US20070081948A1 - Dry powder composition comprising a benzodiazepine for pulmonary inhalation - Google Patents

Dry powder composition comprising a benzodiazepine for pulmonary inhalation Download PDF

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US20070081948A1
US20070081948A1 US10/571,884 US57188404A US2007081948A1 US 20070081948 A1 US20070081948 A1 US 20070081948A1 US 57188404 A US57188404 A US 57188404A US 2007081948 A1 US2007081948 A1 US 2007081948A1
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composition
particles
benzodiazepine
vortex chamber
powder
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David Morton
David Ganderton
John Staniforth
Mike Tobyn
Stephen Eason
Quentin Harmer
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Vectura Ltd
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Vectura Ltd
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Priority claimed from GB0321612A external-priority patent/GB0321612D0/en
Priority claimed from GB0321608A external-priority patent/GB0321608D0/en
Priority claimed from GB0409133A external-priority patent/GB0409133D0/en
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    • 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
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • 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
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • 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
    • 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
    • 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
    • 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
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B02—CRUSHING, PULVERISING, OR DISINTEGRATING; PREPARATORY TREATMENT OF GRAIN FOR MILLING
    • B02C—CRUSHING, PULVERISING, OR DISINTEGRATING IN GENERAL; MILLING GRAIN
    • B02C19/00—Other disintegrating devices or methods
    • B02C19/06—Jet mills

Definitions

  • the present invention relates to dry powder pharmaceutical compositions comprising a benzodiazepine for administration by inhalation, and in particular, benzodiazepine dry powder compositions and inhaler devices for dispensing the same.
  • Benzodiazepines are sedative-hypnotic agents that were first introduced in 1960. They are commonly used for a variety of situations that include seizure control, anxiety, alcohol withdrawal, insomnia, control of drug-associated agitation, as muscle relaxants, and as preanesthetic agents. They also are combined frequently with other medications for conscious sedation before procedures or interventions. Because of their widespread popularity, these drugs can be abused. In addition, they are also known to be used in overdose, either alone or in association with other substances.
  • benzodiazepines include clobazam, clonazepam, diazepam, lorazepam and midazolam. Any benzodiazepines may be employed in the present invention, including these well-known benzodiazepines, as well as less common ones.
  • Clobazam is a 1,5 benzodiazepine having the chemical name 7-chloro-1,5-dihydro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4(3H)-dione.
  • Clonazepam is a 1,4 benzodiazepine having the chemical name 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-1,4-benzodiazepin-2-one.
  • Diazepam has the chemical name 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one.
  • Lorazepam has the chemical name 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one and midazolam has the chemical name 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a] [1,4]benzodiazepine.
  • the benzodiazepine is preferably either clobazam or clonazepam.
  • Clobazam is particularly preferred because, based upon the available literature, it is believed that this benzodiazepine exhibits fewer side effects tham other benzodiazepines. See, for example, Trimble et al, Benzodiazepines, page 5 (2000). Moreover, it is believed that the side effects will be further reduced when clobazam is delivered to the lungs via inhalation.
  • benzodiazepines are generally formulated for administration by intravenous injection or for rectal administration, especially when intended for treating epilepsy. Both of these modes of administration are clearly inconvenient in certain circumstances and unpleasant for the patient.
  • Some oral benzodiazepine formulations are available, usually in the form of tablets. However, the oral formulations suffer from the draw back that they require significantly greater doses of the benzodiazepine in order to achieve the same effect as the intravenous injections or rectally administered formulations.
  • Rivotril clonazepam
  • the recommended dose of benzodiazepine when taking the tablets is 4-8 mg per day, compared to the 1 mg intravenous injection.
  • oral dosing suffers from the disadvantage that there is a relatively long delay between administration and the onset of the therapeutic effect. First pass metabolism of the benzodiazepine is also an issue.
  • the patent discloses the coadministration of a medicament, such as a benzodiazepine, with a pharmaceutically acceptable co-solvent system comprising an aliphatic alcohol, a glycol, and water, and their combinations with a biological surfactant such as a bile salt or a lecithin.
  • a pharmaceutically acceptable co-solvent system comprising an aliphatic alcohol, a glycol, and water, and their combinations with a biological surfactant such as a bile salt or a lecithin.
  • the aqueous co-solvent system is said to control and promote the rate and extent of transmucosal permeation and absorption of the active agent.
  • nasal administration is not very pleasant for the patient, especially when regular administration is required over a period of time. Caking within the nasal cavity can occur, causing discomfort.
  • This route of administration also suffers from the problem than only a limited volume of the benzodiazepine formulation can be administered. Above this, the formulation will actually be swallowed and has little or no therapeutic effect.
  • compositions comprising benzodiazepine by inhalation have also been contemplated.
  • U.S. Pat. No. 5,457,100 discloses treatments for panic disorders and seizure disorders, wherein compositions comprising a benzodiazepine are inhaled. The treatment is primarily envisaged as an emergency treatment and the dose of benzodiazepine is delivered to the patient without too much accuracy.
  • the compositions comprise a propellant and are dispensed using conventional devices, such as aerosolised metered dose pumps, manual metered dose pumps and metered dose spray-producing squeeze bottles.
  • WO 02/094244 discloses inhalation of a benzodiazepine in the form of an aerosol formed by heating a composition containing the benzodiazepine to form a vapour and subsequently allowing the vapour to condense into an aerosol.
  • a condensation aerosol requires an inhalation device which has at least three elements, namely an element for heating the composition to form a vapour, an element allowing the vapour to cool, and an element allowing the aerosol thereby formed to be inhaled. It is alleged that this composition and mode of administration rapidly produces a peak plasma concentration of the benzodiazepine.
  • inhalable benzodiazepine dry powder compositions according to the invention will achieve a therapeutic effect within 15 minutes of administration. This is a significantly faster time to therapeutic effect than that achieved when benzodiazepine compositions are administered orally or rectally.
  • benzodiazepines are known to have a relatively high first pass metabolism and the resulting metabolites are less effective therapeutically than the benzodiazepines themselves.
  • By administering benzodiazepines via the pulmonary route much more of the unmetabolised drug is delivered systemically. This should allow the benzodiazepine to be administered in smaller doses than is typically required via the oral or rectal routes.
  • benzodiazepines in Trimble et al, “Benzodiazepines” at page 69, doses of 10 mg every 6-8 hours are mentioned.
  • compositions for adjunctive therapy comprising a primary drug in combination with an adjunctive drug, the adjunctive drug including a benzodiazepine, preferably clobazam, administered by inhalation.
  • the primary drug may be carbamazepine, clonazepam, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, piracetam, primidone, tigabine, topiramate, valproate, vagabatrin, acetazolmide, adrenocorticotropic hormone, mephytoin, mesuximide, nitrazepam and pharmaceutically acceptable salts thereof.
  • Another advantage of pulmonary administration of benzodiazepines for the treatment of seizure disorders is that it does not require the dose to travel through the digestive system of the patient. This is significant because, during a seizure, the digestive process of the patient may be disrupted. Therefore, even if a patient successfully swallows the oral medication just prior to a seizure, the seizure itself may actually prevent the medication from being digested and therefore from having its desired therapeutic effect. In contrast, as long as a patient is able to successfully inhale an inhalable benzodiazepine formulation, the drug should be absorbed systemically.
  • Pulmonary inhalation is also more socially acceptable to patients than rectal or intramuscular administration.
  • Intramuscular administration involves injection, which is uncomfortable for many patients and for children in particular. Rectal administration is also inconvenient and uncomfortable.
  • seizure patients are children who may require administration of their medication whilst at school. School personnel may be reluctant to give rectal doses or to provide injections.
  • Even nasal administration has its disadvantages, often leading to caking within the nasal cavity and discomfort to the patient.
  • a pharmaceutical composition comprising benzodiazepine is provided, for administration by inhalation.
  • the composition is a dry powder composition.
  • the composition is suitable for pulmonary inhalation.
  • the pharmaceutical compositions comprising benzodiazepine are for use in therapy.
  • the compositions are for treating epilepsy.
  • the compositions are useful for treating seizures in general, including partial and acute repetitive seizures.
  • the compositions may also be used to treat the condition called Status Epilepticus.
  • status epilepticus may be used to describe any continuing type of seizure.
  • the compositions may also be used to treat Acute Panic Disorder.
  • the compositions according to the present invention may also be used as a sedative or as premedication (pre-operative medication).
  • the composition is not for use in treating seizure disorders or panic disorders.
  • compositions of the present invention may be dispensed using either pressurised metered dose inhalers (pMDIs) or dry powder inhalers (DPIs).
  • pMDIs pressurised metered dose inhalers
  • DPIs dry powder inhalers
  • Pressurised metered dose inhalers typically have two components. Firstly, there is a canister component in which the drug particles (in this case a benzodiazepine) are stored under pressure in a suspension or solution form. Secondly, there is a receptacle component used to hold and actuate the canister. Typically, a canister will contain multiple doses of the formulation, although it is possible to have single dose canisters as well.
  • the canister component typically includes a valved outlet from which the contents of the canister can be discharged.
  • Aerosol medication is dispensed from the pMDI by applying a force on the canister component to push it into the receptacle component thereby opening the valved outlet and causing the medication particles to be conveyed from the valved outlet through the receptacle component and discharged from an outlet of the receptacle.
  • the medication particles are “atomised”, forming an aerosol. It is intended that the patient coordinate the discharge of aerosolised medication with his or her inhalation, so that the medication particles are entrained in the patient's inspiratory flow and conveyed to the lungs.
  • pMDIs use propellants to pressurise the contents of the canister and to propel the medication particles out of the outlet of the receptacle component.
  • the formulation is provided in liquid form, and resides within the container along with the propellant.
  • the propellant can take a variety of forms.
  • the propellant can comprise a compressed gas or liquefied gas.
  • dry powder inhaler In a dry powder inhaler, the dose to be administered is stored in the form of a non-pressurised dry powder and, on actuation of the inhaler, the particles of the powder are inhaled by the patient.
  • Dry powder inhalers can be “passive” devices in which the patient's breath is the only source of gas which provided a motive force in the device.
  • active devices a source of compressed gas is used.
  • the dry powder compositions according to the present invention may be dispensed using an active or a passive DPI. Examples of passive inhaler devices include Rotahalet and Diskhaler (GlaxoSmithKline) and the Turbohaler (Astra-Draco).
  • active inhalers examples include the inhaler marketed under the name InhanceTM by Nektar Therapeutics and used in their ExuberaTM product providing inhaled insulin, and Vectura Limited's AspirairTM device.
  • InhanceTM by Nektar Therapeutics and used in their ExuberaTM product providing inhaled insulin
  • Vectura Limited 's AspirairTM device.
  • a particularly preferred active dry powder inhaler is described in more detail below.
  • the dose of the composition of the present invention required to provide the desired therapeutic effect will contain from about 0.25 mg to about 20 mg of a benzodiazepine or a pharmaceutically acceptable salt thereof.
  • the dose comprises from about 0.5 mg to about 10 mg.
  • the dose will comprise from about 1 mg to about 7 mg, and most preferably from about 2 mg to about 3 mg of said benzodiazepine.
  • a dry powder composition comprising a benzodiazepine is provided, having a good dosing efficiency. This, in combination with the advantages afforded by pulmonary administration of a dry powder formulation, allows the benzodiazepine to be administered in smaller doses than required when using the currently available compositions and modes of administration.
  • the dosing efficiency is achieved by optimising the dry powder composition comprising the benzodiazepine, and/or the device used to dispense the composition.
  • Good dosing efficiency will have a large number of benefits. For example, as it is possible to repeatedly and reliably deliver a higher proportion of the active agent in a dose, it will be possible to reduce the size of the doses whilst still achieving the same therapeutic effect. This is clearly very attractive.
  • the present invention may help to reduce the incidence of side effects by reducing the dose administered to all patients.
  • the metered dose (MD) of a dry powder formulation is the total mass of active agent present in the metered form presented by the inhaler device in question.
  • the MD might be the mass of active agent present in a capsule for a Cyclohaler (trade mark), or in a foil blister in an Aspirair (trade mark) device.
  • the emitted dose is the total mass of the active agent emitted from the device following actuation. It does not include the material left inside or on the surfaces of the device.
  • the ED is measured by collecting the total emitted mass from the device in an apparatus frequently identified as a dose uniformity sampling apparatus (DUSA), and recovering this by a validated quantitative wet chemical assay.
  • DUSA dose uniformity sampling apparatus
  • the fine particle dose is the total mass of active agent which is emitted from the device following actuation which is present in an aerodynamic particle size smaller than a defined limit. This limit is generally taken to be 5 ⁇ m if not expressly stated to be an alternative limit, such as 3 ⁇ m or 1 ⁇ m, etc.
  • the FPD is measured using an impactor or impinger, such as a twin stage impinger (TSI), multi-stage impinger (MSI), Andersen Cascade Impactor or a Next Generation Impactor (NGI). Each impactor or impinger has a pre-determined aerodynamic particle size collection cut points for each stage.
  • the FPD value is obtained by interpretation of the stage-by-stage active agent recovery quantified by a validated quantitative wet chemical assay where either a simple stage cut is used to determine FPD or a more complex mathematical interpolation of the stage-by-stage deposition is used.
  • the fine particle fraction is normally defined as the FPD divided by the ED and expressed as a percentage.
  • FPF(ED) the FPF of ED
  • FPF(ED) (FPD/ED) ⁇ 100%.
  • the fine particle fraction may also be defined as the FPD divided by the MD and expressed as a percentage.
  • FPF(MD) the FPF of MD
  • FPF(MD) (FPD/MD) ⁇ 100%.
  • the FPF(MD) can also be termed the ‘Dose Efficiency’ and is the amount of the dose of the pharmaceutical dry powder formulation which, upon being dispensed from the delivery device, is below a specified aerodynamic particle size.
  • impaction parameter is defined as the velocity of the particle times the square of its aerodynamic diameter. Consequently, the probability associated with delivery of a particle through the upper airways region to the target site of action, is related to the square of its aerodynamic diameter. Therefore, delivery to the lower airways, or the deep lung is dependant on the square of its aerodynamic diameter, and smaller aerosol particles are very much more likely to reach the target site of administration in the user and therefore able to have the desired therapeutic effect.
  • Particles having aerodynamic diameters in the range of 5 ⁇ m to 2 ⁇ m will generally be deposited in the respiratory bronchioles whereas smaller particles having aerodynamic diameters in the range of 3 to 0.05 ⁇ m are likely to be deposited in the alveoli. So, for example, high dose efficiency for particles targeted at the alveoli is predicted by the dose of particles below 3 ⁇ m, with the smaller particles being most likely to reach that target site.
  • the active agent in the formulation must be in the form of very fine particles, for example, having a mass median aerodynamic diameter (MMAD) of less than 10 ⁇ m. It is well established that particles having an MMAD of greater than 10 ⁇ m are likely to impact on the walls of the throat and generally do not reach the lung. Particles having an MMAD in the region of 5 ⁇ m to 2 ⁇ m will generally be deposited in the respiratory bronchioles whereas particles having an MMAD in the range of 3 to 0.05 ⁇ m are likely to be deposited in the alveoli or be absorbed into the bloodstream.
  • MMAD mass median aerodynamic diameter
  • the MMAD of the active particles is not more than 10 ⁇ m, and preferably not more than 5 ⁇ m, more preferably not more than 3 ⁇ m, and may be less than 1 ⁇ m.
  • at least 90% by weight of the active particles in a dry powder formulation should have an MMAD of not more than 10 ⁇ m, preferably not more than 5 ⁇ m, more preferably not more than 3 ⁇ m and most preferably not more than 2 ⁇ m.
  • the active particles When dry powders are produced using conventional processes, the active particles will vary in size, and often this variation can be considerable. This can make it difficult to ensure that a high enough proportion of the active particles are of the appropriate size for administration to the correct site. It is therefore desirable to have a dry powder formulation wherein the size distribution of the active particles is as narrow as possible. This will improve dose efficiency and reproducibility.
  • compositions of the present invention are preferably formulated to reduce the loss of the pharmaceutically active agent, so that a high dosing efficiency can be achieved.
  • loss of the pharmaceutically active agent it is meant that the active agent is not dispensed by the delivery device, or it is not dispensed in a manner that will result in it reaching the lower respiratory tract or deep lung, where the active particles should be deposited in order to have their desired therapeutic effect.
  • the agglomeration of the fine particles in the composition leads to loss of the active agent.
  • the fine particles of active agent tend to agglomerate and if these agglomerates are not broken up upon actuation of the dispensing device, the active agent particles will not reach the desired part of the lung. It has been found that the deagglomeration of the fine powder particles can be greatly enhanced by the addition of force control agents which reduce particle cohesion to allow agglomerates to break up more easily, as well as by the methods used to prepare the particles.
  • Fine particles that is, those with an MMAD of less than 10 ⁇ m, are thermodynamically unstable due to their high surface area to volume ratio, which provides a significant excess surface free energy and encourages the particles to agglomerate.
  • agglomeration of fine particles and adherence of such particles to the walls of the inhaler are problems that result in the fine particles leaving the inhaler as large, stable agglomerates, or being unable to leave the inhaler and remaining adhered to the interior of the inhaler, or even clogging or blocking the inhaler.
  • the tendency of fine particles to agglomerate means that the FPF of a given dose is highly unpredictable and a variable proportion of the fine particles will be administered to the lung, or to the correct part of the lung, as a result.
  • dry powder formulations often include additive material.
  • the additive material is intended to decrease the cohesion between particles in the dry powder formulation. It is thought that the additive material interferes with the weak bonding forces between the small particles, helping to keep the particles separated and reducing the adhesion of such particles to one another, to other particles in the formulation if present and to the internal surfaces of the inhaler device. Where agglomerates of particles are formed, the addition of particles of additive material decreases the stability of those agglomerates so that they are more likely to break up in the turbulent air stream created on actuation of the inhaler device, whereupon the particles are expelled from the device and inhaled. As the agglomerates break up, the active particles return to the form of small individual particles which are capable of reaching the lower lung.
  • dry powder formulations which include distinct particles of additive material (generally of a size comparable to that of the fine active particles).
  • the additive material may form a coating, generally a discontinuous coating, on the active particles and/or any carrier particles.
  • the additive material is an anti-adherent material and it will tend to reduce the cohesion between particles and will also prevent fine particles becoming attached to the inner surfaces of the inhaler device.
  • the additive material is an anti-friction agent or glidant and will give better flow of the pharmaceutical composition in the inhaler.
  • the additive materials used in this way may not necessarily be usually referred to as anti-adherents or anti-friction agents, but they will have the effect of decreasing the cohesion between the particles or improving the flow of the powder.
  • the additive materials are often referred to as force control agents (FCAs) and they usually lead to better dose reproducibility and higher fine particle fractions.
  • an FCA is an agent whose presence on the surface of a particle can modify the adhesive and cohesive surface forces experienced by that particle, in the presence of other particles. In general, its function is to reduce both the adhesive and cohesive forces.
  • the optimum amount of additive material to be included in a dry powder formulation will depend on the chemical composition and other properties of the additive material and of the active material, as well as upon the nature of other particles such as carrier particles, if present.
  • the efficacy of the additive material is measured in terms of the fine particle fraction of the composition.
  • additive materials usually consist of physiologically acceptable material, although the additive material may not always reach the lung.
  • the additive particles may not always reach the lung.
  • the additive particles may not always reach the lung.
  • the additive particles are attached to the surface of carrier particles, they will generally be deposited, along with those carrier particles, at the back of the throat of the user.
  • the composition further comprises an additive material.
  • Preferred additive materials for use in dry powder formulations include amino acids, peptides and polypeptides having a molecular weight of between 0.25 and 1000 kDa and derivatives thereof, dipolar ions such as zwitterions, phospholipids such as lecithin, metal stearates such as magnesium stearate, sodium stearyl fumate or colloidal silicon dioxide.
  • the dry powder compositions may include one or more FCAs in an amount form about 0.1% to about 40% by weight, preferably from about 0.15% to 10% by weight, more preferably from about 0.2% to about 5% by weight, and most preferably from about 0.5% to about 2% by weight.
  • the FCA is an amino acid or a phospholipid
  • it is preferably provided in an amount form about 0.1% to about 10% by weight, more preferably about 0.5% to about 5% by weight, and most preferably about 2% by weight.
  • at least 95% by weight of the micronised amino acid or phospholipid has a particle diameter of less than 150 ⁇ m, preferably less than 100 ⁇ m and most preferably less than 501 ⁇ m.
  • FCA is a metal stearate or sodium stearyl fumarate
  • it is preferably provided in an amount from about 0.05% to about 10%, more preferably from about 0.15% to about 2%, and most preferably from about 0.15% to about 0.5%, by weight.
  • particle size of particles of the dry powder formulation is the volume weighted particle size.
  • the particle size may be calculated by a laser diffraction method.
  • the particle also includes an indicator material on the surface of the particle, advantageously the particle size of the coated particles is also within the preferred size ranges indicated for the uncoated particles.
  • the benzodiazepine formulation is a “carrier free” formulation, which includes only the benzodiazepine and one or more additive materials.
  • the powder formulation includes a benzodiazepine, preferably clobazam or clonazepam, and an additive material.
  • the powder includes at least 60% by weight of the benzodiazepine based on the weight of the powder.
  • the powder comprises at least 70%, more preferably at least 80% by weight of benzodiazepine based on the weight of the powder.
  • the powder comprises at least 90%, and more preferably at least 95%, of benzodiazepine based on the weight of the powder.
  • the amounts of additive material included in the dry powder composition is preferably as small as possible.
  • the most preferred powder composition would, therefore, comprise more than 99% by weight of benzodiazepine.
  • the particles if the powder have a particle size of less than 20 ⁇ m, preferably less than 10 ⁇ m and more preferably less than 5 ⁇ m.
  • the size of the benzodiazepine particles of the powder should be within the range of from 0.1 ⁇ m to 5 ⁇ m for effective delivery to the lower lung.
  • the additive material is in the form of particles of material, it may be advantageous for particles of the additive material to have a size range above the preferred range for delivery to the lower lung.
  • the additive material may comprise an amino acid.
  • amino acids When present as an additive material in a dry powder composition, amino acids have been found to give a high respirable fraction of the active material and also enhance the flow properties of the powder.
  • a preferred amino acid is leucine, in particular L-leucine.
  • L-leucine Although the L-form of the amino acids is disclosed herein as being preferred, the D- and DL-forms may also be used.
  • the additive material may comprise one or more of the following amino acids: leucine, isoleucine, lysine, valine, methionine, cysteine and phenylalanine.
  • the powder comprises at least 80% and preferably at least 90% by weight of benzodiazepine (or its pharmaceutically acceptable salts) based on the weight of the powder.
  • the powder includes not more than 8%, more preferably not more than 5% by weight of additive material based on the weight of the powder.
  • the additive material may also be magnesium stearate or colloidal silicon dioxide.
  • dry powder formulations often include coarse carrier particles of excipient material mixed with fine particles of active material. Rather that sticking to one another, the fine active particles tend to adhere to the surfaces of the coarse carrier particles whilst in the inhaler device, but are supposed to release and become dispersed upon actuation of the dispensing device and inhalation into the respiratory tract, to give a fine suspension.
  • the carrier particles preferably have MMADs greater than 40 ⁇ m.
  • Carrier particles may be of any acceptable excipient material or combination of materials.
  • the carrier particles may be composed of one or more materials selected from sugar alcohols, polyols and crystalline sugars.
  • suitable carriers include inorganic salts such as sodium chloride and calcium carbonate, organic salts such as sodium lactate and other organic compounds such as polysaccharides and oligosaccharides.
  • the carrier particles are of a polyol.
  • the carrier particles may be particles of crystalline sugar, for example mannitol, dextrose or lactose.
  • the carrier particles are of lactose.
  • compositions of the present invention also comprise carrier particles.
  • substantially all (by weight) of the carrier particles have a diameter which lies between 10 ⁇ m and 1000 ⁇ m, more preferably between 50 ⁇ m and 1000 ⁇ m.
  • the diameter of substantially all (by weight) of the carrier particles is less than 355 ⁇ m and lies between 20 ⁇ m and 250 ⁇ m.
  • the carrier particles Preferably at least 90% by weight of the carrier particles have a diameter between from 60 ⁇ m to 1000 ⁇ m.
  • the relatively large diameter of the carrier particles improves the opportunity for other, smaller particles to become attached to the surfaces of the carrier particles and to provide good flow and entrainment characteristics and improved release of the active particles in the airways to increase deposition of the active particles in the lower lung.
  • the ratios in which the carrier particles (if present) and composite active particles are mixed will, of course, depend on the type of inhaler device used, the type of active particles used and the required dose.
  • the carrier particles may be present in an amount of at least 50%, more preferably 70%, advantageously 90% and most preferably 95% based on the combined weight of the composite active particles and the carrier particles.
  • a further difficulty is encountered when adding coarse carrier particles to a composition of fine active particles and that difficulty is ensuring that the fine particles detach from the surface of the large particles upon actuation of the delivery device.
  • composition additive materials including FCAs of the nature discussed above.
  • Compositions comprising fine active particles and additive materials are disclosed in WO 97/03649 and WO 96/23485.
  • the powder composition may further comprise fine particles of an excipient material, which may, for example, be a material such as one of those mentioned herein as being suitable for use as a carrier material.
  • an excipient material such as one of those mentioned herein as being suitable for use as a carrier material.
  • materials such as crystalline sugars such as dextrose or lactose.
  • the fine excipient particles may be of the same material as the carrier particles, or of a different material.
  • the particle size of the fine excipient material will generally not exceed 30 ⁇ m, and preferably does not exceed 20 ⁇ m.
  • the carrier particles and/or fine excipient particles can constitute an indicator material.
  • the carrier particles and/or any fine particle excipient may comprise mannitol.
  • the powder for inhalation may be prepared by mixing the components of the powder together.
  • the powder may be prepared by mixing together particles of active material and the carrier material and/or additive material.
  • the type of equipment used will depend on the particular formulation used. For example, for certain formulations a relatively low shear mixer such as the Inversina Variable Tumbler Mixer may be used. For other formulations, a higher shear mixer such as Retch Grindomix mixer is more appropriate. For yet other formulations, a mechanofusion system such as the Hosokawa Mechano-Fusion mill may be used. In some cases, spheronisation may be advantageous.
  • the dry powder compositions of the present invention are such that a fine particle fraction of at least 35% is produced upon actuation of the inhaler device. It is more preferred that the fine particle fraction be greater than or equal to 50%. It is particularly preferred that the fine particle fraction be greater than or equal to 60%. It is especially preferred that the fine particle fraction be greater than or equal to 70%. It is most preferred that the fine particle fraction be greater than or equal to 80%.
  • the term fine particle fraction is used here to denote the fraction of the total amount of active material delivered by the device which has a diameter of not more than 5 ⁇ m. The total amount of active material delivered by the device is in general less than the amount of active material that is metered in the device or is present in a pre-metered dose within the device.
  • a benzodiazepine dry powder-composition for use in an inhaler device.
  • Such compositions preferably further comprise a carrier material.
  • the powder will preferably generate a fine particle fraction of at least 35%, preferably at least 50%, more preferably at least 60% and most preferably at least 70%, upon actuation of the inhaler device.
  • the powder formulation Upon actuation of the dispensing device, the powder formulation becomes entrained in an airflow which is generated (actively or passively) within the device.
  • the manner in which the powder becomes entrained in this airflow and is then expelled from the device is also crucial in ensuring that as much of the active agent is dispensed as possible.
  • This deagglomeration is possible where the airflow is controlled so that it applies shear forces on the powder formulation as it becomes entrained in the airflow. These shear forces can serve to break up agglomerated particles, thereby enhancing the FPF and FPD of the powder.
  • One way in which deagglomeration of agglomerates in the dry powder formulation may be achieved during powder entrainment within the dispensing device it to arrange the airflow so that it applies shear forces to the powder, breaking the agglomerates apart.
  • the entrainment of the dry powder formulation in an airflow will be affected by the properties of the formulation itself, as well as the device used.
  • entrainment of a fine powder that is, one which does not include a population of larger particles, such as carrier particles, is more difficult than entrainment of a powder comprising a combination of large and fine particles.
  • the arrangement of the device itself also affects the powder entrainment. In particular, it is the path of the airflow through the powder and out of the device which will determine any deagglomeration, powder entrainment and powder velocity, etc.
  • a method comprising entraining agglomerated particles in a gas flow.
  • the method comprises depositing the agglomerate particles onto one or more surfaces, and applying, via the gas flow, a shear to the deposited agglomerated particles to deagglomerate them.
  • a “high turbulence inhaler device” is to be understood as meaning an inhaler device which is configured to generate relatively high turbulence within the device and/or a relatively high incidence of impaction of powder upon internal surfaces and/or obstructions within the device, whereby efficient de-agglomeration of agglomerated powder particles occurs in use of the device.
  • the dry powder inhaler devices in which the powder composition of the present invention will be commonly used include “single dose” devices, for example the RotahalerTM, the SpinhalerTM and the DiskhalerTM in which individual doses of the powder composition are introduced into the device in, for example, a capsule or a blister. “Multiple dose” devices may also be used, such as the TurbohalerTM in which, on actuation of the inhaler, one dose of the powder is removed from a reservoir of the powder material contained in the device.
  • a form of device that promotes high turbulence offers advantages in that a higher fine particle fraction will be obtainable than in the use of other forms of device.
  • Such devices include, for example, the TurbohalerTM or NovolizerTM, and may be devices of the kind in which generation of an aetosolised cloud of powder is driven by inhalation of the patient or of the kind having a dispersal device for generating or assisting in the generation of the aerosolised cloud of powder for inhalation.
  • the method comprises entraining a powdered substance in a gas flow stream from an inlet port of a vortex chamber having a substantially circular cross-section.
  • the method further comprises directing the gas flow through the vortex chamber in a tangential direction; directing the gas flow through the vortex chamber so as to aerosolise the powder composition; and directing the gas flow with the powder composition out of the vortex chamber in an axial direction through an exit port.
  • the velocity of the gas flow at a distance of 300 mm outside of the exit port is less than the velocity of the gas flow at the inlet port.
  • the method comprises entraining a powdered composition including agglomerated particles in a gas flow upstream from an inlet port of the vortex chamber.
  • the method comprises directing the gas flow through the inlet port into the vortex chamber; depositing the agglomerated particles onto one or more of the walls of the vortex chamber; applying, via the gas flow through the vortex chamber, a shear to the deposited agglomerated particles to deagglomerate the particles; and directing the gas flow, including the deagglomerated particles, out of the vortex chamber; wherein the velocity of the gas flow at a distance of 300 mm outside the exit port is less than the velocity of the gas flow at the inlet port.
  • the invention further provides an arrangement for generating an air flow through a chamber containing powder, so that the powder becomes entrained in the air flow and is carried out of the chamber via an exit port.
  • the chamber has an axis and a wall curved around the axis and the air rotates around this axis.
  • the airflow is also directed through an inlet port of the chamber, wherein the direction of the airflow through the inlet port is tangential to the chamber wall.
  • the direction of the airflow through the exit port is parallel to the axis.
  • a cross-sectional area of the airflow through the chamber is in a normal plane to the airflow and decreases with increasing distance from the inlet port.
  • an inhaler for providing the airflow and deagglomeration discussed above.
  • Such inhalers comprise an aerosolising device including a substantially tangential inlet port and a substantially axial exit port.
  • the inhalers also comprise one or more sealed blisters (or capsules) containing the pharmaceutical dry powder composition to be dispensed, and an input device for removably receiving one of these blisters. Upon actuation, the inhaler couples the tangential inlet port with the powder composition in the received blister.
  • the aerosolising device is in the form of a vortex chamber of substantially circular cross-section having a substantially tangential inlet port and a substantially axial outlet port.
  • the ratio of the diameter of the vortex chamber to the diameter of the exit port is between 4 and 12.
  • the aerosolising device is in the form of a vortex chamber of substantially circular cross-section having a substantially tangential inlet port, wherein the inlet port has an outer wall which defines the maximum extent of the inlet port in the radially outward direction of the vortex chamber.
  • the extent of the outer wall in the axial direction of the vortex chamber is substantially equal to the maximum extent of the inlet port in the axial direction of the vortex chamber, the outer wall is substantially parallel with a wall of the vortex chamber.
  • the aerosolising device is in the form of a vortex chamber of substantially circular cross-section having a substantially tangential inlet port.
  • a bottom surface defines the furthest extent of the vortex chamber from the exit port in the axial direction, and the bottom surface further defines the furthest axial extent of the inlet port from the exit port.
  • the aerosolising device is in the form of a vortex chamber of substantially circular cross-section having a substantially tangential inlet port and an inlet conduit arranged to supply a powdered composition entrained in a gas flow to the inlet port, in use, wherein the cross-sectional area of the inlet conduit decreases towards the vortex chamber.
  • the inlet conduit is, upon actuation of the inhaler, coupled to the powder composition in the received blister.
  • the aerosolising device is in the form of a vortex chamber of substantially circular cross-section having a substantially tangential inlet port and an arcuate inlet conduit arranged to supply a powdered composition entrained in a gas flow to the inlet port, in use.
  • the inlet conduit is, upon actuation of the inhaler, coupled to the powder composition in the received blister.
  • the aerosolising device is in the form of a vortex chamber having an axis defined, at least in part, by a wall which forms a curve about the axis.
  • the vortex chamber has a cross-sectional area in a plane bounded by the axis, and the plane extends in one direction radially from the axis at a given angular position ( ⁇ ) about the axis.
  • the vortex chamber has a substantially tangential inlet port and a substantially axial exit port, and said cross-sectional area of the vortex chamber decreases with increasing angular position ( ⁇ ) in the direction, in use, of the gas flow between the inlet port and the outlet port.
  • the aerosolising device is in the form of a vortex chamber having an axis defined, at least in part, by a wall which forms a curve about the axis.
  • the vortex chamber has a substantially tangential inlet port and a substantially axial exit port.
  • the vortex chamber is further defined by a base, and the distance (d) between the base and a plane which is normal to the axis and is located on the opposite side of the base to the exit port increase with radial position (r) relative to the axis.
  • the aerosolising device includes as chamber defined by a top wall, a bottom wall, and a lateral wall, the lateral wall being curved about an axis which intersects the top wall and the bottom wall.
  • the chamber encloses a cross-sectional area defined by the axis, the top wall, the bottom wall and the lateral wall, and the chamber has an inlet port and an outlet port.
  • the inlet port is tangential to the lateral wall
  • the outlet port is co-axial with the axis
  • the cross-sectional area decreases with increasing angular position from the inlet port in a direction of a gas flow through the inlet port.
  • the aerosolising device is a chamber including a wall, a base, an inlet port and an exit port.
  • the chamber has an axis that is co-axial with the exit port and intersects the base.
  • the wall is curved about the base, the inlet port is tangential to the wall, and a height between the base and a plane normal to the axis at the exit port decreases as a radial position from the axis to the inlet port increases.
  • compositions in accordance with the invention comprise a benzodiazapine for administration by inhalation, but do not consist or consist essentially of clobazam (i.e., of the drug alone or in substantial isolation), consist of or comprise clobazam and leucine, and/or consist of or comprise clobazam and magnesium stearate.
  • the clobazam may be in the form of a pharmaceutically acceptable salt.
  • compositions in accordance with the invention can consist or consist essentially of clobazam, consist of or comprise clobazam and leucine, or consist of or comprise clobazam and magnesium stearate.
  • Pharmaceutical compositions in accordance with this last aspect are preferably formed by mechanofusion and/or jet-milling.
  • the clobazam may be in the form of a pharmaceutically acceptable salt.
  • compositions in accordance with the invention comprise a benzodiazapine for administration by inhalation, but do not comprise clobazam.
  • pharmaceutical composition comprises clobazam
  • it is prepared by spray-drying, spray-drying using a spray dryer comprising means for producing droplets moving at a controlled velocity, or co-spray drying with a force control agent.
  • the clobazam may be in the form of a pharmaceutically acceptable salt.
  • FIG. 1 shows an inhaler and blister in accordance with an embodiment of the present invention.
  • FIG. 2 is a top cross-section of a vortex nozzle 1 .
  • FIG. 3 is a side cross-section of a vortex chamber in accordance with an embodiment of the invention.
  • FIG. 4 is a sectional view along line B-B of the vortex chamber of FIG. 3 .
  • FIG. 5 ( a ) is a side view of a vortex chamber with a round inlet port.
  • FIG. 5 ( b ) is a sectional view along line D-D of the vortex chamber of FIG. 5 ( a ).
  • FIG. 6 ( a ) is a side view of a vortex chamber with a rectangular inlet port.
  • FIG. 6 ( b ) is a sectional view along line E-E of the vortex chamber of FIG. 6 ( a ).
  • FIG. 7 shows a vortex chamber with an arcuate inlet conduit.
  • FIGS. 8 to 11 show detail of embodiments of the exit port of the inhaler in accordance with the invention.
  • FIG. 12 illustrates an asymmetric vortex chamber in accordance with an embodiment of the invention.
  • FIG. 13 is a sectional view of a vortex chamber in accordance with another asymmetric inhaler in accordance with an embodiment of the invention.
  • FIG. 14 is a perspective view of a vortex chamber according to FIG. 13 .
  • FIG. 15 is a sectional view of the vortex chamber of FIG. 14 .
  • FIG. 16 is a perspective view of a detail of the vortex chamber of FIGS. 14 and 15 ;
  • FIG. 17 is a plan view of the detail of FIG. 16 .
  • FIG. 18 is a plan view of a variation of the detail of FIG. 17 .
  • FIGS. 19 to 21 show variations of the interface between the wall and the base of a vortex chamber according to the embodiments of FIGS. 13-18 .
  • FIGS. 22 (A) and 22 (B) illustrate the particle size distribution of the lactose of Example 1.
  • FIG. 23 shows a perspective view of the prototype inhaler used to perform inhalation testing.
  • FIG. 24 shows the inhaler of FIG. 23 with its cover removed to show the breath actuation mechanism and vortex nozzle.
  • FIG. 25 is a cross-section view through the vortex nozzle taken along line AA in FIG. 24 .
  • FIG. 26 a is a cross-section view taken along line BB in FIG. 24 showing the nozzle valve in the closed position.
  • FIG. 26 b is a cross-section view taken along line BB in FIG. 24 showing the nozzle valve in the open position.
  • FIGS. 27 a is a cross-section view taken along line BB in FIG. 24 showing the nozzle valve in the closed position.
  • FIG. 27 b is a cross-section view taken along line BB in FIG. 24 showing the nozzle valve in the open position.
  • FIG. 28 shows the results of a particle size analysis of a preferred micronised leucine.
  • FIGS. 1 a and 1 b show schematically alternative embodiments of an inhaler that can be used to deliver the powder formulations described above to a patient.
  • FIG. 1 a shows a breath-actuated embodiment while FIG. 1 b shows a manually actuated embodiment.
  • Inhalers of this type are described in WO 02/089880 and WO 02/089881, both published on Nov. 14, 2002, the entire disclosures of which are hereby incorporated by reference.
  • FIGS. 2-7 correspond to the inhalers described in WO 02/089880
  • FIGS. 12-21 correspond to the inhalers described in WO 02/089881
  • FIGS. 8-11 show preferred exit port configurations that can be used in connection with any of these inhalers.
  • the inhaler comprises a nozzle 3000 including a vortex chamber 1 and having an exit port 2 and an inlet port 3 for generating an aerosol of the powder formulation.
  • the vortex chamber 1 is located in a mouthpiece 10 through which the user inhales to use the inhaler.
  • Air passages may be defined between the vortex chamber 1 and the mouthpiece 10 so that the user is able to inhale air in addition to the powdered medicament.
  • the powder formulation is stored in a blister 60 defined by a support 70 and a pierceable foil lid 75 .
  • the support 70 has a cavity formed therein for holding the powder formulation.
  • the open end of the cavity is sealed by the lid 75 .
  • An air inlet conduit 7 of the vortex chamber 1 terminates in a piercing head (or rod) 50 which pierces the pierceable foil lid 75 .
  • a reservoir 80 is connected to the blister 60 via a passage 78 .
  • a regulated air supply 90 charges the reservoir 80 with a gas (e.g., air, in this example) to a predetermined pressure (e.g. 1.5 bar).
  • the blister contains from 1 to 5 mg of powder formulation, preferably 1, 2 or 3 mg of powder formulation.
  • the support 70 is also made of foil. Such blisters are commonly referred to in the art as double-foil blisters.
  • the support 70 is made of a polymer. It is believed that the foil support 70 provides greater protection against moisture and oxidation than the polymer support 70 .
  • a valve 40 when the user inhales, a valve 40 is opened by a breath-actuated mechanism 30 , forcing air from the pressurised air reservoir through the blister 60 where the powdered formulation is entrained in the air flow.
  • the manually actuated inhaler of FIG. 1 b requires the depression of a button 12 to open the valve 40 and create the aforementioned air flow.
  • Either embodiment may be used with a face mask 45 that attaches to the mouthpiece 10 .
  • FIG. 1 b the manually-actuated embodiment of FIG. 1 b is used.
  • the face mask 45 is placed over the nose and mouth of a patient (not shown) and the actuation button 12 depressed to open the valve 40 and create the necessary airflow to carry the formulation particles to the lung, the process of which is discussed below.
  • the air flow transports the powder formulation to the vortex chamber 1 , where a rotating vortex of powder formulation and air is created between the inlet port 3 and the outlet port 2 .
  • the powdered formulation entrained in the airflow enters the vortex chamber in a very short time (typically less than 0.3 seconds and preferably less than 20 milliseconds) and, in the case of a pure drug formulation (i.e., no carrier), a portion of the powder formulation sticks to the walls of the vortex chamber.
  • This powder is subsequently aerosolised by the high shear forces present in the boundary layer adjacent to the powder.
  • the action of the vortex deagglomerates the particles of powder formulation, or in the case of a formulation comprising a drug and a carrier, strips the drug from the carrier, so that an aerosol of powdered formulation exits the vortex chamber 1 via the exit port 2 .
  • the aerosol is inhaled by the user through the mouthpiece 10 .
  • the vortex chamber 1 can be considered to perform two functions: deagglomeration, the breaking up of clusters of particles into individual, respirable particles; and filtration, preferentially allowing particles below a certain size to escape more easily from the exit port 2 .
  • Deagglomeration breaks up cohesive clusters of powdered formulation into respirable particles, and filtration increases the residence time of the clusters in the vortex chamber 1 to allow more time for them to be deagglomerated.
  • Deagglomeration can be achieved by creating high shear forces due to velocity gradients in the airflow in the vortex chamber 1 . The velocity gradients are highest in the boundary layer close to the walls of the vortex chamber.
  • the vortex chamber 1 of FIGS. 2 to 7 is in the form of a substantially cylindrical chamber.
  • the vortex chamber 1 has a frustoconical portion in the region of the exit port 2 .
  • the inlet port 3 is substantially tangential to the perimeter of the vortex chamber 1 and the exit port 2 is generally concentric with the axis of the vortex chamber 1 .
  • gas enters the vortex chamber 1 tangentially via the inlet port 3 and exits axially via the exit port 2 .
  • a vortex is created in which shear forces are generated to deagglomerate the particles of medicament.
  • the length of the exit port 2 is preferably minimized to reduce the possibility of deposition of the drug on the walls of the exit port 2 .
  • the vortex chamber 1 is machined from polyetheretherketone (PEEK), acrylic, or brass, although a wide range of alternative materials is possible.
  • the ratio of the diameter of the vortex chamber to the diameter of the exit port can be significant in maximising the fine particle fraction of the medicament aerosol which is expelled from the exit port.
  • the ratio of the diameter of the vortex chamber to the diameter of the exit port may be between 4 and 12. It has been found that when the ratio is between 4 and 12 the proportion of particles of the powdered medicament with an effective diameter in the range 1 to 3 microns is maximised.
  • the ratio is preferably greater than 5, most preferably greater than 6 and preferably less than 9, most preferably less than 8. In the preferred arrangement, the ratio is 7.1.
  • the diameter of the vortex chamber is between 2 and 12 mm.
  • the diameter of the vortex chamber is preferably greater than 4 mm, most preferably at least 5 mm and preferably less than 8 mm, most preferably less than 6 mm.
  • the diameter of the vortex chamber is 5 mm.
  • the height of the vortex chamber is generally between 1 and 8 mm.
  • the height of the vortex chamber is preferably less than 4 mm, most preferably less than 2 mm.
  • the height of the vortex chamber is 1.6 mm.
  • the vortex chamber is substantially cylindrical.
  • the vortex chamber may take other forms.
  • the vortex chamber may be frustoconical.
  • the aerosolising device comprises an exit port, for example as described above.
  • the diameter of the exit port is generally between 0.5 and 2.5 mm.
  • the diameter of the exit port is preferably greater than 0.6 mm and preferably less than 1.2 mm, most preferably less than 1.0 mm. In the preferred embodiment, the diameter of the exit port is 0.7 mm.
  • FIGS. 3 and 4 show the general form of the vortex chamber of the inhaler of FIG. 1 .
  • the geometry of the vortex chamber is defined by the dimensions listed in Table 1. The preferred values of these dimension are also listed in Table 1. It should be noted that the preferred value of the height h of the conical part of the chamber is 0 mm, because it has been found that the vortex chamber functions most effectively when the top of the chamber is flat.
  • the proportion of the particles of medicament emitted in the aerosol having an effective particle diameter of less than 6.8 microns generated by the vortex chamber depends on the ratio of the diameters of the chamber D and the exit port D e .
  • the normalised average 6.8 micron particle fraction is the emitted 6.8 micron particle fraction divided by the 6.8 micron particle fraction of the powdered medicament loaded into the inhaler.
  • the medicament used was pure IntalTM sodium cromoglycate (Fisons UK). TABLE 2 Relationship between emitted 6.8 micron particle fraction and ratio of vortex chamber diameter to exit port diameter.
  • Average particle fraction Normalised average particle Ratio D/D e ⁇ 6.8 ⁇ m (%) fraction ⁇ 6.8 ⁇ m (%) 2.0 64.7 73.1 3.1 70.8 79.9 4.0 75.5 85.2 6.0 81.0 91.4 7.1 83.5 94.3 8.0 83.2 93.9 8.6 80.6 91.0
  • FIGS. 5 a and 5 b show a vortex chamber 1 in which the inlet port 3 has a circular cross-section.
  • a portion of the airflow entering the vortex chamber via the inlet port 3 follows the lateral wall 12 of the vortex chamber 1 .
  • the powder entrained in this airflow is therefore introduced directly into the airflow at the boundary layer adjacent the lateral wall 12 of the vortex chamber 1 , where the velocity gradient in the radial direction is at a maximum.
  • the maximal velocity gradient results in maximal shear forces on the agglomerated particles of the powder and thus maximum deagglomeration.
  • FIGS. 6 a and 6 b show a vortex chamber 1 in which the inlet port 3 has a rectangular cross-section.
  • the rectangular cross-section maximises the length of the perimeter of the inlet port that is coincident with the wall 12 of the vortex chamber 1 , such that the maximum air flow is introduced into the boundary layer of the vortex.
  • the rectangular cross-section maximises the width of the perimeter of the inlet port 3 that is coincident with the bottom surface 13 of the vortex chamber 1 . In this way, deposition of powder in the vortex chamber 1 is prevented, because the vortex occupies the entire chamber 1 .
  • the inlet port 3 of FIGS. 6 a and 6 b is supplied by an inlet conduit 7 which tapers towards the vortex chamber 1 .
  • the inlet conduit 7 is defined by an inner wall 14 and an outer wall 15 .
  • the outer wall 15 is substantially tangential to the wall 12 of the vortex chamber 1 .
  • the spacing of the inner wall 14 from the outer wall 15 decreases towards the vortex chamber 1 , so that the inner wall 14 urges the air flow into the vortex chamber 1 towards the boundary layer.
  • the decreasing cross-sectional area of the inlet conduit 7 causes the flow of velocity to increase, thereby reducing deposition of powder on the way to the vortex chamber 1 .
  • a further improvement can also be achieved if the upper surface 16 of the vortex chamber 1 is flat, as shown in FIGS. 8 to 10 , rather than conical as shown in FIGS. 1, 3 , 5 and 6 .
  • the upper surface 16 of the vortex chamber 1 is substantially perpendicular to the wall 12 of the chamber 1 , and to the axis of the vortex.
  • FIGS. 8 to 11 show various options for the exit port 2 of the vortex chamber 1 .
  • the characteristics of the exit plume of the aerosol are determined, at least in part, by the configuration of the exit port 2 .
  • the velocity at the exit port 2 will be approximately 40 m/s. This velocity can be reduced to a typical inhalation velocity of 2 m/s within a few centimetres of the chamber or nozzle by providing a strongly divergent aerosol plume.
  • the exit port 2 is a simple orifice defined through the upper wall 17 of the vortex chamber 1 .
  • the thickness of the upper wall 17 means that the exit port 2 has a length which is greater than its diameter.
  • the tubular exit port tends to reduce the divergence of the exit plume.
  • the exit port 11 is annular and is also defined by a knife edge. This arrangement produces an exit plume that slows down more quickly than a circular jet, because the annular exit port has a greater perimeter than a circular port of the same diameter and produces a jet that mixes more effectively with the surrounding static air.
  • multiple orifices form the exit port 2 and produce a number of smaller plumes which break up and slow down in a shorter distance than a single large plume.
  • FIG. 7 shows an embodiment of the vortex chamber 1 in which the inlet conduit 7 is arcuate and tapers towards the vortex chamber 1 .
  • the arcuate inlet conduit 7 urges the entrained particles of powdered formulation towards the outer wall 15 of the inlet conduit 7 .
  • the powder when the powder enters the vortex chamber 1 through the inlet port 3 the powder is introduced directly into the boundary layer next to the wall 12 of the vortex chamber 1 , where shear forces are at a maximum. In this way, improved deagglomeration is achieved.
  • the inhaler in accordance with embodiments of the invention is able to generate a relatively slow moving aerosol with a high fine particle fraction.
  • the inhaler is capable of providing complete and repeatable aerosolisation of a measured dose of powdered drug and of delivering the aerosolised dose into the patient's inspiratory flow at a velocity less than or equal to the velocity of the inspiratory flow, thereby reducing deposition by impaction in the patient's mouth.
  • the efficient aerosolising system allows for a simple, small and low cost device, because the energy used to create the aerosol is small.
  • the fluid energy required to create the aerosol can be defined as the integral over time of the pressure multiplied by the flow rate. This is typically less than 5 joules and can be as low as 3 joules.
  • FIGS. 12-21 show asymmetric inhalers in accordance with other embodiments of the present invention with similar components bearing identical reference numbers to the embodiments described above.
  • the vortex chamber 1 has an asymmetric shape.
  • the wall 12 of the vortex chamber 1 is in the form of a spiral or scroll.
  • the inlet port 3 is substantially tangential to the perimeter of the vortex chamber 1 and the exit port 2 is generally concentric with the axis of the vortex chamber 1 .
  • gas enters the vortex chamber 1 tangentially via the inlet port 3 and exits axially via the exit port 2 .
  • the radius R of the vortex chamber 1 measured from the centre of the exit port 2 decreases smoothly from a maximum radius R max at the inlet port 3 to a minimum radius R min .
  • the effective radius of the vortex chamber 1 decreases as the air flow and entrained particles of medicament circulate around the chamber 1 . In this way, the effective cross-sectional area of the vortex chamber 1 experienced by the air flow decreases, so that the air flow is accelerated and there is reduced deposition of the entrained particles of medicament.
  • the flow of air has gone through 2 B radians (360 E)
  • the air flow is parallel to the incoming airflow through the inlet port 3 , so that there is a reduction in the turbulence caused by the colliding flows.
  • the vortex chamber 1 is machined from PEEK, acrylic, or brass, although a wide range of alternative materials is possible. For manufacturing ease, the radius of the vortex chamber 1 may decrease in steps rather than smoothly.
  • FIG. 13 shows the general form of the vortex chamber of the inhaler of FIG. 12 .
  • the geometry of the vortex chamber is defined by the dimensions listed in Table 3. The preferred values of these dimension are also listed in Table 3. It should be noted that the preferred value of the height h of the conical part of the chamber is 0 mm, because it has been found that the vortex chamber functions most effectively when the top (roof 16 ) of the chamber is flat.
  • the 6.8 micron particle fraction of the aerosol generated by the vortex chamber 1 according to FIG. 12 is improved relative to a circular vortex chamber of FIGS. 1-11 .
  • FIGS. 14 to 18 show another asymmetric inhaler in accordance with the present invention in which the vortex chamber 1 includes a ramp 20 which reduces the height of the vortex chamber 1 from the bottom up with increasing angular displacement 2 from the inlet port 3 .
  • a substantially circular region 21 in the centre of the vortex chamber 1 remains flat.
  • the cross-section of the ramp 20 may be a curve, such as a conic section.
  • the value of the radius (or radii) of,the curve may increase with increasing angular displacement 2 about the axis of the vortex chamber 1 .
  • the ramp 20 has a triangular cross-section, with an angle $ between the base and the upper surface of the ramp 20 .
  • the joints between the ramp 20 and the wall 12 of the vortex chamber and the ramp 20 and the base of the vortex chamber 1 are curved, for example with a fillet radius, to prevent unwanted deposition in this region.
  • the vertical face (normal to the base) of the ramp 20 where the ramp meets the inlet 3 is likely to attract deposition because of the abrupt change in height.
  • the profile of the face (looking axially) to form a smooth entry, as shown in FIG. 17 , contiguous with the inner edge of the inlet 3 air travelling from the inlet scours the face and prevents powder build up.
  • the profile is a straight line at 40° (angle N in FIG. 18 ) to the centre line of the inlet, joined to the inlet wall by a tangent curve. This profile follows the pattern of deposition that would be seen in a similar nozzle without a ramp.
  • the profile is a curve moving radially inward as shown in FIG. 17 . At one end it joins the inner wall of the inlet tangentially. At the other end it joins a continuation of the inner curve of the tamp at the point where the ramp meets the base.
  • FIGS. 22 (A) and 22 (B) show the results of a particle size analysis of two batches of the lactose performed with a Mastersizer 2000, manufactured by Malvern Instruments, Ltd. (Malvern, UK).
  • the lactose had a volume weighted mean of from about 50 to about 55 microns, a d 10 of from about 4 to about 10 microns, a d 50 of from about 50 to about 55 microns, and a d 90 of from about 85 to about 95 microns wherein d 10 d 50 d 90 refer to the diameter of 10%, 50%, and 90% of the analyzed lactose.
  • the benzodiazepine clobazam is micronised such that 90% of the particles had a diameter of less than 5 ⁇ m.
  • Example 1 50 grams if the lactose of Example 1 was placed into a metal mixing vessel of a suitable mixer. 50 grams of the micronised benzodiazepine are then added. An additional 50 grams of the lactose of Example 1 is then added to the mixing vessel, and the resultant mixture is tumbled for 15 minutes. The resultant blend is then passed through a 150 ⁇ m screen. The screened blend (i.e. the portion of the blend that passed through the screen) is then reblended for 15 minutes.
  • the mixer used is an Inversina Variable Speed Tumbler Mixer, which is a low shear mixer distributed by Christison Scientific Equipment Ltd of Gateshead, UK.
  • the mixer used was a Retch Grindomix mixer is a higher shear mixer which is also distributed by Christison Scientific Equipment Ltd. Disaggregation was shown to be sensitive to the intensity of the mixing process but a consistent fine particle fraction (about 60%) was obtained using a low shear mixer equipped with a metal vessel such as the Inversina mixer referenced above.
  • Example 2 The formulation of Example 2 is incorporated into blisters in the following manner. Three milligrams of the benzodiazepine-lactose formulation were placed in each blister. As described above in connection with FIG. 1 , the base of each blister is a cold-formed aluminum blister, formed from a laminate of oriented polyamide (exterior), 45 microns of aluminum (center), and PVC (interior). The lid of the blister is made of a hard-rolled 30 micron lidding foil, having a heat seal lacquer. After the formulation is loaded into the interior of the blisters, the blisters are sealed by placing the lid over the blister base, and heat sealing the lid to the base via the heat seal lacquer.
  • the inhaler comprises a reservoir 80 (not shown) which provides a charge of compressed air, a base block 2000 , an airway 2004 , a mouthpiece 10 through which the dose is inhaled, a blister loader 2010 by which the dose is presented to the inhaler, a crank arm 2015 by which the dose blister ( 60 - 70 ) is pierced, a vortex nozzle 3000 for aerosolizing the dose, and an exit valve 2020 by which the aerosolized dose is released into the mouthpiece 10 .
  • the user places a foil blister (not shown) onto the blister loader 2010 and inserts the blister loader into the device in the position shown in FIG. 23 .
  • the user then pierces the blister by moving the crank arm 2015 from a rest position to a pierce position in which it locks.
  • the reservoir 80 is then charged from a compressed air line (not shown) such that the reservoir 80 contains a volume of pressurized air (typially 15 ml) at a relatively low pressure (typically 1.5 bar gauge).
  • the compressed air is prevented from leaving the device by the valve 2020 at the exit to the vortex nozzle 3000 .
  • the device is now primed to deliver the dose.
  • breath actuation vane 2025 moves, opening the exit valve 2020 and releasing the compressed air in the reservoir.
  • the air flows through the blister, entraining the dose of powder and carrying it to the vortex nozzle 3000 .
  • the powder experiences high centrifugal and shear forces which deagglomerate the dose before delivering it to the user via the mouthpiece 10 as a finely dispersed aerosol.
  • the vortex nozzle 3000 comprises an inlet conduit 3 , a vortex chamber 1 , an outlet port 2 and a nozzle seal 3010 .
  • the compressed gas and entrained dry powder dose from the blister enters the vortex chamber via an inlet tube 7 and inlet conduit 3 and leaves the nozzle 3000 via the exit port 2 .
  • the inlet conduit 3 joins the vortex chamber 1
  • the outer wall of the chamber has a radius of 3.35 mm.
  • the radius of the chamber reduces linearly to 2.5 mm at point 3025 .
  • the radius is then constant at 2.5 mm as the wall of the chamber continues in counter-clockwise direction until it intersects the inlet conduit.
  • the height of the vortex chamber is 1.6 mm.
  • the inlet tube 7 has an internal diameter of 1.22 mm and feeds into the inlet conduit 3 .
  • the inlet conduit 3 tapers in section from a 1.22 mm diameter where it joins the inlet tube 7 to its narrowest point where the inlet conduit 3 joins the vortex chamber 1 and has a height of 1.1 mm high and a width of 0.5 mm. As such, the inlet conduit 3 does not extend to the full height of the vortex chamber, which is 1.6 mm.
  • the outlet port 2 diameter is 0.7 mm and the thickness of the outlet port 2 is 0.35 mm.
  • the breath actuated mechanism comprises a valve 2020 at the outlet port of the vortex nozzle, a valve spring 2030 biased to open the valve, a breath actuation vane 2040 that rotates in response to inhalation by a user, and an inspiratory air inlet 2035 through which air is drawn when a user inhales through the mouthpiece 10 .
  • the valve 2020 includes a resilient valve seal 2023 mounted on a valve arm 2022 which in turn is rotatably mounted on a valve arm pivot 2021 .
  • the valve seal 2023 covers and seals the vortex nozzle outlet port 2 .
  • the vortex nozzle outlet port 2 In the open position ( FIG. 26 b ) the vortex nozzle outlet port 2 is open to allow the dose to exit the nozzle 3000 .
  • the breath actuation vane 2040 is rotatably mounted on a vane pivot 2045 .
  • the vane 2040 includes a vane roller 2046 which is rotatably mounted on the vane 2045 and is free to rotate, and a vane return spring (not shown) which biases the vane 2040 to the closed position as shown in FIG. 26 a.
  • a vane return spring (not shown) which biases the vane 2040 to the closed position as shown in FIG. 26 a.
  • the breath actuated mechanism can be reset for the next dose by rotating the valve reset lever 2050 through 90 degrees and then returning it to its original position.
  • the reset lever 2050 acts on the valve arm 2022 to close the valve (by causing the valve seal 2023 to cover output port 2 ) and allow the breath actuation vane 2040 to return to its closed position under the influence of the vane return spring (not shown).
  • FIG. 27 a shows a manually actuated mechanism in a closed position with a button 12 operably connected to the inspiratory air inlet 2035 , constructed and arranged so that pushing the button 12 will cause the vane 2040 to rotate about its pivot 2045 and create an air flow in the same manner described above with reference to FIG. 26 a.
  • FIG. 27 b shows a manually actuated inhaler with the button 12 fully depressed and the inhaler in the open position as in FIG. 26 b.
  • the manually actuated mechanism is reset in the same manner as the breath actuated mechanism, by rotating the valve reset lever 2050 through 90 degrees and then returning it to its original position.
  • the inhaler of FIGS. 23 to 27 can be used in conjunction with three instruments, a Multi-Stage Liquid Impinger (MSLI) (U.S.P. 26, chapter 601, Apparatus 4 (2003), an Anderson Cascade Impactor (ACI) (U.S.P. 26, chapter 601, Apparatus 3 (2003), and a Dosage Unit Sampling Apparatus (DUSA) (U.S.P. 26 chapter 601, Apparatus B (2003).
  • MSLI Multi-Stage Liquid Impinger
  • ACI Anderson Cascade Impactor
  • DUSA Dosage Unit Sampling Apparatus
  • Each of these devices has an input for receiving the mouthpiece 10 of the inhaler of FIGS. 23 to 27 .
  • the DUSA is used to measure the total amount of drug which leaves the inhaler. With data from this device, the metered and delivered dose is obtained.
  • the delivered dose is defined as the amount of drug that leaves the inhaler. This includes the amount of drug in the throat of the DUSA device, in the measuring section of the DUSA device and the subsequent filters of the DUSA device. It does not include drug left in the blister or other areas of the inhaler of FIGS. 23-27 , and does not account for drug “lost” in the measuring process of the DUSA device.
  • the metered does includes all of the drug which leaves the blister.
  • the MSLI is a device for estimating deep lung delivery of a dry powder formulation.
  • the MSLI includes a five stage cascade impactor which can be used for determining the particle size (aerodynamic size distribution) of Dry Powder Inhalers (DPIs) in accordance with USP 26, Chapter 601 Apparatus 4 (2003).
  • DPIs Dry Powder Inhalers
  • the ACI is another device for estimating deep lung delivery of a dry powder formulation.
  • the ACI is multi-stage cascade impactor which can be used for determining the particle size (aerodynamic size distribution) of Dry Powder Inhalers (DPI) in accordance with USP 26, Chapter 601 Apparatus 3 (2003).
  • DPI Dry Powder Inhalers
  • the MSLI and the ACI testing devices can be used to determine, inter alia, the fine particle dose, or FPD (the amount of drug, e.g., in micrograms, that is measured in the sections of the testing device which correlates with deep lung delivery) and the fine particle fraction, or FPF, (the percentage of the metered dose which is measured in the sections of the testing device which correlates with deep lung delivery).
  • FPD the amount of drug, e.g., in micrograms, that is measured in the sections of the testing device which correlates with deep lung delivery
  • FPF fine particle fraction
  • Composition Amount ( ⁇ g) Percent Clobazam 3000 75.00 Lactose 990 24.75 Magnesium Stearate 10 00.25 Total 4000 100
  • This formulation is prepared in the manner set forth above with regard to Example 2, except that the magnesium stearate is added to the mixture along with the clobazam.
  • composition Amount ( ⁇ g) Percent Clobazam 4000 80 Lactose 920 18 Micronised leucine 80 2 Total 5000 100
  • This formulation is prepared in the manner set forth above with regard to Example 2, except that the leucine is added to the mixture along with the clobazam.
  • FIG. 28 shows the results of a particle size analysis of a preferred micronised leucine performed with the Mastersizer 2000, manufactured by Malvern Instruments, Ltd. (Malvern, UK). As illustrated, the exemplified micronised leucine has a volume weighted mean particle diameter of less than 6 ⁇ m.
  • composition Amount ( ⁇ g) Percent Clobazam 4000 99.9 Micronised Leucine 40.4 0.1 Total 4040.4 100
  • Example 5 2 g of the leucine described in Example 5 are mixed in a Turbula mixer with 198 g of the clobazam powder described in Example 2. the resulting powder is agglomerated using a milling procedure. 50 g samples of the powder were milled in a porcelain ball mill (manufactured by Pascall Engineering Company) having a diameter of approximately 150 mm, using steel grinding balls. 4040.4 mg of the milled powder is then placed into each of 49 blisters.
  • a porcelain ball mill manufactured by Pascall Engineering Company
  • NTI Next Generation Impactor
  • the in-vitro testing was performed using an Aspirair (trade mark) device, which is an active inhaler device.
  • the formulations were composed of one or more of the following constituents:
  • micronised clobozam 1.01 g was weighed out, and then gently pressed through a 300 ⁇ m metal sieve, using the rounded face of a metal spatula. This formulation was recorded as “3A”. 9.37 g of micronised clobozam was then combined with 0.50 g of micronised L-leucine in the MechanoFusion system. The material was processed at a setting of 20% power for 5 minutes, followed by a setting of 80% power for 10 minutes. This material was recorded as “4A”. After blending, this powder was then gently pushed through a 300 ⁇ m metal sieve with a spatula. This material was recorded as “4B”.
  • micronised clobozam was then combined with 0.50 g of magnesium steatate in the MechanoFusion system.
  • the material was processed at a setting of 20% power for 5 minutes, followed by a setting of 80% power for 10 minutes. This material was recorded as “5A”. After blending, this powder was rested overnight, and then was gently pushed through a 300 ⁇ m metal sieve with a spatula. This material was recorded as “5B”.
  • micronised clobozam 9.5 g was then combined with 0.50 g of micronised L-leucine in the MechanoFusion system.
  • the material was processed at a relatively low speed setting of 20% power for 5 minutes. This process was intended only to produce a good mix of the components. This material was recorded as “6A”.
  • this powder was rested overnight, and then was gently pushed through a 300 ⁇ m metal sieve with a spatula. This material was recorded as “6C”.
  • micronised clobozam 9.5 g was then combined with 0.50 g of magnesium stearate in the MechanoFusion system. The material was processed at a setting of 20% power for 5 minutes. This material was recorded as “7A”.
  • this powder was gently pushed through a 300 ⁇ m metal sieve with a spatula. This material was recorded as “7C”.
  • a batch of re-condensed leucine (also referred to as “Aerocine”) was produced by subliming to vapour a sample of leucine in a tube furnace, and re-condensing as a very finely dispersed powder as the vapour cooled. This batch was identified as “8A”.
  • micronised clobozam 9.5 g was then combined with 0.50 g of Aerocine, in the MechanoFusion system.
  • the material was processed at a setting of 20% power for 5 minutes, followed by a setting of 80% power for 10 minutes. This material was recorded as “8B”. After blending, this powder was rested overnight, and then was gently pushed through a 300 ⁇ m metal sieve with a spatula. This material was recorded as “8C”.
  • micronised clobozam 9.5 g was combined with 0.50 g of Aerocine in the MechanoFusion system. The material was processed at a setting of 20% power for 5 minutes. 7.00 g of this powder was then fed into the AS50 spiral jet mill, set with an injector pressure of about 7 bar and a grinding pressure of about 5 bar. The resulting material was recovered and recorded as “9A”.
  • the co-jet milled formulations exhibited exceptional FPFs when dispensed from an active dry powder inhaler device.
  • the FPFs observed were significantly better that those of the mechanofused formulations and those formulations which did not include an additive material. This improvement would appear to be largely due to reduced throat deposition, which was less than 8% for the co-jet milled formulations, compared to 15% for the pure drug and up to 27% for the mechanofused formulations.
  • the mean ED was 1965 ⁇ g, with an RSD (relative standard deviation) of 2.8%. This material consequently demonstrated excellent through life dose reproducibility.
  • a further composition according to the present invention may be prepared as follows. 12.0 g micronised benzodiazepine, such as clobozam, and 4.0 g lecithin S PC-3 (Lipoid GMBH) are weighed into a beaker. The powder is transferred to the Hosokawa AMS-MINI MechanoFusion system via a funnel attached to the largest port in the lid with the equipment running at 3.5%, The port is sealed and the cooling water switched on. The equipment is run at 20% for 5 minutes followed by 50% for 10 minutes. The equipment is switched off, dismantled and the resulting formulation recovered mechanically.
  • a further composition according to the present invention may be prepared as follows. 20 g of a mix comprising 20% micronised benzodiazepine, such as clobozam, 78% Sorbolac 400 lactose and 2% magnesium stearate are weighed into the Hosokawa AMS-MINI MechanoFusion system via a funnel attached to the largest port in the lid with the equipment running at 3.5%. The port is sealed and the cooling water switched on. The equipment is run at 20% for 5 minutes followed by 80% for 10 minutes. The equipment is switched off, dismantled and the resulting formulation recovered mechanically.
  • micronised benzodiazepine such as clobozam
  • Sorbolac 400 lactose lactose
  • magnesium stearate magnesium stearate
  • a further composition according to the present invention may be prepared as follows.
  • 20 g of a mix comprising 95% micronised benzodiazepine, such as clobozam, and 5% magnesium stearate are weighed into the Hosokawa AMS-MINI MechanoFusion system via a funnel attached to the largest port in the lid with the equipment running at 3.5%. The port is sealed and the cooling water switched on. The equipment is run at 20% for 5 minutes followed by 80% for 10 minutes. The equipment is switched off, dismantled and the resulting powder recovered mechanically.
  • stage 2 20 g of a mix comprising 99% Sorbolac 400 lactose and 1% magnesium stearate are weighed into the Hosokawa AMS-MINI MechanoFusion system via a funnel attached to the largest port in the lid with the equipment running at 3.5%. The port is sealed and the cooling water switched on. The equipment is run at 20% for 5 minutes followed by 80% for 10 minutes. The equipment is switched off, dismantled and the resulting powder recovered mechanically. Following this, 16 g of powder from stage 2 are combined with 4 g of powder from stage 1 in a small high shear blender, for 10 minutes to produce the formulation.

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US13/337,596 Abandoned US20120138056A1 (en) 2003-09-15 2011-12-27 Dry powder composition comprising co-jet milled particles for pulmonary inhalation
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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080127972A1 (en) * 2004-11-23 2008-06-05 Vectura Limited Dry Powder Inhaler Formulations Comprising Surface-Modified Particles With Anti-Adherent Additives
US20080220078A1 (en) * 2004-11-30 2008-09-11 Vectura Limited Pharmaceutical Formulations
US20100196286A1 (en) * 2008-12-01 2010-08-05 Armer Thomas A Inhalation delivery methods and devices
US20100192945A1 (en) * 2008-12-23 2010-08-05 Robert Owen Cook Inhalation devices and related methods for administration of sedative hypnotic compounds
US7928089B2 (en) 2003-09-15 2011-04-19 Vectura Limited Mucoactive agents for treating a pulmonary disease
US8303991B2 (en) 2000-11-30 2012-11-06 Vectura Limited Method of making particles for use in a pharmaceutical composition
US20130064804A1 (en) * 2011-09-14 2013-03-14 Naidu Lp BIO-REPLENISHMENT (BioRep) FOR IMPROVING SLEEP ARCHITECTURE
US20140230518A1 (en) * 2008-03-03 2014-08-21 Alcotek, Inc. Calibration and Accuracy Check System
WO2018183528A1 (fr) * 2017-03-28 2018-10-04 Concentrx Pharmaceuticals, Inc. Dispositifs et procédés d'administration de médicaments en poudre sèche
US20180344648A1 (en) * 2015-11-30 2018-12-06 Piramal Enterprises Limited Clobazam tablet formulation and process for its preparation
US10238601B2 (en) 2000-11-30 2019-03-26 Vectura Limited Particles for use in a pharmaceutical composition
US10251894B2 (en) 2012-11-30 2019-04-09 The Regents Of The University Of California Anticonvulsant activity of steroids
US10322139B2 (en) 2012-01-23 2019-06-18 Sage Therapeutics, Inc. Neuroactive steroid formulations and methods of treating CNS disorders
US10376660B2 (en) 2011-09-07 2019-08-13 Concentrx Pharmaceuticals, Inc. Dry powder inhalation device
US10426786B2 (en) 2012-08-13 2019-10-01 The Regents Of The University Of California Mitigation of epileptic seizures by combination therapy using benzodiazepines and neurosteroids
US10478505B2 (en) 2011-09-23 2019-11-19 The Regents Of The University Of California Edible oils to enhance delivery of orally administered steroids
US10940156B2 (en) 2016-03-08 2021-03-09 Sage Therapeutics, Inc. Neuroactive steroids, compositions, and uses thereof
US11103448B2 (en) 2003-09-15 2021-08-31 Vectura Limited Manufacture of pharmaceutical compositions

Families Citing this family (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120321717A1 (en) * 2003-04-14 2012-12-20 Vectura Ltd. Devices and pharmaceutical compositions for enhancing dosing efficiency
US20070104763A1 (en) * 2005-11-10 2007-05-10 Navinta Llc Composition of fentanyl citrate oral solid transmucosal dosage form, excipient and binding material therefore, and methods of making
DE102005059602A1 (de) * 2005-12-14 2007-06-21 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verfahren zur Mikronisierung
GB0613161D0 (en) * 2006-06-30 2006-08-09 Novartis Ag Organic Compounds
GB0716907D0 (en) 2007-08-31 2007-10-10 Archimedes Dev Ltd Pharmaceutical powder compositions
US20110224232A1 (en) * 2008-05-06 2011-09-15 Board Of Regents, The University Of Texas System Treatment of Pulmonary Fungal Infection With Voriconazole via Inhalation
US9925282B2 (en) 2009-01-29 2018-03-27 The General Hospital Corporation Cromolyn derivatives and related methods of imaging and treatment
WO2010111132A2 (fr) 2009-03-27 2010-09-30 Bend Research, Inc. Procédé de séchage par pulvérisation
EP2421518A2 (fr) * 2009-04-24 2012-02-29 Schering Corporation Préparations d'agglomérat comprenant des agents pharmaceutiques actifs ayant des tailles de particules ciblées
GB0921481D0 (en) * 2009-12-08 2010-01-20 Vectura Ltd Process and product
CN103179864B (zh) 2010-07-16 2015-07-29 洲际大品牌有限责任公司 由具有增强的分散性的粉末形成饮料的方法和装置
EP2611529B1 (fr) 2010-09-03 2019-01-23 Bend Research, Inc. Procedede de séchage par pulvérisation
US8815294B2 (en) 2010-09-03 2014-08-26 Bend Research, Inc. Pharmaceutical compositions of dextran polymer derivatives and a carrier material
WO2012031133A2 (fr) 2010-09-03 2012-03-08 Bench Research, Inc. Appareil de séchage par atomisation et procédés d'utilisation de cet appareil
US9248584B2 (en) 2010-09-24 2016-02-02 Bend Research, Inc. High-temperature spray drying process and apparatus
TW201304822A (zh) 2010-11-15 2013-02-01 Vectura Ltd 組成物及用途
TW201306847A (zh) 2010-11-30 2013-02-16 Vectura Ltd 組成物及用途
DE102011102614A1 (de) * 2011-05-27 2012-11-29 Roland Nied Verfahren zum Betrieb einer Strahlmühle sowie Strahlmühle
ITMI20120092A1 (it) * 2012-01-26 2013-07-27 Micro Macinazione S A Compositi di inclusione farmaco-carrier preparati con processo di attivazione meccano-chimica mediante mulini a getto di fluido ad alta energia
SG10201703243QA (en) * 2012-02-28 2017-06-29 Iceutica Holdings Inc Inhalable pharmaceutical compositions
GB201205632D0 (en) * 2012-03-30 2012-05-16 Vectura Ltd Method and apparatus
CN109846862A (zh) 2012-10-25 2019-06-07 通用医疗公司 治疗阿尔茨海默病及相关疾病的组合疗法
WO2014106727A1 (fr) * 2013-01-03 2014-07-10 Vectura Limited Inhalateur et formulation
SG11201505835QA (en) * 2013-01-28 2015-08-28 Incozen Therapeutics Pvt Ltd Methods of treating autoimmune, respiratory and inflammatory disorders by inhalation of roflumilast n-oxide
GB201307659D0 (en) 2013-04-26 2013-06-12 Korea Coast Guard Commissioner Preparation of drug particles by micronisation
US9393202B2 (en) 2013-04-26 2016-07-19 Chiesi Farmaceutici S.P.A Particle size reduction of an antimuscarinic compound
US10525005B2 (en) 2013-05-23 2020-01-07 The General Hospital Corporation Cromolyn compositions and methods thereof
EP3052092A2 (fr) * 2013-10-02 2016-08-10 Vectura Limited Procédé et appareil
US10188757B2 (en) 2013-10-22 2019-01-29 The General Hospital Corporation Cromolyn derivatives and related methods of imaging and treatment
HUE049339T2 (hu) 2014-09-09 2020-09-28 Vectura Ltd Glikopirrolátot tartalmazó készítmény, eljárás és berendezés
WO2016067252A1 (fr) 2014-10-31 2016-05-06 Glaxosmithkline Intellectual Property Development Limited Formulation de poudre
US9968125B2 (en) 2015-01-09 2018-05-15 Philip Morris Products S.A. Nicotine—diketopiperazine microparticle formulations and methods of making the same
WO2017042341A1 (fr) 2015-09-09 2017-03-16 Vectura Limited Procédé de broyage à jet
US10149844B2 (en) 2015-09-16 2018-12-11 Philip Morris Products S.A. Inhalable nicotine formulations, and methods of making and using thereof
US9585835B1 (en) * 2015-09-16 2017-03-07 Sansa Corporation (Barbados) Inc. Inhalable nicotine formulations and methods of making and using the same
US11224594B2 (en) 2015-09-16 2022-01-18 Philip Morris Products S.A. Nicotine formulations and methods of making and using the same
US20170071248A1 (en) 2015-09-16 2017-03-16 Sansa Corporation (Barbados) Inc. System and Method for Controlling the Harshness of Nicotine-Based Dry Powder Formulations
CA3033079A1 (fr) 2016-08-31 2018-03-08 The General Hospital Corporation Macrophages/microglies dans la neuro-inflammation associee aux maladies neurodegeneratives
IT201600098452A1 (it) * 2016-09-30 2018-03-30 Micro Macinazione Sa Apparecchiatura per la micronizzazione di materiale polveroso con capacita’ di prevenire incrostazioni
GB201700727D0 (en) 2017-01-16 2017-03-01 Teva Pharma Inhalers and airflow adaptors therefor
JP7202376B2 (ja) 2017-07-20 2023-01-11 エーゼットセラピーズ， インコーポレイテッド クロモリンナトリウムおよびイブプロフェンの粉末製剤
WO2020010049A1 (fr) 2018-07-02 2020-01-09 The General Hospital Corporation FORMULATIONS EN POUDRE DE CROMOGLYCATE DE SODIUM ET D'α-LACTOSE
WO2020217143A1 (fr) * 2019-04-23 2020-10-29 Glenmark Pharmaceutical Limited Composition de poudre sèche inhalable comprenant du glycopyrronium, de l'indacatérol et de la fluticasone
WO2023187393A1 (fr) 2022-03-31 2023-10-05 Hovione Scientia Limited Combinaison de formulation à base de support et de composite d'inhalation
WO2023247952A1 (fr) 2022-06-21 2023-12-28 Hovione Scientia Limited Composition pharmaceutique cristalline pour inhalation comprenant des particules composites de sucre et de lipide et processus de fabrication
WO2024009079A1 (fr) 2022-07-04 2024-01-11 Hovione Scientia Limited Composition pharmaceutique pour inhalateur à poudre sèche de poudre sèche cristalline enrobée destinée a l'inhalation

Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5457100A (en) * 1991-12-02 1995-10-10 Daniel; David G. Method for treatment of recurrent paroxysmal neuropsychiatric
US6284282B1 (en) * 1998-04-29 2001-09-04 Genentech, Inc. Method of spray freeze drying proteins for pharmaceutical administration
US20010055571A1 (en) * 2000-05-10 2001-12-27 Wermeling Daniel P. System and method for intranasal administration of lorazepam
US6475523B1 (en) * 1995-07-24 2002-11-05 Vectura Limited Powders comprising anti-adherant materials for use in dry powder inhalers
US6514482B1 (en) * 2000-09-19 2003-02-04 Advanced Inhalation Research, Inc. Pulmonary delivery in treating disorders of the central nervous system
US20030162835A1 (en) * 2000-06-27 2003-08-28 Staniforth John Nicholas Method of making particles for use in a pharmaceutical composition
US20030164436A1 (en) * 2002-03-01 2003-09-04 Rooker Alexander T. Display support
US20030175214A1 (en) * 2000-04-17 2003-09-18 Staniforth John Nicholas Formulations for use in inhaler devices
US6627211B1 (en) * 1999-07-26 2003-09-30 Sk Corporation Transnasal anticonvulsive compositions and modulated process
US20030185764A1 (en) * 2000-04-17 2003-10-02 Staniforth John Nicholas Pharmaceutical formulations for dry powder inhalers
US20040037485A1 (en) * 2002-06-07 2004-02-26 Cidra Corporation Pressure transducer featuring large diameter optical waveguide having bragg grating and being configured for reducing the bulk modulus of compressibility thereof
US20040047810A1 (en) * 2000-11-30 2004-03-11 Staniforth John Nicholas Pharmaceutical compositions for inhalation
US20040071635A1 (en) * 2000-11-30 2004-04-15 Staniforth John Nicholas Particles for use in a pharmaceutical composition
US20040096516A1 (en) * 1999-03-05 2004-05-20 Chiesi Farmaceutici S.P.A. Modified carrier particles for use in dry powder inhalers
US20060257491A1 (en) * 2003-09-15 2006-11-16 Vectura Limited Dry powder composition comprising co-jet milled particles for pulmonary inhalation
US20070043030A1 (en) * 2003-09-15 2007-02-22 Vectura Limited Pharmaceutical compositions for treating premature ejaculation by pulmonary inhalation

Family Cites Families (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4374082A (en) * 1981-08-18 1983-02-15 Richard Hochschild Method for making a pharmaceutical and/or nutritional dosage form
FR2627696B1 (fr) * 1988-02-26 1991-09-13 Fournier Innovation Synergie Nouvelle forme galenique du fenofibrate
GB9501841D0 (en) * 1995-01-31 1995-03-22 Co Ordinated Drug Dev Improvements in and relating to carrier particles for use in dry powder inhalers
US5747002A (en) * 1995-04-05 1998-05-05 Genentech, Inc. Preparation of sodium chloride aerosol formulations
CA2347856C (fr) * 1998-11-13 2009-02-17 Jago Research Ag Poudre seche pour inhalation
GB9827145D0 (en) * 1998-12-09 1999-02-03 Co Ordinated Drug Dev Improvements in or relating to powders
WO2000061108A1 (fr) † 1999-04-14 2000-10-19 Glaxo Group Limited Preparation pharmaceutique en aerosol
CA2270306C (fr) † 1999-04-27 2000-09-26 Bernard Charles Sherman Compositions pharmaceutiques comprenant un melange de fenofibrate microfin
GB0009468D0 (en) 2000-04-17 2000-06-07 Vectura Ltd Improvements in or relating to formulations for use in inhaler devices
GB0012260D0 (en) 2000-05-19 2000-07-12 Astrazeneca Ab Novel composition
AU2002222118A1 (en) 2000-11-30 2002-06-11 Vectura Limited Pharmaceutical compositions for inhalation
DE10061932A1 (de) † 2000-12-13 2002-10-24 Pharmatech Gmbh Wirkstoffhaltige Mikropartikel und Verfahren zur Herstellung der Mikropartikel durch Abrasion
DE10130449A1 (de) * 2001-06-23 2003-01-09 Martin Schmidt Inhalierbare Sedativa und Hypnotika für den medizinischen Gebrauch
WO2003041693A1 (fr) * 2001-11-09 2003-05-22 Alexza Molecular Delivery Corporation Administration de diazepam a travers une voie pulmonaire
WO2003072080A1 (fr) * 2002-02-22 2003-09-04 Advanced Inhalation Research, Inc. Formulations inhalables destinees a une liberation prolongee
EP1531798B1 (fr) * 2002-03-20 2012-06-06 Civitas Therapeutics, Inc. Apport pulmonaire de levodopa
US7405207B2 (en) * 2002-06-17 2008-07-29 Epigenesis Pharmaceuticals, Inc. Nebulizer formulations of dehydroepiandrosterone and methods of treating asthma or chronic obstructive pulmonary disease using compositions thereof
US20040121003A1 (en) 2002-12-19 2004-06-24 Acusphere, Inc. Methods for making pharmaceutical formulations comprising deagglomerated microparticles
BRPI0409380A (pt) * 2003-04-14 2006-04-18 Vectura Ltd composições farmacêuticas
US20060147389A1 (en) * 2004-04-14 2006-07-06 Vectura Ltd. Devices and pharmaceutical compositions for enhancing dosing efficiency
CA2522158C (fr) † 2003-04-14 2018-03-20 Vectura Ltd. Dispositifs et compositions pharmaceutiques destines a ameliorer l'efficacite du dosage
US20120321717A1 (en) * 2003-04-14 2012-12-20 Vectura Ltd. Devices and pharmaceutical compositions for enhancing dosing efficiency
US7032748B2 (en) 2003-05-28 2006-04-25 Conklin William M Portable dispensers for fastening means
EP1663164A2 (fr) 2003-09-15 2006-06-07 Vectura Limited Procedes de preparation de compositions pharmaceutiques
GB0425758D0 (en) * 2004-11-23 2004-12-22 Vectura Ltd Preparation of pharmaceutical compositions

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5457100A (en) * 1991-12-02 1995-10-10 Daniel; David G. Method for treatment of recurrent paroxysmal neuropsychiatric
US6475523B1 (en) * 1995-07-24 2002-11-05 Vectura Limited Powders comprising anti-adherant materials for use in dry powder inhalers
US20050152849A1 (en) * 1995-07-24 2005-07-14 Vectura Limited Powders comprising anti-adherent materials for use in dry powder inhalers
US6284282B1 (en) * 1998-04-29 2001-09-04 Genentech, Inc. Method of spray freeze drying proteins for pharmaceutical administration
US20040096516A1 (en) * 1999-03-05 2004-05-20 Chiesi Farmaceutici S.P.A. Modified carrier particles for use in dry powder inhalers
US6627211B1 (en) * 1999-07-26 2003-09-30 Sk Corporation Transnasal anticonvulsive compositions and modulated process
US20030175214A1 (en) * 2000-04-17 2003-09-18 Staniforth John Nicholas Formulations for use in inhaler devices
US20030185764A1 (en) * 2000-04-17 2003-10-02 Staniforth John Nicholas Pharmaceutical formulations for dry powder inhalers
US20010055571A1 (en) * 2000-05-10 2001-12-27 Wermeling Daniel P. System and method for intranasal administration of lorazepam
US20030162835A1 (en) * 2000-06-27 2003-08-28 Staniforth John Nicholas Method of making particles for use in a pharmaceutical composition
US6514482B1 (en) * 2000-09-19 2003-02-04 Advanced Inhalation Research, Inc. Pulmonary delivery in treating disorders of the central nervous system
US20040047810A1 (en) * 2000-11-30 2004-03-11 Staniforth John Nicholas Pharmaceutical compositions for inhalation
US20040071635A1 (en) * 2000-11-30 2004-04-15 Staniforth John Nicholas Particles for use in a pharmaceutical composition
US20030164436A1 (en) * 2002-03-01 2003-09-04 Rooker Alexander T. Display support
US20040037485A1 (en) * 2002-06-07 2004-02-26 Cidra Corporation Pressure transducer featuring large diameter optical waveguide having bragg grating and being configured for reducing the bulk modulus of compressibility thereof
US20060257491A1 (en) * 2003-09-15 2006-11-16 Vectura Limited Dry powder composition comprising co-jet milled particles for pulmonary inhalation
US20070043030A1 (en) * 2003-09-15 2007-02-22 Vectura Limited Pharmaceutical compositions for treating premature ejaculation by pulmonary inhalation

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9962338B2 (en) 2000-11-30 2018-05-08 Vectura Limited Method of making particles for use in a pharmaceutical composition
US8303991B2 (en) 2000-11-30 2012-11-06 Vectura Limited Method of making particles for use in a pharmaceutical composition
US8956661B2 (en) 2000-11-30 2015-02-17 Vectura Limited Method of making composite particles for use in pharmaceutical compositions and composite particles and compositions thereof
US10973771B2 (en) 2000-11-30 2021-04-13 Vectura Limited Method of making particles for use in a pharmaceutical composition
US10238601B2 (en) 2000-11-30 2019-03-26 Vectura Limited Particles for use in a pharmaceutical composition
US9931304B2 (en) 2000-11-30 2018-04-03 Vectura Limited Method of making particles for use in a pharmaceutical composition
US7928089B2 (en) 2003-09-15 2011-04-19 Vectura Limited Mucoactive agents for treating a pulmonary disease
US11103448B2 (en) 2003-09-15 2021-08-31 Vectura Limited Manufacture of pharmaceutical compositions
US20110236492A1 (en) * 2004-11-23 2011-09-29 Vectura Limited Dry powder inhaler formulations comprising surface-modified particles with anti-adherent additives
US20080127972A1 (en) * 2004-11-23 2008-06-05 Vectura Limited Dry Powder Inhaler Formulations Comprising Surface-Modified Particles With Anti-Adherent Additives
US9585834B2 (en) 2004-11-23 2017-03-07 Vectura Limited Dry powder inhaler formulations comprising surface-modified particles with anti-adherent additives
US9642800B2 (en) 2004-11-23 2017-05-09 Vectura Limited Dry powder inhaler formulations comprising surface-modified particles with anti-adherent additives
US20080220078A1 (en) * 2004-11-30 2008-09-11 Vectura Limited Pharmaceutical Formulations
US20140230518A1 (en) * 2008-03-03 2014-08-21 Alcotek, Inc. Calibration and Accuracy Check System
US20100196286A1 (en) * 2008-12-01 2010-08-05 Armer Thomas A Inhalation delivery methods and devices
US20100192945A1 (en) * 2008-12-23 2010-08-05 Robert Owen Cook Inhalation devices and related methods for administration of sedative hypnotic compounds
US9161912B2 (en) 2008-12-23 2015-10-20 Map Pharmaceuticals, Inc. Inhalation devices and related methods for administration of sedative hypnotic compounds
US8555875B2 (en) 2008-12-23 2013-10-15 Map Pharmaceuticals, Inc. Inhalation devices and related methods for administration of sedative hypnotic compounds
US10376660B2 (en) 2011-09-07 2019-08-13 Concentrx Pharmaceuticals, Inc. Dry powder inhalation device
US11752282B2 (en) 2011-09-07 2023-09-12 Concentrx Pharmaceuticals, Inc. Dry powder inhalation device
US20130064804A1 (en) * 2011-09-14 2013-03-14 Naidu Lp BIO-REPLENISHMENT (BioRep) FOR IMPROVING SLEEP ARCHITECTURE
US10478505B2 (en) 2011-09-23 2019-11-19 The Regents Of The University Of California Edible oils to enhance delivery of orally administered steroids
US10322139B2 (en) 2012-01-23 2019-06-18 Sage Therapeutics, Inc. Neuroactive steroid formulations and methods of treating CNS disorders
US11426417B2 (en) 2012-01-23 2022-08-30 Sage Therapeutics, Inc. Neuroactive steroid formulations and methods of treating CNS disorders
US11510929B2 (en) 2012-08-13 2022-11-29 The Regents Of The University Of California Mitigation of epileptic seizures by combination therapy using benzodiazepines and neurosteroids
US10426786B2 (en) 2012-08-13 2019-10-01 The Regents Of The University Of California Mitigation of epileptic seizures by combination therapy using benzodiazepines and neurosteroids
US10251894B2 (en) 2012-11-30 2019-04-09 The Regents Of The University Of California Anticonvulsant activity of steroids
US20180344648A1 (en) * 2015-11-30 2018-12-06 Piramal Enterprises Limited Clobazam tablet formulation and process for its preparation
US10940156B2 (en) 2016-03-08 2021-03-09 Sage Therapeutics, Inc. Neuroactive steroids, compositions, and uses thereof
US11554125B2 (en) 2016-03-08 2023-01-17 Sage Therapeutics, Inc. Neuroactive steroids, compositions, and uses thereof
US11185647B2 (en) 2017-03-28 2021-11-30 Concentrx Pharmaceuticals, Inc. Devices and methods for delivering dry powder medicaments
JP2020515366A (ja) * 2017-03-28 2020-05-28 コンセントリクス ファーマシューティカルズ，インコーポレイテッド 乾燥粉末薬物を送達するための装置および方法
US10456537B2 (en) 2017-03-28 2019-10-29 Concentrx Pharmaceuticals, Inc. Devices and methods for delivering dry powder medicaments
WO2018183528A1 (fr) * 2017-03-28 2018-10-04 Concentrx Pharmaceuticals, Inc. Dispositifs et procédés d'administration de médicaments en poudre sèche
US11911560B2 (en) 2017-03-28 2024-02-27 Concentrx Pharmaceuticals, Inc. Devices and methods for delivering dry powder medicaments

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WO2005025541A2 (fr) 2005-03-24
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US20180177721A1 (en) 2018-06-28
WO2005025536A3 (fr) 2005-05-12
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US20160158150A1 (en) 2016-06-09
EP1663155A2 (fr) 2006-06-07
WO2005025536A8 (fr) 2006-12-28
GB0321607D0 (en) 2003-10-15
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US11103448B2 (en) 2021-08-31
CA2539041A1 (fr) 2005-03-24
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US8182838B2 (en) 2012-05-22
EP2286797B1 (fr) 2018-03-14
WO2005025536A2 (fr) 2005-03-24
US20060257491A1 (en) 2006-11-16
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PL1663155T3 (pl) 2012-04-30

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