WO1994021298A1 - Compositions pharmaceutiques stabilisees et leurs procedes de preparation - Google Patents
Compositions pharmaceutiques stabilisees et leurs procedes de preparation Download PDFInfo
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- WO1994021298A1 WO1994021298A1 PCT/FR1994/000296 FR9400296W WO9421298A1 WO 1994021298 A1 WO1994021298 A1 WO 1994021298A1 FR 9400296 W FR9400296 W FR 9400296W WO 9421298 A1 WO9421298 A1 WO 9421298A1
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- virus
- heavy water
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- 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
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to stabilized pharmaceutical compositions and methods for their preparation.
- the present invention relates more particularly to the stabilization of prophylactic, or therapeutic or diagnostic agents consisting of or containing macromolecules or macromolecular complexes.
- therapeutic or protective agents act in the aqueous medium of the inter- or intracellular spaces, or the mucous surfaces.
- hydrophobic medium constituting the membrane, lipid phases or in the environment of hydrophobic amino acids.
- the old therapeutic compounds of relatively low molecular weights have been characterized by a certain ease of formulation in tablets, emulsions, suspensions or solutions.
- Certain macromolecules - such as nucleic acids, and their complexes with proteins (and their cof actors), complex carbohydrates, lipids - and their complexes, are becoming of increasing interest as vaccines, or therapeutics or diagnostic.
- degradation enzymes proteolytic enzymes, nucleases, lipases, glycolytic enzymes
- oxidizing or reducing agents such as oxygen, or organic or inorganic chemicals
- Thermal denaturation cannot be avoided, due to the many weak chemical bonds which characterize biological macromolecules. However, this can be limited, for example, by keeping the temperatures relatively low (refrigeration or freezing). Sometimes small increases in temperature can produce dramatic changes in the activity of biological agents. Such changes involve the breakdown of a molecular organization which depends on cooperative effects not associated with the specific denaturation of a specific protein or nucleic acid.
- adjuvants such as MgCl2, (for the polio vaccine), polyethylene glycol, etc. can be used; however, these can have the disadvantage of not always (depending on the concentrations) being physiologically appropriate.
- the hydrogen bonds between the water molecules order the structure.
- the structure can be highlighted with X-ray or neutron diffraction techniques.
- water molecules form a kind of layer, the depth of several water molecules. Like a cage, this layer, reinforced by hydrogen bonds - between water molecules and between water molecules and macromolecules - has the effect of preserving the integrity of the content.
- the electronic structure of water allows the free exchange of protons (nuclei of hydrogen atoms) between the elements of the water lattice and with favorable sites on macromolecules in aqueous medium.
- Heavy water or deuterium oxide, D2O or 2 H2 ⁇
- D2O deuterium oxide
- the deuterium nucleus has the advantage of not having a nuclear spin.
- H2O medium in a magnetic field, the radio frequency signals emitted by the excited nuclei cannot be detected, because all the hydrogens in the water create an enormous background noise.
- D2O medium water does not contribute to background noise, and the proton magnetic resonance technique has become very powerful - especially for molecules which contain protons ( 1 H) and which are solubilized by D2O.
- One of the aims of the invention is to provide stabilized, physiologically compatible pharmaceutical compositions.
- One of the aims of the invention is to provide a set of stabilized pharmaceutical compositions, in which the doses of pharmaceutical agents can be reduced compared to the same non-stabilized therapeutic compositions.
- One of the other aspects of the invention is to propose a simple process for the preparation of a set of stabilized pharmaceutical, in particular therapeutic, vaccinating or diagnostic compositions.
- the stabilized pharmaceutical composition of the invention comprising one or more macromolecule (s) chosen from nucleic acids, lipids or carbohydrates and / or one or more macromolecular complex (s), is characterized in that it comprises one or more pharmaceutically acceptable vehicle (s), at least one of these vehicles containing heavy water (D2O).
- hydrogen is composed of 0.0156% deuterium. This can be purified by distillation or electrolysis of water, to obtain pure heavy water, which can then be electrolyzed to obtain pure deuterium.
- the invention relates to the use of D2O, or mixtures of D2O and H2O, as agents for stabilizing macromolecules chosen from nucleic acids, lipids or carbohydrates or macromolecular complexes in aqueous phase (solutions, suspensions or emulsions) .
- deuterium oxide or heavy water
- the H or D nuclei which exchange freely between water molecules and between the numerous sites of dissolved, suspended or emulsified biological macromolecules.
- D and H are freely exchangeable between labile hydrogen sites, for example all hydrogens in the body of water, or many hydrogens in biological macromolecules.
- Other hydrogens, sometimes hidden in the hydrophobic medium, are less accessible, but after a variable period, can also be exchanged.
- the physical properties of the solutions show a linear scaling of the physical properties (such as density or boiling point or molar values for the energy of hydrogen bonds).
- the macromolecules and macromolecular complexes referred to in the invention are such that they have a molecular weight of at least 1500 Da, and advantageously greater than 5000 Da.
- the stabilization of the macromolecules is such that for a given temperature, for example around 40 ° C., one can observe an increase in stability of the macromolecules or complexes macromolecular, preserved in a solution containing D2O, compared to these same macromolecules or macromolecular complexes preserved in a solution containing H-2O.
- this stabilization results in an increase in the number of active viral particles by a factor of approximately 10 3 to approximately 10 4 .
- the macromolecules targeted in the invention are nucleic acids, carbohydrates or lipids.
- macromolecular complexes they are advantageously chosen from protein-carbohydrate, protein-lipid, nucleic acid-carbohydrate, nucleic acid-lipid, nucleic acid-protein complexes, optionally complexed with carbohydrates and / or lipids, and from viruses .
- nucleic acids DNA, for applications in vivo (for example: gene therapy) and in vitro (for example: diagnostic applications); RNA, ribozymes for in vivo applications (modifications of nucleic acids or nucleic acid / protein complexes); DNA and RNA are part of the genomes of viruses used as vectors in therapy or vaccinology; natural or artificial DNA / RNA complexes; the nucleic acids used can be those existing in natural or artificial forms (created by genetic engineering);
- lipid macromolecules play important roles in cell membranes, but apart from relatively small molecules like prostaglandins and group A vitamins, these agents have not found many therapeutic applications; their interest lies in their macromolecular complexes and in particular in their uses in liposomes used as delivery systems for other therapeutic agents;
- macromolecular complexes the most typical are nucleic acid and protein complexes, or proteins and carbohydrates; a virus is a macromolecular complex optionally composed of nucleic acids, proteins, carbohydrates and lipids (for example, the influenza virus or the HIN virus); there may also be mentioned artificial complexes, such as a lipid layer coating a therapeutic agent, targeted by activities localized in the lipid layer, having a specificity of binding with components of the targeted target.
- compositions involved in the present invention can be defined by:
- composition corresponding to the combination for the administration of the variants according to B and C to a patient comprises the following characteristics:
- one or more macromolecule (s) and / or one or more macromolecular complex (s) are maintained separately with respect to one or more pharmaceutically acceptable vehicle (s), and on the other hand at least two elements are kept separate from each other, and each comprise one or more macromolecule (s) and / or one or more macromolecular complex (s), at least one of these elements being in the presence of a pharmaceutically acceptable vehicle containing heavy water, the macromolecule (s), the macromolecular complex (s), the pharmaceutically acceptable vehicle (s) and the above elements being intended to be collected for administration to a patient.
- the macromolecules and / or the macromolecular complexes may or may not be stored with the pharmaceutically acceptable vehicle containing heavy water.
- compositions are such that the macromolecules or the macromolecular complexes are either in suspension, or in solution, or in emulsion in the pharmaceutical vehicle.
- compositions are such that the macromolecule (s) and / or the macromolecular complex (s) and the pharmaceutically acceptable vehicle are maintained separately and are intended for be collected for administration to a patient.
- the macromolecules and / or the macromolecular complexes can be lyophilized and mixed with the pharmaceutically acceptable vehicle shortly before administration to a patient, or at the time of this administration.
- the volume of the pharmaceutical vehicle varies from approximately 0.1 ml to approximately 20 ml, in particular from approximately 0.1 ml to approximately 5 ml, and the quantity of macromolecule or macromolecular complex varies from about l ⁇ g to about
- the amount of macromolecule or macromolecular complex is approximately 10 ⁇ g for a volume of approximately 1 ml of pharmaceutical vehicle.
- the pharmaceutical vehicle is a mixture of H2O-D2O and the weight ratio between D2O and H2O varies from approximately 10% to approximately 100%, advantageously approximately 40 % to about 95%, and preferably about 80% to about 95%.
- D2O H2O mixtures containing high concentrations of D2O (90-100%), give stabilization equivalent to a reduction of ambient temperature by a factor of 4-5 ° C (i.e. in 95% of D2O at 25 ° C - for example - a macromolecule undergoes a degradation effect which is equivalent to that normally observed in H2O at 20 ° C ).
- D2O D2O
- the high concentrations of D2O offer significant protection against the consequences of microbial contamination. Few microbes tolerate D2O concentrations above 70%. Heavy water is effectively a self-sterilizing medium (note that certain microbes, generally non-pathogenic, can be adapted to life in D2O medium).
- compositions of the invention are non-toxic. Indeed, it is known that D2O at a concentration of less than 10% of body water has no significant toxic effect. (See A. Barbour, HG, (1937), Yale J. Biol. Med. 9, 551 - B: Barbour, HG, (1938), Am. J. Cancer, 32, 440- C: Barbour, HG (1938 ), J. Pharm. Exp. Therap., 62, 158 - D: Barbour, HG, (1936), J. Pharm. Exp. Rherap., 58, 460).
- the pharmaceutical vehicle can contain a stabilizing adjuvant, advantageously MgCl2, of carboxymethyl cellulose, polyethylene glycol, carbohydrate molecules, such as glycerol, glucose, sucrose, (and other C6 sugars), pentose sugars and their polymers (starches for example), these carbohydrate molecules which can be complexed with polyethylene glycol, polyethylene glycol advantageously having a molecular weight of approximately 500 to approximately 5000 daltons, and in particular approximately from 1000 to approximately 5000 daltons .
- a stabilizing adjuvant advantageously MgCl2
- carboxymethyl cellulose polyethylene glycol
- carbohydrate molecules such as glycerol, glucose, sucrose, (and other C6 sugars), pentose sugars and their polymers (starches for example)
- these carbohydrate molecules which can be complexed with polyethylene glycol, polyethylene glycol advantageously having a molecular weight of approximately 500 to approximately 5000 daltons, and in particular approximately from 1000 to approximately 5000 da
- D2O (and its mixtures) can also be used with regulators of tone, pH, viscosity and other stabilizing agents such as those indicated above.
- the weight ratio between the stabilization aid and the pharmaceutical vehicle is such that the pharmaceutical vehicle does not have a viscosity greater than about 0.2 Pascal-seconds (20 centipoise).
- the weight ratio between the stabilization adjuvant and the pharmaceutical vehicle is less than about 30%, and is advantageously from about 1% to about 30%, and more preferably about 10% at around 30%.
- compositions of the invention are those used:
- a diagnostic agent in particular for the diagnosis of measles, meningitis or HIV or,
- the invention also relates to a process for preparing a pharmaceutical composition of the invention, characterized in that it comprises the following steps:
- Dialysis is advantageously used in the case where the pharmaceutical composition contains a fragile active substance, poorly resistant to other physical treatments.
- the invention also relates to a process for the manufacture of a stabilized preparation of viral origin, containing macromolecular complexes, characterized in that said macromolecular complexes are placed in solution, suspension or emulsion in a medium containing heavy water.
- - viral glycoprotein proteins whether surface or internal and whether they are obtained from virus or by known genetic recombination, for example the surface protein of hepatitis B virus,
- viral vectors such as adenoviruses, poxviruses such as canary pox, or vaccinia virus expressing proteins of viral or bacterial origin (see for example the European patent: EP 083 286),
- RNA or DNA the nucleic acids (RNA or DNA), encapsulated or not, known for example under the name of "naked DNA” by the European patent application EP 465 529 (WO 90/11092), or the American patent USP 4 394 448, which describes the encapsulation of DNA or DNA fragments in lipid vesicles.
- the invention also relates to a method for stabilizing a vaccine preparation of viral origin, in particular of a viral suspension, characterized in that it comprises a stage of incorporation of heavy water:
- Heavy water can be added at any stage involved in the process for preparing the viral suspension, preferably after recovery of the viral particles, at the end of the stage of culturing cells infected with the virus.
- heavy water can be used for the preparation of the viral suspension, before lyophilization and / or for the rehydration of the above lyophilized vaccine.
- Heavy water is preferably used at the rehydration stage.
- the vaccines to which the invention advantageously applies are the following: influenza, chickenpox, measles, mumps, rubella, dengue, HIV, herpes.
- FIG. 1 represents the thermostability, at 37 ° C., of a pharmaceutical composition according to the invention.
- the abscissa axis corresponds to time (expressed in days) and the ordinate axis corresponds to the logarithm of the concentration of viral particles (expressed in DICC50 / ml unit, DICC50 being the cytotoxic infectious dose in the cell).
- the curve represented by diamonds corresponds to a pharmaceutical composition in aqueous solution; the curve represented by squares corresponds to a pharmaceutical composition in aqueous solution, containing MgCl2 (in an amount of 1M) as an adjuvant; the curve represented by triangles corresponds to a pharmaceutical composition of the invention, dissolved in 95% heavy water; the curve represented by crosses corresponds to a pharmaceutical composition of the invention, dissolved in D2O and containing MgCl2 (in an amount of 1M) as an adjuvant.
- FIG. 2 represents the thermostability at 42 ° C. of a pharmaceutical composition according to the invention.
- the abscissa axis corresponds to time (expressed in days) and the ordinate axis corresponds to the logarithm of the concentration of viral particles (expressed in DICC5 unit () / ml).
- the curve represented by diamonds corresponds to a pharmaceutical composition in aqueous solution; the curve represented by squares corresponds to a pharmaceutical composition in aqueous solution, containing MgCl2 (in an amount of 1M) as an adjuvant; the curve represented by triangles corresponds to a pharmaceutical composition of the invention, dissolved in 95% heavy water; the curve represented by crosses corresponds to a pharmaceutical composition of the invention, dissolved in D2O and containing MgCl2 (in an amount of 1M) as an adjuvant.
- FIG. 3 represents the thermostability at 45 ° C. of a pharmaceutical composition according to the invention.
- the abscissa axis corresponds to time (expressed in days) and the ordinate axis corresponds to the logarithm of the concentration of viral particles (expressed in DICC5o / ml unit).
- the curve represented by diamonds corresponds to a pharmaceutical composition in aqueous solution; the curve represented by squares corresponds to a pharmaceutical composition in aqueous solution, containing MgCl2 (in an amount of 1M) as an adjuvant; the curve represented by triangles corresponds to a pharmaceutical composition of the invention, dissolved in 95% heavy water; the curve represented by crosses corresponds to a pharmaceutical composition of the invention, dissolved in D2O and containing MgCl2 (in an amount of 1M) as an adjuvant.
- Suspensions of the Sabin virus type 3 of equal titers (5 ⁇ 10 6 DICC5 () / 50 ⁇ l) are prepared in the following media: a) Dulbecco-MEM in normal water (corresponding to the abbreviation "medium H") on the face);
- H-Mg medium 1M MgCl2 in H2O, Tris buffered at pH 7.2 (corresponding to the abbreviation "H-Mg medium” in the figure);
- FIG. 5 represents the thermal inactivation of the Sabin-type poliovirus
- Part A of Figure 5 corresponds to 3 days of incubation
- Part B of Figure 5 corresponds to 7 days of incubation.
- FIG. 6 represents the thermal inactivation of the Sabin-type poliovirus
- Part A of Figure 6 corresponds to 3 days of incubation
- Part B of Figure 6 corresponds to 7 days of incubation.
- FIG. 7 represents the stabilization of the Sabin type 3 poliovirus, with various concentrations of heavy water and of MgC12. The same experimental conditions as those described in FIG. 4 are combined, except for the concentration of D2O (part A of FIG. 7) or MgCl2 (part B of FIG. 7).
- results are expressed as the difference between the initial titer of the viral suspension stored at -30 ° C (log of DICC5Q / 50 ⁇ l) and the titer of each of the samples after 3 days of incubation at 45 ° C.
- FIG. 8 represents the presence or absence of sedimentation of PNN (nucleosome nucleus), according to the ionic strength of the water, and according to the presence or not of heavy water.
- the PNN was sedimented at pH 7.75 (in the middle of D2O, pH 8.15 according to the glass electrode) 0.2 mM EDTA, at an ionic strength according to Table 1 below. All sedimentation is carried out in the CENTRISCAN MSE, an analytical ultracentrifuge, in the rotor comprising 6 measuring cells at 50,000 rpm. Parts A to C correspond to a measurement interval of 6 minutes, parts D to G correspond to a measurement interval of 8 minutes, wavelength: 254nm; sample concentration: 0.5 to 1.0 mg / ml.
- the abscissa axis corresponds to the measurement radius and the ordinate axis to the DNA concentration. This figure demonstrates that heavy water consolidates PNN particles as much as ionic strength.
- the immunogenicity of the attenuated viruses in the Sabin polio vaccine depends on their degree of infection at the time of administration.
- the levels of taking the oral polio vaccine (OPV) are linked to the dose of each of the three viral strains 1, 2 and 3, making up the vaccine.
- OSV oral polio vaccine
- One explanation for the fairly low catch levels in some Third World countries may be the breaks in the cold chain before the administration of the vaccine.
- Sabin vaccine strain 3 is very critical because of its relatively poor immunogenicity and thermostability.
- the World Health Organization currently requests that OPV be stabilized by the addition of MgCl2 (concentration 1 M) in the vaccine. Far from being the ideal solution (loss of less than 0.5 log of activity after seven days at 45 ° C), this method is currently the best compromise. It is demonstrated here that according to the invention, 95% heavy water offers, even without any other adjuvant, stabilization equivalent or superior to that offered by MgCl2, by following the entirely standard methods (apart, of course, the using heavy water).
- the type 3 strain is responsible for most of the problems associated with the Sabin vaccine. For this reason, this virus has been the target of preliminary studies.
- the Sabin 3 strain is chosen as a model.
- the virus culture is carried out according to conventional methods.
- the addition of heavy water is carried out by resuspending the virus pellet (sedimented in an ultracentrifuge according to standard conditions) in D2O (19 volumes) and a PBS buffer (phosphate buffered saline) 20 times concentrated (1 volume). Ultracentrifugation is without significant discomfort for viruses.
- the comparative studies are made with standard media (H2O, H2 ⁇ / MgCl2 and MgCl2 + D2O).
- the concentration of the virus is adjusted to approximately 10 0 units / ml in 95% D2 ⁇ .
- Viruses are subjected to different thermal conditions according to the curves shown below.
- the nucleus of the nucleosome is made up of four pairs of protein molecules, the histones H2a H2b, H3 and H4. Each protein octamer is surrounded by 144 base pairs of DNA, completing 1.75 superhelical turns (Noll M. (1974) Nature 251, 249-251; Kornberg RD (1974) Science 184, 868-871; Finch J. et al. (1977) Nature 269, 29-35).
- Gordon studied the effect of ionic strength (in H2O medium) on the sedimentation properties of PNN (Gordon V.C. et al. (1978) Proc. Nat. Acad. Sci (USA). 75, 660-663).
- the example below illustrates the important differences between the stabilization properties of plain and heavy water towards PNN.
- PNN can be considered as a kind of model system of the family of nucleic acid / protein complexes.
- the sedimentation of PNNs is dependent on the ionic composition of the water. Very obvious is the disintegration of PNNs in low H2O medium ion power (Fig 4A). In heavy water, this degradation of PNNs does not appear (Fig 4D). Even the ionic dependence of the sedimentation value (in Svedburg units - s) becomes very limited (See Table 2 and Fig 4). The disaggregated PNN (4A), after dialysis against heavy water, becomes again a discrete particle with a characteristic sedimentation for a PNN.
- G- C redialysed 0 11.1 * 63.22 values corrected according to viscosity and density of D2O.
- Example 4 Stabilization of the poliovirus vaccine in different solutions containing heavy water.
- D2O takes place during the preparation of the mixture of three monovalent vaccines (Sabin type 1, type 2, type 3) prepared in aqueous solution.
- the final D2O concentration is 80%.
- Varicella virus is a fragile virus.
- the usual stabilizing solution of the Varicella vaccine was prepared in aqueous solution and in solution containing heavy water (D2O), at a concentration of 80%.
- a virus harvest was diluted in the same proportions with each of the stabilizers and lyophilized.
- the lyophilized products were rehydrated in their respective solvent.
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Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU62851/94A AU6285194A (en) | 1993-03-17 | 1994-03-17 | Stabilised pharmaceutical compositions and methods for preparing same |
EP94910435A EP0689457A1 (fr) | 1993-03-17 | 1994-03-17 | Compositions pharmaceutiques stabilisees et leurs procedes de preparation |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR93/03060 | 1993-03-17 | ||
FR9303060A FR2702660B1 (fr) | 1993-03-17 | 1993-03-17 | Compositions thérapeutiques stabilisées et leur procédé de préparation. |
Publications (1)
Publication Number | Publication Date |
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WO1994021298A1 true WO1994021298A1 (fr) | 1994-09-29 |
Family
ID=9445053
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR1994/000296 WO1994021298A1 (fr) | 1993-03-17 | 1994-03-17 | Compositions pharmaceutiques stabilisees et leurs procedes de preparation |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0689457A1 (fr) |
CN (1) | CN1119414A (fr) |
AU (1) | AU6285194A (fr) |
CA (1) | CA2158140A1 (fr) |
FR (1) | FR2702660B1 (fr) |
WO (1) | WO1994021298A1 (fr) |
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2293100A (en) * | 1994-09-15 | 1996-03-20 | Medeva Europ Ltd | Pharmaceutical compositions with deuterium oxide |
WO2003018614A1 (fr) * | 2001-08-24 | 2003-03-06 | Wako Pure Chemical Industries, Ltd. | Procede de stabilisation de l'alteration d'une substance dans un milieu aqueux |
EP1708651A1 (fr) * | 2004-01-27 | 2006-10-11 | Osteotech, Inc., | Greffe osseuse stabilisee |
WO2011154119A1 (fr) | 2010-06-07 | 2011-12-15 | Sanofi Pasteur Sa | Fabrication d'un vaccin sec stabilisé à administration par voie orage à partir d'un virus vivant atténué |
US8911759B2 (en) | 2005-11-01 | 2014-12-16 | Warsaw Orthopedic, Inc. | Bone matrix compositions and methods |
US9011537B2 (en) | 2009-02-12 | 2015-04-21 | Warsaw Orthopedic, Inc. | Delivery system cartridge |
US9034358B2 (en) | 2003-12-31 | 2015-05-19 | Warsaw Orthopedic, Inc. | Bone matrix compositions and methods |
US9333082B2 (en) | 2007-07-10 | 2016-05-10 | Warsaw Orthopedic, Inc. | Delivery system attachment |
US9415136B2 (en) | 2003-12-31 | 2016-08-16 | Warsaw Orthopedic, Inc. | Osteoinductive demineralized cancellous bone |
US9421199B2 (en) | 2014-06-24 | 2016-08-23 | Sydnexis, Inc. | Ophthalmic composition |
US9554920B2 (en) | 2007-06-15 | 2017-01-31 | Warsaw Orthopedic, Inc. | Bone matrix compositions having nanoscale textured surfaces |
US9717822B2 (en) | 2007-06-15 | 2017-08-01 | Warsaw Orthopedic, Inc. | Bone matrix compositions and methods |
US10813923B1 (en) | 2015-04-23 | 2020-10-27 | Sydnexis, Inc. | Ophthalmic composition |
US11052095B2 (en) | 2015-05-29 | 2021-07-06 | Sydnexis, Inc. | D2O stabilized pharmaceutical formulations |
US11382909B2 (en) | 2014-09-05 | 2022-07-12 | Sydnexis, Inc. | Ophthalmic composition |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN117752780A (zh) * | 2017-12-07 | 2024-03-26 | 默沙东有限责任公司 | 登革病毒疫苗组合物的制剂 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0332826A1 (fr) * | 1988-02-03 | 1989-09-20 | Teva Pharmaceutical Industries Limited | Compositions pharmaceutiques injectables à stabilité améliorée et procédés pour les préparer |
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1993
- 1993-03-17 FR FR9303060A patent/FR2702660B1/fr not_active Expired - Fee Related
-
1994
- 1994-03-17 CA CA002158140A patent/CA2158140A1/fr not_active Abandoned
- 1994-03-17 EP EP94910435A patent/EP0689457A1/fr not_active Withdrawn
- 1994-03-17 WO PCT/FR1994/000296 patent/WO1994021298A1/fr not_active Application Discontinuation
- 1994-03-17 CN CN94191508A patent/CN1119414A/zh active Pending
- 1994-03-17 AU AU62851/94A patent/AU6285194A/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0332826A1 (fr) * | 1988-02-03 | 1989-09-20 | Teva Pharmaceutical Industries Limited | Compositions pharmaceutiques injectables à stabilité améliorée et procédés pour les préparer |
Non-Patent Citations (18)
Title |
---|
C.HEYDE ET AL.: "HEAVY WATER (D2O) PROTECTIVE EFFECT ON PROTEINS IN PHARMACEUTICALS.FOR EXAMPLE:HUMAN CHOLINESTERASE", Z.NATURFORSCH., vol. 46, no. 9-10, 1991, pages 789 - 793 * |
C.S.PITTENDRIGH ET AL.: "VERY RAPID ENHANCEMENT BY DEUTERIUM OXIDE OF THE TEMPERATURE-TOLERANCE OF ADULT DROSOPHILA", PROC.NAT.ACAD.SCI. USA, vol. 71, no. 2, 1974 * |
CHEMICAL ABSTRACTS, vol. 105, no. 17, 27 October 1986, Columbus, Ohio, US; abstract no. 148271w * |
CHEMICAL ABSTRACTS, vol. 116, no. 4, 27 January 1992, Columbus, Ohio, US; abstract no. 28099b * |
CHEMICAL ABSTRACTS, vol. 70, no. 21, 26 May 1969, Columbus, Ohio, US; abstract no. 94238d * |
CHEMICAL ABSTRACTS, vol. 71, no. 23, 8 December 1969, Columbus, Ohio, US; abstract no. 110159g * |
CHEMICAL ABSTRACTS, vol. 72, no. 15, 13 April 1970, Columbus, Ohio, US; abstract no. 76039b * |
CHEMICAL ABSTRACTS, vol. 80, no. 23, 10 June 1974, Columbus, Ohio, US; abstract no. 130872y * |
CHEMICAL ABSTRACTS, vol. 83, no. 1, 7 July 1975, Columbus, Ohio, US; abstract no. 2787z * |
CHEMICAL ABSTRACTS, vol. 95, no. 19, 9 November 1981, Columbus, Ohio, US; abstract no. 164216n * |
CHEMICAL ABSTRACTS, vol. 95, no. 5, 3 August 1981, Columbus, Ohio, US; abstract no. 37552u * |
K.JUNG: "EFFECT OF HEAVY WATER ON THE THERMAL RESISTANCE OF MICROORGANISMS", NUCL.SCI.ABSTR., vol. 23, no. 12, 1969, pages 22242 * |
P.R.M.STEELE ET AL.: "FACTORS AFFECTING THE VIABILITY OF FREEZE THAWED T4 BACTERIOPHAGE.II.INFLUENCE OF CERTAIN ELECTROLYTES ON THE DEGREE OF INACTIVATION.", J. HYG., vol. 67, no. 4, 1969, pages 679 - 690 * |
U.LEMM ET AL.: "STABILIZATION OF BIOCHEMICALLY ACTIVE PROTEINS BY HEAVY WATER", STUD.BIOPHYS., vol. 84, no. 1, 1981, pages 69 - 70 * |
U.LEMM ET AL.: "STABILIZATION OF ENZYMES AND ANTISERUMS BY HEAVY WATER", EUR.J.BIOCHEM., vol. 116, no. 3, 1981, pages 441 - 445 * |
V.YA.ALEKSANDROV ET AL.: "EFFECT OF HEAVY WATER (WATER-D2) ON THE RESISTANCE OF PROCOLLAGEN TO THERMAL DENATURATION AND TO THE ACTION OF COLLAGENASE", DOKL.AKAD.NAUK.SSSR, vol. 220, no. 6, 1975, pages 1445 - 1448 * |
V.YA.ALEKSANDROV: "STABILIZING EFFECT OF HEAVY WATER (D2O) ON THE CELL", TSITOLOGIYA, vol. 28, no. 8, 1986, pages 790 - 795 * |
Y.B.POPOV ET AL.: "EFFECT OF DEUTERIUM OXIDE ON THE HEAT RESISTANCE OF STAPHYLOPHAGE.", BIOFIZIKA, vol. 14, no. 1, 1969, pages 186 - 187 * |
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Also Published As
Publication number | Publication date |
---|---|
FR2702660A1 (fr) | 1994-09-23 |
CA2158140A1 (fr) | 1994-09-29 |
AU6285194A (en) | 1994-10-11 |
CN1119414A (zh) | 1996-03-27 |
EP0689457A1 (fr) | 1996-01-03 |
FR2702660B1 (fr) | 1995-05-24 |
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