pump could also be prevented.
  • Table 12 shows the effect of HSA on the recovery of CNTF when a 2.0 mg/ml solution of CNTF was subjected to repeated cycles of freeze/thawing.
  • the formulations used in the experiments shown in Table 12 were composed of: 10 mM citrate acid (pH 6.0), 10% glycerol, 200 mM NaCl, 25% propylene glycol, and 1.5 mg/ml CNTF.
  • CNTF used for the experiments shown in Table 13 was: 10 mM citrate acid (pH 6.0), 10% glycerol, 200 mM NaCl, 25% propylene glycol, and 0.01 mg/ml CNTF.
  • HSA is critical in protecting from loss of CNTF by absorption to the surface area of containers.
  • CNTF amino acids - - such as lysine, arginine and cysteine - -
  • a preferred formulation of CNTF is comprised of 3-5% lysine.
  • a formulation comprised of polyethylene glycol, glycerol and lysine has been found to be useful to deliver CNTF from an implantable pump for periods of time up to one week.
  • Glycerol has been shown to be a key excipient for increasing the thermal stability of CNTF (see Example 2).
  • the effect of adding ethanol to glycerol on thermal stability is shown in Table 16.
  • Intrathecal CNTF formulations were tested for chemical and physical stability.
  • Table 19 shows a comparison of the thermal stability of the same intrathecal CNTF formulations.
  • CNTF formulations containing 4% PEG 8000, 10% glycerol, 5% lysine, and buffered by 10 mM citrate acid (pH 7.5) exhibited the best physical and thermal stability.
  • the formulation containing 4% PEG 8000 exhibited the best overall thermal and physical stabilities .
  • CNTF in the intrathecal formulation does not precipitate upon incubation at room temperature for up to 17 days.
  • This intrathecal formulation of CNTF was less stable at 37oC. However, no significant amount of precipitation was detected after one day of incubation at 37oC, and precipitation only became significant upon prolonged incubation.
  • the catheter tube was emptied and the amount of CNTF remaining in solution determined.
  • the intrathecal formulation of CNTF was incubated in a Medication Cassette Reservoir for the Pharmacia Deltec external pump. The reservoir bag was incubated at 30oC, and samples removed as a function of time and analyzed for CNTF. The results are shown in Table 24.
  • the intrathecal formulations of the present invention thus represents a major advance in solving the problem of CNTF adsorption out of solution.
  • EXAMPLE 10 LYOPHILIZED FORMULATIONS OF CNTF.
  • Lyophilization is a way of providing for the long term storage of biological proteins with minimal degradation, aggregation and/or nonspecific adsorption. Experiments were conducted to determine formulations of CNTF suitable for lyophilization.
  • CNTF formulations were analyzed under a variety of conditions by reverse phase HPLC (RP-HPLC), cation exchange chromatography (CEX), and size
  • Formulation I was comprised of 0.5 mg/ml CNTF, 85 mg/ml sucrose, 2.0 mg/ml polysorbate 80, 4.0 mg/ml cysteine, 0.1 mg/ml disodium EDTA, and 2.0 mg/ml citric acid (pH 5.0).
  • Formulation II was comprised of 0.5 mg/ml CNTF, 85 mg/ml sucrose, 2.0 mg/ml polysorbate 80, 4.0 mg/ml cysteine, 0.1 mg/ml disodium EDTA, and 2.0 mg/ml tromethamine (pH 7.6).
  • Formulation III was comprised of 0.5 mg/ml CNTF, 80 mg/ml polyethylene glycol 3350, 50 mg/ml lysine, 20 mg/ml arginine, 4.0 mg/ml cysteine, 0.58 mg/ml sodium chloride, and 1.6 mg/ml histidine (pH 7.5).
  • the three lyophilizable formulations of CNTF (I, II, III) were stored at 2-8oC, room temperature, 37oC and 45oC for 0, 1.4, 6, and 10 week periods.
  • the stability of the formulations was determined by RP- HPLC, CEX, and SEC analysis. The results are shown in Table 27.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Toxicology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Psychology (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des formulations pharmaceutiques comprenant un facteur neurotrophique ciliaire utiles pour le traitement thérapeutique de lésions du système nerveux périphérique. Des formulations à base dudit facteur neurotrophique ciliaire idéales pour l'administration intrathécale sont également décrites.
PCT/US1995/002153 1994-02-22 1995-02-21 Formulations pharmaceutiques comprenant un facteur neurotrophique ciliaire WO1995022560A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU18476/95A AU1847695A (en) 1994-02-22 1995-02-21 Pharmaceutical formulations of cntf

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US20024394A 1994-02-22 1994-02-22
US08/200,243 1994-02-22

Publications (1)

Publication Number Publication Date
WO1995022560A1 true WO1995022560A1 (fr) 1995-08-24

Family

ID=22740901

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1995/002153 WO1995022560A1 (fr) 1994-02-22 1995-02-21 Formulations pharmaceutiques comprenant un facteur neurotrophique ciliaire

Country Status (2)

Country Link
AU (1) AU1847695A (fr)
WO (1) WO1995022560A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996035446A1 (fr) * 1995-05-12 1996-11-14 The Rockefeller University Traitement de la maladie d'alzheimer par modulation des synapsines
WO1997012635A1 (fr) * 1995-10-02 1997-04-10 Cytotherapeutics, Inc. Procede de traitement de la sclerose laterale amyotrophique
WO2002094308A1 (fr) * 2001-05-22 2002-11-28 Centre National De La Recherche Scientifique Transfert genique neuronal ameliore
WO2005049061A3 (fr) * 2003-11-20 2005-10-20 Novo Nordisk As Formulations peptidiques a base de propylene glycol optimales pour la production et l'utilisation dans des dispositifs d'injection
US8114959B2 (en) 2003-06-03 2012-02-14 Novo Nordisk A/S Stabilized pharmaceutical peptide compositions
US8614181B2 (en) 2003-06-03 2013-12-24 Novo Nordisk A/S Stabilized pharmaceutical peptide compositions
US8710181B2 (en) 2004-08-31 2014-04-29 Novo Nordisk A/S Use of tris(hydroxymethyl) aminomethane for the stabilization of peptides, polypeptides and proteins
US8748376B2 (en) 2004-11-12 2014-06-10 Novo Nordisk A/S Stable formulations of peptides
US8846618B2 (en) 2001-06-28 2014-09-30 Novo Nordisk A/S Stable formulation of modified GLP-1
US11110063B2 (en) 2017-08-25 2021-09-07 MAIA Pharmaceuticals, Inc. Storage stable sincalide formulations
US11318191B2 (en) 2020-02-18 2022-05-03 Novo Nordisk A/S GLP-1 compositions and uses thereof
US11752198B2 (en) 2017-08-24 2023-09-12 Novo Nordisk A/S GLP-1 compositions and uses thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4061736A (en) * 1975-02-02 1977-12-06 Alza Corporation Pharmaceutically acceptable intramolecularly cross-linked, stromal-free hemoglobin
US5130298A (en) * 1989-05-16 1992-07-14 Ethicon, Inc. Stabilized compositions containing epidermal growth factor
US5141856A (en) * 1989-01-05 1992-08-25 Synergen, Inc. Expression of purified ciliary neurotrophic factor
US5272135A (en) * 1991-03-01 1993-12-21 Chiron Ophthalmics, Inc. Method for the stabilization of methionine-containing polypeptides

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4061736A (en) * 1975-02-02 1977-12-06 Alza Corporation Pharmaceutically acceptable intramolecularly cross-linked, stromal-free hemoglobin
US5141856A (en) * 1989-01-05 1992-08-25 Synergen, Inc. Expression of purified ciliary neurotrophic factor
US5130298A (en) * 1989-05-16 1992-07-14 Ethicon, Inc. Stabilized compositions containing epidermal growth factor
US5272135A (en) * 1991-03-01 1993-12-21 Chiron Ophthalmics, Inc. Method for the stabilization of methionine-containing polypeptides

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996035446A1 (fr) * 1995-05-12 1996-11-14 The Rockefeller University Traitement de la maladie d'alzheimer par modulation des synapsines
WO1997012635A1 (fr) * 1995-10-02 1997-04-10 Cytotherapeutics, Inc. Procede de traitement de la sclerose laterale amyotrophique
WO2002094308A1 (fr) * 2001-05-22 2002-11-28 Centre National De La Recherche Scientifique Transfert genique neuronal ameliore
EP1262188A1 (fr) * 2001-05-22 2002-12-04 Centre National De La Recherche Scientifique (Cnrs) Transfer neuronale de gènes amélioré
US8846618B2 (en) 2001-06-28 2014-09-30 Novo Nordisk A/S Stable formulation of modified GLP-1
US8114959B2 (en) 2003-06-03 2012-02-14 Novo Nordisk A/S Stabilized pharmaceutical peptide compositions
US8614181B2 (en) 2003-06-03 2013-12-24 Novo Nordisk A/S Stabilized pharmaceutical peptide compositions
US8114833B2 (en) 2003-11-20 2012-02-14 Novo Nordisk A/S Propylene glycol-containing peptide formulations which are optimal for production and for use in injection devices
EP3300721B2 (fr) † 2003-11-20 2025-01-08 Novo Nordisk A/S Formulations de peptides contenant du propylène glycol qui sont optimales pour la production et destinées à être utilisées dans des dispositifs d'injection
EP2394656A3 (fr) * 2003-11-20 2012-01-18 Novo Nordisk A/S Formulations de peptide contenant du propylèneglycol qui sont optimales pour la production et l'utilisation dans des dispositifs d'injection
WO2005049061A3 (fr) * 2003-11-20 2005-10-20 Novo Nordisk As Formulations peptidiques a base de propylene glycol optimales pour la production et l'utilisation dans des dispositifs d'injection
EP1687019B1 (fr) 2003-11-20 2017-11-22 Novo Nordisk A/S Formulations peptidiques a base de propylene glycol optimales pour la production et l'utilisation dans des dispositifs d'injection
EP3300721B1 (fr) 2003-11-20 2019-03-06 Novo Nordisk A/S Formulations de peptides contenant du propylène glycol qui sont optimales pour la production et destinées à être utilisées dans des dispositifs d'injection
US8710181B2 (en) 2004-08-31 2014-04-29 Novo Nordisk A/S Use of tris(hydroxymethyl) aminomethane for the stabilization of peptides, polypeptides and proteins
US8748376B2 (en) 2004-11-12 2014-06-10 Novo Nordisk A/S Stable formulations of peptides
US11752198B2 (en) 2017-08-24 2023-09-12 Novo Nordisk A/S GLP-1 compositions and uses thereof
US12214017B2 (en) 2017-08-24 2025-02-04 Novo Nordisk A/S GLP-1 compositions and uses thereof
US11318100B2 (en) 2017-08-25 2022-05-03 MAIA Pharmaceuticals, Inc. Storage stable sincalide formulations
US11737983B2 (en) 2017-08-25 2023-08-29 MAIA Pharmaceuticals, Inc. Storage stable sincalide formulations
US11110063B2 (en) 2017-08-25 2021-09-07 MAIA Pharmaceuticals, Inc. Storage stable sincalide formulations
US11318191B2 (en) 2020-02-18 2022-05-03 Novo Nordisk A/S GLP-1 compositions and uses thereof

Also Published As

Publication number Publication date
AU1847695A (en) 1995-09-04

Similar Documents

Publication Publication Date Title
US20230047111A1 (en) Pharmaceutical formulations of tnf-alpha antibodies
RU2126265C1 (ru) Фармацевтические композиции с фактором роста нерва
EP2586459B1 (fr) Formulations antagonistes du VEGF
US20200254052A1 (en) Sincalide Formulations
US5096885A (en) Human growth hormone formulation
US5919443A (en) Stable lyophilized pharmaceutical preparations of G-CSF
JP4353544B2 (ja) アミリン作動薬ペプチド用製剤
CA2487585A1 (fr) Formulations de peptides agonistes de l'amyline
WO1995022560A1 (fr) Formulations pharmaceutiques comprenant un facteur neurotrophique ciliaire
JPH05331071A (ja) カルシトニン遺伝子関連ペプチド類の凍結乾燥組成物および安定化法
KR100807650B1 (ko) Ｎ-[ｏ-(ｐ-피발로일옥시벤젠술포닐아미노)벤조일]글리신·모노나트륨염·4수화물의 동결 건조 제제 및 그 제조 방법
EP0803256B1 (fr) Medicaments destines a soulager les effets secondaires provoques par des immunodepresseurs
WO1995022342A1 (fr) Formulations pharmaceutiques du facteur neurotrophe ciliaire
KR101095647B1 (ko) 당단백질 호르몬 조성물
AU778208C (en) GRF-containing lyophilized pharmaceutical compositions
JP7630625B2 (ja) 改善された凍結乾燥製剤
EA048998B1 (ru) Улучшенный лиофилизированный состав
AU2005200879B2 (en) GRF-containing lyophilized pharmaceutical compositions
JP2009149684A (ja) アミリン作動薬ペプチド用製剤
JPS62149623A (ja) 安定なｇｒｆ製剤

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AM AT AU BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU JP KE KG KP KR KZ LK LR LT LU LV MD MG MN MW MX NL NO NZ PL PT RO RU SD SE SI SK TJ TT UA UZ VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE MW SD SZ UG AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

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
NENP Non-entry into the national phase

Ref country code: CA

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载