WO2008040841A1 - Système déshydratant pour réguler l'humidité dans des poudres d'inhalation - Google Patents

Système déshydratant pour réguler l'humidité dans des poudres d'inhalation Download PDF

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Publication number
WO2008040841A1
WO2008040841A1 PCT/FI2007/050486 FI2007050486W WO2008040841A1 WO 2008040841 A1 WO2008040841 A1 WO 2008040841A1 FI 2007050486 W FI2007050486 W FI 2007050486W WO 2008040841 A1 WO2008040841 A1 WO 2008040841A1
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WIPO (PCT)
Prior art keywords
desiccant
humidity
salt
air
inhalation
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PCT/FI2007/050486
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English (en)
Inventor
Vesa-Pekka Lehto
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Lab Pharma Ltd.
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Publication date
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Publication of WO2008040841A1 publication Critical patent/WO2008040841A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
    • B01J20/04—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising compounds of alkali metals, alkaline earth metals or magnesium
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
    • B01J20/04—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising compounds of alkali metals, alkaline earth metals or magnesium
    • B01J20/043—Carbonates or bicarbonates, e.g. limestone, dolomite, aragonite
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
    • B01J20/04—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising compounds of alkali metals, alkaline earth metals or magnesium
    • B01J20/045—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising compounds of alkali metals, alkaline earth metals or magnesium containing sulfur, e.g. sulfates, thiosulfates, gypsum
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
    • B01J20/04—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising compounds of alkali metals, alkaline earth metals or magnesium
    • B01J20/046—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising compounds of alkali metals, alkaline earth metals or magnesium containing halogens, e.g. halides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
    • B01J20/2805—Sorbents inside a permeable or porous casing, e.g. inside a container, bag or membrane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/06—Solids
    • A61M2202/062—Desiccants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/06—Solids
    • A61M2202/064—Powder

Definitions

  • the invention concerns a desiccant system for controlling the humidity of a powder formulation intended to be inhaled from a powder inhaler.
  • the desic- cant preferably consists of magnesium chloride, which may be anhydrous or a hexahydrate. Both forms of salts show substantially greater water absorption capacity than silica gel. Moreover, they are able to maintain a very stable relative humidity around the inhalation powder. Other salts having a fixed relative humidity point lower than 50% RH as saturated water solutions can also be used.
  • the invention also concerns a powder inhalation apparatus wherein the desiccant system described above is utilized.
  • the invention further provides a method for efficiently regulating the humidity inside the medicament chamber of a powder inhalation apparatus.
  • the invention additionally concerns the use of the new form of desiccant for controlling the humidity of inhalable powder formulations.
  • Powder inhalers are used for producing inhalable drug particles to be inhaled into the lungs.
  • the clinical effect depends on the amount of inhalable particles, which is normally much smaller than the total drug dose delivered.
  • the diameter of these particles is some micrometers.
  • Powder inhalers can be di- vided roughly into two categories: reservoir-based multi-dose inhalers (MDPIs) and devices using pre-metered doses (capsules, blisters).
  • MDPIs reservoir-based multi-dose inhalers
  • capsules, blisters pre-metered doses
  • each dose must be metered from the drug reservoir by a mechanism and the dose must be transferred out of the reservoir for inhalation. Therefore, because of the moving/sliding parts, it is difficult to construct an airtight reservoir.
  • the device should be usable for months, or even up to one year or longer, even small clearances in critical parts are hazard- ous in respect of moisture penetration if no desiccant is used inside or outside the drug reservoir.
  • the plastic to plastic sliding parts do not hinder the penetration of water vapor and the powder formulation can ad(ab)sorb moisture freely.
  • MDPIs not only MDPIs, but also capsules and blisters for inhalation powders often need protection against moisture.
  • a well-known way of protecting any inhaler or powder formulation from moisture is to place it in an impermeable bag or container together with a conventional desiccant pack
  • This pack is normally a plastic container filled with silica gel and provided with a permeable membrane to facilitate the penetration of moisture into the desiccant.
  • the powder formulation may consist of plain micronized drug particles, or the particles may be mixed with other particulate excipients, usually coarser lactose monohydrate.
  • the micronization of the drug substance is carried out by air jet milling. I n this method, the larger drug particles are violently crushed through collisions and the particle size distribution is wide, typically from 0.5 to 10 micrometers.
  • Other micronization methods are spray drying, ball milling, supercritical precipitation and microcrystallization which may produce unstable material as well.
  • the amount and mean particle size in the dose delivered from powder inhalers must be within a certain range during storage and shelf-life of the product.
  • the physical and chemical stability of the product must be tested by the manufacturer. I n accelerated stability studies, the product is stored at an elevated temperature and humidity where the chemical and physical changes are also accelerated.
  • the most common reason for the poor stability of powder formulations is the decrease in the amount of inhalable particles and an increase in the variation of unit dose content (dose accuracy). This means that the clinical effect decreases and the variation between individual doses increases. This deterioration of the formulation is caused by physical changes that lead to the agglomeration of the drug particles with each other and the carrier sugar. Drug particles are less prone to separate during inhalation and the flow properties are poorer, thus making dose metering inaccurate.
  • the desiccant should maintain the humidity around the powder constant at different humidity levels and temperatures for several months, preferably several years. No such construction has as yet been described.
  • One solution is to improve moisture control around the powder formulation.
  • Slica gel is a reversible drying agent, which is in equilibrium with ambient relative humidity. When totally dry, it can adsorb 17 w-% at 35% RH and 30 w-% at 80% RH at 25 0 C. If silica gel is brought from 80% RH back to 35% RH, it will release 13 w-% of its dry weight as moisture in order to reach an equilibrium under the new conditions.
  • the adsorption kinetics of silica gel depends on temperature and the capacity decreases when the temperature increases.
  • Silica gel is the only desiccant used in the powder inhalers on the market. It is considered very safe and its use has been approved by the medical authorities. It is, however, not the ideal desiccant for the purpose. Its capacity is relatively low and it is not able to maintain the internal humidity stable (Lehto and Lankinen, Int. J. Pharm. 275, 155 (2004)).
  • the aim of the present invention is to develop a system that can maintain the maximum relative humidity around the powder formulation below 50% RH for a prolonged period.
  • the solubility is 54.3 g / 100 cm 3 .
  • 1 gram may absorb 1.84 g of water as a saturated solution, maintaining the ambient relative humidity below 33%.
  • the solubility is 302 g / 100 cm 3 , and 1 gram may absorb 0.33 g of water.
  • the solubility is 258 g / 100 cm 3 and thus 1 gram of the salt may absorb 0.39 g of water; with this salt the ambient humidity generated is below 23 %.
  • Dried silica gel is capable of absorbing ca. 11 w-% at 23% RH and ca. 20 w- % at 33% RH.
  • 1 g of silica gel may absorb 0.11 g water to reach 23% RH and 0.20 g to reach 33 % RH. Consequently, the capacity of anhydrous magnesium chloride is 9.2-fold compared with silica gel, 1.7-fold for hexahydrate and 3.5-fold for potassium acetate.
  • salts which are able to maintain a fixed relative humidity as saturated water solutions are used as desiccants.
  • Salts which are non-toxic and have a fixed point humidity lower than 50% RH are preferred.
  • examples of such salts include magnesium chloride, calcium chloride and potassium acetate.
  • Some of the salts may also contain crystalline water, such as magnesium chloride and calcium chloride.
  • the desiccant must be able to have vapor contact with the powder formulation without any risk of contamination. However, vapor contact with ambient air should be avoided as effectively as possible. This can be achieved by placing the desiccant in a closed plastic container, the plastic material being permeable to water vapor. Vapor contact with ambient air can be minimized by:
  • US 6 244 432 discloses a gun case humidity control device for use in maintaining a desired humidity in the gun case, a water vapor permeable pouch and a thickened saturated solution having a suitable humidity control point. Materials and the water permeabilities of the pouch have been specified. The water solution/suspension contains water, 20-70% of the selected salt and a thickener.
  • US 5 936 178 discloses the same principle of humidity regulation: a thickened saturated salt solution in a water vapor permeable pouch is used in storage containers. Examples include moisture regulation for stringed instruments, cigars, gummy bears/ licorice, dried fruit, electronic devices, fine jewelry, fire arms, painting, sculptures, tapestries as well as the objects themselves and whatever else is best stored under conditions of constant humidity.
  • US 6 921 026 B2 discloses an identical solution for maintaining a desired humidity in food packages, but in addition to containing an oxygen scavenger.
  • US 2002/0014305 A1 discloses a desiccant composition mix which comprises salt and modified starch. A large number of salts having different fixed points of humidity are named. The desiccant is placed in a special water- permeable film container. Modified starch forms a gel with water and a deliquescent salt, thus diminishing the risk of leaks through permeable film container.
  • the desiccant is placed in a tightly sealed plastic container, which is placed inside a drug reservoir. Moisture permeability through the desiccant container is higher than that of the drug reservoir. I n this system, the desiccant (silica gel) only desiccates the inside of the reservoir. However, because each dose must be metered and taken outside the reservoir for inhalation, the dose metering system must be carefully constructed. The drawback is that the invention was designed for silica gel, which is not ideal for the purpose due to its sorption behavior and the limited adsorption capacity of silica gel as these issues were discussed above.
  • the desiccant system according to the invention is characterized in the subsequently presented independent claim 1 , and preferred embodiments in the dependent claims 2 - 8.
  • the invention also concerns an inhalation apparatus utilizing the desiccant system.
  • the apparatus is defined in the subsequently presented independent claim 9, and its preferred embodiments in the dependent claims 10 - 15.
  • the invention further provides a method for regulating the humidity in an inhalation apparatus, and the characteristics of this method are presented in the subsequent independent claim 15.
  • the invention also concerns the use of the desiccant for controlling the humidity of inhalation powders, the desiccant being dry when placed in the container but capable of maintaining a fixed point of humidity as a saturated solution of at least one salt.
  • the saturated salt solution having a relatively low fixed relative humidity would be an ideal desiccant for powder inhalers be- cause it might be able to maintain a stable relative humidity around the powder formulation and would have a higher absorption capacity than silica gel or other conventional solid desiccant materials.
  • the system would have to be absolutely safe with respect to patient safety and no contamination between the powder formulation and the salt solution should be possible.
  • the solution should have water vapor contact with the formulation for desiccant purposes.
  • All prior art desiccant packs based on saturated salt solutions are based on permeable membranes, microporous laminates or water repellent fabrics such as Gore- Tex and Tyvek. These kinds of materials are not considered suitable for the present purpose due to the safety issue.
  • the aim was to study qualitatively the absorption kinetics of magnesium chloride hexahydrate as a saturated salt solution.
  • the solution with some undissolved crystals (2.5 g) was placed in a silicone rubber pouch and the pouch was sealed with silicone.
  • the pouch was placed in a 60 ml polycarbonate bottle provided with a humidity sensor.
  • the water permeabilities of the pouch and the bottle were measured as 1300 and 104 ng/(min-%RH), respectively.
  • the closed bottle was placed in a closed desiccator containing saturated sodium chloride solution at the bottom inducing 75.3% RH as fixed humidity.
  • the relative humidity and mass increase (absorbed water) were measured for 200 days.
  • the relative humidity inside the bottle is 35 - 36% RH for140 days and after that starts to increase due to the dissolution of the crystals (ca. 2.5 g salt / 0.85 g H 2 O).
  • the absorption capacity is thus 34 w-%.
  • the non-saturated solution still acts as a desiccant and the mass increase is quite linear during the monitoring. When extrapolated linearly, it can be approximated that it would take at least 300 days to reach 50% RH and 500 - 600 days to reach the ambient humidity (75.3%).
  • the important features of the Taifun drug reservoir are that the desiccant container is made of injection moulded polycarbonate and located inside the reservoir, the reservoir is made of polypropylene, and there are compliant seals around the round dose pin which slides through the seals and transfers the dose into a dose slot for inhalation.
  • the desiccant container is relatively permeable to moisture but the reservoir is not. When the moisture ingress is very slow, a saturated salt solution in a polycarbonate con- tainer may be able to regulate the internal humidity within a narrow RH- range for a long time.
  • Magnesium chloride hexahydrate (J.T. Baker), potassium acetate (J.T. Baker) and anhydrous magnesium chloride (J.T. Baker) were the model salts. Ca. 300 mg of the salts were enclosed in the Taifun polycarbonate desiccant containers, the polycarbonate lid being glued with Araldite Standard. The total volume of the container was 1 ml and the wall thickness 0.5 mm. Dry and moist magnesium chloride hexahydrate and potassium acetate were used to find out the possible differences. Dry anhydrous magnesium chloride was also used to find out its performance.
  • the desiccant containers were placed in the Taifun polypropene drug reservoirs provided with calibrated humidity sensors (SHT 15, Sensirion AG, Switzerland; the specified accuracy being ⁇ 2 % RH).
  • the sensor pins were fixed on the reservoir walls through small holes, glued with TiO 2 doped Araldite Standard.
  • the reservoirs were closed with a polypropylene lid as in a normal assembly.
  • the two holes for the dose pin were closed with metal knobs to ensure minimal moisture penetration.
  • the drug reservoirs were then placed in a desiccator containing saturated potassium chloride solution for generating the storage conditions of 84.2% RH at room temperature.
  • the increase of mass (absorbed water) in the drug reservoirs and the sensor indicating the relative humidity inside the drug reservoirs were monitored for several months.
  • FIG. 3a Adding 60 mg of extra water certainly produces a saturated salt solution inside the desiccant container. I nside the drug reservoir, the humidity changes from an initial value of 27% to 35% within one day, to 37% within 51 days and to 37% RH within 1 12 days.
  • the corresponding values for mass increase (water absorption) were 0.7, 6.3 and 12.7 mg, respectively.
  • the increase in mass is 0.109 mg/day and is presumed to be stable until all of the salt is dissolved.
  • the constant humidity inside the desiccant container must be ca. 33% RH while the ambient humidity around the drug reservoir is very close to 84.2% RH. However, the humidity inside the drug reservoir is very stable during the observation time and seems to settle at ca. 37% RH. This is only ca. 4% RH higher than the generated humidity of saturated magnesium chloride hexahydrate solution.
  • the capacity of the used desiccant can be calculated. I n this case, the exact amount of the salt was 308 mg with 60 mg of extra water. The salt is able to absorb 102 mg of water, of which 60 mg was used and 42 mg of the capacity remained. With an increase in mass of 0.109 mg/day, the solution remains saturated for more than one year and regulates the humidity inside the drug reservoir to ca. 37% RH. It is noteworthy, that the capacity can be increased by decreasing the amount of the extra water, and thus the time for regulating the humidity may be prolonged.
  • the saturated solution was able to release water through the walls of the desiccant container into the drug reservoir and further to the ambient air through the reservoir walls.
  • the most important information is that in utmost humidity, the change in the internal humidity is minimal and in this case only ca. 7% RH.
  • magnesium chloride hexahydrate contains 53 w-% of crystalline water
  • the amount of anhydrous salt (303 mg) used is capable of absorbing 344 mg of crystalline water. This means that it takes more than 9 years to turn the anhydrate form into the hexahydrate form. After that, the salt will act as a saturated solution and the permeating water will dissolve the crystals of MgQ 2 . The behavior of that phase is depicted in Figure 4a.
  • the invention gives new opportunities for controlling the humidity of powder formulations for inhalation.
  • the superior water absorption capacity makes it possible to control the humidity surrounding the powder formulation for a very long period of time. I n most cases, it is beneficial that the variation in internal humidity is very slight and almost independent of ambient humidity. Hence, even hygroscopic drug formulations can be stored and used in a powder inhaler provided with this invention, which minimizes physical changes and agglomeration in the drug formulation caused by humidity.
  • a modern approach for protecting polypeptides from chemical and physical changes is to hide the molecules in a protective "glassy" matrix.
  • These well-known matrices may consist of sugars or polyalcohols such as mannitol and trehalose, for instance.
  • the additives When spray-dried with the polypeptide drug, the additives may form amorphous (glassy) particles of suitable size for inhalation. Changes in the active configuration or even chemical degradation are prevented when the drug molecules are in the rigid matrix.
  • the glassy matrix is amorphous, it is thermodynamically unstable and tends to recrystallize. If this occurs, the system is disturbed and the physical/chemical stability of the formulation is questionable.
  • This recrystallization depends on the glass transition temperature (T 9 ), at which the mobility of the molecules increases so that recrystallization can take place. This phenomenon is dependent on ambient humidity, so that increased humidity decreases the Tg according to a certain (Gordon-Taylor) equation. Therefore, increasing relative humidity increases the rate of physical changes in this kind of formulations.
  • T 9 temperature for trehalose is 79 0 C in dry conditions, but much lower at higher levels of humidity. Trehalose- based glassy formulations must, therefore, be protected from high humidity.
  • Mannitol has a low Tg temperature and it is easily crystallized during processing and hence, it may produce particles which are more resistant to moisture.
  • ambient humidity was 84.2% and the desiccant container and the drug reservoir were injection-moulded parts of a commercial powder inhaler.
  • the equilibrium humidity was quite close to the fixed point humidity of the desiccants (magnesium chloride and potassium acetate) and the permeation differences were within a proper range.
  • the equilibrium humidity around the inhalation powder should not exceed 50% RH at which most powder formulations remain stable. It is estimated, that when magnesium chloride or potassium acetate are used as desiccants, permeation into the desiccant container should be at least five times greater than permeation into the space outside (powder space) surrounding the desiccant container. Finally, the sensitivity of the powder formulation to moisture is decisive for the selection of proper desiccants, constructions and construction materials.
  • the desiccant container for the purpose of this inven- tion can be made of solid plastic and no membranes or porous materials are necessary. This finding eliminates the risk of contamination between the inhalation powder and the desiccant material.
  • a liquid desiccant can be used to control the humidity of an inhalation powder and yet have a more precise control of humidity and higher capacity compared with the conventional desiccant silica gel.
  • the preferred deliquescent salts are safe and have been approved for oral and/or intravenous use for humans.
  • the salts are low-priced and they can be handled and filled in normal atmosphere without becoming excessively moist. Some absorption of moisture is beneficial to initiate the desiccant performance as saturated solution.
  • an anhydrous salt may be used, but then the initial humidity may be very low, like with anhydrous magnesium chlo- ride, acting as a chemical absorbent in the beginning.
  • the desiccant container may be placed in or outside the drug chamber, or outside the capsule or blister, if the prerequisites for construction and materials are met.

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Abstract

La présente invention concerne un système déshydratant pour réguler l'humidité d'une poudre d'inhalation, ledit système comprenant un récipient hermétique contenant un déshydratant sec, et une chambre de médicament contenant la poudre d'inhalation, le récipient hermétique étant disposé à l'intérieur de la chambre de médicament ou dans son environnement proche, ledit déshydratant étant capable de maintenir une valeur fixe d'humidité sous la forme d'une solution saturée d'au moins un sel.
PCT/FI2007/050486 2006-10-04 2007-09-12 Système déshydratant pour réguler l'humidité dans des poudres d'inhalation WO2008040841A1 (fr)

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FI20065636 2006-10-04
FI20065636A FI20065636A0 (fi) 2006-10-04 2006-10-04 Dessikanttijärjestelmä irtohaloitavien jauheiden kosteuden säätämiseksi

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012028663A1 (fr) 2010-08-31 2012-03-08 Glaxo Group Limited Produits médicamenteux pour inhalation sous forme de poudre sèche présentant propriétés de régulation d'humidité et leurs procédés d'administration
WO2012028662A1 (fr) 2010-08-31 2012-03-08 Glaxo Group Limited Produits médicamenteux pour inhalation sous forme de poudre sèche présentant propriétés de régulation d'humidité et leurs procédés d'administration
WO2016033242A1 (fr) * 2014-08-26 2016-03-03 Innovosciences Llc Modulation thermique d'un médicament inhalable
US10737042B2 (en) 2014-08-26 2020-08-11 Michael Edward Breede Thermal modulation of an inhalable medicament
US11090294B2 (en) 2009-12-01 2021-08-17 Glaxo Group Limited Combinations of a muscarinic receptor antagonist and a beta-2 adrenoreceptor agonist
US11116721B2 (en) 2009-02-26 2021-09-14 Glaxo Group Limited Pharmaceutical formulations comprising 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl) phenol
WO2023117967A1 (fr) 2021-12-21 2023-06-29 Chiesi Farmaceutici S.P.A. Formulations en poudre sèche remplies dans un inhalateur présentant une résistance à l'humidité améliorée
WO2023117985A1 (fr) 2021-12-21 2023-06-29 Chiesi Farmaceutici S.P.A. Formulations de poudre sèche remplies dans un inhalateur présentant une résistance à l'humidité améliorée

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US4423080A (en) * 1975-03-10 1983-12-27 Bedrosian And Associates Controlled atmosphere produce package
WO1994014492A2 (fr) * 1992-12-18 1994-07-07 Schering Corporation Inhalateur pour medicaments en poudre
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US11116721B2 (en) 2009-02-26 2021-09-14 Glaxo Group Limited Pharmaceutical formulations comprising 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl) phenol
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EP3461474B1 (fr) 2010-08-31 2020-11-11 GlaxoSmithKline Intellectual Property Development Limited Produits médicamenteux pour inhalation sous forme de poudre sèche présentant propriétés de régulation d'humidité et leurs procédés d'administration
EP2611422B1 (fr) 2010-08-31 2018-10-31 GlaxoSmithKline Intellectual Property Development Limited Produits médicamenteux pour inhalation sous forme de poudre sèche présentant propriétés de régulation d'humidité et leurs procédés d'administration
JP2013536799A (ja) * 2010-08-31 2013-09-26 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッド 水分制御特性を示す乾燥粉末吸入薬物製品及びその投与方法
EP2611423B1 (fr) 2010-08-31 2015-06-24 GlaxoSmithKline Intellectual Property Development Limited Produits médicamenteux pour inhalation sous forme de poudre sèche présentant propriétés de régulation d'humidité et leurs procédés d'administration
JP2015129169A (ja) * 2010-08-31 2015-07-16 グラクソ グループ リミテッドＧｌａｘｏ Ｇｒｏｕｐ Ｌｉｍｉｔｅｄ 水分制御特性を示す乾燥粉末吸入薬物製品及びその投与方法
EP2954888A1 (fr) 2010-08-31 2015-12-16 GlaxoSmithKline Intellectual Property Development Limited Produits médicamenteux pour inhalation sous forme de poudre sèche présentant propriétés de régulation d'humidité et leurs procédés d'administration
WO2012028662A1 (fr) 2010-08-31 2012-03-08 Glaxo Group Limited Produits médicamenteux pour inhalation sous forme de poudre sèche présentant propriétés de régulation d'humidité et leurs procédés d'administration
JP2013536800A (ja) * 2010-08-31 2013-09-26 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッド 水分制御特性を示す乾燥粉末吸入薬物製品及びその投与方法
US20130156828A1 (en) * 2010-08-31 2013-06-20 Osama Ahmed Aswania Dry Powder Inhalation Drug Products Exhibiting Moisture Control Properties and Methods of Administering the Same
WO2012028663A1 (fr) 2010-08-31 2012-03-08 Glaxo Group Limited Produits médicamenteux pour inhalation sous forme de poudre sèche présentant propriétés de régulation d'humidité et leurs procédés d'administration
US10737042B2 (en) 2014-08-26 2020-08-11 Michael Edward Breede Thermal modulation of an inhalable medicament
US10300228B2 (en) 2014-08-26 2019-05-28 Innovosciences, Llc Thermal modulation of an inhalable medicament
WO2016033242A1 (fr) * 2014-08-26 2016-03-03 Innovosciences Llc Modulation thermique d'un médicament inhalable
WO2023117967A1 (fr) 2021-12-21 2023-06-29 Chiesi Farmaceutici S.P.A. Formulations en poudre sèche remplies dans un inhalateur présentant une résistance à l'humidité améliorée
WO2023117985A1 (fr) 2021-12-21 2023-06-29 Chiesi Farmaceutici S.P.A. Formulations de poudre sèche remplies dans un inhalateur présentant une résistance à l'humidité améliorée

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