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WO2002032402A1 - Composition et procede pour liquides injectables stables - Google Patents

Composition et procede pour liquides injectables stables Download PDF

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Publication number
WO2002032402A1
WO2002032402A1 PCT/US2000/028244 US0028244W WO0232402A1 WO 2002032402 A1 WO2002032402 A1 WO 2002032402A1 US 0028244 W US0028244 W US 0028244W WO 0232402 A1 WO0232402 A1 WO 0232402A1
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WO
WIPO (PCT)
Prior art keywords
composition according
component
glass
microparticles
particles
Prior art date
Application number
PCT/US2000/028244
Other languages
English (en)
Inventor
Bruce Joseph Roser
Arcadio Garcia De Castro
James Maki
Original Assignee
Cambridge Biostability Ltd.
Idea, Inc.
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
Priority to ES04013422T priority Critical patent/ES2337252T3/es
Priority to AU2001211986A priority patent/AU2001211986B2/en
Priority to MXPA03003236A priority patent/MXPA03003236A/es
Priority to EP00973483A priority patent/EP1328255A1/fr
Priority to CNB008199655A priority patent/CN100339066C/zh
Priority to PT04013422T priority patent/PT1452171E/pt
Priority to JP2002535640A priority patent/JP2004513093A/ja
Priority to CA2424656A priority patent/CA2424656C/fr
Priority to PCT/US2000/028244 priority patent/WO2002032402A1/fr
Priority to PL00360052A priority patent/PL360052A1/xx
Application filed by Cambridge Biostability Ltd., Idea, Inc. filed Critical Cambridge Biostability Ltd.
Priority to CA2689856A priority patent/CA2689856C/fr
Priority to KR10-2003-7004941A priority patent/KR20030096224A/ko
Priority to AU1198601A priority patent/AU1198601A/xx
Priority to NZ525026A priority patent/NZ525026A/en
Publication of WO2002032402A1 publication Critical patent/WO2002032402A1/fr
Priority to NO20031706A priority patent/NO20031706D0/no

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Classifications

    • 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
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules

Definitions

  • Vaccines or drugs in solution ready for injection are inherently unstable and need refrigeration.
  • the pharmaceutical industry has traditionally tackled the instability problem by freeze-drying drugs. This is expensive, inconvenient and inherently dangerous, since incorrect reconstitution of dried drugs can result in wrong doses or contaminated solutions.
  • Many attempts have been made over the past 100 years to develop robust, stable, ready-to-inject liquid formulations with pitiful lack of success. Only inherently tough small molecule drugs can survive in aqueous solution with a useful shelf life.
  • Vaccination campaigns require medically trained staff to ensure that the dose is correctly injected and shows no signs of degradation.
  • the need to reconstitute some vaccines, such as measles, yellow fever and BCG, in the field is also a serious concern. This must be done precisely to ensure correct dosage and it also introduces a potential source of contamination, which has frequently led to clinical disasters.
  • the hypersonic Shockwave of helium gas that is used to drive these powder injectors has a limited power and cannot deliver its dose of fine particles intramuscularly. This is because the low-mass particles cannot achieve adequate momentum for deep penetration.
  • the intradermal delivery of DNA vaccines coated on to colloidal gold particles is adequate for good immunogenicity
  • the common vaccines, adjuvanted with insoluble aluminum or calcium salts induce unacceptable skin irritation. They must be given intramuscularly. What is required is a flexible system capable of a range of delivery depths, from intradermal to deep intramuscular, similar to that achievable by existing needle and syringe technology.
  • the sugar solution containing an active molecule As the sugar solution containing an active molecule is dried, it can either crystallize when the solubility limit of the sugar is reached, or can become a supersaturated syrup.
  • the ability of the sugar to resist crystallization is a crucial property of a good stabilizer. Trehalose is good at this (Green JL. & Angel CA. Phase relations and vitrification in saccharide water solutions and the trehalose anomaly J. Phys. Chem. 93 2880-2882 (1989)) but not unique. Further drying progressively solidifies the syrup, which turns into a glass at a low residual water content. Imperceptibly, the active molecules change from liquid solution in the water to solid solution in the dry sugar glass. Chemical diffusion is negligible in a glass and therefore chemical reactions virtually cease.
  • Biomolecules immobilized in sugar glass are also stable in non-aqueous industrial solvents in which they themselves and the sugar are both insoluble (Cleland JL. and Jones AJS. "Excipient stabilization of polypeptides treated with organic solvents" US Patent No.5,589,167. (1994)). Since the sugar glass acts as an impermeable barrier in a non-solvent liquid, the biomolecules in solid solution in the glass are protected both from the chemical reactivity of the solvent and from the environment. Providing the liquid itself is stable, sensitive products in suspended glass particles constitute a stable two phase liquid formulation. Industrial solvents of the kind described by Cleland and Jones (1994) have a limited utility in processing. Substituting a bio-compatible non-aqueous liquid would enable stable liquid formulations of even the most unstable drugs, vaccines and diagnostics to be formulated.
  • HLB Hydrophilic / Lipophilic Balance
  • Reducing particles to sub-micron size may also, in theory, be achieved after the particles are suspended in the oil, with high-pressure micro-homogenizing equipment such as the Micro fluidizer (Constant Systems Inc.). This involves an extra step to the process and we have found it not to be very efficient in breaking down spray-dried sugar glass microspheres, which have very high mechanical strength because of their spherical shape. This mandates multiple passes through the equipment. Even then, this tends to leave a number of the larger particles untouched and therefore would require a subsequent filtration or sedimentation step to remove them. Also, the high viscosity of the suspensions in the usual oily vehicles makes them difficult both to draw up into the syringe and requires that they be injected slowly. It precludes fast flows through fine nozzles such as are experienced in a liquid jet injector system.
  • PFCs Perfluorocarbons
  • They are novel, extremely stable liquids produced by the complete fluorination of certain organic compounds. They cannot be classified as either hydrophilic or lipophilic, as they are in fact essentially immiscible with both oil and water or any other solvent whether polar or non-polar, except other PFCs. (Reviewed in Krafft MP & Riess JG. "Highly fluorinated amphiphiles and colloidal systems, and their applications in the biomedical field. A contribution.” Biochimie 80489-514 1998). Furthermore, they do not participate in hydrophobic interactions with oils nor hydrophilic interactions with water or hydrophilic materials.
  • Perfluorooctyl bromide in the form of a PFC-in-water emulsion and under the trade name OxygentTM (Alliance Pharmaceutical Corp.) is presently being evaluated in humans as an alternative to blood transfusion for certain surgical procedures. PFCs have also been used by inhalation, as liquids, into the lungs as a treatment for respiratory distress syndrome in premature babies.
  • Perfluorophenanthrene under the trade name VitreonTM (Vitrophage Inc.), is used to prevent collapse of the capsule of the eye during surgery and to permit repositioning of detached retinas.
  • PFCs have also been used as contrast media for Magnetic Resonance Imaging (MRI) and for this purpose it has been reported that hydrophilic powders may be suspended in them in order to either improve their imaging properties or make them more palatable.. (Kirkland W.D. "Composition and method for delivering active agents" US patent 5,770, 181. 1998). This patent also suggests the use of PFCs as the continuous phase for delivering particulate water- soluble drugs.
  • the invention herein uses a two-phase system, with PFCs as the continuous phase containing a discontinuous glass phases in suspension, as drug delivery preparations.
  • Perfluorocarbon based preparations present major advantages in that different PFCs may be blended to obtain final mixtures with densities ranging from approximately 1.5 to 2.5 g / cm 3 . This allows for the particles to be formulated with densities matching the suspension fluid in order that they do not float or sink to the bottom of the container but remain in the form of a stable suspension. Particles therefore need not be of submicron size as required in oil based preparations to prevent sedimentation, but may vary greatly in size. The ultimate particle diameter is governed only by the purpose of the preparation.
  • Preparations intended for needle injection or jet injection could contain particles in the range of 0.1 to 100 micrometers, or preferably 1 to 10 micrometers. This allows for a great simplification in the manner of manufacture of the particles and avoids the necessity for extremely small particle size production by milling.
  • Particles can be made by conventional spray drying or by freeze-drying followed by simple dry or wet milling. When a high solids content in the suspension is needed it is desirable that the particles be spherical in shape. Irregularly shaped particles have a much greater tendency to "bind" together inhibiting free-flow, while spherical particles have an inherent “lubricity” enabling solids contents of well over 20% to be achieved. Such particles are easily made by spray-drying, spray-freeze-drying or emulsion solidification.
  • the suspended powders if formulated appropriately, need no surfactants, producing stable suspensions from which the sugar glass particles dissolve almost instantly when shaken with water. If minor aggregation is perceived as a problem, small amounts of a FHC surfactant such as described inKrafft and Riess (1998) may be advantageously added to the PFC fluid either before or after the admixture of the stable powder. Like the PFCs, these FHCs are inherently extremely inert and non- reactive. There is thus no solvation of the particles and no chemical reaction between the suspended particles and the PFC phase. Because both the sugar glass particles and the PFC liquid are environmentally stable there is no degradation due to light, high temperatures, oxygen etc.
  • PFCs are excellent electrical insulators and therefore it is easy to achieve monodisperse suspensions of particles carrying the same small surface electrostatic charge. They are dry and completely non- hygroscopic liquids. Their very low water content maintains the dryness of the suspended powders, preventing the dissolution or degradation of the incorporated actives. Their unique lack of solvent properties make them ideal for suspending either hydrophilic or hydrophobic particles and means that the final suspensions are compatible with virtually any materials used in containers or delivery devices.
  • a density-regulating agent in the particles.
  • a density-regulating agent in the particles.
  • This maybe either a soluble salt such as sodium or potassium chloride or sulphate or more preferably, an insoluble material such as barium sulphate, calcium phosphate titanium dioxide or aluminum hydroxide.
  • a soluble salt such as sodium or potassium chloride or sulphate or more preferably, an insoluble material such as barium sulphate, calcium phosphate titanium dioxide or aluminum hydroxide.
  • the insoluble, non-toxic materials are preferred since the release of large amounts of ionic salts in the body can cause considerable local pain and irritation.
  • the insoluble materials may, in some cases, such as in vaccine preparations, be part of the active preparation as an adjuvant.
  • the density regulator may be in solid solution in the sugar glass particles or an insoluble particulate material in suspension in the sugar glass. When correctly formulated, the sugar glass particles are approximately density matched with the PFC liquid, are buoyancy neutral, and neither float nor settle but remain in stable suspension without caking.
  • PFC liquids are good electrical insulators, with a typical resistivity of greater than 10 13 ohm.cm, tiny surface charges on the suspended particles can have significant effects on suspension stability.
  • they are preferably manufactured containing an excipient such as lysine or aspartic acid capable of donating a weak residual electrostatic charge to the dry particles. This prevents aggregation by ensuring charge repulsion of the particles, similar to that seen in stable colloids.
  • small amounts of FHC surfactants such as perfluorodecanoic acid may be advantageously dissolved in the PFCs to give dispersed, preferably monodisperse, suspensions.
  • These particles may be manufactured in a number of ways, including air, spray or freeze-drying and need not to be particularly small but may be a heterogeneous mix of sizes ranging between O.l ⁇ and lOO ⁇ in diameter. For some applications even millimeter-sized particles may be suitable.
  • the use of these stable suspensions is restricted to neither parenteral use as exemplified above nor oral use as exemplified in Kirkland (1995).
  • the PFC liquid vehicle is so non-toxic and non-reactive, it is an ideal vehicle for mucosal, including intrapulmonary, intranasal, intraocular, intra rectal and intravaginal delivery.
  • the ability, provided by this patent, to produce stable, sterile and non- irritant formulations for mucosal delivery of even very unstable drugs or vaccines is a considerable advance.
  • the very dry and completely non-hygroscopic nature of the PFC liquid greatly assists in the maintenance of sterility of these preparations during prolonged storage and intermittent use as micro-organisms cannot grow in the absence of water
  • the stable PFC formulations described herein are ideal for generating fine mists of liquid STASIS droplets for intrapulmonary delivery.
  • the size of the particles which constitute the discontinuous suspended phase in the PFC droplets is important and should not exceed 1 to 5 ⁇ m, preferably 0.1 to 1 ⁇ m in diameter.
  • the particle size is less important and can be up to 100 ⁇ m or even several mm in diameter.
  • Alkaline phosphatase (Sigma Aldrich Ltd.) was stabilized in a glass based on mannitol 33.3%, calcium lactate 33.3% and degraded gelatin 33.3%> (Byco C, Croda Colloids Ltd.), spray dried as microspheres and stored at 55°C either as dry powder or as a stable suspension in Perfiuorodecalin. The activity remained around the 100% mark (103% at 20d and 94%> at 30d). There was more loss in the dry powder which was not suspended in PFC (around 80% of activity remained) Figure 2
  • a commercial tetanus toxoid vaccine (#T022 kindly supplied by Evans Medeva pic) was formulated as a density-matched powder using added calcium phosphate in 20%> trehalose solution. It was freeze-dried by spraying into liquid nitrogen using a two fluid nozzle followed by freeze drying the frozen microsphere powder in a Labconco freeze dryer with the initial shelf temperature at — 0°C throughout primary drying. The antibody response of six group of 10 Guinea Pigs was measured 4, 8 and 12 weeks after being injected with the same dose of ASSIST stabilized Tetanus Toxoid vaccine reconstituted in saline buffer or as anhydrous preparations in oil or PFC.
  • the response to STASIS vaccine density-matched with calcium phosphate (group 3) is essentially the same as the control vaccine reconstituted in aqueous buffer (group 1) and the powder in oil vaccine (group 2) while control animals injected with the non-aqueous vehicles only (groups 4 & 5) showed no response.
  • Particles were produced by spray drying from aqueous solution using a Labplant model SD 1 spray dryer using sugars and other excipients.
  • Typical formulations were:
  • the particles were produced using a two-fluid nozzle with a liquid orifice of 0.5 mm internal diameter. A half-maximum nozzle airflow was found optimal and the drying chamber operated at an inlet temperature of 135°C and an outlet temperature of 70-75°C.
  • the particles were collected in a glass cyclone and subjected to secondary drying in a vacuum oven using a temperature ramp to 80°C over 4 hours. On cooling they were suspended in PFC using ultrasound. Either a 30 second burst of ultrasonic energy from a titanium probe in an MSE MK 2 ultrasonic cabinet operating at about 75%o power or immersion in a Decon FS200 Frequency sweep Ultrasonic bath for up to 10 minutes was found to be sufficient.
  • the resulting suspension was monodisperse and consisted of spherical glass particles ranging in size from about 0.5 to 30 ⁇ with a mean of about 10 ⁇ as judged microscopically.
  • the mannitol / calcium lactate particles rose to the top of the PFC layer over several minutes but could readily be resuspended with gentle shaking.
  • the trehalose / calcium phosphate particles were almost density matched with the PFC and formed a stable suspension.
  • Spray dried powders of sugar glass particles were suspended in perfluorohexane, perfluorodecalin and perfluorophenanthrene at 1, 10, 20 and 40%> w/v. They were found to give monodisperse suspensions with little tendency to aggregate. The addition of 0.1% perfluorodecanoic acid to the PFC inhibited any slight tendency to aggregate on surfaces. These suspensions were found to pass easily through a 25 g needle by aspiration or ejection.
  • the enzyme formulated in these microspheres consisting of a Mannitol-based glass suspended in perfluorodecalin show retention of close to 100% of enzyme activity for more than 30 days at 55°C (Fig 1).
  • Spray-freeze-dried particles Particles were also made by spraying liquid droplets into liquid nitrogen and then vacuum-drying the frozen powder. These particles were less dense than the spray dried powders and formed pastes in PFCs at concentrations higher than 20% w/v. At lower concentrations they formed monodisperse suspension after sonication. Typical formulations used were substance final concentration w/w
  • sucrose octaacetate and trehalose octaacetate readily form glasses when either quenched from the melt or dried rapidly from solution of chloroform or dichloromethane.
  • Their use has been described as controlled release matrices for drug delivery (Roser et al "Solid delivery systems for controlled release of molecules incorporated therein and methods of making same"
  • a trehalose octaacetate powder was made by melting in a muffle furnace and quenching the melt on a stainless steel plate.
  • the resultant glass disks were ground in a pestle and mortar and then in a high-speed homogenizer to produce a fine powder.
  • Formulations were: a) Trehalose 10% w/v Sodium sulphate 10% w/v Alkaline phosphatase 20 U/ml In 5 mM Tris / HC1 buffer pH 7.6 b) Trehalose 10% w/v Sodium sulphate 10%> w/v Paranitrophenyl phosphate 0.44%) w/v
  • Sugar glass particles i.e. trehalose obtained by either of the conventional drying methods show typical densities around 1.5 g/cm 3 .
  • the Perfluorocarbons we tested typically have densities ranging from 1.68 to 2.03 g/cm 3 (Table I). For this reason when formulated into a suspension, sugar glass particles tend to float on the
  • Powders may however be modified in order to produce a stable suspension in PFC in which they have neutral buoyancy and neither settle nor float. This may be achieved through the addition of high-density materials prior to particle formation. These may be water soluble or insoluble.
  • Tricalcium orthophosphate has a density of 3.14 g/cm 3 , is approved as an adjuvant for vaccines and is practically insoluble in water. Powders made to contain around 50%> calcium phosphate show an increased density around 2 g/cm 3 and at 20% solids form stable suspensions in perfluorophenanthrene.
  • powders which at 20% solids in PFCs form stable suspensions include:
  • Soluble salts such as sodium sulphate with a density of 2.7 g/cm 3 may also be used as a density-increasing agent.
  • Certain vaccines are formulated adsorbed on to insoluble gels or particles which act as adjuvants.
  • Aluminum hydroxide and calcium phosphate are extensively used for this purpose. These insoluble adj uvants may themselves be used to increase the density of the particles to be suspended. In this case the high-density material is not completely inert but in fact adsorbs the active macromolecule from solution. It is necessary to demonstrate that this adsorption does not denature the active.
  • alkaline phosphatase was used as a model active/vaccine. The following solution was made Adjuvant grade calcium phosphate 10% w/v (Superphos Kemi a/s)
  • the solution was then well mixed for 10 minutes at 37°C to allow the alkaline phosphatase to be adsorbed by the calcium phosphate. This change in absorption per minute was measured by centrifuging the calcium phosphate, sampling the supernatant and measuring its enzyme kinetics using p-nitrophenyl phosphate as substrate and a wavelength of 405nm.
  • the solution was spray-dried to produce a fine powder. Any desorption of the enzyme after rehydration of the powder was measured in the supernatant as above.
  • the powder was suspended at 20% w/v in perfluorophenanthrene and found to produce a stable suspension.
  • the density of the particles may be matched to that of the PFC vehicle by the inclusion of the adjuvant calcium phosphate. No significant desorption or loss of enzyme activity takes place during the formulation process.
  • EXAMPLE 11 EXAMPLE 11 :
  • a STASIS preparation of the mannitol base glass as in example 1 was suspended in perfluorodecalin and loaded into a surgically clean, pump-action, polypropylene atomizer which is normally used clinically to deliver oxymetazoline nasal decongestant (Sudafed, Warner Lambert). Two sprays of the suspension were delivered into each nostril of a human volunteer who were asked to comment on the degree of discomfort experienced. The volunteer reported no discomfort at all. There was no observable side effects of the administration.

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Abstract

L'invention concerne une composition destinée à administrer un composé stable et bioactif à un sujet et comportant un premier et un second composant, le premier composant contenant des microparticules d'un verre de glucide ou un verre de phosphate contenant l'agent bioactif. Le verre de glucide ou de phosphate peut comporter un composé facilitant la formation du verre, et le second composant comporte au moins un perfluorocarbone liquide biocompatible, dans lequel le premier composant est insoluble et dispersé. Le perfluocarbone peut comporter un tensio-actif.
PCT/US2000/028244 2000-10-13 2000-10-13 Composition et procede pour liquides injectables stables WO2002032402A1 (fr)

Priority Applications (15)

Application Number Priority Date Filing Date Title
PCT/US2000/028244 WO2002032402A1 (fr) 2000-10-13 2000-10-13 Composition et procede pour liquides injectables stables
MXPA03003236A MXPA03003236A (es) 2000-10-13 2000-10-13 Composicion y metodo para liquidos inyectables estables.
EP00973483A EP1328255A1 (fr) 2000-10-13 2000-10-13 Composition et procede pour liquides injectables stables
CNB008199655A CN100339066C (zh) 2000-10-13 2000-10-13 稳定的注射液组合物和方法
PT04013422T PT1452171E (pt) 2000-10-13 2000-10-13 Suspensões líquidas farmacêuticas
JP2002535640A JP2004513093A (ja) 2000-10-13 2000-10-13 安定注射液用の組成物および方法
CA2424656A CA2424656C (fr) 2000-10-13 2000-10-13 Composition et procede pour liquides injectables stables
ES04013422T ES2337252T3 (es) 2000-10-13 2000-10-13 Suspensiones liquidas farmaceuticas.
AU2001211986A AU2001211986B2 (en) 2000-10-13 2000-10-13 Composition and method for stable injectable liquids
PL00360052A PL360052A1 (en) 2000-10-13 2000-10-13 Composition and method for stable injectable liquids
CA2689856A CA2689856C (fr) 2000-10-13 2000-10-13 Composition et procede pour liquides injectables stables
KR10-2003-7004941A KR20030096224A (ko) 2000-10-13 2000-10-13 안정한 주사가능 액체를 위한 조성물 및 방법
AU1198601A AU1198601A (en) 2000-10-13 2000-10-13 Composition and method for stable injectable liquids
NZ525026A NZ525026A (en) 2000-10-13 2000-10-13 A two-component composition comprising particles of sugar glass and a biocompatible liquid perfluorocarbon
NO20031706A NO20031706D0 (no) 2000-10-13 2003-04-11 Preparat og fremgangsmåter for stabile injiserbare v¶sker

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2000/028244 WO2002032402A1 (fr) 2000-10-13 2000-10-13 Composition et procede pour liquides injectables stables

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WO2002032402A1 true WO2002032402A1 (fr) 2002-04-25

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Country Status (12)

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EP (1) EP1328255A1 (fr)
JP (1) JP2004513093A (fr)
KR (1) KR20030096224A (fr)
CN (1) CN100339066C (fr)
AU (2) AU1198601A (fr)
CA (2) CA2424656C (fr)
ES (1) ES2337252T3 (fr)
MX (1) MXPA03003236A (fr)
NO (1) NO20031706D0 (fr)
PL (1) PL360052A1 (fr)
PT (1) PT1452171E (fr)
WO (1) WO2002032402A1 (fr)

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WO2004037293A1 (fr) * 2002-10-22 2004-05-06 Dainippon Pharmaceutical Co., Ltd. Composition stabilisee
WO2005025542A1 (fr) * 2003-09-16 2005-03-24 Ltt Bio-Pharma Co., Ltd. Grain fin contenant un medicament liposoluble encapsule, procede de production de celui-ci et preparation contenant celui-ci
GB2413075A (en) * 2004-04-13 2005-10-19 Cambridge Biostability Ltd Liquids containing suspended water soluble glass particles
WO2005099669A1 (fr) 2004-04-13 2005-10-27 Cambridge Biostability Limited Liquides contenant des particules de verre en suspension
WO2007039769A1 (fr) * 2005-10-04 2007-04-12 Cambridge Biostability Limited Compositions pharmaceutiques stabilisees dans des particules a base de verre
GB2437147A (en) * 2005-11-21 2007-10-17 Cambridge Biostability Ltd Pharmaceutical device for the administration of substances to patients
WO2010146536A1 (fr) 2009-06-18 2010-12-23 Koninklijke Philips Electronics N.V. Suspension de particules comprenant un médicament
WO2011007327A2 (fr) 2009-07-16 2011-01-20 Koninklijke Philips Electronics N.V. Suspension pour usage thérapeutique et dispositif d'administration de ladite suspension
WO2011042542A1 (fr) 2009-10-08 2011-04-14 Azurebio, S. L. Formulation de médicaments et de vaccins sous forme d'aiguilles injectables percutanées
AU2009205073B2 (en) * 2008-01-18 2012-04-12 Asahi Kasei Pharma Corporation Stable pharmaceutical composition
US8309134B2 (en) 2008-10-03 2012-11-13 Southwest Research Institute Modified calcium phosphate nanoparticle formation
US8404850B2 (en) 2008-03-13 2013-03-26 Southwest Research Institute Bis-quaternary pyridinium-aldoxime salts and treatment of exposure to cholinesterase inhibitors
US8722706B2 (en) 2008-08-15 2014-05-13 Southwest Research Institute Two phase bioactive formulations of bis-quaternary pyridinium oxime sulfonate salts
US8946200B2 (en) 2006-11-02 2015-02-03 Southwest Research Institute Pharmaceutically active nanosuspensions
US9028873B2 (en) 2010-02-08 2015-05-12 Southwest Research Institute Nanoparticles for drug delivery to the central nervous system
US9884498B2 (en) 2014-03-24 2018-02-06 Seiko Epson Corporation Tape printing device and tape printing system

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KR20160137543A (ko) * 2014-03-27 2016-11-30 노파르티스 아게 활성 약제 성분의 흡입을 위한 분무-건조되는 수-중-유-중-고체 분산액

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WO1998041188A2 (fr) * 1997-03-18 1998-09-24 Quadrant Holdings Cambridge Limited Particule stable dans des formulations liquides
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WO2005025542A1 (fr) * 2003-09-16 2005-03-24 Ltt Bio-Pharma Co., Ltd. Grain fin contenant un medicament liposoluble encapsule, procede de production de celui-ci et preparation contenant celui-ci
GB2413075B (en) * 2004-04-13 2009-01-21 Cambridge Biostability Ltd Liquids containing suspended glass particles
WO2005099669A1 (fr) 2004-04-13 2005-10-27 Cambridge Biostability Limited Liquides contenant des particules de verre en suspension
RU2363447C2 (ru) * 2004-04-13 2009-08-10 Кембридж Биостабилити Лимитед Жидкости, содержащие суспендированные стекловидные частицы
GB2413075A (en) * 2004-04-13 2005-10-19 Cambridge Biostability Ltd Liquids containing suspended water soluble glass particles
WO2007039769A1 (fr) * 2005-10-04 2007-04-12 Cambridge Biostability Limited Compositions pharmaceutiques stabilisees dans des particules a base de verre
AU2006298559B2 (en) * 2005-10-04 2012-01-12 Nova Bio-Pharma Technologies Limited Pharmaceutical compositions stabilized in glassy particles
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WO2010146536A1 (fr) 2009-06-18 2010-12-23 Koninklijke Philips Electronics N.V. Suspension de particules comprenant un médicament
WO2011007327A3 (fr) * 2009-07-16 2011-12-29 Koninklijke Philips Electronics N.V. Suspension pour usage thérapeutique et dispositif d'administration de ladite suspension
WO2011007327A2 (fr) 2009-07-16 2011-01-20 Koninklijke Philips Electronics N.V. Suspension pour usage thérapeutique et dispositif d'administration de ladite suspension
WO2011042542A1 (fr) 2009-10-08 2011-04-14 Azurebio, S. L. Formulation de médicaments et de vaccins sous forme d'aiguilles injectables percutanées
US9028873B2 (en) 2010-02-08 2015-05-12 Southwest Research Institute Nanoparticles for drug delivery to the central nervous system
US9884498B2 (en) 2014-03-24 2018-02-06 Seiko Epson Corporation Tape printing device and tape printing system

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CA2689856A1 (fr) 2002-04-25
PL360052A1 (en) 2004-09-06
CA2424656A1 (fr) 2002-04-25
EP1328255A1 (fr) 2003-07-23
CN1527699A (zh) 2004-09-08
NO20031706L (no) 2003-04-11
AU2001211986B2 (en) 2007-04-26
CA2424656C (fr) 2010-03-23
CA2689856C (fr) 2013-09-24
NO20031706D0 (no) 2003-04-11
AU1198601A (en) 2002-04-29
CN100339066C (zh) 2007-09-26
JP2004513093A (ja) 2004-04-30
MXPA03003236A (es) 2004-12-03
KR20030096224A (ko) 2003-12-24
ES2337252T3 (es) 2010-04-22
PT1452171E (pt) 2010-03-08

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